BACKGROUND: Treatment-induced accelerated tumor growth is a progression pattern reported with immune checkpoint inhibitors that has never been evaluated in randomized phase III studies because it requires two pretreatment scans. This study aimed to develop clinically relevant and applicable criteria for fast progression (FP), incorporating tumor growth kinetics and early death from disease progression to analyze data from the randomized phase III OAK study. METHODS: The OAK study evaluated the efficacy and safety of atezolizumab versus docetaxel as second-line or third-line treatment for stage IIIb/IV non-small cell lung cancer. FP rates and associated baseline factors were analyzed. FP was defined as either a ≥50% increase in the sum of largest diameters (SLDs) within 6 weeks of treatment initiation or death due to cancer progression within 12 weeks (absent post-baseline scan). RESULTS: Forty-two of 421 patients (10%) receiving atezolizumab and 37 of 402 (9%) receiving docetaxel had FP. Twenty patients with FP (48%) receiving atezolizumab versus 12 (30%) receiving docetaxel had a ≥50% SLD increase within 6 weeks. FP was significantly associated with an ECOG (Eastern Cooperative Oncology Group) performance status of 1 (vs 0), ≥3 metastatic sites at baseline, and failure of preceding first-line treatment within 6 months, but not with epidermal growth factor receptor mutation, programmed cell death 1 ligand 1 or tumor mutational burden. Overall survival in patients with FP and a ≥50% SLD increase at week 6 was similar with atezolizumab and docetaxel (unstratified HR 0.89 (95% CI 0.41 to 1.92)). CONCLUSIONS: FP rates were similar with atezolizumab and docetaxel in the OAK study, suggesting that FP may not be unique to checkpoint inhibitors, although the underlying mechanisms may differ from those of chemotherapy. Applying the FP criteria to other phase III checkpoint inhibitor trials may further elucidate the risk factors for FP. TRIAL REGISTRATION NUMBER: NCT02008227.
- Gandara, D.
- Reck, M.
- Moro-Sibilot, D.
- Mazieres, J.
- Gadgeel, S.
- Morris, S.
- Cardona, A.
- Mendus, D.
- Ballinger, M.
- Rittmeyer, A.
- Peters, S.
Keywords
- immunotherapy
- lung neoplasms
- independent medical writer under the guidance of the authors. DG reports research
- grants from Amgen, Merck, and Roche/Genentech
- personal fees for consulting or
- advisory roles for Inivata, Lilly, Merck, Roche/Genentech, and Samsung Bioepis
- and
- institutional grants with no personal income for CellMax, Guardant Health, IO
- Biotech, and Oncocyte. MR reports grants and non-financial support from F.
- Hoffmann-La Roche during the conduct of the study and personal fees from AbbVie,
- Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Celgene, Lilly,
- Merck, Merck Sharpe and Dohme, Novartis, Pfizer, and Roche outside the submitted
- work. SP reports personal fees for speaking or attending advisory boards, and has
- participated in investigation in trials for Amgen, AstraZeneca,
- Boehringer-Ingelheim, Bristol-Myers Squibb, Clovis, F. Hoffmann-La Roche, Illumina,
- Merck Sharp and Dohme, Merck Serono, Novartis, and Pfizer
- and personal fees for
- speaking or attending advisory boards for AbbVie, Bayer, Biocartis, Bioinvent,
- Daiichi Sankyo, Debiopharm, Eli Lilly, Foundation Medicine, Janssen, Merrimack,
- Pharma Mar, Regeneron, Sanofi, Seattle Genetics, and Takeda. DM-S reports grants,
- personal fees, and non-financial support from Roche/Genentech related to the current
- work, and from AbbVie, AstraZeneca, Boehringer, Bristol-Myers Squibb, and Pfizer
- personal fees and non-financial support from Merck Sharp and Dohme
- and personal
- fees from Novartis and Takeda. JM reports grants, personal fees, and non-financial
- support from Roche/Genentech related to the current work, and from
- Bristol-Myers-Squibb
- grants or personal fees for participation in advisory boards
- or speaking for Amgen, AstraZeneca, Lilly/ImClone, Merck Sharp and Dohme, Novartis,
- and Pierre Fabre
- and personal fees and non-financial support for participation in
- advisory boards or speaking for Pfizer. SMG reports personal fees from
- Genentech/Roche related to the current work, and from AstraZeneca, Takeda,
- Boehringer-Ingelheim, Bristol-Myers Squibb, Novocure, Xcovery, and AbbVie. SM is an
- employee of and has ownership interest in F. Hoffmann-La Roche. AC is an employee of
- F. Hoffmann-La Roche. DM is an employee of Genentech, Inc. MB is an employee of
- Genentech, Inc. AR reports personal fees from Roche/Genentech related to this work,
- and from Lilly, Bristol-Myers Squibb, Boehringer-Ingelheim, AstraZeneca, Merck
- Sharpe and Dohme, Pfizer, AbbVie, and Novartis.
