Blood-based tumor mutational burden as a biomarker for atezolizumab in non-small cell lung cancer: the phase 2 B-F1RST trial
Edward S Kim, Vamsidhar Velcheti, Tarek Mekhail, Cindy Yun, Sarah M Shagan, Sylvia Hu, Young Kwang Chae, Ticiana A Leal, Jonathan E Dowell, Michaela L Tsai, Christopher S R Dakhil, Philip Stella, Yanling Jin, David S Shames, Erica Schleifman, David A Fabrizio, See Phan, Mark A Socinski, Edward S Kim, Vamsidhar Velcheti, Tarek Mekhail, Cindy Yun, Sarah M Shagan, Sylvia Hu, Young Kwang Chae, Ticiana A Leal, Jonathan E Dowell, Michaela L Tsai, Christopher S R Dakhil, Philip Stella, Yanling Jin, David S Shames, Erica Schleifman, David A Fabrizio, See Phan, Mark A Socinski
Abstract
Tumor mutational burden (TMB) in circulating tumor DNA (ctDNA) has shown promise in predicting benefit from PD-L1/PD-1 inhibitors in retrospective studies. Aiming to assess blood TMB (bTMB) prospectively, we conducted B-F1RST ( NCT02848651 ), an open-label, phase 2 trial that evaluated bTMB as a predictive biomarker for first-line atezolizumab monotherapy in locally advanced or metastatic stage IIIB-IVB non-small cell lung cancer (n = 152). The co-primary endpoints were investigator-assessed objective response rate (ORR) per RECIST version 1.1 and investigator-assessed progression-free survival (PFS) between high and low bTMB subgroups at the pre-defined bTMB ≥ 16 (14.5 mutations per megabase) cutoff. Secondary endpoints included investigator-assessed PFS, overall survival (OS) and duration of response at various bTMB cutoffs, as well as safety. Investigator-assessed PFS in the bTMB ≥ 16 versus bTMB < 16 groups was not statistically significant. However, bTMB ≥ 16 was associated with higher ORR, and ORR improved as bTMB cutoffs increased. No new safety signals were seen. In exploratory analyses, patients with maximum somatic allele frequency (MSAF) < 1% had higher ORR than patients with MSAF ≥ 1%. However, further analysis showed that this effect was driven by better baseline prognostics rather than by MSAF itself. At 36.5-month follow-up, an exploratory analysis of OS found that bTMB ≥ 16 was associated with longer OS than bTMB < 16. Further study and assay optimization will be required to develop bTMB as a predictive, standalone biomarker of immunotherapy or for use in conjunction with other biomarkers.
Conflict of interest statement
The authors declare the following competing interests: E.S.K. has received consulting fees from AstraZeneca, Merck and Roche/Genentech. V.V. has received fees for consulting or serving on advisory boards for Bristol Myers Squibb, Merck, GlaxoSmithKline, Foundation Medicine, AstraZeneca, EMD Serono, Novartis and Novocure. T.M declares no competing interests. C.Y. is an employee of Genentech and holds stock in Roche. S.M.S. is an employee of Genentech and holds stock in Roche. S.H. is employed by Genentech and holds stock in Roche. Y.K.C. has received research grants from AbbVie, Bristol Myers Squibb, Biodesix, Lexent Bio and Freenome and fees for serving on advisory boards for Roche/Genentech, Bristol Myers Squibb, AstraZeneca, Merck, Foundation Medicine, Counsyl, Neogenomics, Guardant Health, Boehringher Ingelheim, Biodesix, ImmuneOncia, Lilly Oncology, Merck, Takeda, Pfizer, Tempus, Lunit and Jazz Pharmaceuticals. T.A.L. has received fees for serving on advisory boards for Jazz Pharmaceuticals, AstraZeneca, EMD Serono, Merck, Blueprint, Debio and Bayer and consultancy for Boehringer Ingelheim, Daiichi Sankyo, Genentech and Jazz Pharmaceuticals. T.A.L. has also served as a non-compensated member of the steering committee for the SAPPHIRE trial, sponsored by Mirati Therapeutics. J.E.D. has received fess for serving on advisory boards for AstraZeneca, Genentech and Janssen. M.L.T., S.R.D. and P.S. declare no competing interests. Y.J. is an employee of and holds stock in Roche. D.S.S. is an employee of Genentech and holds stock in Roche. E.S. is an employee of Genentech and holds stock in Roche. D.A.F. is an employee of Foundation Medicine and holds stock in Roche. S.P. is an employee of Genentech and holds stock in Roche. M.A.S. has received research grants from Genentech, Spectrum, AstraZeneca, Novartis and Daichii Sankyo and has received fees for serving on speaker bureaus for Genentech, AstraZeneca, Bayer, Novartis, Guardant and Amgen.
© 2022. The Author(s).
Figures
References
- Herbst RS, et al. Atezolizumab for first-line treatment of PD-L1-selected patients with NSCLC. N. Engl. J. Med. 2020;383:1328–1339. doi: 10.1056/NEJMoa1917346.
- Carbone DP, et al. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N. Engl. J. Med. 2017;376:2415–2426. doi: 10.1056/NEJMoa1613493.
- Kowanetz M, et al. Abstract OA20.01: Tumor mutation burden (TMB) is associated with improved efficacy of atezolizumab in 1L and 2L+ NSCLC patients. J. Thorac. Oncol. 2017;12:S321–S322. doi: 10.1016/j.jtho.2016.11.343.
- Herbst RS, et al. Association between tissue TMB (tTMB) and clinical outcomes with pembrolizumab monotherapy (pembro) in PD-L1-positive advanced NSCLC in the KEYNOTE-010 and -042 trials. Ann. Oncol. 2019;30:v851–v934. doi: 10.1093/annonc/mdy545.
- Peters S, et al. Abstract CT074: Tumor mutational burden (TMB) as a biomarker of survival in metastatic non-small cell lung cancer (mNSCLC): blood and tissue TMB analysis from MYSTIC, a phase III study of first-line durvalumab ± tremelimumab vs chemotherapy. Cancer Res. 2019;79:CT074–CT074.
- Borghaei H, et al. Nivolumab (Nivo) + platinum-doublet chemotherapy (Chemo) vs chemo as first-line (1L) treatment (Tx) for advanced non-small cell lung cancer (NSCLC) with <1% tumor PD-L1 expression: results from CheckMate 227. J. Clin. Oncol. 2018;36:9001–9001. doi: 10.1200/JCO.2018.36.15_suppl.9001.
- Lim C, et al. Biomarker testing and time to treatment decision in patients with advanced nonsmall-cell lung cancer. Ann. Oncol. 2015;26:1415–1421. doi: 10.1093/annonc/mdv208.
- Jamal-Hanjani M, et al. Tracking the evolution of non-small-cell lung cancer. N. Engl. J. Med. 2017;376:2109–2121. doi: 10.1056/NEJMoa1616288.
- Cai W, et al. Intratumoral heterogeneity of ALK-rearranged and ALK/EGFR coaltered lung adenocarcinoma. J. Clin. Oncol. 2015;33:3701–3709. doi: 10.1200/JCO.2014.58.8293.
- Gandara DR, 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. 2018;24:1441–1448. doi: 10.1038/s41591-018-0134-3.
- Kim ES, et al. Abstract 4855: Primary efficacy results from B-F1RST, a prospective phase II trial evaluating blood-based tumour mutational burden (bTMB) as a predictive biomarker for atezolizumab (atezo) in 1L non-small cell lung cancer (NSCLC) Ann. Oncol. 2018;29:viii744. doi: 10.1093/annonc/mdy424.067.
- Socinski M, et al. Abstract CT194: Exploratory subgroup analysis of atezolizumab (atezo) clinical characteristics in patients (pts) with low circulating tumor DNA (ctDNA) in B-F1RST—a phase II trial evaluating blood-based tumor mutational burden (bTMB) in NSCLC. Cancer Res. 2019;79:CT194.
- Motta G, et al. Considerations about tumor size as a factor of prognosis in NSCLC. Ann. Ital. Chir. 1999;70:893–897.
- Hirsch FR, et al. The prognostic and predictive role of histology in advanced non-small cell lung cancer: a literature review. J. Thorac. Oncol. 2008;3:1468–1481. doi: 10.1097/JTO.0b013e318189f551.
- Cuyún Carter G, et al. A comprehensive review of nongenetic prognostic and predictive factors influencing the heterogeneity of outcomes in advanced non-small-cell lung cancer. Cancer Manag. Res. 2014;6:437–449. doi: 10.2147/CMAR.S63603.
- Hellmann MD, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N. Engl. J. Med. 2019;381:2020–2031. doi: 10.1056/NEJMoa1910231.
- Rizvi NA, et al. Abstract LBA6: Durvalumab with or without tremelimumab vs platinum-based chemotherapy as first-line treatment for metastatic non-small cell lung cancer: MYSTIC. Ann. Oncol. 2018;29:mdy511.005–mdy511.005. doi: 10.1093/annonc/mdy511.005.
- Dziadziuszko R, et al. Abstract 1281O: Atezolizumab vs platinum-based chemotherapy in blood-based tumour mutational burden–positive NSCLC: results of the blood first assay screening trial (BFAST) phase 3 Cohort C. Ann. Oncol. 2021;32:S950–S951. doi: 10.1016/j.annonc.2021.08.1883.
- Sholl LM, et al. The promises and challenges of tumor mutation burden as an immunotherapy biomarker: a perspective from the International Association for the Study of Lung Cancer Pathology Committee. J. Thorac. Oncol. 2020;15:1409–1424. doi: 10.1016/j.jtho.2020.05.019.
- Keytruda (pembrolizumab) [prescribing information] (2020).
- Turajlic S, et al. Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. Lancet Oncol. 2017;18:1009–1021. doi: 10.1016/S1470-2045(17)30516-8.
- Jardim DL, Goodman A, de Melo Gagliato D, Kurzrock R. The challenges of tumor mutational burden as an immunotherapy biomarker. Cancer Cell. 2021;39:154–173. doi: 10.1016/j.ccell.2020.10.001.
- Goodman AM, et al. MHC-I genotype and tumor mutational burden predict response to immunotherapy. Genome Med. 2020;12:45. doi: 10.1186/s13073-020-00743-4.
- Nabet BY, et al. Noninvasive early identification of therapeutic benefit from immune checkpoint inhibition. Cell. 2020;183:363–376. doi: 10.1016/j.cell.2020.09.001.
- Rizvi H, et al. Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing. J. Clin. Oncol. 2018;36:633–641. doi: 10.1200/JCO.2017.75.3384.
- Goldberg SB, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol. 2016;17:976–983. doi: 10.1016/S1470-2045(16)30053-5.
- Raja R, et al. Early reduction in ctDNA predicts survival in patients with lung and bladder cancer treated with durvalumab. Clin. Cancer Res. 2018;24:6212–6222. doi: 10.1158/1078-0432.CCR-18-0386.
- Goldstraw P, et al. The IASLC Lung Cancer Staging Project: proposals for revision of the TNM stage groupings in the forthcoming (8th) edition of the TNM Classification for Lung Cancer. J. Thorac. Onc. 2015;11:39–51. doi: 10.1016/j.jtho.2015.09.009.
Source: PubMed