1392P - Safety and efficacy of crizotinib in MET mutated (METmut) advanced non-small cell lung Cancer (aNSCLC): Results from the Drug Rediscovery Protocol (DRUP)

Background

METmuts occur in 3% of NSCLC and are associated with poor survival. Despite known sensitivity of METmut NSCLC to MET inhibition, no EMA approved therapies existed for this indication before 2022. In this study, safety and efficacy of oral tyrosine kinase (TK) inhibitor crizotinib, approved for ALK+ and ROS1+ NSCLC, were evaluated in METmut aNSCLC.

Methods

In DRUP (NCT0295234), cancer patients (pts) are treated with drugs outside their labeled indication, based on their molecular profile. Previously treated and treatment naïve pts with METmut aNSCLC were included and treated with crizotinib 250 mg BID until disease progression or intolerable toxicity. Pts with known symptomatic, untreated brain metastases were excluded. Primary endpoints were clinical benefit (CB: RECIST v1.1 confirmed objective response (OR) or stable disease (SD) ≥ 16 weeks) and safety. Pts were enrolled using a Simon like 2-stage model, with 8 pts in stage 1 and if ≥ 1/8 pts had CB, 24 pts in stage 2.

Results

Between 09/2018 and 10/2022, 44 pts were screened, 30 started treatment and 24 were evaluable for response. Median age was 75 [IQR, 69 – 78]. ECOG performance status was 0, 1 and 2 in 6 (25%), 12 (50%) and 6 (25%) pts, respectively. 19 pts (79%) were treatment naïve, 5 (21%) had received checkpoint blockade and/or platinum based chemotherapy. 1 (4%) complete response (CR), 14 (58%) partial responses and 2 (8%) SDs ≥ 16 weeks were observed, with resulting OR-rate of 62% (95% CI, 41 – 81) and CB-rate of 71% (95% CI, 49 – 87). After 20.2 months median follow-up, median progression-free and overall survival were 8.3 (95% CI, 6.0 – NA) and 13.0 months (95% CI, 8.0 – NA), respectively. 23 treatment-related grade ≥ 3 adverse events occurred in 12/30 pts (40%) and led to treatment discontinuation in 2 (6%). The pt who achieved CR had a TK domain mutation (p.H1094Y), all others exon 14 skipping METmuts. Post hoc whole genome sequencing of pre-treatment biopsies of 11 pts (46%) did not reveal any biomarkers for (non-)response.

Conclusions

Crizotinib proved highly effective in pts with METmut aNSCLC, with a manageable toxicity profile. Additional research is warranted to identify biomarkers for response.

Clinical trial identification

NCT0295234.

Editorial acknowledgement

Legal entity responsible for the study

Netherlands Cancer Institute, Amsterdam, The Netherlands.

Funding

Stelvio for Life; Dutch Cancer Society (KWF).

Disclosure

E.F. Smit: Financial Interests, Institutional, Advisory Board: AstraZeneca, Daiichi Sankyo, MSD, Boehringer Ingelheim, Roche, Eli Lilly, Takeda, Sanofi, Janssen, BMS; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Merck Seranno; Financial Interests, Institutional, Other, DSMB member: DSI; Financial Interests, Institutional, Local PI: Pfizer, AZ, Genmab, DSI, Sanofi. L. Hendriks: Financial Interests, Institutional, Advisory Board: Amgen, Boehringer Ingelheim, Lilly, Novartis, Pfizer, Takeda, BMS, Merck, Janssen, MSD; Financial Interests, Personal, Other, mentorship with key opinion leaders funded by AstraZeneca: AstraZeneca; Financial Interests, Institutional, Invited Speaker, for educational webinar: AstraZeneca, Lilly; Financial Interests, Institutional, Invited Speaker, educational webinar/interview: Bayer; Financial Interests, Institutional, Invited Speaker, educationals: MSD; Financial Interests, Personal, Invited Speaker, for webinars: Medtalks; Financial Interests, Institutional, Advisory Board, one time also personal: Roche; Financial Interests, Institutional, Other, performing interviews at conference: Roche; Financial Interests, Personal, Other, travel support: Roche; Financial Interests, Institutional, Other, podcast on brain metastases: Takeda; Financial Interests, Personal, Invited Speaker, payment for post ASCO round table discussion: VJOncology; Financial Interests, Personal, Invited Speaker, payment for post ASCO/ESMO/WCLC presentations, educational committee member: Benecke; Financial Interests, Institutional, Invited Speaker, payment for post ESMO/ASCO discussion: high5oncology; Financial Interests, Institutional, Other, educational webinar: Janssen; Financial Interests, Personal, Other, member of the committee that revised these guidelines: Dutch guidelines NSCLC, brain metastases and leptomeningeal metastases; Financial Interests, Institutional, Research Grant, for IIS: Roche, Boehringer Ingelheim, AstraZeneca, Takeda; Financial Interests, Institutional, Local PI: AstraZeneca, GSK, Novartis, Merck Serono, Roche, Takeda, Blueprint Medicines, Mirati, AbbVie, MSD, Gilead; Financial Interests, Institutional, Research Grant, donation for health care improvement project: Merck; Financial Interests, Institutional, Research Grant, funding for healthcare improvement project: Pfizer; Non-Financial Interests, Other, Chair metastatic NSCLC for lung cancer group: EORTC; Non-Financial Interests, Other, secretary NVALT studies foundation: NVALT. S.M..S. Hashemi: Other, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Janssen, GSK, MSD, Novartis, Novartis, Roche, Takeda. H. Gelderblom: Financial Interests, Institutional, Local PI: Daiichi, Deciphera, Novartis, Cytovation; Financial Interests, Institutional, Coordinating PI: Boehringer Ingelheim, AmMax Bio, Debiopharm. E.E. Voest: Financial Interests, Personal, Advisory Board, Hourly rate, to charity: Biogeneration Ventures; Financial Interests, Institutional, Advisory Board, Hourly rate, no compensation in 2019-2020: InteRNA; Financial Interests, Personal, Member of Board of Directors, independent, non-executive director and share holder: Sanofi; Financial Interests, Personal, Other, Founder, strategic adviser and share holder: Mosaic Therapeutics; Financial Interests, Personal, Ownership Interest, Mandatory shares as part of board membership: Sanofi; Financial Interests, Personal, Ownership Interest, Start up company with shares: Mosaic Therapeutics; Financial Interests, Institutional, Coordinating PI, DRUP trial: Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Clovis Oncology, Eisai, Ipsen, MSD, Novartis, Pfizer, GSK, Seattle Genetics; Financial Interests, Institutional, Coordinating PI, DRUP trialDRUG Access Protocol: Bayer, Roche; Financial Interests, Institutional, Coordinating PI, DRUG Access Protocol: Sanofi; Non-Financial Interests, Other, Supervisory Board: HMF – Hartwig Medical Foundation; Non-Financial Interests, Principal Investigator, Senior group leader: Oncode Institute; Non-Financial Interests, Advisory Role, Editorial Board: JAMA Oncology; Non-Financial Interests, Leadership Role, Board of Directors: Cancer Core Europe. All other authors have declared no conflicts of interest.