Abstract 1239P
Background
Most pts with epidermal growth factor receptor mutation-positive (EGFRm) NSCLC treated with osimertinib, a third-generation, irreversible, CNS-active EGFR-tyrosine kinase inhibitor (TKI), eventually develop resistance. MET alterations are common resistance mechanisms to osimertinib. The phase II ORCHARD platform study (NCT03944772) aims to characterise 1L osimertinib resistance mechanisms and identify optimal post-progression therapies. This interim analysis reports use of osimertinib + savolitinib, an oral, potent and highly selective MET-TKI, in adults with EGFRm advanced NSCLC and MET alterations (MET amplification / MET exon 14 skipping).
Methods
Pts were allocated to treatment cohorts after disease progression on 1L osimertinib, based on molecular profiling of a tumour biopsy with NGS. Pts whose tumours harbour MET alterations were allocated to osimertinib 80 mg qd + savolitinib 300 or 600 mg qd. Primary endpoint: investigator assessed objective response rate (ORR; RECIST v1.1). Other endpoints include duration of response and safety / tolerability. Interim data cut-off (DCO): Jan 2021.
Results
Of 20 pts that received osimertinib + savolitinib, median duration on prior 1L osimertinib was 414 (197–1722) days. At DCO, 17 pts were evaluable for confirmed response. ORR was 41% (n=7; 80% CI: 25, 59); 7 pts (41%) had partial response, 7 (41%) had stable disease and 1 (6%) had disease progression as their best response; 2 pts (12%) were not evaluable. Overall, 6 / 20 pts (30%) reported a grade ≥3 adverse event (AE), most commonly pneumonia and decreased neutrophil count (each n=2; 10%); 6 / 20 pts (30%) reported a serious AE. Three pts (15%) discontinued combination treatment due to AEs. No deaths due to AEs were reported.
Conclusions
Osimertinib + savolitinib showed preliminary activity in pts with MET alterations after 1L osimertinib. Based on interim efficacy, enrolment will continue to 30 pts as pre-specified per protocol. The safety profile was acceptable and consistent with known profiles of osimertinib / savolitinib. Further exploration of this combination is underway in the SAVANNAH study (NCT03778229).
Clinical trial identification
NCT03944772.
Editorial acknowledgement
Medical writing support for the development of this abstract, under the direction of the authors, was provided by Gemma White, MSc, of Ashfield MedComms, an Ashfield Health company, and funded by AstraZeneca.
Legal entity responsible for the study
AstraZeneca.
Funding
AstraZeneca.
Disclosure
H.A. Yu: Financial Interests, Personal and Institutional, Research Grant: AstraZeneca; Financial Interests, Personal and Institutional, Research Grant: Pfizer; Financial Interests, Personal and Institutional, Research Grant: Eli Lilly; Financial Interests, Personal and Institutional, Research Grant: Cullinan; Financial Interests, Personal and Institutional, Research Grant: Novartis; Financial Interests, Personal and Institutional, Research Grant: Daiichi Sankyo. H. Ambrose: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. C. Baik: Financial Interests, Personal and Institutional, Research Grant: Novartis; Financial Interests, Personal and Institutional, Research Grant: Pfizer; Financial Interests, Personal and Institutional, Research Grant: Loxo Oncology; Financial Interests, Personal and Institutional, Research Grant: Genentech Inc.; Financial Interests, Personal and Institutional, Research Grant: Spectrum Pharmaceuticals; Financial Interests, Personal and Institutional, Research Grant: Blueprint Medicines; Financial Interests, Personal and Institutional, Research Grant: Daiichi Sankyo Inc.; Financial Interests, Personal and Institutional, Research Grant: Rain Therapeutics; Financial Interests, Personal and Institutional, Research Grant: AbbVie; Financial Interests, Personal and Institutional, Research Grant: Turning Point Therapeutics; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca; Financial Interests, Personal and Institutional, Research Grant: Eli Lilly; Financial Interests, Personal and Institutional, Research Grant: Janssen; Financial Interests, Personal, Advisory Role, Consulting Fees: AstraZeneca; Financial Interests, Personal, Advisory Role, Consulting Fees: Blueprint Medicines; Financial Interests, Personal, Advisory Role, Consulting Fees: Daiichi Sankyo; Financial Interests, Personal, Advisory Role, Consulting Fees: Takeda; Financial Interests, Personal, Advisory Role, Consulting Fees: Turning Point Therapeutics. B.C. Cho: Financial Interests, Personal, Advisory Board: Kanaph Therapeutics Inc.; Financial Interests, Personal, Advisory Board: BridgeBio Therapeutics; Financial Interests, Personal, Advisory Board: Cyrus Therapeutics; Financial Interests, Personal, Advisory Board: Guardant Health; Financial Interests, Personal, Member of the Board of Directors: Interpark Bio Convergence Corp.; Financial Interests, Personal and Institutional, Research Grant: Novartis; Financial Interests, Personal and Institutional, Research Grant: Bayer; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca; Financial Interests, Personal and Institutional, Research Grant: Mogam Institute; Financial Interests, Personal and Institutional, Research Grant: Dong-A ST; Financial Interests, Personal and Institutional, Research Grant: Champions Oncology; Financial Interests, Personal and Institutional, Research Grant: Janssen; Financial Interests, Personal and Institutional, Research Grant: Yuhan; Financial Interests, Personal and Institutional, Research Grant: Ono Pharmaceuticals; Financial Interests, Personal and Institutional, Research Grant: Dizal Pharma; Financial Interests, Personal and Institutional, Research Grant: MSD; Financial Interests, Personal and Institutional, Research Grant: AbbVie; Financial Interests, Personal and Institutional, Research Grant: Medpacto; Financial Interests, Personal and Institutional, Research Grant: GI Innovation; Financial Interests, Personal and Institutional, Research Grant: Eli Lilly; Financial Interests, Personal and Institutional, Research Grant: Blueprint Medicines; Financial Interests, Personal and Institutional, Research Grant: Interpark Bio Convergence Corp; Financial Interests, Personal, Advisory Role, Consulting fees: Novartis; Financial Interests, Personal, Advisory Role, Consulting fees: AstraZeneca; Financial Interests, Personal, Advisory Role, Consulting fees: Boehringer Ingelheim; Financial Interests, Personal, Advisory Role, Consulting fees: Roche; Financial Interests, Personal, Advisory Role, Consulting fees: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role, Consulting fees: Ono Pharmaceuticals; Financial Interests, Personal, Advisory Role, Consulting fees: Yuhan; Financial Interests, Personal, Advisory Role, Consulting fees: Pfizer; Financial Interests, Personal, Advisory Role, Consulting fees: Eli Lilly; Financial Interests, Personal, Advisory Role, Consulting fees: Janssen; Financial Interests, Personal, Advisory Role, Consulting fees: Takeda; Financial Interests, Personal, Advisory Role, Consulting fees: MSD; Financial Interests, Personal, Advisory Role, Consulting fees: Medpacto; Financial Interests, Personal, Advisory Role, Consulting fees: Blueprint Medicines; Financial Interests, Personal, Ownership Interest, Founder: DAAN Biotherapeutics. E. Cocco: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. S.B. Goldberg: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Genentech; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Spectrum; Financial Interests, Personal, Advisory Board: Blueprint Medicine; Financial Interests, Personal, Advisory Board: Sanofi Genzyme; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Regeneron; Financial Interests, Personal, Advisory Board: Takeda; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Research Grant: Boehringer Ingelheim. J.W. Goldman: Financial Interests, Personal and Institutional, Research Grant: Advaxis; Financial Interests, Personal and Institutional, Research Grant: Array Biopharma; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca; Financial Interests, Personal and Institutional, Research Grant: BMS; Financial Interests, Personal and Institutional, Research Grant: Eli Lilly; Financial Interests, Personal and Institutional, Research Grant: Genentech/Roche; Financial Interests, Personal and Institutional, Research Grant: G1 Therapeutics; Financial Interests, Personal and Institutional, Research Grant: Merck; Financial Interests, Personal and Institutional, Research Grant: Pfizer Inc.; Financial Interests, Personal, Other, Travel: AstraZeneca. S. Kraljevic: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. A.J. de Langen: Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role: Boehringer Ingelheim; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Eli Lilly; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Research Grant: BMS; Financial Interests, Personal, Research Grant: Boehringer Ingelheim; Financial Interests, Personal, Research Grant: MSD. I. Okamoto: Financial Interests, Personal, Other, Honoraria: AstraZeneca; Financial Interests, Personal, Other, Honoraria: Taiho Pharmaceutical; Financial Interests, Personal, Invited Speaker, Honoraria: Ono Pharmaceutical; Financial Interests, Personal, Other, Honoraria: MSD Oncology; Financial Interests, Personal, Other, Honoraria: Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: Chugai Pharma; Financial Interests, Personal, Other, Grants/patents received or pending: Pfizer Inc.; Financial Interests, Personal, Other, Grants/patents received or pending: Boehringer Ingelheim; Financial Interests, Personal, Other, Grants/patents received or pending: Taiho Pharmaceutical; Financial Interests, Personal, Other, Grants/patents received or pending: Ono Pharmaceutical; Financial Interests, Personal, Other, Grants/patents received or pending: MSD Oncology; Financial Interests, Personal, Other, Grants/patents received or pending: Astellas Pharma; Financial Interests, Personal, Other, Grants/patents received or pending: Bristol Myers Squibb; Financial Interests, Personal, Officer, Grants/patents received or pending: Chugai Pharma; Financial Interests, Personal, Officer, Grants/patents received or pending: AbbVie. Z. Piotrowska: Financial Interests, Personal, Advisory Role, Consultancy fees: AstraZeneca; Financial Interests, Personal, Advisory Role, Consultancy fees: Blueprint Medicines; Financial Interests, Personal, Advisory Role, Consultancy fees: Janssen; Financial Interests, Personal, Advisory Role, Consultancy fees: Takeda; Financial Interests, Personal, Advisory Role, Consultancy fees: Jazz Pharmaceuticals; Financial Interests, Personal, Advisory Role, Consultancy fees: C4 Therapeutics; Financial Interests, Personal, Other, Grants/patents received or pending: Novartis; Financial Interests, Personal, Other, Grants/patents received or pending: Takeda; Financial Interests, Personal, Other, Grants/patents received or pending: Spectrum Pharmaceuticals; Financial Interests, Personal, Other, Grants/patents received or pending: AstraZeneca; Financial Interests, Personal, Other, Grants/patents received or pending: Tesaro; Financial Interests, Personal, Other, Grants/patents received or pending: Cullinan; Financial Interests, Personal, Other, Grants/patents received or pending: Daiichi Sankyo; Financial Interests, Personal, Other, Grants/patents received or pending: AbbVie. M. Pluta: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. S. Powar: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. N. Reguart Aransay: Financial Interests, Personal, Advisory Board: Pfizer Inc.; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board: Guardant Health; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Takeda; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Research Grant: Pfizer; Financial Interests, Personal, Research Grant: Novartis; Financial Interests, Personal, Research Grant: MSI; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Janssen; Financial Interests, Personal, Invited Speaker: Guardant Health; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Takeda; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Sanofi. J.W. Riess: Financial Interests, Personal, Other, Honoraria: Blueprint Medicine; Financial Interests, Personal, Other, Honoraria: EcoRI; Financial Interests, Personal, Other, Honoraria: Medtronic; Financial Interests, Personal, Other, Honoraria: Daiichi Sankyo; Financial Interests, Personal, Other, Honoraria: EMD Serrano; Financial Interests, Personal, Other, Honoraria: Janssen; Financial Interests, Personal, Advisory Role, Consultancy fees: Novartis; Financial Interests, Personal, Advisory Role, Consultancy fees: Boehringer Ingelheim; Financial Interests, Personal, Advisory Role, Consultancy fees: Genentech; Financial Interests, Personal, Advisory Role, Consultancy fees: Blueprint Medicine. X. Le: Financial Interests, Personal, Advisory Role, Consultancy fees: EMD Serono (Merck KGaA); Financial Interests, Personal, Advisory Role, Consultancy fees: AstraZeneca; Financial Interests, Personal, Advisory Role, Consultancy fees: Spectrum Pharmaceutics; Financial Interests, Personal, Advisory Role, Consultancy fees: Daiichi Sankyo; Financial Interests, Personal, Advisory Role, Consultancy fees: Eli Lilly; Financial Interests, Personal, Funding, Research grant pending: Eli Lilly; Financial Interests, Personal, Funding, Research grant pending: Eli Lilly.