A WIN Consortium phase I study exploring avelumab, palbociclib, and axitinib in advanced non-small cell lung cancer

Abstract

Background: The Worldwide Innovative Network (WIN) Consortium has developed the Simplified Interventional Mapping System (SIMS) to better define the cancer molecular milieu based on genomics/transcriptomics from tumor and analogous normal tissue biopsies. SPRING is the first trial to assess a SIMS-based tri-therapy regimen in advanced non-small cell lung cancer (NSCLC).

Methods: Patients with advanced NSCLC (no EGFR, ALK, or ROS1 alterations; PD-L1 unrestricted; ≤2 prior therapy lines) received avelumab, axitinib, and palbociclib (3 + 3 dose escalation design).

Results: Fifteen patients were treated (five centers, four countries): six at each of dose levels 1 (DL1) and DL2; three at DL3. The most common ≥Grade 3 adverse events were neutropenia, hypertension, and fatigue. The recommended Phase II dose (RP2D) was DL1: avelumab 10 mg/kg IV q2weeks, axitinib 3 mg po bid, and palbociclib 75 mg po daily (7 days off/21 days on). Four patients (27%) achieved a partial response (PR) (progression-free survival [PFS]: 14, 24, 25 and 144+ weeks), including two after progression on pembrolizumab. Four patients attained stable disease (SD) that lasted ≥24 weeks: 24, 27, 29, and 64 weeks. At DL1 (RP2D), four of six patients (66%) achieved stable disease (SD) ≥6 months/PR (2 each). Responders included patients with no detectable PD-L1 expression and low tumor mutational burden.

Conclusions: Overall, eight of 15 patients (53%) achieved clinical benefit (SD ≥ 24 weeks/PR) on the avelumab, axitinib, and palbociclib combination. This triplet showed antitumor activity in NSCLC, including in tumors post-pembrolizumab progression, and was active at the RP2D, which was well tolerated. NCT03386929 clinicaltrial.gov.

Keywords: NSCLC; VEGFR; CDK4/6; anti-PD-L1; genomics; phase I; transcriptomics.

Conflict of interest statement

Dr. Benjamin Solomon discloses advisory board participation with AstraZeneca and Bayer. Dr. Ana Callejo receives advisory role and/or travel compensation from: Bristol‐Myers Squibb, F. Hoffman‐LaRoche, Pfizer, Boehringer Ingelheim, MSD Oncology, Kyowa Kirin, Celgene, Leo Pharma, Medscape, Kern Pharma. Dr. Jair Bar receives advisory board fee from Abbvie, AstraZeneca, Bayer, Bristol‐Myers Squibb, Boehringer Ingelheim, Causalis, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda; Research support (for the institution) from Abbvie, AstraZeneca, ImmuneAI, Merck Sharp & Dohme, Novartis, OncoHost, Roche, Takeda. Dr. Lyudmila Bazhenova has stock and other ownership interests in Epic Sciences; consulting or advisory role in Neuvogen, Janssen, Daichi Sankyo, Boehringer Ingelheim, Merck, Regeneron, Bristol‐Myers Squibb, Novartis; and receives research funding from BeyondSpring. Dr. Pierre Saintigny receives research grants from the following companies: AstraZeneca, Roche, Bristol‐Myers‐Squibb, Healthcare company Hitachi, Ose Immunotherapeutics, HTG Molecular Diagnostcs, Illumina, Cellenion, Vortex Biosceinces and Inivata. Dr. Vladimir Lazar, Catherine Bresson and Fanny Wunder are full time employees of Worldwide Innovative Network (WIN) Association—WIN Consortium. Worldwide Innovative Network (WIN) Association—WIN Consortium is the owner of the patent family entitled “Method for Selecting Personalized Tri‐Therapy for Cancer Treatment.” The inventor is Dr. Vladimir Lazar. Dr. J. Jack Lee receives honorarium from AstraZeneca for participating the AAZPIRE Education Program. Shai Magidi receives consultancy from Worldwide Innovative Network (WIN) Association—WIN Consortium. Dr. Amir Onn receives consulting fees from Roche Israel, MSD Israel, Boehringer Ingelheim and AstraZeneca. Dr. Brian Leyland Jones serves on the Board/ is an officer of NFCR, receives speaker's bureau fees from Puma, Genentech, Exelixis, Bayer. Dr. Richard L. Schilsky receives research grants in support of a clinical trial that he directs for the American Society of Clinical Oncology from the following companies: AstraZeneca, Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, Genentech, Lilly, Merck, Pfizer, Seattle Genetics. Dr. Schilsky serves as a consultant to: Brylogyx, Cellworks Group, Clarify Precision Oncology, EQRx, Scandion Oncology. Dr. Enriqueta Felip receives advisory board and/or speaker's bureau fee from Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol‐Myers Squibb, Eli Lilly, F. Hoffman‐LaRoche, Glaxi Smith Kline, Janssen, Medical Trends, Medscape, Merck Sharp & Dohme, Merck Serono, Peptomyc, Peervoice, Pfizer, Puma, Regeneron, Sanofi, Springer, Syneos Health, Takeda, Touch Medical; on the board of Grifols, Independent member. Receives research funding from Fundacion Merck Salud, Grant for Oncology Innovation (GOI) EMD Serono. Dr. Razelle Kurzrock receives research funding from Genentech, Merck Serono, Pfizer, Boehringer Ingelheim, TopAlliance, Takeda, Incyte, Debiopharm, Medimmune, Sequenom, Foundation Medicine, Konica Minolta, Grifols, Omniseq, and Guardant, as well as consultant and/or speaker fees and/or advisory board for X‐Biotech, Neomed, Pfizer, Actuate Therapeutics, Roche, Turning Point Therapeutics, TD2/Volastra, Bicara Therapeutics, Inc., has an equity interest in IDbyDNA and CureMatch Inc, serves on the Board of CureMatch and CureMetrix, and is a co‐founder of CureMatch. All other authors declare no potential conflict of interest.

© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Figures

FIGURE 1

Waterfall plot of responses (n = 15 patients treated; (14 patients are shown; one patient [ID#9, Table 3]) was not evaluable because did not receive the full course of therapy due to infusion reaction to the first avelumab dose and withdrew consent during course 2; patient ID#15 had evaluable, but not measurable disease that was considered stable as best response). PFS, progression‐free survival; *Patient who received prior checkpoint inhibitor

FIGURE 2

Kaplan–Meier curve of progression‐free survival of patients on study