2032MO - Correlation of safety and efficacy in atezolizumab therapy across indications

Background

The association between safety and efficacy of immune checkpoint inhibitors (ICI) is known, but association between severity of ICI toxicity and impact of specific organ systems affected by immune-related adverse event (irAE) and cancer outcomes is poorly understood. While most irAEs are mild to moderate, severe irAEs pose clinical challenges that may require immunosuppression, hormonal replacement, and/or permanent discontinuation of ICIs.

Methods

We evaluated the association between safety and efficacy across 14 clinical trials (n=9521) involving atezolizumab as mono (IO) or with chemo (C-IO) therapy as compared to chemotherapy (C) in Non-Small Cell Lung (NSCLC, n=8), Small-Cell Lung (SCLC, n=1), Renal Cell (RCC, n=2), Urothelial (UC, n=2), and Triple -Negative Breast Cancers (TNBC, n=1). We applied a mixed-effect Cox proportional hazard model for time-varying covariates to address immortal time bias, adjusted for baseline factors associated with occurrence of irAEs and OS to control for confounding bias, and focused on the five most common irAEs (dermatologic, thyroid dysfunction, hepatitis, pneumonitis, and colitis) to avoid low statistical power for rare events. Association between irAE grade (G) by CTCAE and specific organ involvement with overall survival was assessed.

Results

For patients treated with IO or C-IO, G1-2 irAEs were associated with improved OS (HR = 0.65, p<0.01) and G3-4 irAEs showed slight increase in risk of death (HR = 1.18, p=0.06) versus patients without irAEs. By specific irAE, G1-2 skin irAEs, thyroid dysfunction or pneumonitis were associated with improved OS. However, G3-4 pneumonitis and colitis were associated with worse OS. There was no association with hepatitis and OS by any grade. Findings were consistent across indications.

Conclusions

This is the largest analysis to date demonstrating correlation between irAEs and improved OS for atezolizumab by severity grade, and most common irAEs by organ. We identify that low-grade irAEs are significantly associated with improved OS, while specific high-grade toxicities are associated with poorer OS, underscoring the importance of early recognition and management of toxicity to further optimize benefit/risk balance of ICI therapy.

Clinical trial identification

NCT01846416, NCT02031458, NCT02008227, NCT02409342, NCT02366143, NCT02367794, NCT02763579, NCT02367781, NCT02657434, NCT01984242, NCT02420821, NCT02425891, NCT02108652, NCT02302807

Editorial acknowledgement

Legal entity responsible for the study

F. Hoffmann-La Roche.

Funding

F. Hoffmann-La Roche.

Disclosure

J. Naidoo: Financial Interests, Personal, Advisory Board: Merck, AstraZeneca, Roche/Genentech, Bristol Myers Squibb, Takeda, Pfizer, Amgen, NGM Pharmaceuticals, Kaleido Biosciences, AbbVie, Elevation Oncology; Financial Interests, Personal, Other, independent adjudication of adverse events: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: AstraZeneca, Merck, Novartis, Bristol Myers Squibb; Financial Interests, Institutional, Local PI: Mirati. G. Durán-Pacheco: Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance: F. Hoffmann-La Roche Ltd; Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd. V. Maiya: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd., Genentech Inc.; Non-Financial Interests, Personal, Funding, Research funding: Support for third-party editing assistance: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd., Genentech Inc. M. Socinski: Non-Financial Interests, Personal, Funding, Research funding: Support for third-party writing assistance: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Speaker’s Bureau: Genentech Inc., Genentech Inc., AstraZeneca, Mirati, Janssen, Jaze, Guidant, Merck, Requiem, Eli Lilly, Blueprint; Financial Interests, Personal, Research Funding: Genentech Inc.; Financial Interests, Personal, Research Grant: Genentech Inc., AstraZeneca, Mirati, Spectrum, Daiichi, Novartis, Takeda, BeiGene; Financial Interests, Personal, Speaker, Consultant, Advisor: Eli Lilly, BeiGene, Spectrum, Arcus; Financial Interests, Personal, Advisory Board: BMS, Spectrum, BeiGene, Genentech Inc. G.P. Sonpavde: Financial Interests, Personal, Advisory Board: EMD Serono/Pfizer, Bristol Myers Squibb, Genentech, Merck, Sanofi, Seattle Genetics, Exelixis, Janssen, Bicycle Therapeutics, Immunomedics/Gilead, Scholar Rock, G1 Therapeutics, Loxo Oncology, Lucence, Tempus, Syapse; Financial Interests, Personal, Advisory Board, Editor of Bladder cancer virtual center of excellence for Practice Update: Elsevier; Financial Interests, Personal, Other, Member of Data Safety Monitoring Board: Mereo; Financial Interests, Personal, Other, Author of chapter: Uptodate; Financial Interests, Personal, Invited Speaker: Research to practice, Seattle Genetics, Gilead, Exelixis, Janssen; Financial Interests, Personal, Advisory Board, to develop a trial in bladder cancer: Servier Pharmaceuticals; Financial Interests, Institutional, Research Grant: Sanofi, Gilead, QED, Predicine, EMD Serono, Jazz Pharma; Non-Financial Interests, Principal Investigator, Steering committee of trial: Bristol Myers Squibb; Non-Financial Interests, Principal Investigator: G1 Therapeutics; Non-Financial Interests, Leadership Role, Steering Committee of trial: QED; Non-Financial Interests, Other, Steering Committee of trial: Merck; Other, Spouse employment: Myriad Genetics. J. Puente: Financial Interests, Personal, Advisory Board: Astellas, AstraZeneca, Janssen, MSD, Pfizer, Eisai, Ipsen, Roche, BMS, Merck; Financial Interests, Personal, Invited Speaker: Astellas, AstraZeneca, Janssen, MSD, Bayer, Pfizer, Eisai, Roche, BMS, Merck; Financial Interests, Institutional, Research Grant: Astellas, Roche, Merck. L. Essioux, C.A. Carter, S.G. Chandler: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd. J.V. Cardona, R. Mohindra: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd.