Advertisement

EGFR exon 20 insertions in advanced non-small cell lung cancer: A new history begins

  • Jordi Remon
    Correspondence
    Corresponding author at: Medical Oncology Department, Centro Integral Oncológico Clara Campal (HM-CIOCC) Barcelona, HM Delfos, Avinguda de Vallcarca, 151, 08023 Barcelona, Spain.
    Affiliations
    Department of Medical Oncology, Centro Integral Oncológico Clara Campal (HM-CIOCC), Hospital HM Delfos, HM Hospitales, Barcelona, Spain
    Search for articles by this author
  • Lizza E.L. Hendriks
    Affiliations
    Department of Respiratory Medicine, Maastricht University Medical Centre, GROW School for Oncology and Developmental Biology, Maastricht, the Netherlands
    Search for articles by this author
  • Andres F. Cardona
    Affiliations
    Clinical and Translational Oncology Group, Clínica del Country, Bogotá, Colombia

    Foundation for Clinical and Applied Cancer Research – FICMAC, Bogotá, Colombia

    Clinical Research and Biology Systems Department, Universidad el Bosque, Bogotá, Colombia
    Search for articles by this author
  • Benjamin Besse
    Affiliations
    Gustave Roussy, Department of Cancer Medicine, Villejuif, France

    Université Paris-Saclay, Orsay, France
    Search for articles by this author
Published:September 14, 2020DOI:https://doi.org/10.1016/j.ctrv.2020.102105

      Highlights

      • EGFR exon 20 insertion mutations occur in ~2–3% of all NSCLC cases.
      • Activity of 1st to 3rd generation EGFR-TKI is less in EGFR ex20ins versus common mutations.
      • Osimertinib might play a role in the treatment of EGFR ex20ins mutations.
      • Poziotinib, mobocertinib and amivantamab are promising new EGFR ex20ins treatments.
      • The specific role of EGFR ex20ins variants merits further evaluation.

      Abstract

      Although targeted therapy is standard of care in a large subset of oncogenic addicted non-small cell lung cancers (NSCLC), until recently, this therapeutic approach has not been feasible for all genomic alterations such as for those tumors harboring Epidermal Growth Factor Receptor (EGFR) exon 20 insertion (ex20ins) mutations. Despite being the third most common EGFR mutation, a limited efficacy of first- and second-generation EGFR tyrosine kinase inhibitors (TKI) exists. This is related to the heterogeneity at the molecular level in EGFR ex20ins mutation variants and the finding that this mutation promotes active kinase conformation but does not increase the affinity for EGFR TKI. As a result, the prognosis of this population is diminished. Therefore, chemotherapy remained the most suitable strategy in this subset of EGFR mutant NSCLC patients. Recently, new treatment strategies have been reported in this landscape, either with new EGFR TKI or bispecific antibodies, which may establish a new standard of care in the coming future for these patients. Future research should focus on elucidating the oncogenic degree of all EGFR ex20ins variants, the potential role of combination strategies either with chemotherapy or immune checkpoint inhibitors, and the most appropriate first-line treatment strategy in this subgroup. Finally, the knowledge of mechanisms of acquired resistance to these new agents upon progression is a priority for personalising treatment at that time. It is in this framework, that we provide a thorough overview on this subject.

      Keywords

      Introduction

      Epidermal Growth Factor Receptor (EGFR) exon 20 insertion (ex20ins) mutations occur in ~2–3% of all non-small cell lung cancer (NSCLC) cases, representing ~10–12% of all cancers with documented EGFR mutation [
      • Oxnard G.R.
      • Lo P.C.
      • Nishino M.
      • Dahlberg S.E.
      • Lindeman N.I.
      • Butaney M.
      • et al.
      Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions.
      ,
      • Riess J.W.
      • Gandara D.R.
      • Frampton G.M.
      • Madison R.
      • Peled N.
      • Bufill J.A.
      • et al.
      Diverse EGFR Exon 20 insertions and co-occurring molecular alterations identified by comprehensive genomic profiling of NSCLC.
      ,
      • Cardona A.F.
      • Rojas L.
      • Zatarain-Barrón Z.L.
      • Freitas H.C.
      • Granados S.T.
      • Castillo O.
      • et al.
      EGFR exon 20 insertion in lung adenocarcinomas among Hispanics (geno1.2-CLICaP).
      ,
      • Arcila M.E.
      • Nafa K.
      • Chaft J.E.
      • Rekhtman N.
      • Lau C.
      • Reva B.A.
      • et al.
      EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics.
      ]. These mutations are the third most common EGFR mutation subtype after the common sensitizing EGFR mutations, i.e. the exon 19 deletions and exon 21 L858R mutation [
      • Arcila M.E.
      • Nafa K.
      • Chaft J.E.
      • Rekhtman N.
      • Lau C.
      • Reva B.A.
      • et al.
      EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics.
      ].
      In contrast to common EGFR mutations where frequency varies according to ethnicity (12% Caucasian vs. ~50% in Asian population) [
      • Midha A.
      • Dearden S.
      • McCormack R.
      EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII).
      ], there is no clear difference by ethnicity in the frequency of EGFR ex20ins mutations [
      • Oxnard G.R.
      • Lo P.C.
      • Nishino M.
      • Dahlberg S.E.
      • Lindeman N.I.
      • Butaney M.
      • et al.
      Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions.
      ,
      • Riess J.W.
      • Gandara D.R.
      • Frampton G.M.
      • Madison R.
      • Peled N.
      • Bufill J.A.
      • et al.
      Diverse EGFR Exon 20 insertions and co-occurring molecular alterations identified by comprehensive genomic profiling of NSCLC.
      ,
      • Cardona A.F.
      • Rojas L.
      • Zatarain-Barrón Z.L.
      • Freitas H.C.
      • Granados S.T.
      • Castillo O.
      • et al.
      EGFR exon 20 insertion in lung adenocarcinomas among Hispanics (geno1.2-CLICaP).
      ,
      • Arcila M.E.
      • Nafa K.
      • Chaft J.E.
      • Rekhtman N.
      • Lau C.
      • Reva B.A.
      • et al.
      EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics.
      ,
      • Pan Y.
      • Zhang Y.
      • Li Y.
      • Hu H.
      • Wang L.
      • Li H.
      • et al.
      Prevalence, clinicopathologic characteristics, and molecular associations of EGFR exon 20 insertion mutations in East Asian patients with lung adenocarcinoma.
      ,
      • Sasaki H.
      • Endo K.
      • Takada M.
      • Kawahara M.
      • Kitahara N.
      • Tanaka H.
      • et al.
      EGFR exon 20 insertion mutation in Japanese lung cancer.
      ] (Fig. 1). Indeed, similar to other oncogenic drivers, EGFR ex20ins mutations are found more often in women, non-smokers, and in those with adenocarcinoma histology [
      • Oxnard G.R.
      • Lo P.C.
      • Nishino M.
      • Dahlberg S.E.
      • Lindeman N.I.
      • Butaney M.
      • et al.
      Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions.
      ]. The incidence of baseline brain metastases in EGFR ex20ins NSCLC patients ranges from 23% to 39% [
      • Cardona A.F.
      • Rojas L.
      • Zatarain-Barrón Z.L.
      • Freitas H.C.
      • Granados S.T.
      • Castillo O.
      • et al.
      EGFR exon 20 insertion in lung adenocarcinomas among Hispanics (geno1.2-CLICaP).
      ,
      • Yang G.
      • Li J.
      • Xu H.
      • Yang Y.
      • Yang L.
      • Xu F.
      • et al.
      EGFR exon 20 insertion mutations in Chinese advanced non-small cell lung cancer patients: Molecular heterogeneity and treatment outcome from nationwide real-world study.
      ]. This percentage is similar to patients with common EGFR driver mutations [
      • Soria J.-C.
      • Ohe Y.
      • Vansteenkiste J.
      • Reungwetwattana T.
      • Chewaskulyong B.
      • Lee K.H.
      • et al.
      Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.
      ,
      • Nakagawa K.
      • Garon E.B.
      • Seto T.
      • Nishio M.
      • Ponce Aix S.
      • Paz-Ares L.
      • et al.
      Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial.
      ] or other druggable genomic alterations [
      • Patil T.
      • Smith D.E.
      • Bunn P.A.
      • Aisner D.L.
      • Le A.T.
      • Hancock M.
      • et al.
      The incidence of brain metastases in stage IV ROS1-rearranged non-small cell lung cancer and rate of central nervous system progression on crizotinib.
      ,
      • Drilon A.
      • Lin J.J.
      • Filleron T.
      • Ni A.
      • Milia J.
      • Bergagnini I.
      • et al.
      Frequency of brain metastases and multikinase inhibitor outcomes in patients with RET-rearranged lung cancers.
      ]. NSCLC patients with EGFR ex20ins mutations have a worse prognosis [
      • Leduc C.
      • Merlio J.P.
      • Besse B.
      • Blons H.
      • Debieuvre D.
      • Bringuier P.P.
      • et al.
      Clinical and molecular characteristics of non-small-cell lung cancer (NSCLC) harboring EGFR mutation: results of the nationwide French Cooperative Thoracic Intergroup (IFCT) program.
      ,
      • Beau-Faller M.
      • Prim N.
      • Ruppert A.-M.
      • Nanni-Metéllus I.
      • Lacave R.
      • Lacroix L.
      • et al.
      Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network.
      ], either compared with those with common EGFR mutations (median overall survival [OS]: 16.5 months versus 33.0 months, p = 0.06, respectively) [
      • Oxnard G.R.
      • Lo P.C.
      • Nishino M.
      • Dahlberg S.E.
      • Lindeman N.I.
      • Butaney M.
      • et al.
      Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions.
      ] or uncommon EGFR mutations (OS 16.8 months versus 22.5 month, p < 0.001) [
      • Wu J.-Y.
      • Yu C.-J.
      • Shih J.-Y.
      Effectiveness of treatments for advanced non-small-cell lung cancer with exon 20 insertion epidermal growth factor receptor mutations.
      ]. However, outcome is similar to the EGFR wild-type population (median OS of 20.0 months, p = 0.60) [
      • Oxnard G.R.
      • Lo P.C.
      • Nishino M.
      • Dahlberg S.E.
      • Lindeman N.I.
      • Butaney M.
      • et al.
      Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions.
      ].
      Figure thumbnail gr1
      Fig. 1Non-small cell lung cancer EGFR exon 20 insertion mutation population.
      EGFR ex20ins mutations are located in the tyrosine kinase domain of EGFR. These mutations are heterogeneous at the molecular level but can be characterized as in frame insertions or duplications of between 3 and 21 bp (corresponding to 1–7 amino acids) clustered between amino acid positions 762 and 774 of the EGFR protein [
      • Vyse S.
      • Huang P.H.
      Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer.
      ], the most common are reported in Fig. 2A. EGFR ex20ins are positioned towards the C-terminal of the C-helix (positions 761–766), or in the loop that immediately follows it (positions 767–775, almost 90% of cases), pushing the C-helix into an active conformation [
      • Oxnard G.R.
      • Lo P.C.
      • Nishino M.
      • Dahlberg S.E.
      • Lindeman N.I.
      • Butaney M.
      • et al.
      Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions.
      ,
      • Riess J.W.
      • Gandara D.R.
      • Frampton G.M.
      • Madison R.
      • Peled N.
      • Bufill J.A.
      • et al.
      Diverse EGFR Exon 20 insertions and co-occurring molecular alterations identified by comprehensive genomic profiling of NSCLC.
      ,
      • Cardona A.F.
      • Rojas L.
      • Zatarain-Barrón Z.L.
      • Freitas H.C.
      • Granados S.T.
      • Castillo O.
      • et al.
      EGFR exon 20 insertion in lung adenocarcinomas among Hispanics (geno1.2-CLICaP).
      ]. The C-helix is a key regulatory element that dictates the activation status of EGFR by rotating from an outward to an inward position, permitting specific interactions with the active site that stabilizes dimerization-competent EGFR [
      • Vyse S.
      • Huang P.H.
      Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer.
      ]. Unlike common EGFR mutations, EGFR ex20ins mutations do not affect the ATP-binding pocket required for kinase activity but instead form a wedge at the end of the C-helix that promotes active kinase conformation but does not increase the affinity for EGFR tyrosine kinase inhibitors (TKI) [
      • Yasuda H.
      • Park E.
      • Yun C.-H.
      • Sng N.J.
      • Lucena-Araujo A.R.
      • Yeo W.-L.
      • et al.
      Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer.
      ]. This lack of drug affinity could be caused by steric hindrance secondary to a prominent shift of the C-helix and phosphate-binding loop of EGFR into the drug-binding pocket [
      • Robichaux J.P.
      • Elamin Y.Y.
      • Tan Z.
      • Carter B.W.
      • Zhang S.
      • Liu S.
      • et al.
      Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer.
      ].
      Figure thumbnail gr2
      Fig. 2A) Impact of deletions and insertions on EGFR activation, and incidence of EGFR exon 20 insertions variants in NSCLC. (modified from Vyse et al. - Signal Transduct Target Ther. 2019); B) Potential treatment strategies in EGFR exon 20 insertions lung tumors.
      Some clinical characteristics have been associated with specific EGFR ex20ins variants. In a recent cohort (N = 88), according to age, the V769_D770insASV variant and the A763_Y764insFQEA variant were more prevalent in patients ≥65 years and younger than 65, respectively. Similarly, the V769_D770insASV, H773_V774insNPH, V774_C775insHV and D770_N771insSVD variants were more common in the female population (p = 0.006) and among never smokers (p = 0.04). Finally one-third of patients with brain metastases had the H773_V774insPH variant [
      • Cardona A.F.
      • Rojas L.
      • Zatarain-Barrón Z.L.
      • Freitas H.C.
      • Granados S.T.
      • Castillo O.
      • et al.
      EGFR exon 20 insertion in lung adenocarcinomas among Hispanics (geno1.2-CLICaP).
      ], but other cohorts have reported that the most common EGFR ex20ins variant in patients with brain metastases was the V769_D770insASV (21%) [
      • Yang G.
      • Li J.
      • Xu H.
      • Yang Y.
      • Yang L.
      • Xu F.
      • et al.
      EGFR exon 20 insertion mutations in Chinese advanced non-small cell lung cancer patients: Molecular heterogeneity and treatment outcome from nationwide real-world study.
      ]. Finally, whether different EGFR ex20ins have a different prognostic outcome or major brain tropism merit further evaluation in larger cohorts.
      Although almost all EGFR ex20ins mutations are mutually exclusive with other mutations, some series have reported co-occurring genomic alterations affecting mutations in TP53 (in up to 65%) [
      • Riess J.W.
      • Gandara D.R.
      • Frampton G.M.
      • Madison R.
      • Peled N.
      • Bufill J.A.
      • et al.
      Diverse EGFR Exon 20 insertions and co-occurring molecular alterations identified by comprehensive genomic profiling of NSCLC.
      ,
      • Yang G.
      • Li J.
      • Xu H.
      • Yang Y.
      • Yang L.
      • Xu F.
      • et al.
      EGFR exon 20 insertion mutations in Chinese advanced non-small cell lung cancer patients: Molecular heterogeneity and treatment outcome from nationwide real-world study.
      ], cyclin dependent kinase inhibitor 2A and 2B (CDKN2A and CDKN2B) (22% and 16%, respectively), NK2 homeobox 1 (NKX2-1) (14%) RB transcriptional co-repressor 1 (RB1) (11%) [
      • Riess J.W.
      • Gandara D.R.
      • Frampton G.M.
      • Madison R.
      • Peled N.
      • Bufill J.A.
      • et al.
      Diverse EGFR Exon 20 insertions and co-occurring molecular alterations identified by comprehensive genomic profiling of NSCLC.
      ], and PIK3CA [
      • Cardona A.F.
      • Rojas L.
      • Zatarain-Barrón Z.L.
      • Freitas H.C.
      • Granados S.T.
      • Castillo O.
      • et al.
      EGFR exon 20 insertion in lung adenocarcinomas among Hispanics (geno1.2-CLICaP).
      ,
      • Arcila M.E.
      • Nafa K.
      • Chaft J.E.
      • Rekhtman N.
      • Lau C.
      • Reva B.A.
      • et al.
      EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics.
      ,
      • Yang G.
      • Li J.
      • Xu H.
      • Yang Y.
      • Yang L.
      • Xu F.
      • et al.
      EGFR exon 20 insertion mutations in Chinese advanced non-small cell lung cancer patients: Molecular heterogeneity and treatment outcome from nationwide real-world study.
      ]. Co-occurring genomic alterations in other known lung cancer drivers were rare (5%) [
      • Riess J.W.
      • Gandara D.R.
      • Frampton G.M.
      • Madison R.
      • Peled N.
      • Bufill J.A.
      • et al.
      Diverse EGFR Exon 20 insertions and co-occurring molecular alterations identified by comprehensive genomic profiling of NSCLC.
      ], and EGFR amplifications were found in up to 22% of cases [
      • Riess J.W.
      • Gandara D.R.
      • Frampton G.M.
      • Madison R.
      • Peled N.
      • Bufill J.A.
      • et al.
      Diverse EGFR Exon 20 insertions and co-occurring molecular alterations identified by comprehensive genomic profiling of NSCLC.
      ,
      • Yang G.
      • Li J.
      • Xu H.
      • Yang Y.
      • Yang L.
      • Xu F.
      • et al.
      EGFR exon 20 insertion mutations in Chinese advanced non-small cell lung cancer patients: Molecular heterogeneity and treatment outcome from nationwide real-world study.
      ]. However, one recent cohort in Hispanic patients has reported that up to one-third of EGFR ex20ins NSCLC shared a common EGFR sensitizing mutation, which conferred a better prognosis [
      • Cardona A.F.
      • Rojas L.
      • Zatarain-Barrón Z.L.
      • Freitas H.C.
      • Granados S.T.
      • Castillo O.
      • et al.
      EGFR exon 20 insertion in lung adenocarcinomas among Hispanics (geno1.2-CLICaP).
      ]. In contrast, less than 1% of Chinese NSCLC patients harboring an EGFR ex20ins mutation had co-occurrence of a common sensitizing EGFR mutations [
      • Yang G.
      • Li J.
      • Xu H.
      • Yang Y.
      • Yang L.
      • Xu F.
      • et al.
      EGFR exon 20 insertion mutations in Chinese advanced non-small cell lung cancer patients: Molecular heterogeneity and treatment outcome from nationwide real-world study.
      ].
      Unlike common EGFR mutant NSCLC, currently, there are no approved targeted therapies available for patients whose tumor harbours an EGFR ex20ins mutation, and novel treatment approaches are needed. Recently, new treatment opportunities strategies have been reported in this landscape either with new EGFR TKI or bispecific antibodies (Fig. 2B), which may establish a new standard of care in the coming future for these patients. It is in this framework, that we provide a thorough overview on this subject.

      Outcome with EGFR tyrosine kinase inhibitors

      EGFR ex20ins mutations induce a steric hindrance of the drug-binding pocket, which prevents binding of EGFR TKI. Preclinical models and patient-derived experimental models confirmed that EGFR ex20ins in the domain immediately following the C-helix confer poor response to all known first-generation (erlotinib and gefitinib) and second-generation EGFR TKI (afatinib, neratinib and dacomitinib). EGFR ex20ins are on average 100 times less sensitive than the common sensitizing EGFR mutations [
      • Yasuda H.
      • Park E.
      • Yun C.-H.
      • Sng N.J.
      • Lucena-Araujo A.R.
      • Yeo W.-L.
      • et al.
      Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer.
      ,
      • Robichaux J.P.
      • Elamin Y.Y.
      • Tan Z.
      • Carter B.W.
      • Zhang S.
      • Liu S.
      • et al.
      Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer.
      ,
      • Yang M.
      • Xu X.
      • Cai J.
      • Ning J.
      • Wery J.P.
      • Li Q.-X.
      NSCLC harboring EGFR exon-20 insertions after the regulatory C-helix of kinase domain responds poorly to known EGFR inhibitors.
      ]. However, not all EGFR ex20ins mutations have the same degree of resistance, and based on preclinical data, EGFR ex20ins A763_Y7764insFQEA is generally considered the unique variant sensitive to first- or second generation EGFR TKI [
      • Yasuda H.
      • Park E.
      • Yun C.-H.
      • Sng N.J.
      • Lucena-Araujo A.R.
      • Yeo W.-L.
      • et al.
      Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer.
      ,
      • Robichaux J.P.
      • Elamin Y.Y.
      • Tan Z.
      • Carter B.W.
      • Zhang S.
      • Liu S.
      • et al.
      Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer.
      ], which has also been confirmed in the clinic [
      • Yasuda H.
      • Park E.
      • Yun C.-H.
      • Sng N.J.
      • Lucena-Araujo A.R.
      • Yeo W.-L.
      • et al.
      Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer.
      ,
      • Hasegawa H.
      • Yasuda H.
      • Hamamoto J.
      • Masuzawa K.
      • Tani T.
      • Nukaga S.
      • et al.
      Efficacy of afatinib or osimertinib plus cetuximab combination therapy for non-small-cell lung cancer with EGFR exon 20 insertion mutations.
      ,
      • Tu H.-Y.
      • Ke E.-E.
      • Yang J.-J.
      • Sun Y.-L.
      • Yan H.-H.
      • Zheng M.-Y.
      • et al.
      A comprehensive review of uncommon EGFR mutations in patients with non-small cell lung cancer.
      ]. Similarly, retrospective clinical data confirmed that NSCLC patients harboring classical EGFR mutations (N = 129) had significantly longer median PFS when treated with erlotinib, gefitinib or afatinib compared with patients (N = 9) with EGFR ex20ins mutations (14 months versus 2 months, p < 0.0001) [
      • Robichaux J.P.
      • Elamin Y.Y.
      • Tan Z.
      • Carter B.W.
      • Zhang S.
      • Liu S.
      • et al.
      Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer.
      ]. This limited efficacy has also been endorsed by results from other cohorts, reporting a response rate (RR) ranging from 0% to 28%, and median PFS of ~3 months, not supporting first- or second-generation EGFR TKI as the best upfront treatment option for this subset of EGFR-mutant tumors [
      • Oxnard G.R.
      • Lo P.C.
      • Nishino M.
      • Dahlberg S.E.
      • Lindeman N.I.
      • Butaney M.
      • et al.
      Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions.
      ,
      • Cardona A.F.
      • Rojas L.
      • Zatarain-Barrón Z.L.
      • Freitas H.C.
      • Granados S.T.
      • Castillo O.
      • et al.
      EGFR exon 20 insertion in lung adenocarcinomas among Hispanics (geno1.2-CLICaP).
      ,
      • Yang G.
      • Li J.
      • Xu H.
      • Yang Y.
      • Yang L.
      • Xu F.
      • et al.
      EGFR exon 20 insertion mutations in Chinese advanced non-small cell lung cancer patients: Molecular heterogeneity and treatment outcome from nationwide real-world study.
      ,
      • Leduc C.
      • Merlio J.P.
      • Besse B.
      • Blons H.
      • Debieuvre D.
      • Bringuier P.P.
      • et al.
      Clinical and molecular characteristics of non-small-cell lung cancer (NSCLC) harboring EGFR mutation: results of the nationwide French Cooperative Thoracic Intergroup (IFCT) program.
      ,
      • Beau-Faller M.
      • Prim N.
      • Ruppert A.-M.
      • Nanni-Metéllus I.
      • Lacave R.
      • Lacroix L.
      • et al.
      Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network.
      ,
      • Tu H.-Y.
      • Ke E.-E.
      • Yang J.-J.
      • Sun Y.-L.
      • Yan H.-H.
      • Zheng M.-Y.
      • et al.
      A comprehensive review of uncommon EGFR mutations in patients with non-small cell lung cancer.
      ,
      • Yang J.C.-H.
      • Sequist L.V.
      • Geater S.L.
      • Tsai C.-M.
      • Mok T.S.K.
      • Schuler M.
      • et al.
      Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6.
      ,
      • Kuiper J.L.
      • Hashemi S.M.S.
      • Thunnissen E.
      • Snijders P.J.F.
      • Grünberg K.
      • Bloemena E.
      • et al.
      Non-classic EGFR mutations in a cohort of Dutch EGFR-mutated NSCLC patients and outcomes following EGFR-TKI treatment.
      ,
      • Naidoo J.
      • Sima C.S.
      • Rodriguez K.
      • Busby N.
      • Nafa K.
      • Ladanyi M.
      • et al.
      Epidermal growth factor receptor exon 20 insertions in advanced lung adenocarcinomas: clinical outcomes and response to erlotinib.
      ]. Likewise, at least one study identified that the majority of patients with NSCLC harboring EGFR-A763_Y764insFQEA responded to clinical doses of first-, second- and third-generation EGFR TKIs [
      • Gergis C.
      • Rangachari D.
      • Fujii M.
      • Varkaris A.
      • VanderLaan P.A.
      • Kobayashi S.
      • et al.
      EGFR-A763_Y764insFQEA: a unique exon 20 insertion mutation that displays sensitivity to all classes of approved lung cancer EGFR tyrosine kinase inhibitors.
      ]. These data may suggest that knowledge of the specific EGFR ex20ins variant may have potential clinical implications for making treatment decisions.
      Osimertinib, a third generation EGFR TKI, is the preferred first-line treatment option in NSCLC harboring a common EGFR mutation [
      • Ramalingam S.S.
      • Vansteenkiste J.
      • Planchard D.
      • Cho B.C.
      • Gray J.E.
      • Ohe Y.
      • et al.
      Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC.
      ], and has also reported clinical activity in uncommon EGFR mutations [
      • Cho J.H.
      • Lim S.H.
      • An H.J.
      • Kim K.H.
      • Park K.U.
      • Kang E.J.
      • et al.
      Osimertinib for patients with non-small-cell lung cancer harboring uncommon EGFR mutations: a multicenter, open-label, phase II trial (KCSG-LU15-09).
      ]. Although some authors have reported that EGFR ex20ins mutations induce large changes within the drug-binding pocket that sterically hinder the binding of third-generation inhibitors, others have reported in vitro evidence [
      • Hirano T.
      • Yasuda H.
      • Tani T.
      • Hamamoto J.
      • Oashi A.
      • Ishioka K.
      • et al.
      In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer.
      ] as well as across xenograft models [
      • Floc’h N.
      • Martin M.J.
      • Riess J.W.
      • Orme J.P.
      • Staniszewska A.D.
      • Ménard L.
      • et al.
      Antitumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR exon 20 insertions.
      ], about the efficacy of osimertinib in this subset of EGFR mutant cancers. However, clinical data is scarce and divergent [

      Ji J, Aredo J, Piper-Valillo A, Huppert L et al. Osimertinib in non-small cell lung cancer (NSCLC) with atypical EGFR activating mutations: A retrospective multicenter study. J Clin Oncol 38: 2020 (Suppl; Abstr 9570) n.d. https://doi.org/10.1200/JCO.2020.38.15_suppl.9570.

      ]. Among 17 EGFR ex20ins NSCLC patients, osimertinib resulted in a RR of 5% and median PFS and OS of 3.6 months and 8.7 months, respectively [
      • van Veggel B.
      • Madeira R.
      • Santos J.F.V.
      • Hashemi S.M.S.
      • Paats M.S.
      • Monkhorst K.
      • Heideman D.a.M.
      • et al.
      Osimertinib treatment for patients with EGFR exon 20 mutation positive non-small cell lung cancer.
      ]. In contrast, osimertinib resulted in a RR of 67% (4/6) among Chinese EGFR ex20ins NSCLC patients (including one patient with a known sensitizing variant A763_Y764insFQEA and one patient with the variant p.A767_V769dup) [
      • Fang W.
      • Huang Y.
      • Hong S.
      • Zhang Z.
      • Wang M.
      • Gan J.
      • et al.
      EGFR exon 20 insertion mutations and response to osimertinib in non-small-cell lung cancer.
      ]. Finally, the phase II ECOG-ACRIN 5162 trial [

      Piotrowska Z, Wang Y, Sequist LV, Ramalingam S, et al. ECOG-ACRIN 5162: A phase II study of osimertinib 160 mg in NSCLC with EGFR exon 20 insertions. J Clin Oncol 38: 2020 (Suppl; Abstr 9513) n.d. https://doi.org/10.1200/JCO.2020.38.15_suppl.9513.

      ] has assessed osimertinib at 160 mg in 21 previously treated EGFR ex20ins NSCLC patients. Although the trial did not meet the primary endpoint of a 30% RR, osimertinib reported a confirmed RR of 24% (disease control rate in 85% of cases) and the median PFS was 9.6 months. The RR occurred in EGFR ex20ins mutations variants reported as not sensitive to EGFR TKI in preclinical models. Grade ≥ 3 treatment related adverse events (TRAE) included anemia (n = 2), fatigue (n = 2), prolonged QT interval (n = 2) and 1 patient discontinued treatment due to AEs. These data suggest that osimertinib may play a role in the therapeutic strategy of EGFR ex20ins. However, the benefit of osimertinib appears lower than in patients with common EGFR mutations. The ongoing KCSG-LUG17-19 trial (NCT03414814) is also assessing the efficacy of osimertinib in this population (Table 1). Whether osimertinib at 80 mg daily has the same clinical activity than higher doses, the role of dose escalation as well as correlation between EGFR ex20ins variants and osimertinib efficacy and activity of the drug in patients with brain metastases merits further evaluation.
      Table 1Ongoing clinical trials assessing the efficacy of EGFR exon 20 insertion inhibitors in non-small cell lung cancer patients.
      NCT numberPhasePopulationTreatmentNumber of patients needed
      Numbers for total study given (not specifically for EGFRex20ins cohorts, these data were not available).
      Primary outcomeStatus
      Afatinib
      NCT03727724 (AFACET)IIAdvanced/metastatic NSCLC with EGFRex20insAfatinib 40 mg QD, cetuximab 500 mg/m2 iv Q2W37DCR after 18 weeksRecruiting
      Osimertinib
      NCT03414814 (KCSG LU17-19)IIPretreated advanced/metastatic NSCLC with EGFRex20insOsimertinib 80 mg QD28ORRActive, not recruiting
      NCT02496663IPreviously treated NSCLC with EGFR mutation including EGFRex20insOsimertinib 80 mg QD Necitumumab100Safety and tolerabilityRecruiting
      Poziotinib
      NCT04044170IIPreviously treated NSCLC with EGFRex20ins or HER2 ex20insPoziotinib orally114ORRRecruiting
      Mobocertinib (TAK-788)
      NCT03807778 (Japanese population)IPhase II: treatment naive advanced/metastatic NSCLC with EGFRex20insTAK-788 orally63Phase II: ORRRecruiting
      Pyrotinib
      NCT04063462IIPreviously treated NSCLC with EGFRex20ins or HER2 ex20insPyrotinib 400 mg QD60ORRNot yet recruiting
      NCT03574402 (TRUMP)IIArm 9: NSCLC with EGFRex20insPyrotinib either 60 mg PO QD or 40 mg PO BID400ORRRecruiting
      Tarloxotinib
      NCT03805841 (RAIN)IIFor NSCLC: EGFRex20ins or HER2 activating mutation Other solid tumors: NRG1/EGFR fusionTarlaxotinib iv weekly60ORRRecruiting
      BDTX-189
      NCT04209465 (MasterKey-01)I/IISolid malignancies Phase II part allosteric HER2mut or EGFR/HER2 ex20insBDTX-189 orally dosed Phase II based on RP2D184Phase II: ORRRecruiting
      DZD9008
      NCT03974022I/IIAdvanced/metastatic NSCLC with EGFR/HER2 mutations, including EGFRex20insDZD9008160Part B: ORRRecruiting
      TAS6417 (CLN-081)
      NCT04036682I/IIRecurrent/metastatic NSCLC with EGFRex20insCLN-081 QD or BID80Dose expansion: ORRRecruiting
      Abbreviations: NSCLC: non-small cell lung cancer; EGFR: epidermal growth factor receptor; ex: exon; ins: insertion; HER2: human epidermal growth factor receptor2; mut: mutation; QD: once daily; BID: twice daily; ORR: objective response rate; Q2W: every 2 weeks; DCR: disease control rate; TKI: tyrosine kinase inhibitor; CNS: central nervous system; Q3W: every 3 weeks; mg: milligram; NRG1: neuregulin1; AE: adverse events; DOR: duration of response.
      * Numbers for total study given (not specifically for EGFRex20ins cohorts, these data were not available).
      In Ba/F3 cells carrying EGFRA763_Y764insFQEA, Y764_V765insHH, A767_V769dupASV, and D770_N771insNP exon 20 mutations, the combination of afatinib or osimertinib plus cetuximab reported an additive effect and induced a more potent inhibition than either agent alone, with similar IC50 with the combination regardless of the EGFR TKI subtype [
      • Hasegawa H.
      • Yasuda H.
      • Hamamoto J.
      • Masuzawa K.
      • Tani T.
      • Nukaga S.
      • et al.
      Efficacy of afatinib or osimertinib plus cetuximab combination therapy for non-small-cell lung cancer with EGFR exon 20 insertion mutations.
      ]. However, clinical evidence for this combination is limited [
      • Fang W.
      • Huang Y.
      • Gan J.
      • Shao Y.W.
      • Zhang L.
      Durable response of low-dose afatinib plus cetuximab in an adenocarcinoma patient with a novel EGFR Exon 20 insertion mutation.
      ,
      • Fang W.
      • Huang Y.
      • Gan J.
      • Hong S.
      • Zhang L.
      A patient with EGFR Exon 20 insertion-mutant non-small cell lung cancer responded to osimertinib plus cetuximab combination therapy.
      ]. Two ongoing clinical trials, NCT03727724 (afatinib plus cetuximab) and NCT02496663 (osimertinib plus necitumumab), are exploring this strategy (Table 1). The efficacy/toxicity ratio of the combination of EGFR TKI and cetuximab may limit applicability in daily clinical practice.
      Based on the limited efficacy with upfront first- and second-generation EGFR TKI, chemotherapy has been considered the standard upfront treatment in EGFR ex20ins NSCLC [
      • Leduc C.
      • Merlio J.P.
      • Besse B.
      • Blons H.
      • Debieuvre D.
      • Bringuier P.P.
      • et al.
      Clinical and molecular characteristics of non-small-cell lung cancer (NSCLC) harboring EGFR mutation: results of the nationwide French Cooperative Thoracic Intergroup (IFCT) program.
      ]. Recently, in a retrospective Chinese cohort (N = 165), median PFS was significantly longer in patients who received first-line platinum-based chemotherapy compared with all-generation EGFR TKI (6.4 months versus 2.9 months, p < 0.001) [
      • Yang G.
      • Li J.
      • Xu H.
      • Yang Y.
      • Yang L.
      • Xu F.
      • et al.
      EGFR exon 20 insertion mutations in Chinese advanced non-small cell lung cancer patients: Molecular heterogeneity and treatment outcome from nationwide real-world study.
      ]. Indeed, in another retrospective cohort of 84 EGFR exon20ins NSCLC patients, first-line pemetrexed-containing regimens compared with regimens without pemetrexed, were associated with significant longer PFS (p < 0.001) and OS (28.0 months versus 15.4 months, p = 0.009) [
      • Wu J.-Y.
      • Yu C.-J.
      • Shih J.-Y.
      Effectiveness of treatments for advanced non-small-cell lung cancer with exon 20 insertion epidermal growth factor receptor mutations.
      ]. Whether the upfront combination of EGFR TKI plus either chemotherapy [
      • Hosomi Y.
      • Morita S.
      • Sugawara S.
      • Kato T.
      • Fukuhara T.
      • Gemma A.
      • et al.
      Gefitinib alone versus gefitinib plus chemotherapy for non-small-cell lung cancer with mutated epidermal growth factor receptor: NEJ009 study.
      ,
      • Noronha V.
      • Patil V.M.
      • Joshi A.
      • Menon N.
      • Chougule A.
      • Mahajan A.
      • et al.
      Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer.
      ], or an antiangiogenic agent [
      • Nakagawa K.
      • Garon E.B.
      • Seto T.
      • Nishio M.
      • Ponce Aix S.
      • Paz-Ares L.
      • et al.
      Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial.
      ,
      • Yamamoto N.
      • Seto T.
      • Nishio M.
      • Goto K.
      • Okamoto I.
      • Yamanaka T.
      • et al.
      Erlotinib plus bevacizumab (EB) versus erlotinib alone (E) as first-line treatment for advanced EGFR mutation–positive non-squamous non–small-cell lung cancer (NSCLC): Survival follow-up results of JO25567.
      ,
      • Zhou Q.
      • Wu Y.-L.
      • Cheng Y.
      • Liu Y.
      • Chen G.
      • Cui J.
      • et al.
      CTONG 1509: Phase III study of bevacizumab with or without erlotinib in untreated Chinese patients with advanced EGFR-mutated NSCLC.
      ] may have synergistic effect in this subset of EGFR mutant patients, mirroring the data reported among patients with common sensitising EGFR mutations remains unknown, as EGFR ex20ins tumors were not included in these trials. Only one trial included uncommon EGFR mutations (excluding EGFR ex20ins) demonstrating that the magnitude of benefit with the combination of gefitinib and chemotherapy occurred regardless of the EGFR mutation subtype [
      • Noronha V.
      • Patil V.M.
      • Joshi A.
      • Menon N.
      • Chougule A.
      • Mahajan A.
      • et al.
      Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer.
      ].
      Finally, EGFR Ex20ins mutant cell lines display sensitivity to heat shock protein (Hsp90) chaperon system inhibition [
      • Jorge S.E.
      • Lucena-Araujo A.R.
      • Yasuda H.
      • Piotrowska Z.
      • Oxnard G.R.
      • Rangachari D.
      • et al.
      EGFR Exon 20 insertion mutations display sensitivity to hsp90 inhibition in preclinical models and lung adenocarcinomas.
      ]. Luminespib (AUY922) is a highly potent Hsp90 inhibitor. In a phase II trial enrolling 29 EGFR ex20ins NSCLC patients previously treated with at least 1 prior line of therapy, luminespib (70 mg/m2 iv weekly) reported a RR of 17%, and there was no correlation between EGFR ex20ins variant and response to luminespib. The median PFS and OS were of 2.9 months and 12.8 months, respectively, and the most common TRAEs included ocular toxicity, diarrhea and fatigue. Grade 3 AEs were very uncommon, but 21% of patients required dose reductions. All study treatment was stopped on 28 February 2017 due to dissolution of study drug availability; 3 patients were on treatment at study termination [
      • Piotrowska Z.
      • Costa D.B.
      • Oxnard G.R.
      • Huberman M.
      • Gainor J.F.
      • Lennes I.T.
      • et al.
      Activity of the Hsp90 inhibitor luminespib among non-small-cell lung cancers harboring EGFR exon 20 insertions.
      ].

      New treatment strategies

      Poziotinib

      Poziotinib is an orally available quinazoline-based EGFR inhibitor. In vitro, poziotinib had an average IC50 value of 1.0 nM in Ba/F3 cell lines with an EGFR ex20ins mutation, making poziotinib approximately 100 times more potent than osimertinib and 40 times more potent than afatinib [
      • Robichaux J.P.
      • Elamin Y.Y.
      • Tan Z.
      • Carter B.W.
      • Zhang S.
      • Liu S.
      • et al.
      Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer.
      ].
      In a phase I trial, poziotinib reported encouraging efficacy in EGFR-mutant NSCLC and HER2-amplified breast or stomach cancers. The most common AEs were diarrhea, skin rash, stomatitis and pruritus. In line with other irreversible EGFR TKI, the dose-limiting toxicity (DLT) was diarrhea. The recommended phase 2 dose (RP2D) was 16 mg daily [
      • Kim T.M.
      • Lee K.-W.
      • Oh D.-Y.
      • Lee J.-S.
      • Im S.-A.
      • Kim D.-W.
      • et al.
      Phase 1 studies of poziotinib, an irreversible pan-HER tyrosine kinase inhibitor in patients with advanced solid tumors.
      ]. Initial data with poziotinib at 16 mg daily among 11 EGFR ex20ins NSCLC patients reported a RR of 64%, but 55% of patients required a dose reduction [
      • Robichaux J.P.
      • Elamin Y.Y.
      • Tan Z.
      • Carter B.W.
      • Zhang S.
      • Liu S.
      • et al.
      Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer.
      ]. In a phase II, investigator-initiated single-centre trial (NCT03066206), poziotinib was tested in a cohort of EGFR ex20ins or point mutations excluding T790M (N = 50, 92% with EGFR ex20ins) and HER2 ex20ins (N = 13). In the EGFR cohort, 70% of patients had already received ≥2 previous treatment lines, including 34% with previous TKI, and 28% had brain metastases. Poziotinib reported a confirmed RR of 44% and median PFS of 5.5 months. Grade 3–4 TRAEs occurred in 56% of patients, mainly skin rash (35%) and diarrhea (18%); with dose reductions and treatment discontinuation in 60% and 3% of patients, respectively [
      • Heymach J.
      • Negrao M.
      • Robichaux J.
      • Carter B.
      • Patel A.
      • Altan M.
      • et al.
      A phase II trial of poziotinib in EGFR and HER2 exon 20 mutant non-small cell lung cancer (NSCLC).
      ] (Table 2). This encouraging activity prompted to launch the confirmatory international multicentre phase II ZENITH20 study (NCT03318939). However, this trial did not confirm these previous results. The ZENITH20 study [

      Le X, Goldman JW, Clarke JM et al. Poziotinib shows activity and durability of responses in subgroups of previously treated EGFR exon 20 NSCLC patients. J Clin Oncol 38: 2020 (Suppl; Abstr 9514) n.d. https://doi.org/10.1200/JCO.2020.38.15_suppl.9514.

      ] includes four different cohorts of previously treated or untreated EGFR- or HER2-ex20ins NSCLC patients. In cohort 1, enrolling 115 previously treated EGFR ex20ins NSCLC patients; poziotinib reported a RR of 14.8% and disease control rate of 68.7%. Higher RR was observed in EGFR ex20ins near the loop (767–772) compared with those insertions far of the loop (773–775), (21% and 9.1%, respectively). Multiple prior lines of therapy did not impair the RR (14.3%, 13.8%, and 16.2% in patients with one, 2, or 3 or more lines of therapy, respectively). The greatest RRs were observed in those without prior EGFR TKI therapy (17.4%), no brain metastases (15.5%), and an ECOG performance status of 0 (18.9%). The median duration of response (DoR) and PFS were 7.4 months and 4.2 months, respectively. Almost all patients enrolled experienced TRAEs at any grade, with the most common being diarrhea (79%), rash (60%), stomatitis (52%), and paronychia (45%). Grade 3 TRAEs occurred in 60% of patients, being again diarrhea (25%) and rash (28%) as the most common. There were two grade 4 TRAEs, one each of diarrhea and dermatitis acneiformis, and no grade 5 TRAEs. The incidence of treatment-related pneumonitis was 4%, however, prior immune checkpoint inhibitors (ICIs) may have confounded some cases. Dose reductions occurred in 68% of patients, with a median relative dose of 72% and a 10% rate of permanent discontinuation due to treatment related AEs (Table 2) [

      Le X, Goldman JW, Clarke JM et al. Poziotinib shows activity and durability of responses in subgroups of previously treated EGFR exon 20 NSCLC patients. J Clin Oncol 38: 2020 (Suppl; Abstr 9514) n.d. https://doi.org/10.1200/JCO.2020.38.15_suppl.9514.

      ]. Although the trial did not achieve the primary RR endpoint, the ZENITH20 trial continues enrolment with three new cohorts examining the efficacy of poziotinib in twice-daily dosing or daily low dose (Fig. 3).
      Table 2Efficacy of tyrosine kinase inhibitors in EGFR exon 20 insertion mutant NSCLC patients.
      DrugTrialNRR (%)PFS (mo.)Grade 3 TRAE (%)Dose reductions (%)Discontinuations (%)
      OsimertinibECOG-ACRIN 5162 ph II

      Piotrowska Z, Wang Y, Sequist LV, Ramalingam S, et al. ECOG-ACRIN 5162: A phase II study of osimertinib 160 mg in NSCLC with EGFR exon 20 insertions. J Clin Oncol 38: 2020 (Suppl; Abstr 9513) n.d. https://doi.org/10.1200/JCO.2020.38.15_suppl.9513.

      21259.729NR5
      PoziotinibPhase II
      • Heymach J.
      • Negrao M.
      • Robichaux J.
      • Carter B.
      • Patel A.
      • Altan M.
      • et al.
      A phase II trial of poziotinib in EGFR and HER2 exon 20 mutant non-small cell lung cancer (NSCLC).
      50445.556603
      ZENITH 20 cohort 1

      Le X, Goldman JW, Clarke JM et al. Poziotinib shows activity and durability of responses in subgroups of previously treated EGFR exon 20 NSCLC patients. J Clin Oncol 38: 2020 (Suppl; Abstr 9514) n.d. https://doi.org/10.1200/JCO.2020.38.15_suppl.9514.

      11514.34.2606810
      MobocertinibPhase I/II
      • Janne P.A.
      • Neal J.W.
      • Camidge D.R.
      • Spira A.I.
      • Piotrowska Z.
      • Horn L.
      • et al.
      Antitumor activity of TAK-788 in NSCLC with EGFR exon 20 insertions.
      43437.3402514
      AmivantamabPhase I/II

      Park K, Johm T, Kim SW et al. Amivantamab (JNJ-61186372), an anti-EGFR-MET bispecific antibody, in patients with EGFR exon 20 insertion (exon20ins)-mutated non-small cell lung cancer (NSCLC). J Clin Oncol 38: 2020 (Suppl; Abstr 9512) n.d. https://doi.org/10.1200/JCO.2020.38.15_suppl.9512.

      39368.36106
      N: number. RR: Response Rate. PFS: Progression Free Survival. TRAE: treatment related adverse events. NR: not reported.
      The reasons for the differences in RR between both phase II trials remain unknown [
      • Heymach J.
      • Negrao M.
      • Robichaux J.
      • Carter B.
      • Patel A.
      • Altan M.
      • et al.
      A phase II trial of poziotinib in EGFR and HER2 exon 20 mutant non-small cell lung cancer (NSCLC).
      ,

      Le X, Goldman JW, Clarke JM et al. Poziotinib shows activity and durability of responses in subgroups of previously treated EGFR exon 20 NSCLC patients. J Clin Oncol 38: 2020 (Suppl; Abstr 9514) n.d. https://doi.org/10.1200/JCO.2020.38.15_suppl.9514.

      ]. Both reported similar rates of grade ≥3 TRAE (56% and 60%), and dose reductions (60% and 68%). In the former one there were slightly less treatment discontinuations (3% and 10%, respectively), which may suggest that treatment for potential side effects could be more efficient in the single-centre study with probably better trained physicians for managing these toxicities. However, the safety profile of poziotinib remains a challenge, with especially skin and gastrointestinal toxicities, which may have an impact on patients’ quality of life even if these are grade 2 AEs. Evaluation of refined dosing and improved toxicity management to maintain continuous treatment is warranted to assess the potential role of poziotinib in EGFR ex20ins related tumors. Although dose reduction and discontinuation with poziotinib rates were similar to those reported with other second-generation EGFR TKI such as afatinib in the LUX-Lung 7 and 6 trials (42–52% and 6–8%) [
      • Park K.
      • Tan E.-H.
      • O’Byrne K.
      • Zhang L.
      • Boyer M.
      • Mok T.
      • et al.
      Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial.
      ,
      • Sequist L.V.
      • Yang J.C.-H.
      • Yamamoto N.
      • O’Byrne K.
      • Hirsh V.
      • Mok T.
      • et al.
      Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.
      ] and dacomitinib in the ARCHER 1050 trial (66% and 10%, respectively) [
      • Wu Y.-L.
      • Cheng Y.
      • Zhou X.
      • Lee K.H.
      • Nakagawa K.
      • Niho S.
      • et al.
      Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial.
      ], better dose adjustment of poziotinib may enhance treatment compliance and maximize clinical benefit. For afatinib and dacomitinib, it has been reported that incidence and severity of AEs decreased following dose reductions, and tolerability-guided dose modifications enabled patients to continue on treatment without a negative impact in the outcome [
      • Corral J.
      • Mok T.S.
      • Nakagawa K.
      • Rosell R.
      • Lee K.H.
      • Migliorino M.R.
      • et al.
      Effects of dose modifications on the safety and efficacy of dacomitinib for EGFR mutation-positive non-small-cell lung cancer.
      ,
      • Schuler M.
      • Tan E.-H.
      • O’Byrne K.
      • Zhang L.
      • Boyer M.
      • Mok T.
      • et al.
      First-line afatinib vs gefitinib for patients with EGFR mutation-positive NSCLC (LUX-Lung 7): impact of afatinib dose adjustment and analysis of mode of initial progression for patients who continued treatment beyond progression.
      ,
      • Yang J.C.-H.
      • Sequist L.V.
      • Zhou C.
      • Schuler M.
      • Geater S.L.
      • Mok T.
      • et al.
      Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma: post hoc analyses of the randomized LUX-Lung 3 and 6 trials.
      ]. Of note, in the ZENITH20 trial responses could be maintained on a lower dose than 16 mg [

      Le X, Goldman JW, Clarke JM et al. Poziotinib shows activity and durability of responses in subgroups of previously treated EGFR exon 20 NSCLC patients. J Clin Oncol 38: 2020 (Suppl; Abstr 9514) n.d. https://doi.org/10.1200/JCO.2020.38.15_suppl.9514.

      ]. Therefore, new ongoing cohorts from the ZENITH20 study testing lower doses of poziotinib (10 mg QD, and 6 mg or 8 mg BID, Fig. 3) may improve the tolerability and toxicity ratio of the drug with positive impact on the outcome.
      Differences in RR between both phase II trials could also be explained by different activity of poziotinib in the different EGFR ex20ins variants. Although the specific EGFR ex20ins variants have not been reported in the initial phase II study [
      • Heymach J.
      • Negrao M.
      • Robichaux J.
      • Carter B.
      • Patel A.
      • Altan M.
      • et al.
      A phase II trial of poziotinib in EGFR and HER2 exon 20 mutant non-small cell lung cancer (NSCLC).
      ], in the ZENITH20 study, EGFR ex20 near-loop insertions were the most prevalent alterations (>50%) and patients with these near-loop insertions benefited the most from poziotinib. However, in contrast to preclinical models reporting that EGFR ex20ins more sensitive to EGFR TKI are those located in the positions 763–765 [
      • Yasuda H.
      • Park E.
      • Yun C.-H.
      • Sng N.J.
      • Lucena-Araujo A.R.
      • Yeo W.-L.
      • et al.
      Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer.
      ], poziotinib did not report RR in EGFR ex20ins in theses positions, but only one patient had this mutation. The specific role of EGFR ex20ins variants merit further evaluation as in the ZENITH20 trial poziotinib responses were more common in patients with insertions between M766 to D770 of EGFR exon 20 [

      Le X, Goldman JW, Clarke JM et al. Poziotinib shows activity and durability of responses in subgroups of previously treated EGFR exon 20 NSCLC patients. J Clin Oncol 38: 2020 (Suppl; Abstr 9514) n.d. https://doi.org/10.1200/JCO.2020.38.15_suppl.9514.

      ] and other EGFR TKI, such as mobocertinib (TAK788), have demonstrated responses in patients with diverse EGFR ex20ins variants [
      • Janne P.A.
      • Neal J.W.
      • Camidge D.R.
      • Spira A.I.
      • Piotrowska Z.
      • Horn L.
      • et al.
      Antitumor activity of TAK-788 in NSCLC with EGFR exon 20 insertions.
      ].
      Other future challenges with poziotinib are the safety and efficacy of combining the drug either with monoclonal antibodies, such as cetuximab, or Hsp90 inhibitors. Lastly, overall clinical benefit and the mechanisms underlying resistance to poziotinib remain to be determined. In lung cancer models with EGFR ex20ins mutation, the secondary mutation encoding either T790M or C797S render tumor cells resistant to poziotinib [
      • Robichaux J.P.
      • Elamin Y.Y.
      • Tan Z.
      • Carter B.W.
      • Zhang S.
      • Liu S.
      • et al.
      Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer.
      ,
      • Suda K.
      • Nishino M.
      • Koga T.
      • Fujino T.
      • Ohara S.
      • Soh J.
      • et al.
      T790M or C797S confers acquired resistance to tarloxotinib and poziotinib in EGFR Exon 20 insertion-driven lung cancer models in vitro.
      ]. Indeed, in preclinical models in EGFR ex20ins (D770insNPG) genetically engineered mice (GEM), acquired resistance mechanisms to poziotinib were bypass mechanisms such as acquired mutations in ErbB4 and KRAS, as well as reactivation of the MAPK/PI3K pathway. Data coming from matched pre-poziotinib and on-progression samples from 20 out of 50 responding patients revealed acquired EGFR-dependent tyrosine kinase domain point mutations in 4 patients (T790M (2), V774A (1), D770A (1)), suggesting that T790M is a poziotinib resistance driver. Other mechanisms identified in patients included MET, EGFR or CDK6 amplifications [
      • Elamin Y.
      • Robichaux J.
      • Carter B.
      • Altan M.
      • Gibbons D.
      • Fossella F.
      • et al.
      Identification of mechanisms of acquired resistance to poziotinib in EGFR Exon 20 mutant non-small cell lung cancer (NSCLC).
      ]. Whether upfront combination strategies with the aim to delay the onset of resistant mechanisms may increase the efficacy of poziotinib merits further evaluation, with also special attention to additional toxicities.

      Mobocertinib

      Mobocertinib (TAK-788) is another EGFR/HER2 ex20ins TKI; it has reported potent and selective preclinical inhibitory activity against EGFR ex20ins. Mobocertinib was assessed in a phase I/II trial (NCT02716116). In the phase I dose escalation, 101 patients (median age, 61 years; 70% female; 76% ≥2 prior anticancer therapies; 53% brain metastases) were treated with mobocertinib at 5–180 mg daily. The RP2D was determined to be 160 mg [
      • Neal J.
      • Doebele R.
      • Riely G.
      • Spira A.
      • Horn L.
      • Piotrowska Z.
      • et al.
      Safety, PK, and preliminary antitumor Activity of the Oral EGFR/HER2 Exon 20 inhibitor TAK-788 in NSCLC.
      ], and an expansion multicohort phase II trial is ongoing (Fig. 4).
      Figure thumbnail gr4
      Fig. 4Design of the Phase 1/2, Open-Label, Multicenter Trial (NCT02716116) with mobocertinib (TAK-788) (CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; HER, human epidermal growth factor receptor; MRI, magnetic resonance imaging; ORR, objective response rate; PS, performance status; qd, once daily; RECIST, Response Evaluation Criteria in Solid Tumours. Yellow box, results reported). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
      In total, 28 NSCLC patients with refractory EGFR ex20ins were included during the phase I dose escalation or in the phase II expansion cohort 1 with mobocertinib treatment at 160 mg. Out of the patients enrolled, 54% of patients had received ≥3 prior systemic treatments, 61% were previously treated with ICIs, and 43% had brain metastases. Mobocertinib reported a RR of 43% and a median PFS of 7.3 months (Table 2). According to baseline brain metastases status, the RR and PFS were 56% and 8.1 months for those patients without brain metastases (N = 16), whereas among patients with brain metastases (N = 12) the RR and PFS were 25% and 3.7 months, respectively. The antitumor activity of mobocertinib occurred regardless of previous treatment with EGFR TKI or ICI. Of note, there is no clear trend that response to mobocertinib is enriched in specific EGFR ex20ins variants (RR of 40% in 769ASV, 50% in 773NPH, 50% in other EGFR ex20ins, and 50% in patients with unknown variant). Among all patients treated with mobocertinib at 160 mg (N = 72) Grade ≥ 3 TRAEs were reported in 40% of patients, mainly diarrhea, nausea and rash. Dose reductions and treatment discontinuations occurred in 25% and 14% of cases, respectively [
      • Janne P.A.
      • Neal J.W.
      • Camidge D.R.
      • Spira A.I.
      • Piotrowska Z.
      • Horn L.
      • et al.
      Antitumor activity of TAK-788 in NSCLC with EGFR exon 20 insertions.
      ]. The ongoing EXCLAIM extension cohort searches to validate the efficacy (RR) of mobocertinib in 97 previously treated EGFR ex20ins NSCLC patients. While awaiting these results, indirect comparison data from refractory EGFR ex20ins NSCLC patients treated with mobocertinib in the trial versus other second-line treatment options used in the real world setting has reported that PFS (7.3 months versus 3.7 months, p = 0.0003) and RR (43% versus 14%, p = 0.0003) were statistically significant improved with mobocertinib compared with other treatment strategies although patients treated with mobocertinib were more heavily pretreated than patients in the real world data [

      Horn L, Lin HM, Padda SK, Aggarwal Ch et al. Indirect comparison of TAK-788 vs real-world data outcomes in refractory non-small cell lung cancer (NSCLC) with EGFR exon 20 insertions. J Clin Oncol 38: 2020 (Suppl; Abstr 9580) n.d. https://doi.org/10.1200/JCO.2020.38.15_suppl.9580.

      ].
      Based on the results of the cohort 1, the FDA granted a Breakthrough therapy designation for mobocertinib in this subset of EGFR ex20ins mutant population on 27th April 2020. Likewise, with the aim to validate upfront-personalised treatment approach for this subset of EGFR mutant patients, the ongoing phase III EXCLAIM-2 trial (NCT04129502) compares mobocertinib versus platinum-based chemotherapy in 319 treatment naïve EGFR ex20ins NSCLC patients. Crossover is allowed and the primary endpoint is PFS by blinded independent radiological review. Patients are stratified according to baseline brain metastases status and race.

      Amivantamab (JNJ-61186372)

      Amivantamab is a novel, fully humanized anti-EGFR-MET bispecific IgG1 antibody whose mechanism of action can target both EGFR- and MET-driven disease. Amivantamab inhibits tumor growth and progression by three distinct mechanisms. Two of these mechanisms involve inhibition of EGFR and cMet signaling, first by inhibition of ligand-induced activation via blocking ligand binding to each receptor and second by receptor inactivation via degradation. The third mechanism utilizes Fc effector-mediated killing of EGFR- and cMet-expressing tumor cells by antibody-dependent cellular cytotoxicity. Through these mechanisms of action, amivantamab showed activity in multiple xenograft models [
      • Moores S.L.
      • Chiu M.L.
      • Bushey B.S.
      • Chevalier K.
      • Luistro L.
      • Dorn K.
      • et al.
      A novel bispecific antibody targeting EGFR and cMet is effective against EGFR inhibitor-resistant lung tumors.
      ] and BaF3 cells [
      • Yun J.
      • Lee S.-H.
      • Kim S.-Y.
      • Jeong S.-Y.
      • Kim J.-H.
      • Pyo K.-H.
      • et al.
      Antitumor activity of amivantamab (JNJ-61186372), an EGFR-cMet bispecific antibody, in diverse models of EGFR Exon 20 insertion-driven NSCLC.
      ] harboring diverse EGFR mutations (Del19, L858R, T790M, ex20ins, C797S) and MET amplification. In BaF3 cells with multiple ex20ins viability decreased when treated with amivantamab. In contrast, treatment with gefitinib and osimertinib showed limited antiproliferative activity compared to amivantamab. Importantly, in vivo, efficacy of amivantamab was superior to cetuximab or poziotinib [
      • Yun J.
      • Lee S.-H.
      • Kim S.-Y.
      • Jeong S.-Y.
      • Kim J.-H.
      • Pyo K.-H.
      • et al.
      Antitumor activity of amivantamab (JNJ-61186372), an EGFR-cMet bispecific antibody, in diverse models of EGFR Exon 20 insertion-driven NSCLC.
      ]. In a first-in-human CHRYSALIS phase I trial [
      • Park K.
      • Ahn M.
      • Lee S.
      • Kim H.R.
      • Hong M.H.
      • Millington D.
      • et al.
      A first-in-human phase 1 trial of the EGFR-cMET bispecific antibody JNJ-61186372 in patients with advanced non-small cell lung cancer (NSCLC).
      ] (NCT02609776) patients received amivantamab at 140–1400 mg iv weekly for the first 28-day cycle and biweekly thereafter. Amivantamab displayed manageable safety profile with no DLTs during dose escalation up through the 1400 mg dose cohort. Infusion-related reaction, which was mainly limited to the first infusion, and rash (mainly grade 1–2) were the most common AEs. TRAEs grade ≥3 occurred in 9% of patients. The RP2D was 1050 mg (1400 mg for patients ≥80 Kg), and preliminary but clinically significant efficacy was observed in patients with EGFR-mutant NSCLC (N = 108, RR 30%) including EGFR ex20ins mutant NSCLC patients (N = 27, RR 30%) [
      • Park K.
      • Ahn M.
      • Lee S.
      • Kim H.R.
      • Hong M.H.
      • Millington D.
      • et al.
      A first-in-human phase 1 trial of the EGFR-cMET bispecific antibody JNJ-61186372 in patients with advanced non-small cell lung cancer (NSCLC).
      ,
      • Haura E.B.
      • Cho B.C.
      • Lee J.S.
      • Han J.-Y.
      • Lee K.H.
      • Sanborn R.E.
      • et al.
      JNJ-61186372 (JNJ-372), an EGFR-cMet bispecific antibody, in EGFR-driven advanced non-small cell lung cancer (NSCLC).
      ]. A recent analysis reported the data including all 50 enrolled patients with EGFR ex20ins disease who received amivantamab at the RP2D. Among the 39 response-evaluable patients (74% previously treated with platinum-based chemotherapy, median age 61 years, and 51% female), the RR was 36% (41% in previously treated patients) with a median DoR of 10 months. The median PFS was 8.3 months (8.6 months in previously treated). The most common AEs reported were rash (72%), infusion related reaction (60%), and paronychia (34%), stomatitis (16%), pruritus (14%), and diarrhea (6%). Grade ≥ 3 AEs were reported in 36% of patients; and 6% were TRAEs. Dose reductions and discontinuations occurred in 6% and 10%, respectively [

      Park K, Johm T, Kim SW et al. Amivantamab (JNJ-61186372), an anti-EGFR-MET bispecific antibody, in patients with EGFR exon 20 insertion (exon20ins)-mutated non-small cell lung cancer (NSCLC). J Clin Oncol 38: 2020 (Suppl; Abstr 9512) n.d. https://doi.org/10.1200/JCO.2020.38.15_suppl.9512.

      ]. These data support amivantamab as a potential treatment strategy and on March 10th 2020 FDA granted a breakthrough therapy designation for amivantamab in this subset of EGFR mutant patients.

      Other evaluated drugs

      TAS6417 is a robust inhibitor against the most common EGFR mutations (Del19, L858R, T790M). It has as well activity in cells driven by the less common EGFR-G719X, L861Q, and S768I mutations [
      • Udagawa H.
      • Hasako S.
      • Ohashi A.
      • Fujioka R.
      • Hakozaki Y.
      • Shibuya M.
      • et al.
      TAS6417/CLN-081 Is a Pan-mutation-selective EGFR tyrosine kinase inhibitor with a broad spectrum of preclinical activity against clinically relevant EGFR mutations.
      ]. Indeed, TAS6417 targets EGFR ex20ins mutations while sparing wild-type [
      • Hasako S.
      • Terasaka M.
      • Abe N.
      • Uno T.
      • Ohsawa H.
      • Hashimoto A.
      • et al.
      TAS6417, a novel EGFR inhibitor targeting exon 20 insertion mutations.
      ], and selectivity indexes (wild-type EGFR/mutant EGFR ratio of inhibition) favored TAS6417 in comparison with poziotinib and osimertinib, indicating a wider therapeutic window [
      • Udagawa H.
      • Hasako S.
      • Ohashi A.
      • Fujioka R.
      • Hakozaki Y.
      • Shibuya M.
      • et al.
      TAS6417/CLN-081 Is a Pan-mutation-selective EGFR tyrosine kinase inhibitor with a broad spectrum of preclinical activity against clinically relevant EGFR mutations.
      ]. A phase I/II clinical trial (NCT04036682) is ongoing in previously treated EGFR ex20ins mutant NSCLC patients.
      Tarloxotinib is a prodrug that releases an irreversible EGFR/HER2 TKI under physiologically hypoxic conditions. In cell lines, tarloxotinib can overcome intrinsic EGFR ex20ins resistance to standard EGFR TKIs [
      • Estrada-Bernal A.
      • Doak A.E.
      • Le A.T.
      • Zhu H.
      • Chen N.
      • Silva S.
      • et al.
      Antitumor activity of tarloxotinib, a hypoxia-activated EGFR TKI, in patient-derived lung cancer cell lines harboring EGFR exon 20 insertions.
      ]. The ongoing RAIN phase II study (NCT03805841) is assessing the RR of tarloxotinib in EGFR/HER2 ex20ins mutant NSCLC patients and in other solid tumors with NRG1 fusions (Table 1).
      Other ongoing clinical trials with other EGFR/HER2 ex20ins TKI such as pyrotinib [
      • Wang Y.
      • Jiang T.
      • Qin Z.
      • Jiang J.
      • Wang Q.
      • Yang S.
      • et al.
      HER2 exon 20 insertions in non-small-cell lung cancer are sensitive to the irreversible pan-HER receptor tyrosine kinase inhibitor pyrotinib.
      ], BDTX-189 and DZD9008 [
      • Xu Y.
      • Zhang L.
      • Zhu L.
      • Wang Y.
      • Wang M.
      • Yang Z.
      DZD9008, an oral, wild type selective EGFR inhibitor for the treatment of non-small-cell lung cancer with Exon20 insertion and other activating mutations.
      ] are summarized in Table 1.

      Immune checkpoint inhibitors

      Average tumor mutational burden (TMB) in EGFRex20ins NSCLC is low (mean 4.3, range 0 to 40.3 mutations/Mb) [
      • Riess J.W.
      • Gandara D.R.
      • Frampton G.M.
      • Madison R.
      • Peled N.
      • Bufill J.A.
      • et al.
      Diverse EGFR Exon 20 insertions and co-occurring molecular alterations identified by comprehensive genomic profiling of NSCLC.
      ,

      Chen K, Pan G, Xu Y et al. Immune microenvironment features and efficacy of PD-1/PD-L1 blockade in non-small cell lung cancer (NSCLC) patients with EGFR or HER2 exon 20 insertions. J Clin Oncol 38: 2020 (Suppl; Abstr E21540) n.d. https://doi.org/10.1200/JCO.2020.38.15_suppl.e21540.

      ] similar to common sensitizing EGFR mutations [
      • Negrao M.
      • Reuben A.
      • Robichaux J.
      • Le X.
      • Nilsson M.
      • Elamin Y.
      • et al.
      Driver mutations are associated with distinct patterns of response to immune checkpoint blockade in non-small cell lung cancer.
      ]. However, low TMB in the presence of oncogenic driver mutations should not preclude ICI efficacy [
      • Vokes N.
      • Jimenez Alguilar E.
      • Adeni A.
      • Umeton R.
      • Sholl L.
      • Rizvi H.
      • et al.
      Efficacy and genomic correlates of response to anti-PD1/PD-L1 blockade in non-small cell lung cancers harboring targetable oncogenes.
      ]. The programmed death ligand-1 (PD-L1) expression in EGFR ex20ins lung tumors ranges from 37% to 80% [
      • Cardona A.F.
      • Rojas L.
      • Zatarain-Barrón Z.L.
      • Freitas H.C.
      • Granados S.T.
      • Castillo O.
      • et al.
      EGFR exon 20 insertion in lung adenocarcinomas among Hispanics (geno1.2-CLICaP).
      ,

      Chen K, Pan G, Xu Y et al. Immune microenvironment features and efficacy of PD-1/PD-L1 blockade in non-small cell lung cancer (NSCLC) patients with EGFR or HER2 exon 20 insertions. J Clin Oncol 38: 2020 (Suppl; Abstr E21540) n.d. https://doi.org/10.1200/JCO.2020.38.15_suppl.e21540.

      ,
      • Negrao M.
      • Reuben A.
      • Robichaux J.
      • Le X.
      • Nilsson M.
      • Elamin Y.
      • et al.
      Driver mutations are associated with distinct patterns of response to immune checkpoint blockade in non-small cell lung cancer.
      ]. High PD-L1 expression (≥50%) occurs in 10% of cases (N = 9/88) [
      • Cardona A.F.
      • Rojas L.
      • Zatarain-Barrón Z.L.
      • Freitas H.C.
      • Granados S.T.
      • Castillo O.
      • et al.
      EGFR exon 20 insertion in lung adenocarcinomas among Hispanics (geno1.2-CLICaP).
      ], and PD-L1 expression may vary according to different EGFR ex20ins variants [
      • Cardona A.F.
      • Rojas L.
      • Zatarain-Barrón Z.L.
      • Freitas H.C.
      • Granados S.T.
      • Castillo O.
      • et al.
      EGFR exon 20 insertion in lung adenocarcinomas among Hispanics (geno1.2-CLICaP).
      ]. Evidence about the efficacy of ICI in this subset population is scarce [
      • Yang G.
      • Li J.
      • Xu H.
      • Yang Y.
      • Yang L.
      • Xu F.
      • et al.
      EGFR exon 20 insertion mutations in Chinese advanced non-small cell lung cancer patients: Molecular heterogeneity and treatment outcome from nationwide real-world study.
      ]. Compared to common sensitizing EGFR-mutant NSCLC (N = 36) the EGFR ex20ins NSCLC patients (N = 30) significantly achieved longer PFS (2.9 months versus 1.9 months, HR 0.45, p = 0.002) and OS (NR versus 11.5 months, HR 0.2, p < 0.001), as well as a higher RR (25% versus 0%) with ICI [
      • Negrao M.
      • Reuben A.
      • Robichaux J.P.
      • Le X.
      • Nilsson M.B.
      • Wu C.H.
      • et al.
      Association of EGFR and HER-2 exon 20 mutations with distinct patterns of response to immune checkpoint blockade in non-small cell lung cancer.
      ]. These results may suggest that patients with alterations in this particular region have distinct tumor behaviour more suitable to be treated with ICI. However, the limited number of patients included and lack of information about PD-L1 expression and TMB in this cohort does not lead to firm conclusions. Indeed it remains unknown whether ICI monotherapy or in combination with chemotherapy could be suitable in this subset of patients as EGFR mutant tumors were excluded from randomized phase III clinical trials assessing the role of ICI in first-line setting of advanced NSCLC patients [

      Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol 2019:JCO1800149. https://doi.org/10.1200/JCO.18.00149.

      ,
      • Gadgeel S.
      • Rodríguez-Abreu D.
      • Speranza G.
      • Esteban E.
      • Felip E.
      • Dómine M.
      • et al.
      Updated analysis from KEYNOTE-189: pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non-small-cell lung cancer.
      ,
      • Mok T.S.K.
      • Wu Y.-L.
      • Kudaba I.
      • Kowalski D.M.
      • Cho B.C.
      • Turna H.Z.
      • et al.
      Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.
      ]. However, the IMpower130 and IMpower150 phase III clinical trials allowed to enrol tumors with sensitizing common EGFR mutations and other EGFR mutations [
      • West H.
      • McCleod M.
      • Hussein M.
      • Morabito A.
      • Rittmeyer A.
      • Conter H.J.
      • et al.
      Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial.
      ,
      • Reck M.
      • Mok T.S.K.
      • Nishio M.
      • Jotte R.M.
      • Cappuzzo F.
      • Orlandi F.
      • et al.
      Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial.
      ]. Although chemo-immunotherapy did not improve the outcome compared with chemotherapy alone [
      • West H.
      • McCleod M.
      • Hussein M.
      • Morabito A.
      • Rittmeyer A.
      • Conter H.J.
      • et al.
      Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial.
      ,
      • Reck M.
      • Mok T.S.K.
      • Nishio M.
      • Jotte R.M.
      • Cappuzzo F.
      • Orlandi F.
      • et al.
      Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial.
      ], the four-drug combination of bevacizumab plus atezolizumab plus chemotherapy improved the outcome compared with the bevacizumab and chemotherapy combination [
      • Reck M.
      • Mok T.S.K.
      • Nishio M.
      • Jotte R.M.
      • Cappuzzo F.
      • Orlandi F.
      • et al.
      Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial.
      ]. Whether these results can be translated to EGFR ex20ins mutant tumors remains unknown. In the IMpower 150 trial only 12 patients with this mutation were included, not allowing to obtain firm conclusions.

      Future perspective

      Oncogenic addicted EGFR ex20ins mutant NSCLC remains a tumor with poor prognosis despite being potentially druggable with personalised approaches. However, the conformation of the mutation limits the efficacy of conventional TKI and even the selective EGFR ex20ins TKI have reported more limited efficacy than other EGFR TKI targeting common sensitizing EGFR mutations. Indeed, in some cases the toxicity profile linked to EGFR wild type cells such as diarrhea or rash limits their clinical utility. Therefore, there is a clinical need to identify new therapies for patients with EGFR ex20ins mutation.
      Whether different EGFR ex20ins variants may achieve different benefit from these selective TKI remains controversial. Likewise, most of these selective EGFR ex20ins TKI have been tested in previously treated populations, with no data in the first-line setting. Similarly, half of the EGFR ex20ins tumors have a TP53 co-mutation. In NSCLC patients with concomitant EGFR and TP53 mutation, the efficacy of EGFR TKI is decreased compared with those without TP53 mutation [
      • Aggarwal C.
      • Davis C.W.
      • Mick R.
      • Thompson J.C.
      • Ahmed S.
      • Jeffries S.
      • et al.
      Influence of TP53 mutation on survival in patients with advanced EGFR-mutant non–small-cell lung cancer.
      ]. Although in preclinical models the antitumor activity with amivantamab occurred regardless of this co-mutation [
      • Yun J.
      • Lee S.-H.
      • Kim S.-Y.
      • Jeong S.-Y.
      • Kim J.-H.
      • Pyo K.-H.
      • et al.
      Antitumor activity of amivantamab (JNJ-61186372), an EGFR-cMet bispecific antibody, in diverse models of EGFR Exon 20 insertion-driven NSCLC.
      ], the role of co-mutations in the treatment efficacy of EGFR ex20ins TKI merits also further evaluation.
      Despite these limitations, results from clinical trials with selective EGFR ex20ins TKI have been eagerly awaited and they represent an important progress towards the identification of an effective therapeutic option for NSCLC patients with EGFR ex20ins, an area of high unmet medical need. Evaluation of refined dosing of selective EGFR ex20ins TKI and improved toxicity management to maintain continuous treatment with these new agents may improve the outcome. However, evidence is still scarce and based on the limited number of patients included in the phase I/II clinical trials. Indirect trial comparisons report similar efficacy, but different toxicity profiles, without head to head comparison for assessing the best treatment option. Whether EGFR TKIs are more suitable than bi-specific antibodies remains unknown. Indeed, the best place of ICI in this therapeutic strategy is also relevant. Although previous studies in sensitizing EGFR-mutant [
      • Oshima Y.
      • Tanimoto T.
      • Yuji K.
      • Tojo A.
      EGFR-TKI-associated interstitial pneumonitis in nivolumab-treated patients with non-small cell lung cancer.
      ] or ALK-positive [
      • Spigel D.R.
      • Reynolds C.
      • Waterhouse D.
      • Garon E.B.
      • Chandler J.
      • Babu S.
      • et al.
      Phase 1/2 study of the safety and tolerability of nivolumab plus crizotinib for the first-line treatment of anaplastic lymphoma kinase translocation - positive advanced non-small cell lung cancer (CheckMate 370).
      ,
      • Lin J.J.
      • Chin E.
      • Yeap B.Y.
      • Ferris L.A.
      • Kamesan V.
      • Lennes I.T.
      • et al.
      Increased Hepatotoxicity associated with sequential immune checkpoint inhibitor and crizotinib therapy in patients with non-small cell lung cancer.
      ] NSCLC patients have reported that concurrent or sequential ICI and TKI may increase the risk of pneumonitis or hepatotoxicity, clinical trials with TKI in EGFR ex20ins NSCLC have not reported increased pulmonary or hepatic toxicity, despite a high proportion of patients enrolled in the trials had previously received ICI.
      In the close future, the ongoing phase III clinical trials will hopefully confirm the efficacy of a personalised treatment approach in the first-line setting compared with chemotherapy, and potential trials assessing the efficacy of combination strategies either with chemotherapy or antiangiogenics merit also further evaluation in EGFR ex20ins tumors. This potential synergism must be clearly balanced with toxicity for not hampering treatment compliance.
      As almost one-third of EGFR ex20ins mutant patients may have brain metastases at baseline, intracranial efficacy of these drugs is relevant for this population. Finally, the knowledge of the mechanisms of acquired resistance for personalising treatment upon progression is relevant and may help to enhance the outcome of this population. Finally, the best place of ICI in the therapeutic strategy is also relevant.

      Conclusions

      Although rare and initially thought not targetable, promising treatments for EGFR ex20ins with either new EGFR-TKI or anti-EGFR-MET bispecific antibodies have launched a new treatment approach in this subset of the lung cancer population. Special attention should be paid to the balance of toxicity and survival, and the role of the specific EGFR ex20ins mutation variants, as well as intracranial activity. Based on the availability of new drugs, physicians should be aware of treatment opportunities and patients should be tested for EGFR ex20ins mutations.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Appendix A. Supplementary material

      The following are the Supplementary data to this article:

      References

        • Oxnard G.R.
        • Lo P.C.
        • Nishino M.
        • Dahlberg S.E.
        • Lindeman N.I.
        • Butaney M.
        • et al.
        Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions.
        J Thorac Oncol. 2013; 8: 179-184https://doi.org/10.1097/JTO.0b013e3182779d18
        • Riess J.W.
        • Gandara D.R.
        • Frampton G.M.
        • Madison R.
        • Peled N.
        • Bufill J.A.
        • et al.
        Diverse EGFR Exon 20 insertions and co-occurring molecular alterations identified by comprehensive genomic profiling of NSCLC.
        J Thorac Oncol. 2018; 13: 1560-1568https://doi.org/10.1016/j.jtho.2018.06.019
        • Cardona A.F.
        • Rojas L.
        • Zatarain-Barrón Z.L.
        • Freitas H.C.
        • Granados S.T.
        • Castillo O.
        • et al.
        EGFR exon 20 insertion in lung adenocarcinomas among Hispanics (geno1.2-CLICaP).
        Lung Cancer. 2018; 125: 265-272https://doi.org/10.1016/j.lungcan.2018.10.007
        • Arcila M.E.
        • Nafa K.
        • Chaft J.E.
        • Rekhtman N.
        • Lau C.
        • Reva B.A.
        • et al.
        EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics.
        Mol Cancer Ther. 2013; 12: 220-229https://doi.org/10.1158/1535-7163.MCT-12-0620
        • Midha A.
        • Dearden S.
        • McCormack R.
        EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII).
        Am J Cancer Res. 2015; 5: 2892-2911
        • Pan Y.
        • Zhang Y.
        • Li Y.
        • Hu H.
        • Wang L.
        • Li H.
        • et al.
        Prevalence, clinicopathologic characteristics, and molecular associations of EGFR exon 20 insertion mutations in East Asian patients with lung adenocarcinoma.
        Ann Surg Oncol. 2014; 21: S490-S496https://doi.org/10.1245/s10434-013-3452-1
        • Sasaki H.
        • Endo K.
        • Takada M.
        • Kawahara M.
        • Kitahara N.
        • Tanaka H.
        • et al.
        EGFR exon 20 insertion mutation in Japanese lung cancer.
        Lung Cancer. 2007; 58: 324-328https://doi.org/10.1016/j.lungcan.2007.06.024
        • Yang G.
        • Li J.
        • Xu H.
        • Yang Y.
        • Yang L.
        • Xu F.
        • et al.
        EGFR exon 20 insertion mutations in Chinese advanced non-small cell lung cancer patients: Molecular heterogeneity and treatment outcome from nationwide real-world study.
        Lung Cancer. 2020; https://doi.org/10.1016/j.lungcan.2020.03.014
        • Soria J.-C.
        • Ohe Y.
        • Vansteenkiste J.
        • Reungwetwattana T.
        • Chewaskulyong B.
        • Lee K.H.
        • et al.
        Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer.
        N Engl J Med. 2018; 378: 113-125https://doi.org/10.1056/NEJMoa1713137
        • Nakagawa K.
        • Garon E.B.
        • Seto T.
        • Nishio M.
        • Ponce Aix S.
        • Paz-Ares L.
        • et al.
        Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial.
        Lancet Oncol. 2019; 20: 1655-1669https://doi.org/10.1016/S1470-2045(19)30634-5
        • Patil T.
        • Smith D.E.
        • Bunn P.A.
        • Aisner D.L.
        • Le A.T.
        • Hancock M.
        • et al.
        The incidence of brain metastases in stage IV ROS1-rearranged non-small cell lung cancer and rate of central nervous system progression on crizotinib.
        J Thorac Oncol. 2018; 13: 1717-1726https://doi.org/10.1016/j.jtho.2018.07.001
        • Drilon A.
        • Lin J.J.
        • Filleron T.
        • Ni A.
        • Milia J.
        • Bergagnini I.
        • et al.
        Frequency of brain metastases and multikinase inhibitor outcomes in patients with RET-rearranged lung cancers.
        J Thorac Oncol. 2018; 13: 1595-1601https://doi.org/10.1016/j.jtho.2018.07.004
        • Leduc C.
        • Merlio J.P.
        • Besse B.
        • Blons H.
        • Debieuvre D.
        • Bringuier P.P.
        • et al.
        Clinical and molecular characteristics of non-small-cell lung cancer (NSCLC) harboring EGFR mutation: results of the nationwide French Cooperative Thoracic Intergroup (IFCT) program.
        Ann Oncol. 2017; 28: 2715-2724https://doi.org/10.1093/annonc/mdx404
        • Beau-Faller M.
        • Prim N.
        • Ruppert A.-M.
        • Nanni-Metéllus I.
        • Lacave R.
        • Lacroix L.
        • et al.
        Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network.
        Ann Oncol. 2014; 25: 126-131https://doi.org/10.1093/annonc/mdt418
        • Wu J.-Y.
        • Yu C.-J.
        • Shih J.-Y.
        Effectiveness of treatments for advanced non-small-cell lung cancer with exon 20 insertion epidermal growth factor receptor mutations.
        Clin Lung Cancer. 2019; 20: e620-e630https://doi.org/10.1016/j.cllc.2019.06.018
        • Vyse S.
        • Huang P.H.
        Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer.
        Signal Transduct Target Ther. 2019; 4: 5https://doi.org/10.1038/s41392-019-0038-9
        • Yasuda H.
        • Park E.
        • Yun C.-H.
        • Sng N.J.
        • Lucena-Araujo A.R.
        • Yeo W.-L.
        • et al.
        Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer.
        Sci Transl Med. 2013;5:216ra177.; https://doi.org/10.1126/scitranslmed.3007205
        • Robichaux J.P.
        • Elamin Y.Y.
        • Tan Z.
        • Carter B.W.
        • Zhang S.
        • Liu S.
        • et al.
        Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer.
        Nat Med. 2018; 24: 638-646https://doi.org/10.1038/s41591-018-0007-9
        • Yang M.
        • Xu X.
        • Cai J.
        • Ning J.
        • Wery J.P.
        • Li Q.-X.
        NSCLC harboring EGFR exon-20 insertions after the regulatory C-helix of kinase domain responds poorly to known EGFR inhibitors.
        Int J Cancer. 2016; 139: 171-176https://doi.org/10.1002/ijc.30047
        • Hasegawa H.
        • Yasuda H.
        • Hamamoto J.
        • Masuzawa K.
        • Tani T.
        • Nukaga S.
        • et al.
        Efficacy of afatinib or osimertinib plus cetuximab combination therapy for non-small-cell lung cancer with EGFR exon 20 insertion mutations.
        Lung Cancer. 2019; 127: 146-152https://doi.org/10.1016/j.lungcan.2018.11.039
        • Tu H.-Y.
        • Ke E.-E.
        • Yang J.-J.
        • Sun Y.-L.
        • Yan H.-H.
        • Zheng M.-Y.
        • et al.
        A comprehensive review of uncommon EGFR mutations in patients with non-small cell lung cancer.
        Lung Cancer. 2017; 114: 96-102https://doi.org/10.1016/j.lungcan.2017.11.005
        • Yang J.C.-H.
        • Sequist L.V.
        • Geater S.L.
        • Tsai C.-M.
        • Mok T.S.K.
        • Schuler M.
        • et al.
        Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6.
        Lancet Oncol. 2015; 16: 830-838https://doi.org/10.1016/S1470-2045(15)00026-1
        • Kuiper J.L.
        • Hashemi S.M.S.
        • Thunnissen E.
        • Snijders P.J.F.
        • Grünberg K.
        • Bloemena E.
        • et al.
        Non-classic EGFR mutations in a cohort of Dutch EGFR-mutated NSCLC patients and outcomes following EGFR-TKI treatment.
        Br J Cancer. 2016; 115: 1504-1512https://doi.org/10.1038/bjc.2016.372
        • Naidoo J.
        • Sima C.S.
        • Rodriguez K.
        • Busby N.
        • Nafa K.
        • Ladanyi M.
        • et al.
        Epidermal growth factor receptor exon 20 insertions in advanced lung adenocarcinomas: clinical outcomes and response to erlotinib.
        Cancer. 2015; 121: 3212-3220https://doi.org/10.1002/cncr.29493
        • Gergis C.
        • Rangachari D.
        • Fujii M.
        • Varkaris A.
        • VanderLaan P.A.
        • Kobayashi S.
        • et al.
        EGFR-A763_Y764insFQEA: a unique exon 20 insertion mutation that displays sensitivity to all classes of approved lung cancer EGFR tyrosine kinase inhibitors.
        JCO. 2019; 37: e20593https://doi.org/10.1200/JCO.2019.37.15_suppl.e20593
        • Ramalingam S.S.
        • Vansteenkiste J.
        • Planchard D.
        • Cho B.C.
        • Gray J.E.
        • Ohe Y.
        • et al.
        Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC.
        N Engl J Med. 2020; 382: 41-50https://doi.org/10.1056/NEJMoa1913662
        • Cho J.H.
        • Lim S.H.
        • An H.J.
        • Kim K.H.
        • Park K.U.
        • Kang E.J.
        • et al.
        Osimertinib for patients with non-small-cell lung cancer harboring uncommon EGFR mutations: a multicenter, open-label, phase II trial (KCSG-LU15-09).
        J Clin Oncol. 2020; 38: 488-495https://doi.org/10.1200/JCO.19.00931
        • Hirano T.
        • Yasuda H.
        • Tani T.
        • Hamamoto J.
        • Oashi A.
        • Ishioka K.
        • et al.
        In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer.
        Oncotarget. 2015; 6: 38789-38803
        • Floc’h N.
        • Martin M.J.
        • Riess J.W.
        • Orme J.P.
        • Staniszewska A.D.
        • Ménard L.
        • et al.
        Antitumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR exon 20 insertions.
        Mol Cancer Ther. 2018; 17: 885-896https://doi.org/10.1158/1535-7163.MCT-17-0758
      1. Ji J, Aredo J, Piper-Valillo A, Huppert L et al. Osimertinib in non-small cell lung cancer (NSCLC) with atypical EGFR activating mutations: A retrospective multicenter study. J Clin Oncol 38: 2020 (Suppl; Abstr 9570) n.d. https://doi.org/10.1200/JCO.2020.38.15_suppl.9570.

        • van Veggel B.
        • Madeira R.
        • Santos J.F.V.
        • Hashemi S.M.S.
        • Paats M.S.
        • Monkhorst K.
        • Heideman D.a.M.
        • et al.
        Osimertinib treatment for patients with EGFR exon 20 mutation positive non-small cell lung cancer.
        Lung Cancer. 2020; 141: 9-13https://doi.org/10.1016/j.lungcan.2019.12.013
        • Fang W.
        • Huang Y.
        • Hong S.
        • Zhang Z.
        • Wang M.
        • Gan J.
        • et al.
        EGFR exon 20 insertion mutations and response to osimertinib in non-small-cell lung cancer.
        BMC Cancer. 2019; 19: 595https://doi.org/10.1186/s12885-019-5820-0
      2. Piotrowska Z, Wang Y, Sequist LV, Ramalingam S, et al. ECOG-ACRIN 5162: A phase II study of osimertinib 160 mg in NSCLC with EGFR exon 20 insertions. J Clin Oncol 38: 2020 (Suppl; Abstr 9513) n.d. https://doi.org/10.1200/JCO.2020.38.15_suppl.9513.

        • Fang W.
        • Huang Y.
        • Gan J.
        • Shao Y.W.
        • Zhang L.
        Durable response of low-dose afatinib plus cetuximab in an adenocarcinoma patient with a novel EGFR Exon 20 insertion mutation.
        J Thorac Oncol. 2019; 14: e220-e221https://doi.org/10.1016/j.jtho.2019.05.023
        • Fang W.
        • Huang Y.
        • Gan J.
        • Hong S.
        • Zhang L.
        A patient with EGFR Exon 20 insertion-mutant non-small cell lung cancer responded to osimertinib plus cetuximab combination therapy.
        J Thorac Oncol. 2019; 14: e201-e202https://doi.org/10.1016/j.jtho.2019.04.013
        • Hosomi Y.
        • Morita S.
        • Sugawara S.
        • Kato T.
        • Fukuhara T.
        • Gemma A.
        • et al.
        Gefitinib alone versus gefitinib plus chemotherapy for non-small-cell lung cancer with mutated epidermal growth factor receptor: NEJ009 study.
        J Clin Oncol. 2020; 38: 115-123https://doi.org/10.1200/JCO.19.01488
        • Noronha V.
        • Patil V.M.
        • Joshi A.
        • Menon N.
        • Chougule A.
        • Mahajan A.
        • et al.
        Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer.
        J Clin Oncol. 2020; 38: 124-136https://doi.org/10.1200/JCO.19.01154
        • Yamamoto N.
        • Seto T.
        • Nishio M.
        • Goto K.
        • Okamoto I.
        • Yamanaka T.
        • et al.
        Erlotinib plus bevacizumab (EB) versus erlotinib alone (E) as first-line treatment for advanced EGFR mutation–positive non-squamous non–small-cell lung cancer (NSCLC): Survival follow-up results of JO25567.
        JCO. 2018; 36: 9007https://doi.org/10.1200/JCO.2018.36.15_suppl.9007
        • Zhou Q.
        • Wu Y.-L.
        • Cheng Y.
        • Liu Y.
        • Chen G.
        • Cui J.
        • et al.
        CTONG 1509: Phase III study of bevacizumab with or without erlotinib in untreated Chinese patients with advanced EGFR-mutated NSCLC.
        Ann Oncol. 2019; 30v603https://doi.org/10.1093/annonc/mdz260.002
        • Jorge S.E.
        • Lucena-Araujo A.R.
        • Yasuda H.
        • Piotrowska Z.
        • Oxnard G.R.
        • Rangachari D.
        • et al.
        EGFR Exon 20 insertion mutations display sensitivity to hsp90 inhibition in preclinical models and lung adenocarcinomas.
        Clin Cancer Res. 2018; 24: 6548-6555https://doi.org/10.1158/1078-0432.CCR-18-1541
        • Piotrowska Z.
        • Costa D.B.
        • Oxnard G.R.
        • Huberman M.
        • Gainor J.F.
        • Lennes I.T.
        • et al.
        Activity of the Hsp90 inhibitor luminespib among non-small-cell lung cancers harboring EGFR exon 20 insertions.
        Ann Oncol. 2018; 29: 2092-2097https://doi.org/10.1093/annonc/mdy336
        • Kim T.M.
        • Lee K.-W.
        • Oh D.-Y.
        • Lee J.-S.
        • Im S.-A.
        • Kim D.-W.
        • et al.
        Phase 1 studies of poziotinib, an irreversible pan-HER tyrosine kinase inhibitor in patients with advanced solid tumors.
        Cancer Res Treat. 2018; 50: 835-842https://doi.org/10.4143/crt.2017.303
        • Heymach J.
        • Negrao M.
        • Robichaux J.
        • Carter B.
        • Patel A.
        • Altan M.
        • et al.
        A phase II trial of poziotinib in EGFR and HER2 exon 20 mutant non-small cell lung cancer (NSCLC).
        J Thoracic Oncol. 2018; 13: S323-S324https://doi.org/10.1016/j.jtho.2018.08.243
      3. Le X, Goldman JW, Clarke JM et al. Poziotinib shows activity and durability of responses in subgroups of previously treated EGFR exon 20 NSCLC patients. J Clin Oncol 38: 2020 (Suppl; Abstr 9514) n.d. https://doi.org/10.1200/JCO.2020.38.15_suppl.9514.

        • Park K.
        • Tan E.-H.
        • O’Byrne K.
        • Zhang L.
        • Boyer M.
        • Mok T.
        • et al.
        Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial.
        Lancet Oncol. 2016; 17: 577-589https://doi.org/10.1016/S1470-2045(16)30033-X
        • Sequist L.V.
        • Yang J.C.-H.
        • Yamamoto N.
        • O’Byrne K.
        • Hirsh V.
        • Mok T.
        • et al.
        Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.
        J Clin Oncol. 2013; 31: 3327-3334https://doi.org/10.1200/JCO.2012.44.2806
        • Wu Y.-L.
        • Cheng Y.
        • Zhou X.
        • Lee K.H.
        • Nakagawa K.
        • Niho S.
        • et al.
        Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial.
        Lancet Oncol. 2017; 18: 1454-1466https://doi.org/10.1016/S1470-2045(17)30608-3
        • Corral J.
        • Mok T.S.
        • Nakagawa K.
        • Rosell R.
        • Lee K.H.
        • Migliorino M.R.
        • et al.
        Effects of dose modifications on the safety and efficacy of dacomitinib for EGFR mutation-positive non-small-cell lung cancer.
        Future Oncol. 2019; 15: 2795-2805https://doi.org/10.2217/fon-2019-0299
        • Schuler M.
        • Tan E.-H.
        • O’Byrne K.
        • Zhang L.
        • Boyer M.
        • Mok T.
        • et al.
        First-line afatinib vs gefitinib for patients with EGFR mutation-positive NSCLC (LUX-Lung 7): impact of afatinib dose adjustment and analysis of mode of initial progression for patients who continued treatment beyond progression.
        J Cancer Res Clin Oncol. 2019; 145: 1569-1579https://doi.org/10.1007/s00432-019-02862-x
        • Yang J.C.-H.
        • Sequist L.V.
        • Zhou C.
        • Schuler M.
        • Geater S.L.
        • Mok T.
        • et al.
        Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma: post hoc analyses of the randomized LUX-Lung 3 and 6 trials.
        Ann Oncol. 2016; 27: 2103-2110https://doi.org/10.1093/annonc/mdw322
        • Janne P.A.
        • Neal J.W.
        • Camidge D.R.
        • Spira A.I.
        • Piotrowska Z.
        • Horn L.
        • et al.
        Antitumor activity of TAK-788 in NSCLC with EGFR exon 20 insertions.
        JCO. 2019; 37 (9007 9007)https://doi.org/10.1200/JCO.2019.37.15_suppl.9007
        • Suda K.
        • Nishino M.
        • Koga T.
        • Fujino T.
        • Ohara S.
        • Soh J.
        • et al.
        T790M or C797S confers acquired resistance to tarloxotinib and poziotinib in EGFR Exon 20 insertion-driven lung cancer models in vitro.
        Journal of Thoracic Oncology. 2019; 14: S835https://doi.org/10.1016/j.jtho.2019.08.1801
        • Elamin Y.
        • Robichaux J.
        • Carter B.
        • Altan M.
        • Gibbons D.
        • Fossella F.
        • et al.
        Identification of mechanisms of acquired resistance to poziotinib in EGFR Exon 20 mutant non-small cell lung cancer (NSCLC).
        J Thoracic Oncol. 2019; 14: S282-S283https://doi.org/10.1016/j.jtho.2019.08.567
        • Neal J.
        • Doebele R.
        • Riely G.
        • Spira A.
        • Horn L.
        • Piotrowska Z.
        • et al.
        Safety, PK, and preliminary antitumor Activity of the Oral EGFR/HER2 Exon 20 inhibitor TAK-788 in NSCLC.
        J Thoracic Oncol. 2018; 13: S599https://doi.org/10.1016/j.jtho.2018.08.901
      4. Horn L, Lin HM, Padda SK, Aggarwal Ch et al. Indirect comparison of TAK-788 vs real-world data outcomes in refractory non-small cell lung cancer (NSCLC) with EGFR exon 20 insertions. J Clin Oncol 38: 2020 (Suppl; Abstr 9580) n.d. https://doi.org/10.1200/JCO.2020.38.15_suppl.9580.

        • Moores S.L.
        • Chiu M.L.
        • Bushey B.S.
        • Chevalier K.
        • Luistro L.
        • Dorn K.
        • et al.
        A novel bispecific antibody targeting EGFR and cMet is effective against EGFR inhibitor-resistant lung tumors.
        Cancer Res. 2016; 76: 3942-3953https://doi.org/10.1158/0008-5472.CAN-15-2833
        • Yun J.
        • Lee S.-H.
        • Kim S.-Y.
        • Jeong S.-Y.
        • Kim J.-H.
        • Pyo K.-H.
        • et al.
        Antitumor activity of amivantamab (JNJ-61186372), an EGFR-cMet bispecific antibody, in diverse models of EGFR Exon 20 insertion-driven NSCLC.
        Cancer Discov. 2020; (CD-20-0116)https://doi.org/10.1158/2159-8290.CD-20-0116
        • Park K.
        • Ahn M.
        • Lee S.
        • Kim H.R.
        • Hong M.H.
        • Millington D.
        • et al.
        A first-in-human phase 1 trial of the EGFR-cMET bispecific antibody JNJ-61186372 in patients with advanced non-small cell lung cancer (NSCLC).
        J Thoracic Oncol. 2018; 13: S344-S345https://doi.org/10.1016/j.jtho.2018.08.292
        • Haura E.B.
        • Cho B.C.
        • Lee J.S.
        • Han J.-Y.
        • Lee K.H.
        • Sanborn R.E.
        • et al.
        JNJ-61186372 (JNJ-372), an EGFR-cMet bispecific antibody, in EGFR-driven advanced non-small cell lung cancer (NSCLC).
        JCO. 2019; 37: 9009https://doi.org/10.1200/JCO.2019.37.15_suppl.9009
      5. Park K, Johm T, Kim SW et al. Amivantamab (JNJ-61186372), an anti-EGFR-MET bispecific antibody, in patients with EGFR exon 20 insertion (exon20ins)-mutated non-small cell lung cancer (NSCLC). J Clin Oncol 38: 2020 (Suppl; Abstr 9512) n.d. https://doi.org/10.1200/JCO.2020.38.15_suppl.9512.

        • Udagawa H.
        • Hasako S.
        • Ohashi A.
        • Fujioka R.
        • Hakozaki Y.
        • Shibuya M.
        • et al.
        TAS6417/CLN-081 Is a Pan-mutation-selective EGFR tyrosine kinase inhibitor with a broad spectrum of preclinical activity against clinically relevant EGFR mutations.
        Mol Cancer Res. 2019; 17: 2233-2243https://doi.org/10.1158/1541-7786.MCR-19-0419
        • Hasako S.
        • Terasaka M.
        • Abe N.
        • Uno T.
        • Ohsawa H.
        • Hashimoto A.
        • et al.
        TAS6417, a novel EGFR inhibitor targeting exon 20 insertion mutations.
        Mol Cancer Ther. 2018; 17: 1648-1658https://doi.org/10.1158/1535-7163.MCT-17-1206
        • Estrada-Bernal A.
        • Doak A.E.
        • Le A.T.
        • Zhu H.
        • Chen N.
        • Silva S.
        • et al.
        Antitumor activity of tarloxotinib, a hypoxia-activated EGFR TKI, in patient-derived lung cancer cell lines harboring EGFR exon 20 insertions.
        Mol Cancer Ther. 2018; 17: A157https://doi.org/10.1158/1535-7163.TARG-17-A157
        • Wang Y.
        • Jiang T.
        • Qin Z.
        • Jiang J.
        • Wang Q.
        • Yang S.
        • et al.
        HER2 exon 20 insertions in non-small-cell lung cancer are sensitive to the irreversible pan-HER receptor tyrosine kinase inhibitor pyrotinib.
        Ann Oncol. 2019; 30: 447-455https://doi.org/10.1093/annonc/mdy542
        • Xu Y.
        • Zhang L.
        • Zhu L.
        • Wang Y.
        • Wang M.
        • Yang Z.
        DZD9008, an oral, wild type selective EGFR inhibitor for the treatment of non-small-cell lung cancer with Exon20 insertion and other activating mutations.
        Cancer Res. 2019; 79: 3081https://doi.org/10.1158/1538-7445.AM2019-3081
      6. Chen K, Pan G, Xu Y et al. Immune microenvironment features and efficacy of PD-1/PD-L1 blockade in non-small cell lung cancer (NSCLC) patients with EGFR or HER2 exon 20 insertions. J Clin Oncol 38: 2020 (Suppl; Abstr E21540) n.d. https://doi.org/10.1200/JCO.2020.38.15_suppl.e21540.

        • Negrao M.
        • Reuben A.
        • Robichaux J.
        • Le X.
        • Nilsson M.
        • Elamin Y.
        • et al.
        Driver mutations are associated with distinct patterns of response to immune checkpoint blockade in non-small cell lung cancer.
        J Thoracic Oncol. 2018; 13: S733-S734https://doi.org/10.1016/j.jtho.2018.08.1233
        • Vokes N.
        • Jimenez Alguilar E.
        • Adeni A.
        • Umeton R.
        • Sholl L.
        • Rizvi H.
        • et al.
        Efficacy and genomic correlates of response to anti-PD1/PD-L1 blockade in non-small cell lung cancers harboring targetable oncogenes.
        J Thoracic Oncol. 2018; 13: S422https://doi.org/10.1016/j.jtho.2018.08.474
        • Negrao M.
        • Reuben A.
        • Robichaux J.P.
        • Le X.
        • Nilsson M.B.
        • Wu C.H.
        • et al.
        Association of EGFR and HER-2 exon 20 mutations with distinct patterns of response to immune checkpoint blockade in non-small cell lung cancer.
        J Clin Oncol. 2018; 36: n.d
      7. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol 2019:JCO1800149. https://doi.org/10.1200/JCO.18.00149.

        • Gadgeel S.
        • Rodríguez-Abreu D.
        • Speranza G.
        • Esteban E.
        • Felip E.
        • Dómine M.
        • et al.
        Updated analysis from KEYNOTE-189: pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non-small-cell lung cancer.
        J Clin Oncol. 2020; 38: 1505-1517https://doi.org/10.1200/JCO.19.03136
        • Mok T.S.K.
        • Wu Y.-L.
        • Kudaba I.
        • Kowalski D.M.
        • Cho B.C.
        • Turna H.Z.
        • et al.
        Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.
        Lancet. 2019; 393: 1819-1830https://doi.org/10.1016/S0140-6736(18)32409-7
        • West H.
        • McCleod M.
        • Hussein M.
        • Morabito A.
        • Rittmeyer A.
        • Conter H.J.
        • et al.
        Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial.
        Lancet Oncol. 2019; 20: 924-937https://doi.org/10.1016/S1470-2045(19)30167-6
        • Reck M.
        • Mok T.S.K.
        • Nishio M.
        • Jotte R.M.
        • Cappuzzo F.
        • Orlandi F.
        • et al.
        Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial.
        Lancet Respir Med. 2019; 7: 387-401https://doi.org/10.1016/S2213-2600(19)30084-0
        • Aggarwal C.
        • Davis C.W.
        • Mick R.
        • Thompson J.C.
        • Ahmed S.
        • Jeffries S.
        • et al.
        Influence of TP53 mutation on survival in patients with advanced EGFR-mutant non–small-cell lung cancer.
        JCO Precis Oncol. 2018; : 1-29https://doi.org/10.1200/PO.18.00107
        • Oshima Y.
        • Tanimoto T.
        • Yuji K.
        • Tojo A.
        EGFR-TKI-associated interstitial pneumonitis in nivolumab-treated patients with non-small cell lung cancer.
        JAMA Oncol. 2018; 4: 1112-1115https://doi.org/10.1001/jamaoncol.2017.4526
        • Spigel D.R.
        • Reynolds C.
        • Waterhouse D.
        • Garon E.B.
        • Chandler J.
        • Babu S.
        • et al.
        Phase 1/2 study of the safety and tolerability of nivolumab plus crizotinib for the first-line treatment of anaplastic lymphoma kinase translocation - positive advanced non-small cell lung cancer (CheckMate 370).
        J Thorac Oncol. 2018; 13: 682-688https://doi.org/10.1016/j.jtho.2018.02.022
        • Lin J.J.
        • Chin E.
        • Yeap B.Y.
        • Ferris L.A.
        • Kamesan V.
        • Lennes I.T.
        • et al.
        Increased Hepatotoxicity associated with sequential immune checkpoint inhibitor and crizotinib therapy in patients with non-small cell lung cancer.
        J Thorac Oncol. 2019; 14: 135-140https://doi.org/10.1016/j.jtho.2018.09.001