Treatment Outcomes and Safety of Mobocertinib in Platinum-Pretreated Patients With EGFR Exon 20 Insertion-Positive Metastatic Non-Small Cell Lung Cancer: A Phase 1/2 Open-label Nonrandomized Clinical Trial

Abstract

Importance: Metastatic non-small cell lung cancer (mNSCLC) with EGFR exon 20 insertion (EGFRex20ins) mutations is associated with a poor prognosis. Mobocertinib is an oral tyrosine kinase inhibitor designed to selectively target EGFRex20ins mutations.

Objective: To evaluate treatment outcomes and safety of mobocertinib in patients with previously treated EGFRex20ins-positive mNSCLC.

Design, setting, and participants: This 3-part, open-label, phase 1/2 nonrandomized clinical trial with dose-escalation/dose-expansion cohorts (28 sites in the US) and a single-arm extension cohort (EXCLAIM; 40 sites in Asia, Europe, and North America) was conducted between June 2016 and November 2020 (data cutoff date). The primary analysis populations were the platinum-pretreated patients (PPP) cohort and the EXCLAIM cohort. The PPP cohort included 114 patients with platinum-pretreated EGFRex20ins-positive mNSCLC who received mobocertinib 160 mg once daily from the dose-escalation (n = 6), dose-expansion (n = 22), and EXCLAIM (n = 86) cohorts. The EXCLAIM cohort included 96 patients with previously treated EGFRex20ins-positive mNSCLC (10 were not platinum pretreated and thus were excluded from the PPP cohort).

Interventions: Mobocertinib 160 mg once daily.

Main outcomes and measures: The primary end point of the PPP and EXCLAIM cohorts was confirmed objective response rate (ORR) assessed by independent review committee (IRC). Secondary end points included confirmed ORR by investigator, duration of response, progression-free survival, overall survival, and safety.

Results: Among the PPP (n = 114) and EXCLAIM (n = 96) cohorts, the median (range) age was 60 (27-84) and 59 (27-80) years, respectively; most patients were women (75 [66%] and 62 [65%], respectively) and of Asian race (68 [60%] and 66 [69%], respectively). At data cutoff, median follow-up was 14.2 months in the PPP cohort (median 2 prior anticancer regimens; 40 [35%] had baseline brain metastases), with confirmed ORR of 28% (95% CI, 20%-37%) by IRC assessment and 35% (95% CI, 26%-45%) by investigator assessment; median duration of response by IRC assessment was 17.5 months (95% CI, 7.4-20.3). Median progression-free survival by IRC assessment was 7.3 months (95% CI, 5.5-9.2). Median overall survival was 24.0 months (95% CI, 14.6-28.8). In the EXCLAIM cohort, median follow-up was 13.0 months, with confirmed ORR by IRC assessment of 25% (95% CI, 17%-35%) and by investigator assessment of 32% (95% CI, 23%-43%). The most common treatment-related adverse events were diarrhea and rash.

Conclusions and relevance: In this open-label, phase 1/2 nonrandomized clinical trial, mobocertinib was associated with clinically meaningful benefit in patients with previously treated EGFRex20ins-positive mNSCLC, with a manageable safety profile.

Trial registration: ClinicalTrials.gov Identifier: NCT02716116.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Zhou reported personal fees for lecturing from Eli Lilly China, Sanofi, Roche, Merck Sharp & Dohme, Qilu, Hengrui, Innovent Biologics, Luye Pharma, TopAlliance Biosciences Inc, Amoy Diagnostics, and CStone Pharmaceuticals outside the submitted work. Dr Ramalingam reported grants to institution and personal fees from Takeda for participation in advisory board meeting during the conduct of the study; grants to institution from AstraZeneca, Bristol Myers Squibb, Merck, GlaxoSmithKline, and Genmab; and personal fees for serving on scientific advisory boards from Eisai and GlaxoSmithKline outside the submitted work. Dr T. Kim reported grants from AstraZeneca-Korea Health Industry Development Institute and honoraria or advisory role from AstraZeneca, Boryung, F. Hoffmann-La Roche Ltd/Genentech, Inc, Novartis, Sanofi, and Takeda outside the submitted work. Dr Yang reported grants and personal fees (advisory board) from AstraZeneca; other to institution (advisory board) from Bayer, Janssen, and GlaxoSmithKline; personal fees (advisory board) from Roche, Novartis, Bristol Myers Squibb, and Ono Pharmaceuticals; and personal fees (advisory board) and other to institution (advisory board) from Amgen, Boehringer Ingelheim, Lilly, Pfizer, Merck Sharp & Dohme, Merck, Takeda, Yuhan, and Daiichi Sankyo outside the submitted work. Dr Riely reported grant funding for clinical trial conduct as well as editorial support for manuscript and presentation preparation from Takeda and grants from National Cancer Institute during the conduct of the study; nonfinancial support (provision of investigational agent for another clinical trial) from Takeda; and grants from Roche, Merck, Novartis, Pfizer, and Mirati outside the submitted work. Dr Mekhail reported personal fees from Takeda outside the submitted work. Dr Garcia Campelo reported personal fees from Takeda during the conduct of the study; personal fees from Bristol Myers Squibb, Lilly, Merck Sharp & Dohme, Janssen, Roche, Novartis, and Pfizer outside the submitted work. Dr Felip reported personal fees (advisory board) from AbbVie, Amgen, Bayer, Blueprint Medicines, GSK, Janssen, Merck KGaA, Puma Biotechnology, Sanofi Genzyme, Beigene, Medical Trends, Peptomyc, Regeneron, and Syneos Health; personal fees (speakers bureau) from Medscape, PeerVoice, Springer, prIME Oncology, Touch Medical, and CME Outfitters; personal fees (advisory board and speakers bureau) from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Takeda, and Roche; grants from Grant for Oncology Innovation (GOI) and Fundación Merck Salud; and serving as an independent member of the board for Grífols outside the submitted work. Drs Vincent, H. Lin, Mehta, and Bunn, and Ms Jin reported being employees of Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, during the conduct of the study. Dr Jänne reported grants (sponsored research) and personal fees (consulting on drug development) from Takeda Oncology during the conduct of the study; grants (sponsored research) from Daiichi Sankyo, Puma Biotechnology, Astellas, and Revolution Medicines; grants (sponsored research) and personal fees (consulting on drug development) from AstraZeneca, Boehringer Ingelheim, and Eli Lilly; personal fees (consulting on drug development) from Roche/Genentech, Chugai Pharmaceuticals, Ignyta, Loxo Oncology, SFJ Pharmaceuticals, Voronoi, Daiichi Sankyo, Biocartis, Novartis, Sanofi, Mirati Therapeutics, Transcenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Eisai, Allorion Therapeutics, Accutar Biotech, and AbbVie outside the submitted work; in addition, Dr Jänne had a patent for EGFR mutations licensed to Lab Corp, receiving postmarketing royalties from Dana-Farber Cancer Institute–owned intellectual property on EGFR mutations licensed to Lab Corp. No other disclosures were reported.

Figures

Figure 1.. CONSORT Flow Diagram

EGFRex20ins indicates EGFR exon 20 insertion; NSCLC, non–small cell lung cancer; PD, progressive disease; PPP, platinum-pretreated patients; RECIST, Response Evaluation Criteria in Solid Tumors. aA CONSORT flow diagram for the dose escalation and expansion parts of the study has been published previously.

Figure 2.. Mobocertinib Activity in Platinum-Pretreated Patients With EGFRex20ins Mutation–Positive Metastatic NSCLC (PPP Cohort)

A, Best percentage change from baseline in the sum of the longest diameters of target lesions per independent review committee (IRC) assessment in patients who underwent follow-up imaging and could be evaluated for a response (101 patients). The solid line at −30% indicates the threshold for partial response according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. B, Objective response per IRC assessments by time on treatment in confirmed responders (n = 32). C, Kaplan-Meier–estimated duration of confirmed response per IRC assessments. D, Kaplan-Meier estimates of overall survival (OS). Of the 114 patients in the PPP cohort, 46 (40%) died. Tick marks in Kaplan-Meier plots indicate censored data. ASV indicates V769_D770insASV; CR, complete response; EGFRex20ins, EGFR exon 20 insertion; NPH, H773_V774insNPH; SVD, D770_N771insSVD; NSCLC, non–small cell lung cancer; ORR, objective response rate; PD, progressive disease; PPP, platinum-pretreated patients; PR, partial response; SD, stable disease. aSpecific EGFRex20ins mutations were identified by central tumor sequencing in 68 patients, reported by local test in 27 patients, insertion unknown in 16 patients, and unconfirmed in 3 patients. bThe total number of patients in the table in panel A includes 13 patients with data not shown in the waterfall plot because they could not be evaluated for tumor response (2 with ASV/SVD/NPH mutations, 7 with other EGFRex20ins mutations, 3 with insertion unknown, and 1 with unconfirmed EGFRex20ins mutation). cUnconfirmed complete response.