LBA8 - Phase III study of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in previously untreated advanced renal cell carcinoma (aRCC) of IMDC intermediate or poor risk (COSMIC-313)

Background

C inhibits tyrosine kinases including MET, VEGFR, and TAM kinases (TYRO3, AXL, MER) and promotes an immune-permissive environment, which may enhance response to checkpoint inhibitors. C+N and N+I are both standards of care for first-line aRCC (N+I for intermediate or poor risk). COSMIC-313 (NCT03937219) is evaluating C in combination with N+I vs N+I in previously untreated aRCC of intermediate or poor risk and is the first study to evaluate a triplet therapy against a contemporary immuno-oncology doublet control.

Methods

This global, double-blind, randomized phase III study enrolled previously untreated patients (pts) with clear cell aRCC of IMDC intermediate or poor risk. Pts were randomized to receive C 40 mg QD or matched placebo (P), stratified by region and IMDC risk. Both treatment groups received N (3 mg/kg IV Q3W) + I (1 mg/kg IV Q3W) for 4 cycles followed by N (480 mg IV Q4W); N was administered up to 2 y. The primary endpoint was progression-free survival (PFS) by blinded independent radiology review per RECIST 1.1 in the first 550 randomized pts (PITT population). The secondary endpoint was overall survival (OS) in all randomized pts (ITT population); objective response rate (ORR) and safety were additional endpoints.

Results

From Jun 2019 to Mar 2021, 855 pts were randomized (428, C+N+I; 427, P+N+I); IMDC risk was intermediate for 75% and poor for 25%. The study met the primary PFS endpoint (HR 0.73, 95% CI, 0.57–0.94; p=0.013); median PFS was not reached (NR; 95% CI, 14.0–not estimable) for C+N+I vs 11.3 mo (95% CI, 7.7–18.2) for P+N+I. Prespecified PFS subgroup analyses will be presented. ORR (PITT population) was 43% (95% CI, 37.2–49.2) for C+N+I vs 36% (95% CI, 30.1–41.8) for P+N+I; median duration of response was NR in either treatment group. Grade 3/4 TRAEs occurred in 73% with C+N+I vs 41% with P+N+I; 3 pts (1%) in each arm had grade 5 TRAEs, and a TRAE led to discontinuation of all treatment components in 12% vs 5%.

Conclusions

C+N+I significantly improved PFS vs P+N+I in previously untreated aRCC of IMDC intermediate or poor risk. Safety was consistent with the known profiles of the treatment components. Follow-up for OS is ongoing.

Clinical trial identification

NCT03937219.

Editorial acknowledgement

Julie Lougheed, PhD; Exelixis, Inc.

Legal entity responsible for the study

Exelixis, Inc.

Funding

Exelixis, Inc.

Disclosure

T.K. Choueiri: Financial Interests, Personal, Advisory Board, Advice on GU/RCC drugs: BMS, Pfizer, Merck, Exelixis, AstraZeneca; Financial Interests, Personal, Advisory Board, Advice on Onc drugs: Lilly, EMD Serono, Infinity; Financial Interests, Personal, Advisory Board, Advice on RCC drug: Calithera; Financial Interests, Personal, Invited Speaker, RCC drug: Ipsen; Financial Interests, Personal, Advisory Board, Advice on GU Onc drugs: Surface Oncology; Financial Interests, Personal, Other, Consultant on onc drugs: Analysis Group; Financial Interests, Personal, Invited Speaker, CME, ww2.peerview.com: Peerview; Financial Interests, Personal, Invited Speaker, CME, gotoper.com: PER; Financial Interests, Personal, Invited Speaker, CME, researchtopractice.com: ResearchToPractice; Financial Interests, Personal, Invited Speaker, National Association of Managed Care: NAMC; Financial Interests, Personal, Invited Speaker, ASCO-related event: ASCO-SITC; Financial Interests, Personal, Other, Grant review to Orien Network ($400): ORIEN; Financial Interests, Personal, Advisory Board, Advising oncology strategy: Aptitude Health; Financial Interests, Personal, Invited Speaker, Best of ASCO19 talk: Advent health; Financial Interests, Personal, Invited Speaker, Best of ESMO20 talk ($1000): UAE Society of Onc; Financial Interests, Personal, Invited Speaker, CME, mjhlifesciences.com (OncLive): MJH life sciences; Financial Interests, Personal, Invited Speaker, Grand Rounds: MDACC; Financial Interests, Personal, Invited Speaker, RCC webinar: Cancernet; Financial Interests, Personal, Invited Speaker, CME, Kidney Cancer Association ($1300): France Foundation; Financial Interests, Personal, Invited Speaker, CME, RCC: Springer, WebMed; Financial Interests, Personal, Invited Speaker, CME, ImmunoOncology in RCC: ASiM, CE; Financial Interests, Personal, Invited Speaker, CME, PodCast in RCC ($500.00): Caribou Publishing; Financial Interests, Personal, Invited Speaker, Reimbursement ($432.00): Kidney Cancer Association; Financial Interests, Personal, Other, member of the DSMB for clinical trial: Aravive; Financial Interests, Personal, Invited Speaker, unpaidhttps://www.accru.org/main/public/index.xhtml: ACCRU; Financial Interests, Personal, Invited Speaker, Unpaidhttps://kidneycan.org: KidneyCan; Financial Interests, Personal, Other, External Advisory Board Member: Gustave Roussy; Financial Interests, Personal, Stocks/Shares: Pionyr (not publicly traded), Tempest (publicly traded), Osel (not publicly traded), Nuscan ((not publicly traded)); Financial Interests, Personal, Royalties, For writing and updating chapters in GU Oncology: Up-To-Date online textbook; Financial Interests, Institutional, Funding, National Chair: BMS, Merck, Exelixis, AstraZeneca, Takeda, Tracon, Peloton; Financial Interests, Institutional, Invited Speaker: Roche, Surface Oncology, GSK; Financial Interests, Institutional, Funding, National co-chair: Pfizer, EMD-Serono; Financial Interests, Institutional, Funding, Chair of trial: Lilly; Financial Interests, Institutional, Funding, SC member: Eisai; Financial Interests, Institutional, Funding, National co-chair on 3 ongoing trials: Alliance Cooperative Group; Financial Interests, Institutional, Research Grant, for GU oncology translational research through IION program: BMS; Financial Interests, Institutional, Research Grant, for GU oncology translational research: Exelixis; Financial Interests, Institutional, Research Grant, For Health outcomes research: Roche; Financial Interests, Institutional, Invited Speaker, leads trials as PI: Nikang; Non-Financial Interests, Leadership Role, Co-Chair of the meeting, 2019-: Kidney Cancer Research Summit of KidneyCAN; Non-Financial Interests, Principal Investigator, Trial Global and National PI with GU Cancers, mostly Kidney Cancer: Multiple Academic and Industry entities; Non-Financial Interests, Personal, Other, Track Leader/Session chair/Speaker/Discussant: ASCO; Non-Financial Interests, Personal, Other, Speaker/Discussant/Track Leader: ESMO; Non-Financial Interests, Institutional, Other, Access to genomic database: Foundation Med, Guardant, Invitae; Non-Financial Interests, Personal, Other, Grants reviewers: AACR; Non-Financial Interests, Personal, Other, Reviewer of papers: Various journals (e.g. NEJM, Lancet, JCO); Non-Financial Interests, Personal, Other, Medical writing and editorial assistance support (e.g. ClinicalThinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, Parexel, Oxford PharmaGenesis, pharmagenesis, and others). However, first draft frequently initiated by myself when I am 1st author: Medical Communication; Non-Financial Interests, Member: ASCO, AACR; Non-Financial Interests, Other, Political vote usually as “independent”, not a member of any political party. I am an issue voter: General US Politics; Employee at DFCI. Please see https://www.dana-farber.org/ for mission statement (non-profit hospital). I am also the past President of Medical Staff at DFCI 2015-2018: Dana-Farber Cancer Institute (DFCI); Other, Professor at HMS, Please see https://hms.harvard.edu/ for mission statement (non-profit school): Harvard Medical School (HMS); No financial interest. Institutional.Filed patents related to biomarkers of immune checkpoint blockers, and circulating free methylated DNA. No money made and some patents were abandoned: Filed patents. T.B. Powles: Financial Interests, Personal, Other, Consulting or Advisory Role: Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Esai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, Seattle Genetics; Financial Interests, Institutional, Research Grant: Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Esai, Exelixis, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, Seattle Genetics; Financial Interests, Personal, Travel, Accommodations, Expenses: AstraZeneca, Ipsen, MSD, Pfizer, Roche. L. Albiges: Financial Interests, Institutional, Advisory Role: Astellas Pharma, AstraZeneca, Bellerophon Theraeutics, Bristol-Myers Squibb, Corvus Pharmaceuticals, Eisai, Ipsen, Janssen, Merck, MSD, Novartis, Pfizer, Roche; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: BMS, MSD. M. Burotto: Financial Interests, Personal, Advisory Role: AstraZeneca, BMS, MSD Oncology, Novartis; Financial Interests, Institutional, Advisory Role: Roche/Genentech; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, BMS, MSD Oncology, Roche/Genentech. E. Yanez Riuz: Financial Interests, Personal, Other, Honoraria: Abbott Laboratories; Financial Interests, Personal, Advisory Role: Abbott Laboratories, Bristol-Myers Squibb, Merck Serono; Financial Interests, Institutional, Research Grant: AbbVie, Bristol-Myers Squibb, MSD, Pfizer, Roche; Financial Interests, Personal, Expert Testimony: Abbott Laboratories; Financial Interests, Personal, Travel, Accommodations, Expenses: Bristol-Myers Squibb. M. Maruzzo: Financial Interests, Personal, Advisory Role: Astellas Pharma, Bristol-Myers Squibb, Ipsen, Janssen-Cilag, Merck Serono, MSD, Pfizer. F.A. Barros Schutz: Financial Interests, Personal, Full or part-time Employment: Ipsen; Financial Interests, Personal, Advisory Role: Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Janssen Oncology, Merck Sharp & Dohme, Pfizer, Roche; Financial Interests, Personal, Speaker’s Bureau: Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen Oncology, Merck Sharp & Dohme, Pfizer, Roche; Financial Interests, Institutional, Research Grant: Janssen Oncology; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Astellas Pharma, Bristol-Myers Squibb, Janssen-Cilag, Merck Sharp & Dohme, Roche. D.Y.C. Heng: Financial Interests, Personal, Advisory Role: Astellas Pharma, Bristol-Myers Squibb, Eisai, Ipsen, Janssen, Merck, Novartis, Pfizer; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb, Exelixis, Ipsen, Novartis, Pfizer . F. Wang: Financial Interests, Personal, Full or part-time Employment: Exelixis, Inc.; Financial Interests, Personal, Stocks/Shares: Exelixis, Inc.; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Exelixis, Inc.. F. Mataveli: Financial Interests, Personal, Full or part-time Employment: Exelixis, Inc.; Financial Interests, Personal, Stocks/Shares: Exelixis, Inc.. Y. Chang: Financial Interests, Personal, Full or part-time Employment: Exelixis, Inc.; Financial Interests, Personal, Stocks/Shares: Exelixis, Inc.. C. Suarez Rodriguez: Financial Interests, Personal, Advisory Role: Astellas Pharma, Bristol-Myers Squibb, Eisai, EUSA Pharma, Ipsen, Merck Sharp & Dohme, Pfizer; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Bristol Myers Squibb, Ipsen, Merck Sharp & Dohme, Pfizer, Roche/Genentech; Financial Interests, Institutional, Research Grant: AB Science, Arog, Astellas Pharma, AstraZeneca, Aveo, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Clovis Oncology, Cougar Biotechnology, Deciphera, Exelixis, GlaxoSmithKline, Incyte, Janssen Oncology, Karyopharm Therapeutics, MedImmune, Millennium, Nanobiotix, Novartis, Pfizer, Puma Biotechnology, Roche/Genentech, SFJ Pharmaceuticals Group, Teva; Financial Interests, Personal, Travel, Accommodations, Expenses: Bristol-Myers Squibb, Ipsen, Roche. R.J. Motzer: Financial Interests, Personal, Advisory Role: AstraZeneca, Calithera Biosciences, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly, Merck, Novartis, Pfizer; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb, Eisai, Exelixis, Genentech/Roche, Merck, Novartis, Pfizer; Financial Interests, Personal, Travel, Accommodations, Expenses: Bristol-Myers SquibbBristol-Myers Squibb. All other authors have declared no conflicts of interest.