Virtual Library

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    P09 - Targeted Therapies - EGFR (ID 26)

    • Event: TTLC 2021
    • Type: Poster
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 2/17/2021, 00:00 - 00:00,
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      Response to Standard Therapies and Comprehensive Genomic Analysis for Patients With Lung Adenocarcinoma With EGFR Exon 20 Insertions (ID P09.01)

      00:00 - 00:00  |  Author(s): Noura Choudhury, Noura Choudhury

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MO16 - Prognostic and Predictive Biomarkers IV (ID 97)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO16.06 - Clinical, structural and biochemical characterization of EGFR exon 20 insertion mutations in lung cancer (ID 745)

      16:15 - 17:45  |  Author(s): D.B. Costa, H. Yasuda, E. Park, C. Yun, M.S. Huberman, G.R. Oxnard, L.V. Sequist, G. Riely, R. Soo, M.J. Eck, S.S. Kobayashi

      • Abstract
      • Presentation
      • Slides

      Background
      Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for ~10% of EGFR-mutated non-small-cell lung cancer (NSCLC), for the most part occur at the N-lobe of EGFR after its C-helix (after amino-acid M766) and have unsolved patterns of response to ATP-mimetic EGFR tyrosine kinase inhibitors (TKIs).

      Methods
      To understand the patterns of resistance or response to EGFR TKIs of EGFR exon 20 insertion mutations, we decided to study representative mutations using in vitro systems, structural models and also NSCLCs with these specific EGFR mutations.

      Results
      We selected three mutations located within the C-helix (A763_Y764insFQEA [identical to D761_E762insEAFQ], Y764_V765insHH and M766_A767insAI) and four mutations following the C-helix (A767_V769dupASV [identical to V769_D770insASV], D770_N771insNPG, D770_N771insSVD [identical to S768_D770dupSVD] and H773_V774insH [identical to P772_H773insH]) mutations. Our data indicates almost all EGFR exon 20 insertions are resistant to submicromolar concentrations of gefitinib or erlotinib; data that mirrors the lack of clinical response of NSCLCs with these mutations. The crystal structural and enzyme kinetic studies of a prototypical post C-helix EGFR TKI-resistant insertion, between residues D770_N771 (D770_N771insNPG), highlight that these mutations favor the active conformation (i.e., are activating), don’t alter EGFR’s ATP-binding pocket and are less sensitive than TKI-sensitive mutations. D770_N771insNPG is predicted to be 7.66 fold less sensitive than the TKI-sensitive EGFR-L858R. Unexpectedly, we identified the atypical EGFR-A763_Y764insFQEA as the only EGFR exon 20 insertion hypersensitive to EGFR TKIs using enzyme kinetic and cell line models. In patients with EGFR exon 20 mutated NSCLCs, the response rates to gefitinib or erlotinib were significantly higher for A763_Y764insFQEA (2/3; 66.6%) when compared to all other mutations within or following the C-helix (0/17, 0%; p=0.0158). The unorthodox homology model of A763_Y764insFQEA suggests a mechanism of activation (by shifting the register of the C-helix N-terminal) related to TKI-sensitive mutations (such as L858R or L861Q).

      Conclusion
      Our findings not only explain the intricate interplay between different EGFR mutations and their response to EGFR TKIs, but also have clinical implications for the treatment of EGFR exon 20 insertion mutated NSCLCs. Therefore, based on our data and previously published reports the aforementioned mutations affecting amino acids V765 to V774 should be classified as non-sensitizing to the reversible EGFR TKIs gefitinib and erlotinib. Our models may usher the development of EGFR TKIs specific for EGFR exon 20 insertion mutations.

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    MINI 30 - New Kinase Targets (ID 157)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MINI30.06 - Activity of AUY922 in NSCLC Patients With EGFR Exon 20 Insertions (ID 1744)

      18:30 - 20:00  |  Author(s): Z. Piotrowska, E. Smit, D.B. Costa, M.S. Huberman, G.R. Oxnard, J.F. Gainor, R. Heist, A. Muzikansky, C.G. Azzoli, A. Shaw, C. Lin, W. Liao, C. Ho, M.J. Niederst, L. Fulton, J.A. Engelman, L.V. Sequist, J.C. Yang

      • Abstract
      • Presentation
      • Slides

      Background:
      EGFR exon 20 insertions (ins20) represent a rare subtype (4%) of EGFR mutations and are refractory to EGFR-specific tyrosine kinase inhibitors (TKIs). No effective targeted therapies exist for patients (pts) with ins20; median PFS on the irreversible EGFR TKI Afatinib is 2.8 months (mos). Based on a durable RECIST partial response (PR) to AUY922, a Heat Shock Protein 90 (Hsp90) inhibitor, observed in an EGFR ins20 patient in a previous study (NCT01124864), we designed a phase II investigator-initiated trial to assess the activity of AUY922 in NSCLC pts with EGFR ins20. Since pts with these mutations are rare, we identified other international investigators who have treated ins20 patients with AUY922. Here, we present the results of a pooled international experience of 21 patients with EGFR ins20 treated with AUY922 in the United States, Taiwan and the Netherlands.

      Methods:
      A total of 21 patients with EGFR in20 are included in this analysis. 14 were treated on a single-arm, multi-center, open-label study of AUY922 in advanced NSCLC pts with EGFR ins20 mutations in the US (NCT01854034). Five were treated on a multicenter Taiwanese trial of AUY922 across a variety of molecular NSCLC subtypes (NCT01922583) and two were treated on a compassionate-use basis in the Netherlands. The starting dose of AUY922 was 70mg/m2 IV weekly for all patients.

      Results:
      21 pts, including 14 females and 7 males, average age 55 (range, 27-75) were included in this analysis. The median number of prior therapies was 2 (range, 1-6.) 6 pts received a prior EGFR TKI; none responded to TKI monotherapy. The most common AUY922-related toxicities were grade 1-2 visual changes (18/21; 86%) diarrhea (18/21; 86%) and fatigue (15/21; 71%). The only treatment-related grade 3 toxicities was hypertension (2/21; 1%) and AST elevation (1/21; 0.5%). There was one death on study, related to pre-existing comorbidity/unrelated to AUY922. Among the 21 patients treated, 5 achieved a partial response by RECIST 1.1 (ORR 24%) (Figure 1.) The median PFS estimate is 3.9 mos (95% CI, 2.9 to 10.7.) 6 patients remain on treatment at the time of abstract submission. Updated results and correlation with specific ins20 mutations will be presented. Figure 1



      Conclusion:
      This international experience suggests that AUY922 may be an active therapy for advanced NSCLC pts with EGFR ins20 mutations with an ORR 24% and median PFS 3.9 mo. AUY922 is generally well-tolerated, though reversible low-grade ocular toxicity is common. Further study of AUY922 in this population is warranted.

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    OA10 - EGFR Mutations (ID 382)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Biology/Pathology
    • Presentations: 1
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      OA10.01 - Comprehensive Genomic Profiling and PDX Modeling of EGFR Exon 20 Insertions: Evidence for Osimertinib Based Dual EGFR Blockade (ID 4375)

      11:00 - 12:30  |  Author(s): J.W. Riess, D.R. Gandara, G.M. Frampton, M. Cheng, P. Lara, K. Kelly, C. Ye, R. Madison, N. Peled, J.A. Bufill, G. Dy, S. Ou, D. Cross, C.J. Bult, S.D. Airhart, P.J. Stephens, J. Ross, V. Miller, S. Ali, J. Keck, P. Mack, A.B. Schrock

      • Abstract
      • Slides

      Background:
      EGFR exon 20 insertion mutations (EGFRex20ins) comprise a subset of EGFR activating alterations relatively insensitive to 1[st] and 2[nd] generation EGFR-TKIs. Comprehensive genomic profiling (CGP) integrated with PDX modeling may identify new EGFR-inhibition strategies for EGFRex20ins.

      Methods:
      EGFRex20ins and co-occurring genomic alterations were identified by hybrid-capture based CGP performed on 14,483 consecutive FFPE lung cancer specimens to a mean coverage depth of >650X for 236 or 315 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. An EGFRex20ins(N771_P772>SVDNP)/EGFR-amplified tumor (24 copies) from this cohort was implanted subcutaneously into the flank of NOD.Cg-Prkdc[scid]Il2rg[tm1Wjl]/SzJ (NSG) mice for tumor growth inhibition studies (TGI) with vehicle, erlotinib (50 mg/kg PO daily), osimertinib (25 mg/kg PO daily), and osimertinib (25 mg/kg PO daily) plus cetuximab (10 mg/kg IV, 2x/week) administered for 21 days.

      Results:
      CGP identified 263/14,483 cases (1.8%) with EGFRex20ins, which represent 12% (263/2,251) of EGFR activating mutations in this series. 90% (237/263) were NSCLC-adenocarcinoma, 9% (23/263) were NSCLC-NOS, and 1% (2/263) were sarcomatoid carcinoma. Over 60 unique EGFRex20ins were identified, most commonly D770_N771>ASVDN (21%) and N771_P772>SVDNP (20%); 6% (15/263) harbored EGFR A763_Y764insFQEA, an EGFRex20ins typically sensitive to erlotinib. Among EGFRex20ins cases, EGFR-amplification occurred in 22% (57/263). Putative co-occurring driver alterations including EGFR (ex19del and L858R), Her2, MET and KRAS tended to be mutually exclusive, occurring only in 5% (12/263) of cases. The most common co-occurring alterations affected TP53 (56%), CDKN2A (22%), CDKN2B (16%), NKX2-1 (14%) and RB1 (11%). Average tumor mutation burden was low (mean 4.3 mutations/Mb, range 0-40.3 mutations/Mb). Clinical outcomes to 1st and 2nd generation EGFR-TKIs were obtained for a subset of cases with various EGFRex20ins, and 0/6 patients had responses. However, robust TGI was observed with combination osimertinib and cetuximab in a highly EGFR-amplified PDX model with a conserved EGFRex20ins (N771_P772>SVDNP) not associated with response to earlier generation EGFR-TKI, and was superior to vehicle, erlotinib or osimertinib alone (D21 mean tumor size 70 mm[3] vs. 1000, 800, 225 mm[3] respectively; p-values all <0.001).

      Conclusion:
      Diverse EGFRex20ins were detected in 12% of EGFR-mut NSCLC. Available clinical outcomes data demonstrated lack of response to 1[st] and 2[nd] generation EGFR-TKIs. Identification of co-occurring EGFR-amplification in 22% of cases led to testing of a dual EGFR blockade strategy with an EGFR monoclonal antibody and osimertinib, which demonstrated exceptional tumor growth inhibition in an EGFRex20ins PDX minimally responsive to erlotinib. These findings can rapidly be translated into an ongoing clinical trial of osimertinib and necitumumab.

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    OA 12 - Emerging Genomic Targets (ID 679)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Advanced NSCLC
    • Presentations: 2
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      OA 12.01 - The Preclinical and Clinical Activity of Poziotinib, a Potent, Selective Inhibitor of EGFR Exon 20 Mutant NSCLC (ID 10369)

      11:00 - 12:30  |  Presenting Author(s): Y.Y. Elamin  |  Author(s): Jacqulyne Ponville Robichaux, Vincent K Lam, Anne Tsao, C. Lu, G. Blumenschein, J. Kurie, Julie R Brahmer, S. Li, T. Chen, A. Estrada-Bernal, A. Truini, M. Nilsson, A.T. Le, Z. Tan, S. Zhang, Robert C. Doebele, K. Politi, Z. Yang, S. Liu, Kwok-Kin Wong, John V Heymach

      • Abstract
      • Presentation
      • Slides

      Background:
      Approximately 10% of EGFR mutant NSCLCs have an insertion/mutation in exon 20 of EGFR resulting in primary resistance to currently available tyrosine kinase inhibitors (TKIs). We previously reported that the structural features of poziotinib could potentially enable it to circumvent the steric hindrance induced by exon 20 mutations. Here we further characterize the preclinical activity of poziotinib and report on initial clinical activity of poziotinib in patients with EGFR exon 20 mutations from an ongoing phase II study.

      Method:
      We evaluated poziotinib activity in vitro using human NSCLC cell lines and the BAF3 model as well as several patient-derived xenograft (PDX) models and genetically engineered mouse models (GEMMs) of exon 20 insertion. We launched a phase 2 investigator-initiated trial of poziotinib in patients with metastatic NSCLC with EGFR exon 20 insertions (NCT03066206).

      Result:
      In vitro poziotinib was approximately 100x more potent than osimertinib and 40x more potent than afatinib against a common panel of EGFR exon 20 insertions. Furthermore, it had ~65-fold greater potency against common exon 20 insertions compared with EGFR T790M mutations; 3[rd] generation inhibitors osimertinib, EGF816, and rociletinib were all significantly less potent for exon 20 mutations/insertions compared with T790M. in vivo poziotinib led to >85% reduction in tumor burden in GEM models of EGFR exon 20 insertion (D770insNPG) NSCLC and the PDX model LU0387 (H773insNPH). To date, 8 platinum-refractory patients with EGFR exon 20 insertion mutation metastatic NSCLC have been enrolled in the clinical trial and treated with poziotinib at a dose of 16 mg PO daily. Two patients have reached the first interval-imaging time point (at 8 weeks of therapy per protocol). Both patients exhibited dramatic partial response, with one patient reporting improvement in dyspnea and cough at one week of therapy. In this early stage of the study, one case of grade 3 paronchycia was observed. One additional platinum- and erlotinib-refractory patient with EGFR exon 20 insertion was treated with poziotinib on compassionate basis. The patient achieved partial response after three weeks of treatment.

      Conclusion:
      Poziotinib has selective activity against EGFR exon 20 mutations and potent activity in cell lines, PDX, and GEM models. Three platinum-refractory patients with EGFR exon 20 mutations have been treated thus far and are evaluable for response; all three had partial responses at the time of the initial scan. Updated data from the ongoing phase 2 clinical trial of poziotinib will be presented at the meeting.

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      OA 12.02 - Final Results of a Phase 2 Study of the hsp90 Inhibitor Luminespib (AUY922) in NSCLC Patients Harboring EGFR Exon 20 Insertions (ID 10182)

      11:00 - 12:30  |  Presenting Author(s): Zofia Piotrowska  |  Author(s): D.B. Costa, M. Huberman, Geoffrey R. Oxnard, Justin F Gainor, R. Heist, I.T. Lennes, A. Muzikansky, Alice Shaw, C.G. Azzoli, Lecia V Sequist

      • Abstract
      • Presentation
      • Slides

      Background:
      EGFR exon 20 insertions (ins20) comprise 4-10% of EGFR mutations in NSCLC and are refractory to 1[st]/2[nd] generation EGFR TKIs. No effective targeted therapies exist for patients with EGFR ins20. EGFR is a client protein of the molecular chaperone Heat Shock Protein 90 (hsp90). Here, we present the final results of a phase II investigator-initiated trial to assess the activity of the Hsp90 inhibitor luminespib (AUY922) in NSCLC patients with EGFR ins20 (NCT01854034).

      Method:
      Between 8/2013 and 10/2016, the study enrolled 29 patients with stage IV NSCLC, EGFR ins20 identified on local testing, ECOG PS 0-2, at least one prior line of therapy and no untreated brain metastases. The study was closed on 2/28/17 when the available drug supply was exhausted. Luminespib was given at 70mg/m2 IV weekly. Response was assessed by RECIST 1.1 every 6 weeks; treatment beyond progression was allowed. Dose interruptions and dose reductions were allowed as needed for toxicity management. Primary endpoint was ORR with a target disease control rate (DCR; PR/CR plus SD lasting > 3 mos) of > 20%. Secondary endpoints were PFS, OS, safety and response by EGFR ins20 subtype.

      Result:
      29 patients (18 female/11 male, median age 60 (range, 31-79)) were enrolled. Median number of prior therapies = 1 (range, 1-5.) 4/29 achieved PR and 1 CR (ORR 5/29; 17%). 15 patients had SD and 9 had PD as their best response. mPFS was 2.9 mos (95% CI, 1.4-5.6,) mOS was 13 mos (95% CI, 4.9-19.5.) DCR was 11/29 (38%). Among 19 patients with baseline PS 0-1 and < 2 prior therapies, ORR = 21% and mPFS = 5.1 mos (95% CI, 2.1-11.8.) The most common luminespib-related toxicities were visual changes (22/29; 76%) diarrhea (21/29; 72%) and fatigue (13/29; 45%). Treatment-related grade 3 toxicities included ocular toxicity (1/29; 3%), hypertension (3/29; 10%) and hypophosphatemia (1/29; 3%). All study treatment was stopped on 2/28/17 due to lack of drug availability; 3 patients were on treatment without progression at study termination.

      Conclusion:
      The study met its primary endpoint and suggests that luminespib may be an active therapy for advanced NSCLC patients with EGFR ins20. Luminespib is generally well-tolerated, though reversible low-grade ocular toxicity is common. Further study of luminespib and other Hsp90 inhibitors in this population is warranted, as are novel systems to continue drug supply for benefitting patients when availability of experimental compounds is limited.

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    OA02 - Novel Therapies in ROS1, HER2 and EGFR (ID 893)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 105
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      OA02.06 - A Phase II Trial of Poziotinib in EGFR and HER2 exon 20 Mutant Non-Small Cell Lung Cancer (NSCLC) (ID 14277)

      11:25 - 11:35  |  Presenting Author(s): John V Heymach  |  Author(s): Marcelo Vailati Negrao, Jacqulyne Ponville Robichaux, Brett W. Carter, Anisha Patel, Mehmet Altan, Don Lynn Gibbons, Frank Fossella, George R. Simon, Vincent K Lam, George R Blumenschein, Anne S. Tsao, Jonathan M Kurie, Frank Mott, Daveta Jenkins, Dahlia Mack, Lei Feng, Brent Roeck, Zane Yang, Vassiliki A Papadimitrakopoulou, Yasir Y Elamin

      • Abstract
      • Presentation
      • Slides

      Background

      Insertions/mutations in exon 20 of EGFR or HER2 occur in ~3% of all lung adenocarcinomas. These alterations are characterized by primary resistance to tyrosine kinase inhibitors (TKIs) with response rates of <12%. We previously showed that exon 20 insertions restrict the size of drug-binding pocket, limiting binding of most available TKIs. However, poziotinib can potentially circumvent these steric changes due to its smaller, flexible structure and is a potent inhibitor of EGFR and HER2 exon 20 mutants (Robichaux et al. Nat Med, 2018). Herein, we report the results of an investigator-initiated study of poziotinib in EGFR and HER2 exon 20 mutant NSCLC (NCT03066206).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients ≥18yrs with metastatic NSCLC bearing mutations/insertions in EGFR or HER2 exon 20 (except EGFR T790M) were eligible. Unlimited prior systemic and targeted therapies were permitted. Poziotinib 16mg PO daily was administered until progression, death, or withdrawal. The primary endpoint was objective response rate (ORR) based on RECIST v1.1. Response was evaluated every eight weeks. A Bayesian design was used with a plan to enroll patients in cohorts of 10 and to terminate the study if ORR was ≤20%. Secondary endpoints included DCR, PFS, OS and safety

      4c3880bb027f159e801041b1021e88e8 Result

      As of May 3, 2018, the planned EGFR cohort of 50 patients was fully enrolled, and 40 patients were evaluated for response. 65.1% of patients had received at least two prior lines of therapy for metastatic disease. 60% of patients had ≥grade 3 adverse events; most common were skin-rash (27.5%) and diarrhea (12.5%). 45.0% of patients required dose reduction to 12mg, while 17.5% required dose reduction to 8mg. One patient stopped treatment due to grade 3 skin rash. ORR at eight weeks was 58% (95%-CI 40.9-73.0) and the DCR was 90% (95%-CI 76.3-97.2). Among 23 patients who achieved partial response, 15 responses were confirmed with subsequent scans, five responses were unconfirmed, and three patients are pending confirmation. Responses were observed in 8/13 (62%) patients that were previously treated with TKI. Median PFS was 5.6mo (95%-CI 5.06-NA). Furthermore, 13 patients were enrolled in HER2 cohort. Toxicities were similar to EGFR cohort except one case of grade 5 pneumonitis, assessed to be possibly drug related. Twelve patients were evaluated for response with ORR of 50% (95% CI 21.1-78.9) at eight weeks and DCR of 83%.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In heavily pre-treated population with EGFR and HER2 exon 20 mutant NSCLC, poziotinib demonstrated encouraging antitumor activity in both TKI-naive and -refractory patients, and manageable toxicity profile.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    OA07 - Precision Medicine Involves Biology and Patients (ID 132)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      OA07.03 - Clinical Outcome of Non-Small Cell Lung Cancer with EGFR/HER2 Exon 20 Insertions Identified in the LC-SCRUM-Japan (Now Available) (ID 629)

      11:00 - 12:30  |  Presenting Author(s): Hibiki Udagawa  |  Author(s): Shingo Matsumoto, Yuichiro Ohe, Miyako Satouchi, Naoki Furuya, Young Hak Kim, Takashi Seto, Kenzo Soejima, Daisuke Hayakawa, Terufumi Kato, Shingo Miyamoto, Kadoaki Ohashi, Sho Saeki, Hiromitsu Ohta, Daichi Fujimoto, Akimasa Sekine, Kiyotaka Yoh, Koichi Goto

      • Abstract
      • Presentation
      • Slides

      Background

      In-frame insertions in exon 20 (Ex20ins) of EGFR/HER2 occur in 2-5 % of non-small cell lung cancer (NSCLC). There is no approved targeted therapy for patients with these mutations. Historical control data would be valuable for the development of novel targeted therapies for these rare cancers.

      Method

      A nationwide genome screening project in Japan (LC-SCRUM-Japan) has been established for the development of molecular-targeted therapies for lung cancers. In this project, 161 cancer-related genes have been analyzed by a next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay. The therapeutic efficacy and survival of the patients with non-squamous (non-sq) NSCLC harboring EGFR/HER2 Ex20ins were evaluated using a large-scale clinico-genomic database in the LC-SCRUM-Japan.

      Result

      A total of 3441 advanced non-sq NSCLC patients were successfully analyzed from 2015 to 2018. EGFR Ex20ins were detected in 73 patients (2%; M766_A767insASV/A767_S768insSVD/H773_V774insH/D770_N771insNPH/N771_P772insPH/others=22/17/5/4/4/21) and HER2 Ex20ins were detected in 128 patients (4%; A775_G776insYVMA/G776delinsVC/P780_Y781insGSP/others=95/16/10/7). The median age of the patients was 62 (range, 33-90) years. Eighty-one patients (40%) were male and 114 (57%) were never smoker. Two-hundred patients (99%) were diagnosed as adenocarcinoma and 1 as adenosquamous-cell carcinoma. Based on our database, the median overall survivals in patients with EGFR Ex20ins were 22.4 (95%CI, 15.3-36.8) months, and those with HER2 Ex20ins were 18.8 (13.6-30.3) months. In the patients with EGFR/HER2 Ex20ins, the objective response rate (ORR) and median progression-free survivals (mPFS) of 1st-line platinum-containing chemotherapies were 32% and 6.0 (5.7-7.0) months, respectively. The ORR and mPFS of docetaxel with or without ramucirumab were 26% and 5.1 (3.8-5.9) months, respectively. The ORR and mPFS of PD-1 inhibitor were 0% and 2.0 (1.6-2.6) months, respectively. No significant difference in the therapeutic efficacy of these drugs was observed between the patients with EGFR Ex20ins and HER2 Ex20ins. In 19 patients with EGFR Ex20ins treated with 1st/2nd generation EGFR-TKIs, the ORR was 5% (a M766_A767insASV-positive tumor responded to afatinib) and the mPFS was 2.1 (1.3-4.2) months.

      Conclusion

      The patients with EGFR/HER2 Ex20ins-positive NSCLC showed poor responses to PD-1 inhibitors and 1st/2nd generation EGFR-TKIs. These historical data are highly informative in evaluating the efficacy of novel targeted therapies for EGFR/HER2 Ex20ins-positive NSCLC.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 4
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-89 - A Multicenter Phase 1/2a Trial of CLN-081 in NSCLC with EGFR Exon 20 Insertion Mutations (ID 488)

      09:45 - 18:00  |  Presenting Author(s): Zofia Piotrowska  |  Author(s): David Planchard, Myles Steven Clancy, David Witter, Leigh Zawel, Helena A Yu

      • Abstract

      Background

      First and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are largely ineffective against EGFR exon 20 insertion mutations (ins20) and, while several novel agents targeting EGFR ins20 are in development (poziotinib, TAK-788), preliminary reports suggest that EGFR-related adverse events are common and may limit long-term efficacy (Heymach, WCLC 2018, Neal WCLC 2018). Targeted therapies which are safe and effective in patients with EGFR ins20 are needed. CLN-081 (also known as TAS-6417) is a novel, orally available EGFR TKI that selectively inhibits ins20 mutant EGFRs (Mol Cancer Ther 2018; 17:1648). In a cell-based assay using genetically engineered cell lines, CLN-081 potently inhibited intracellular phosphorylation of a wide spectrum of ins20 mutant EGFRs. The selectivity for mutant over wild type EGFR (WT/mut ratio) ranged from 4 to 134-fold depending on the specific mutation, representing an unprecedented level of mutant specificity.

      Method

      This is an adaptive phase 1/2a trial evaluating CLN-081 as monotherapy in advanced non-small cell lung cancer (NSCLC) harboring EGFR ins20. Dose escalation will proceed initially according to an accelerated titration (AT) design, converting to a rolling six (R6) design based upon pre-specified safety criteria. Cohort expansion in Phase 1 can occur at one or more doses where responses are observed in R6 cohorts. Transition from Phase 1 into Phase 2a is based upon a Simon-Two Stage design. The starting dose will be 60mg. Once daily and twice daily dosing will be explored. Approximately 90 patients will be enrolled. Eligible patients will have advanced, exon 20 insertion mutation positive NSCLC, and at least one prior platinum containing treatment regimen. EGFR ins20 will be identified based on local testing (tissue or plasma). Patients who have discontinued a previous EGFR TKI due to progressive disease will be allowed in AT dose escalation cohorts but will be excluded from R6, and the Phase 1 and 2a expansion cohorts. The primary objectives in Phase 1 are to demonstrate safety and determine the maximum tolerated dose. Secondary Phase 1 objectives include evaluation of PK and preliminary efficacy. The primary objectives in Phase 2a are to define the recommended phase 2 dose and evaluate the overall response rate. The secondary Phase 2a objectives include additional measures of response and confirmation of CLN-081’s safety profile.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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      P1.01-94 - JNJ-61186372, an EGFR-cMet Bispecific Antibody, in EGFR Exon 20 Insertion-Driven Advanced NSCLC (ID 1802)

      09:45 - 18:00  |  Presenting Author(s): Byoung Chul Cho  |  Author(s): Jiyeon Yun, Han Na Kang, Soo-Hwan Lee, Chae-Won Park, Seo-Yoon Jeong, Min Hee Hong, Hye Ryun Kim, Meena Thayu, Joshua C Curtin, Roland E Knoblauch, Matthew V Lorenzi, Amy Roshak

      • Abstract

      Background

      JNJ-61186372 (JNJ-372), a bispecific antibody that targets the EGFR and cMet receptors, is currently being explored in a first-in-human study in patients with non-small cell lung cancer (NSCLC). Preliminary JNJ-372 clinical data have suggested activity in patients with diverse EGFR mutations, including Exon 20 insertions (Exon20ins), which carry primary resistance to tyrosine kinase inhibitors (TKIs; Cho BC et al. Ann Oncol 2018;29(suppl_8):mdy292.118). To better understand the mechanism of JNJ-372 activity in this patient population, we conducted preclinical studies exploring the activity of JNJ-372 in different EGFR Exon20ins models.

      Method

      BaF3 cells were transduced with retrovirus expressing various EGFR Exon20ins, as described. Cell titer glo assays were used to measure cell proliferation; western blot analysis was used to study EGFR and cMet signaling cascade events. For mouse tumor models, JNJ-372 was administered i.p. daily at 10mg/kg or 30mg/kg. Referenced patients with Exon20ins disease were administered 1050mg JNJ-372 i.v. weekly for the first 4-week cycle, then biweekly for each subsequent cycle (Park et al. J Thorac Oncol 2018;13:S344-5).

      Result

      In a dose-dependent manner, JNJ-372 inhibited the growth of BaF3 cells harboring diverse Exon20ins mutations. Mechanistic assays revealed down-modulation of EGFR and cMet receptor levels and decreases in phospho-EGFR and cMet, as well as inhibition of downstream signaling events including p-ERK, p-Akt and p-S6. Cleaved caspase-3 and BIMEL were upregulated at antiproliferative doses, suggesting caspase-mediated cell death as part of the mechanism of action. JNJ-372 demonstrated corresponding antitumor activity in PDC and PDX models harboring different Exon20ins mutations with concomitant inhibition of EGFR signaling and induction of apoptosis. In the ongoing first-in-human trial, two patients with Exon20ins disease (P772_H773insPNP and H773delinsNPY) continue to demonstrate durable clinical benefit (13 and 22 cycles), with maximum tumor reductions of –23% and –63%, respectively, as demonstrated by baseline and postbaseline CT scans.

      Conclusion

      In EGFR Exon20ins disease, JNJ-372 demonstrates preclinical antitumor activity and initial clinical responses. Preclinically, JNJ-372 induces antitumor activity in models of EGFR Exon20ins disease by decreasing EGFR and cMet receptor levels, inhibiting downstream signaling cascades, and activating apoptotic signaling. These results provide an understanding of the activity of JNJ-372 being observed in the ongoing clinical study and support the continued examination of JNJ-372 in NSCLC patients with Exon20ins and other EGFR mutations.

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      P1.01-126 - The Co-Occurring Genomic Landscape of ERBB2 Exon 20 Insertion in Non-Small Cell Lung Cancer (NSCLC) and the Potential Indicator of Response to Afatinib (Now Available) (ID 1284)

      09:45 - 18:00  |  Presenting Author(s): Bo Yuan  |  Author(s): Jun Zhao, Chengzhi Zhou, Xiumei Wang, Bo Zhu, Minglei Zhuo, Cuihua Yi, Hua Zhang, Xilin Dong, Jiemei Feng, Yunpeng Yang, Wangyan Zhou, Zhengtang Chen, Sheng Yang, Yanjun Zhang, Xinghao Ai, Kehe Chen, Xuefan Cui, Difa Liu, Wei Wu, Chunmei Shi, Lian-peng Chang, Jin Li, Rongrong Chen, Shuanying Yang

      • Abstract
      • Slides

      Background

      Human epidermal growth factor receptor 2 (ERBB2, HER-2) 20 exon insertion (ERBB2ex20ins) has been identified as an oncogenic driver in lung cancer, for which no valid therapy is currently approved. Concurrent alterations may elucidate its refractory features. Previous studies on Afatinib, a pan-ERBB inhibitor, have revealed an inconsistent clinical activity of it for this group of patients.

      Method

      Plasma or tissue samples of 112 patients with ERBB2ex20ins were performed next generation sequencing (NGS) for 59 or 1021 cancer-related genes in a Clinical Laboratory Improvement Amendments-certified Laboratory from July 2016 to December 2018. The sequencing data of MSKCC Cohort was downloaded from the public Cancer Genome Atlas Database. The clinical outcomes of 18 patients receiving Afatinib treatment were collected by each contributing doctor in charge and pooled for analysis.

      Result

      Among the 112 patients, most of cases were female (54%, 60/112) and adenocarcinoma (68%, 76/112). Considering the insertions sites, three subtypes were A775ins (71%; 79/112), G776indel (17%; 19/112) and P780ins (12%; 14/112) in the order of frequency. 80.4% (90/112) of patients had at least one additional alteration. The most frequent co-occurring genes were TP53 (66.1%, 74/112), LRP1B (18.2%, 10/55), EPHA5 (9.1%, 5/55), MLL3 (9.1%, 5/55) and RB1 (8.0%; 9/112). Putative other driver aberrations were mutually exclusive from ERBB2ex20ins. Furthermore, cell cycle pathway was the most commonly involved pathway (84.0%; 94/112) of all the concurrent genes. No substantial differences of concurrence in genomic or pathway level were observed among the three ERBB2 insertion subtypes. The co-occurring genomic feature of ERBB2ex20ins in Our Cohort of Chinese people had an overall strong concordance with the MSKCC Cohort from the United States (R2=0.74, P<0.01). For the prognosis, patients had a worse OS when co-occurring mutation in TP53 [median OS:14.5m (95%CI: 12.7m-16.3m) vs 30.3m (95% CI: not reached)], while the OS was not significantly different among three subtypes. The median duration time for patients with disease control of Afatinib was 4.5 months (95%CI: 3.6m-5.4m; range: 2.5m-13.4m). Of note, ERBB2ex20ins in subclonal status was a significantly independent factor relating to shorter PFS of Afatinib [median PFS: 1.2m (95%CI: 0.8-1.6m) vs 4.3m (95%CI: 3.3m-5.3m), P<0.05]. Dynamic detection in two patients found ERBB2 amplification may be a resistance mechanism for Afatinib.

      Conclusion

      Concurrence of genetic alterations in NSCLC patients with ERBB2ex20ins was common. The complex genomic characteristic should be fully considered by stratifying patients according to potentially relevant co-mutations other than ERBB2 insertion sites in the designing regimens for them. In addition, the therapeutic effect of Afatinib on patient with ERBB2ex20ins is limited, the clonal status of ERBB2ex20ins may be an important factor with prognosis value.

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      P1.01-127 - Antitumor Activity of the Oral EGFR/HER2 Inhibitor TAK-788 in NSCLC with EGFR Exon 20 Insertions (ID 1302)

      09:45 - 18:00  |  Presenting Author(s): Gregory J Riely  |  Author(s): Joel W Neal, D. Ross Camidge, Alexander Spira, Zosia Piotrowska, Leora Horn, Daniel B Costa, Anne Tsao, Jyoti D Patel, Shirish Gadgeel, Lyudmila Bazhenova, Viola W. Zhu, HOWARD WEST, Sylvie Vincent, Jian Zhu, Shu Jin, Steven Zhang, Shuanglian Li, Pasi A Jänne

      • Abstract
      • Slides

      Background

      We report results of a phase 1/2 open-label, multicenter study of TAK-788 (NCT02716116), an oral investigational EGFR/HER2 inhibitor.

      Method

      Patients with advanced, previously treated NSCLC received daily TAK-788 in dose escalation and expansion cohorts based on tumor genotype. Antitumor activity was determined for patients with EGFR exon 20 insertions who received TAK-788 160 mg QD. Safety is reported for all patients across all doses and at 160 mg. To improve gastrointestinal tolerability, food intake instructions in this ongoing study were amended to allow for administration with or without a low-fat meal based on emerging clinical pharmacokinetic data in a healthy volunteer study (data on file).

      Result

      As of 14 Sep 2018, 101 patients (median age, 61 y; female, 70%; ≥2 prior anticancer therapies, 76%; brain metastases, 53%) were treated with TAK-788 at 5–180 mg QD. RP2D was determined to be 160 mg QD. 28 patients with EGFR exon 20 insertions were treated with 160 mg QD during dose escalation or in expansion cohort 1 (3.6 months on treatment; 3.8 treatment cycles [medians]); 24 patients remain on treatment. At data cutoff, best response (RECIST v1.1) among 26 patients with ≥1 disease assessment was PR, n=14; SD, n=9; and PD, n=1 (objective response rate, 54%; 95% CI: 33.4%–73.4%); 2 patients were unevaluable. 7/14 objective responses (all PR) were confirmed (6 awaiting confirmation; 1 unconfirmed PR at 160 mg QD); median time to response in these 14 patients was 56 days. 23/26 patients (89%; 95% CI: 69.9%–97.6%) achieved disease control. 23/24 evaluable patients with EGFR exon 20 insertions treated at 160 mg QD had decreased target lesion measurements (median best percent change, -32.6% [-79.1%–3.8%]). Most common TEAEs (≥20%) in patients treated with 160 mg QD: diarrhea (85%), rash (43%), nausea (41%), vomiting (30%), decreased appetite (28%), stomatitis (22%); grade ≥3 TEAEs (≥5%): diarrhea (26%); hypokalemia, nausea, stomatitis (7% each). Among patients treated with 160 mg QD, median dose intensity was 93%, rate of dose reduction due to AEs was 21.7%, and rate of treatment discontinuation due to AEs was 10.9%. There was no clear trend that response to TAK-788 was enriched in any single EGFR exon 20 insertion variant.

      Conclusion

      In NSCLC patients with EGFR exon 20 insertions, TAK-788 demonstrated antitumor activity and a safety profile consistent with other EGFR TKIs.

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    OA04 - New Data from Rare EGFR Alterations (ID 223)

    • Event: WCLC 2020
    • Type: Oral
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 2
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      OA04.03 - Mobocertinib in NSCLC With EGFR Exon 20 Insertions: Results From EXCLAIM and Pooled Platinum-Pretreated Patient Populations (ID 3186)

      11:45 - 12:45  |  Presenting Author(s): Caicun Zhou  |  Author(s): Suresh S. Ramalingam, Baolan Li, Jian Fang, Tae Min Kim, Sang-we Kim, James Chih-Hsin Yang, Gregory J. Riely, Tarek Mekhail, Danny Nguyen, Maria Rosario Garcia Campelo, Enriqueta Felip, Shu Jin, Veronica Bunn, Jianchang Lin, Huamao M Lin, Minal Mehta, Pasi Antero Jänne

      • Abstract
      • Presentation
      • Slides

      Introduction

      Mobocertinib is a potent first-in-class tyrosine kinase inhibitor (TKI) designed to target EGFR exon 20 insertion (EGFRex20ins) mutations. We report first results from the EXCLAIM extension cohort of a phase 1/2 study (NCT02716116) and results in patients with EGFRex20ins-mutant NSCLC who received prior platinum-based therapy from the dose-escalation/expansion parts of the study and the EXCLAIM extension cohort.

      Methods

      This 3-part, open-label, multicenter study included dose-escalation/expansion cohorts and the EXCLAIM extension cohort. Data are presented for all patients treated in EXCLAIM (N=96) and for platinum-pretreated patients from the dose-escalation/expansion cohorts (n=28) and from EXCLAIM (n=86); all received mobocertinib 160 mg orally QD. Enrolled patients had locally advanced/metastatic EGFRex20ins NSCLC, ECOG performance status 0–1, and ≥1 prior line of therapy for locally advanced/metastatic disease. The primary endpoint is confirmed ORR assessed by IRC per RECIST v1.1.

      Results

      In EXCLAIM, 96 patients were enrolled and treated; median age, 59 years [range: 27–80]; female, 65%; Asian, 69%; ≥2 prior systemic anticancer lines, 49% (range: 1–4). Median time on treatment was 6.5 months (range: 0–14). Confirmed ORR was 23% (22/96; 95% CI: 15%–33%) per IRC and 32% (95% CI: 23%–43%) per investigator; median DoR (Kaplan-Meier estimates) was not mature; median PFS was 7.3 months. See Table. In the analysis of platinum-pretreated patients (n=114), median age, 60 years [range: 27–84]; female, 66%; Asian, 60%; ≥2 prior systemic anticancer lines, 59% (range: 1–7). Median time on treatment was 7 months (range: 0–31); 38 patients (33%) remained on treatment as of 29-May-2020. Confirmed ORR was 26% (30/114; 95% CI: 19%–35%) per IRC and 35% (40/114; 26%–45%) per investigator. Median PFS was 7.3 months: 12-month PFS rate was 33% (95% CI: 21%–47%). Responses were observed among all prespecified subgroups, including Asian/non-Asian patients and those with/without baseline stable brain metastases. The most common treatment-related adverse events (TRAEs; ≥30%): diarrhea (90%), rash (45%), paronychia (34%), nausea (32%), decreased appetite (32%), dry skin (30%), and vomiting (30%); grade ≥3 TRAEs (≥5%): diarrhea (22%), anemia (5%), and dyspnea (5%). Nineteen patients (17%) discontinued due to AEs, most commonly diarrhea (4%) and nausea (4%). The safety profile observed in EXCLAIM was largely consistent with that observed in the platinum-pretreated population.

      table for submission.jpg

      Conclusion

      Mobocertinib demonstrated clinically meaningful benefit in previously treated patients with NSCLC and EGFRex20ins mutations, with a manageable safety profile.

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      • Abstract
      • Presentation
      • Slides

      Introduction

      Despite sharing similar tumor biology to other epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) tumors, no targeted therapies have been approved for NSCLC harboring EGFR Exon 20 insertion mutations (Exon20ins). The standard of care remains platinum-based chemotherapy for the front-line, with no clear subsequent options available. Amivantamab (JNJ-61186372) is a novel, fully human EGFR-MET bispecific antibody with immune cell-directing activity that targets activating and resistance EGFR mutations, as well as MET mutations and amplifications, and has received FDA Breakthrough Therapy Designation for the treatment of patients with EGFR Exon20ins NSCLC after platinum-based chemotherapy. Here we present updated results on the Exon20ins cohort from the CHRYSALIS study (NCT02609776).

      Methods

      The dose escalation phase enrolled patients with advanced NSCLC to determine the recommended phase 2 dose (RP2D) of 1050 mg (1400 mg for ≥80 kg) amivantamab. The dose expansion phase assessed the safety and efficacy of amivantamab in patients with EGFR- and MET-mutant NSCLC treated at the RP2D. Disease response was assessed by the investigator per RECIST v1.1 and is presented for those patients with Exon20ins NSCLC who had progressed on prior platinum-based chemotherapy, were treated at the RP2D, and had at least 3 post-baseline disease assessments (18 weeks) or discontinued, progressed, or died prior to the 3rd assessment (the Post-Platinum Cohort). The data cutoff date was 8 Jun 2020.

      Results

      In the Post-Platinum Cohort (n=81), median age was 62 (42 – 84), 59% were women, 49% were Asian, median prior lines of therapy was 2 (1 – 7), and 53% were never-smokers. At a median follow-up of 6.5 months (1.1 – 29.3), investigator-assessed overall response rate (ORR) was 36% (29/81; 95% CI, 25 – 47), with all responders achieving partial response (PR). The clinical benefit rate (≥PR or stable disease ≥11 weeks) was 73% (59/81; 95% CI, 62 – 82). Responses were durable at a median of 6.8 months (95% CI, 5.0 – not reached) with ongoing responses in 18/29 (longest at 16+ months). Median progression-free survival was 8.3 months (95% CI, 5.5 – 12.7) and median overall survival was 22.8 months (95% CI, 14.0 – not reached).

      Among all phase 1 patients, across a variety of EGFR genomic alterations and lines of therapy, treated with amivantamab monotherapy at the RP2D (n=258), the most common adverse events (AEs) were rash (78%), infusion related reaction (IRR; 65%), and paronychia (40%). Additional EGFR-related AEs were stomatitis (19%), pruritus (19%), and diarrhea (11%). Grade ≥3 AEs were reported in 39% of patients; 14% were considered treatment-related, with rash (3%) and IRR (2%) being most frequent. No treatment-related deaths were reported. The incidence of treatment-related AEs leading to dose reduction and discontinuation was 10% and 3%, respectively.

      Conclusion

      Amivantamab treatment led to promising efficacy with durable responses in patients with EGFR Exon20ins NSCLC post-platinum doublet and continues to demonstrate a manageable safety profile in over 250 patients treated at the RP2D. A phase 3 study, PAPILLON, evaluating amivantamab in combination with chemotherapy in the front-line setting is in planning stages.

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    P09 - Health Services Research/Health Economics - Real World Outcomes (ID 121)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Health Services Research/Health Economics
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P09.61 - Epidemiological and Clinical Burden of EGFR Exon 20 Insertion in Advanced NSCLC: Results of a Systematic Literature Review (ID 1271)

      00:00 - 00:00  |  Presenting Author(s): Tracy Li  |  Author(s): Heather Burnett, Helena Emich, Naomi Stapleton, Chris Carroll, Parthiv Mahadevia

      • Abstract
      • Slides

      Introduction

      The burden of epidermal growth factor receptor (EGFR) exon 20 insertion (ex20Ins) mutation is not well understood. A systematic review was conducted to identify the available evidence on mutation frequency, prognostic impact, and clinical, patient-reported, and economic outcomes.

      Methods

      Prespecified PICOS criteria were used to determine study eligibility. MEDLINE, Embase (1974-September 2019), and conference proceedings (2018-2019) were searched. Studies were not limited by intervention, geography, or publication year and were stratified by line of therapy.

      Results

      Eighty-four unique studies were included; 53 reporting mutation frequency, 18 prognostic impact, 35 clinical outcomes, and one humanistic burden. No economic burden data were identified.

      The frequency of ex20Ins mutation ranged from 0.1% to 4% of all NSCLC cases and 1% to 12% of all EGFR mutations with a wide range of test methodologies observed (Table 1). Data on the prognostic impact of ex20Ins were heterogeneous but highlighted poorer treatment outcomes in ex20Ins compared with other EGFR mutations and EGFR wildtype across a wide range of therapies (chemotherapy, TKIs) and treatment lines.

      Seven clinical trials and 37 prospective observational studies reported clinical outcomes for patients with ex20Ins (Table 2). Trends towards better median PFS, OS, and ORR were observed for chemotherapy compared with TKIs as first-line treatments. For subsequent treatment lines, novel targeted therapies provided encouraging preliminary responses while results for chemotherapy were limited. Limited safety data were reported.

      One conference abstract described the symptom burden for ex20Ins patients with fatigue and pain being most common.

      Conclusion

      We found substantial global variations in the frequency of ex20Ins mutation detection. Across the clinical studies, ex20Ins had a worse prognosis compared to common EGFR mutations. Data on emerging ex20Ins targeted therapies are encouraging but limited. More research is needed to understand the humanistic and economic impact of ex20Ins.

      Table 1. The Range of Mutation Frequency Reported Across the Included Studies by Region

      Region

      Frequency of exon 20 ins (%)

      # Studies

      NSCLC

      # Studies

      EGFRm Positive NSCLC

      US

      9

      0.5-2.6%

      7

      5-12%

      Latin America

      7

      1.3-2.1%

      5

      5-8%

      Europe

      13

      0.3-1.3%

      10

      4-12%

      Asia Pacific

      28

      0.1-4.0%

      16

      1-5%

      China

      9

      0.3-2.9%

      7

      2-5%

      Japan

      4

      1.8-2.4%

      2

      2-5%

      Taiwan

      3

      1.3-4.0%

      2

      3-4%

      South

      5

      0.3-3.4%

      4

      1-4%

      South East

      4

      0.1-2.4%

      2

      2-3%

      Australia

      1

      1.4%

      0

      NA

      Table 2. Range of Ex20Ins Clinical Outcomes Across Included Studies: Mean OS and PFS (months) and ORR (%) by Line of Therapy and Treatment Type For Treatment Groups Including >10 Patients

      1L

      2L+

      Mixed LOT

      All Treatments

      mOS

      6.3-28
      [10 studies; 307 patients]

      8-17.1
      [6 studies; 129 patients]

      4.8-29.4
      [7 studies; 235 patients]

      mPFS

      1.8-6.9
      [11 studies; 354 patients

      1.9-7.3
      [10 studies; 215 patients]

      1.4-4.5
      [8 studies; 203 patients]

      ORR

      0-29%
      [7 studies; 250 patients]

      0-43%
      [12 studies; 374 patients]

      0-67%
      [9 studies; 218 patients]

      TKI

      mOS

      7.1-16.8
      [4 studies; 81 patients]

      12.9-15.3
      [2 studies; 47 patients]

      4.8-19
      [4 studies; 125 patients]

      mPFS

      1.8-6.4
      [6 studies; 116 patients]

      1.9-3.7
      [4 studies; 79 patients]

      1.4-3.1
      [7 studies; 206 patients]

      ORR

      6.3-8.7%
      [2 studies; 39 patients]

      0-43%
      [5 studies; 107 patients]

      0-36%
      [6 studies; 142 patients]

      Chemotherapy

      mOS

      15.9-28
      [4 studies; 259 patients]

      17.1
      [1 study; 17 patients]

      26-29.4
      [3 studies; 113 patients]

      mPFS

      3.4-6.9
      [5 studies; 238 patients]

      4.1-4.8
      [3 studies; 58 patients]

      4.5
      [1 study; 22 patients]

      ORR

      23-29%
      [4 studies; 211 patients]

      17-42%
      [2 studies; 24 patients]

      50-63%
      [3 studies; 79 patients]

      Ex20Ins Targeting Therapy

      mOS

      -

      -

      -

      mPFS

      -

      7.3
      [1 study; 28 patients]

      -

      ORR

      -

      14.8-43%
      [4 studies; 214 patients]

      -

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