Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab

Abstract

Although programmed death-ligand 1–programmed death 1 (PD-L1–PD-1) inhibitors are broadly efficacious, improved outcomes have been observed in patients with high PD-L1 expression or high tumor mutational burden (TMB). PD-L1 testing is required for checkpoint inhibitor monotherapy in front-line non-small-cell lung cancer (NSCLC). However, obtaining adequate tumor tissue for molecular testing in patients with advanced disease can be challenging. Thus, an unmet medical need exists for diagnostic approaches that do not require tissue to identify patients who may benefit from immunotherapy. Here, we describe a novel, technically robust, blood-based assay to measure TMB in plasma (bTMB) that is distinct from tissue-based approaches. Using a retrospective analysis of two large randomized trials as test and validation studies, we show that bTMB reproducibly identifies patients who derive clinically significant improvements in progression-free survival from atezolizumab (an anti-PD-L1) in second-line and higher NSCLC. Collectively, our data show that high bTMB is a clinically actionable biomarker for atezolizumab in NSCLC.

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Fig. 1: Development of a bTMB assay and correlation with tTMB.
Fig. 2: Forest plots of HRs for PFS and OS in the POPLAR study.
Fig. 3: Association of clinical outcome and bTMB in the OAK study.
Fig. 4: Forest plots showing the association between the clinical benefit of atezolizumab and bTMB in the OAK study.
Fig. 5: Comparison of PD-L1 expression and bTMB counts in the OAK study.

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Acknowledgements

We thank the patients, their families and the clinical study-site investigators and staff for their contributions to the study. In addition, we acknowledge E. White, M. Coyne, T. Brennan, M. Kennedy, J. He, S. Zhong, G. Young, J. Ma, M. Zhao and G. Frampton for their contributions. This study was funded by F. Hoffmann-La Roche. Editorial support for this manuscript was provided by M. Balbas of Health Interactions and funded by F. Hoffmann-La Roche.

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D.R.G. interpreted the experiments and wrote the paper. S.M.P. designed and interpreted the experiments and wrote the paper. M.K. interpreted the experiments and wrote the paper. E.S. designed and interpreted the experiments and wrote the paper. W.Z. analyzed and interpreted the experiments and wrote the paper. Y.L. analyzed and interpreted the experiments and wrote the paper. A.R. designed and interpreted the experiments and wrote the paper. L.F. designed and interpreted the experiments and wrote the paper. G.O. designed, performed, analyzed and interpreted the experiments. C.M. analyzed the experiments. D.S.L. and D.L. performed and analyzed the experiments. J.S. performed and analyzed the experiments. L.A. interpreted the experiments and wrote the paper. T.R. interpreted the experiments and wrote the paper. C.A.C. designed, analyzed and interpreted the experiments and wrote the paper. P.S.H. interpreted the experiments and wrote the paper. A.S. designed and interpreted the experiments. M.B. designed and interpreted the experiments and wrote the paper. D.F. designed, performed, analyzed and interpreted the experiments and wrote the paper. T.M. interpreted the experiments and wrote the paper. D.S.S. designed, analyzed and interpreted the experiments and wrote the paper.

Corresponding authors

Correspondence to David R. Gandara or Tony Mok or David S. Shames.

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Competing interests

The authors declare the following competing interests: D.R.G. has received a clinical trial grant and consultant fees from Genentech. Y.L., L.A., T.R., A.S. and M.B. are Genentech employees and holders of Roche stock. M.K., E.S., D.S.S., S.M.P., Y.L. and C.A.C. are Genentech employees and holders of Roche stock and have a patent pending for therapeutic and diagnostic methods for cancer. W.Z. is a Genentech employee and has received research funding from Roche. A.R. has received grants from AstraZeneca, Roche/Genentech, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly and Pfizer. L.F. declares no competing interests. D.F. is a Foundation Medicine employee and stockholder and has a patent pending for therapeutic and diagnostic methods for cancer. G.O., C.M., D.S.L., D.L. and J.S. are Foundation Medicine employees and stockholders. P.S.H. is a Genentech employee. T.M. has received grants/research support from AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, SFJ Pharmaceuticals, Roche, Merck Sharp & Dohme, Clovis Oncology, Bristol-Myers Squibb, Eisai and Taiho; speaker’s fees from AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Taiho and Ariad/Takeda; honoraria/honorarium from AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, Boehringer Ingelheim, Merck Serono, Merck Sharp & Dohme, Novartis, SFJ Pharmaceuticals, ACEA Biosciences, Vertex Pharmaceuticals, Bristol-Myers Squibb, OncoGenex Pharmaceuticals, Celgene and Ignyta; is a major stockholder in Sanomics and Cirina; participated in advisory boards for AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, Boehringer Ingelheim, Clovis Oncology, Merck Serono, Merck Sharp & Dohme, Novartis, SFJ Pharmaceuticals, ACEA Biosciences, Vertex Pharmaceuticals, Bristol-Myers Squibb, geneDecode, OncoGenex Technologies, Celgene, Ignyta and Cirina; and is on the board of directors for the International Association for the Study of Lung Cancer (IASLC), the Chinese Lung Cancer Research Foundation, the Chinese Society of Clinical Oncology (CSCO) and the Hong Kong Cancer Therapy Society (HKCTS).

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Supplementary Text and Figures

Supplementary Figures 1–11 and Supplementary Tables 1–7 and 9

Reporting Summary

Supplementary Table 8

Patient-level clinical variables, clinical outcome data and variant calls for bTMB in OAK and POPLAR

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Gandara, D.R., Paul, S.M., Kowanetz, M. et al. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med 24, 1441–1448 (2018). https://doi.org/10.1038/s41591-018-0134-3

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