1887P - Adjuvant everolimus (EVE) in patients (pts) with completely resected very high-risk renal cell cancer (RCC) and clear cell histology: Results from the phase III SWOG S0931 (EVEREST) trial

Background

EVEREST is a ph3 trial of pts with either clear or non-clear cell RCC at intermediate-high or very-high risk for recurrence after nephrectomy, randomized to receive adjuvant EVE 10 mg QD or placebo x 54 wks. Longer recurrence free survival (RFS) for EVE [HR 0.85; 95%CI, 0.72-1.0; P= 0.051] was seen but the nominal significance level (p=0.044) was narrowly missed (Ryan, ASCO22). Placebo-controlled ph3 trials of sunitinib (STRAC) & pembrolizumab (KN546) limited entry to clear cell subtype and reported modest benefits in disease-free survival (DFS) despite other trials of in-class agents reporting no such benefit. Differences in pt recurrence risk have been suggested as a possible factor for the conflicting results. Here we report the results of an analysis of a very high-risk cohort of pts with clear cell in EVEREST.

Methods

Post-nephrectomy RCC pts w/ any clear cell component & very high-risk disease, defined as pT3a (gr 3-4), or pT3b-c (any gr), or T4 (any gr), or node-positive (N+), were identified. Pt characteristics, treatment, and adverse event (AE) data were summarized. A Cox regression model stratified by performance status was used to evaluate RFS & OS.

Results

Of 1,499 pts, 717 had both clear cell & very high-risk disease. 699 were eligible: 348 EVE; 351 placebo. Only 163/348 (47%) of EVE pts completed all treatment as planned while more pts completed planned treatment with placebo [225/351 (64%)]. Grade 3+ AEs were more frequent with EVE (42%) vs placebo (8%). Adjuvant EVE resulted in significant RFS improvement in ITT and per-protocol cohorts.

Table: 1887P

*per-protocol: all pts who received any of their protocol-assigned treatment

Conclusions

EVEREST remains the only phase III adjuvant RCC trial of an mTOR inhibitor. In pts with clear cell RCC at very high-risk for recurrence, adjuvant EVE was associated with significantly improved RFS vs. placebo in a subset of pts comparable to those in STRAC and KN546. These results can inform the design & development of future adjuvant trials in high-risk RCC.

Clinical trial identification

NCT01120249.

Editorial acknowledgement

Legal entity responsible for the study

SWOG.

Funding

NIH /NCI/NCORP awards U10CA180888, U10CA180819, U10CA180820, U10CA180821; in part by Novartis Pharmaceuticals Corporation.

Disclosure

S.K. Pal: Financial Interests, Institutional, Invited Speaker: Eisai, Genentech, Roche, Exelixis, Pfizer, CRISPR Therapeutics, Allogene Therapeutics; Non-Financial Interests, Member: ASCO; Non-Financial Interests, Leadership Role: SWOG; Other, Other, Travel reimbursement: CRISPR, Roche. I. Puzanov: Financial Interests, Personal, Advisory Role: Nouscom, Iovance, Nektar, Regeneron. 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, Other, on the DMC of clinical trial: Aravive; Financial Interests, Personal, Advisory Board, GU cancer drug development: alkermes, Gilead; 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)), CURESPONSE; 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, Member: ASCO, AACR; 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, Other, Political vote usually as “independent”, not a member of any political party. I am an issue voter: General US Politics; Other, Other, 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, Other, Professor at HMS, please see https://hms.harvard.edu/ for mission statement (non-profit school): Harvard Medical School (HMS); Other, Other, 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. N. Agarwal: Financial Interests, Personal, Advisory Board, In the last two calendar years, I participated in the scientific advisory board of these pharma companies between February 2021 to April 2021. None after that: Merck, Aveo, Gilead, Lilly, Exelixis, Foundation Medicine; Financial Interests, Invited Speaker, I am involved in the following phase 3 trials as the trial co-chair: TALAPRO-2, TALAPRO-3 (both Pfizer), and CONTACT-2 (Exelxis): Pfizer, Exelixis; Financial Interests, Institutional, Other, I serve in the leadership of my cancer center (Huntsman Cancer Institute, University of Utah. Salt Lake City, UT, USA). There are multiple research projects sponsored by these companies which pay money to my institution: Arnivas, Astellas, AstraZeneca, Bavarian Nordic, Bayer, BMS, Calithera, Celldex, Crispr, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, GSK, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, New Link Genetics, Novartis, Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon.; Financial Interests, Invited Speaker, I am involved in the steering committee of the trials sponsored by these pharmas with no personal honorarium: AstraZeneca, Calithera, Clovis, Crispr, Eisai, Eli Lilly, Exelixis, Immunomedics, Janssen; Financial Interests, Invited Speaker, I am involved in the steering committee of the trials sponsored by these pharma companies with no personal honorarium: Merck, Nektar, New Link Genetics, Oric, Pfizer, Prometheus, Rexahn, Takeda, and Tracon. R. Uzzo: Financial Interests, Personal and Institutional, Advisory Role: Merck, Pfizer. U.N. Vaishampayan: Financial Interests, Personal and Institutional, Research Grant: BMS, Merck; Financial Interests, Personal, Advisory Role: Alkermes, Bayer, Gilead, Exelixis, Sanofi, Merck, Pfizer; Financial Interests, Personal, Invited Speaker: Bayer, Exelixis, Sanofi. All other authors have declared no conflicts of interest.