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NSCLC, metastatic 1

1979 - Blood-Based Biomarkers for Cancer Immunotherapy: Tumor Mutational Burden in Blood (bTMB) is Associated With Improved Atezolizumab (atezo) Efficacy in 2L+ NSCLC (POPLAR and OAK)


08 Sep 2017


NSCLC, metastatic 1


Cancers in Adolescents and Young Adults (AYA);  Immunotherapy;  Translational Research;  Non-Small Cell Lung Cancer


David Gandara


Annals of Oncology (2017) 28 (suppl_5): v460-v496. 10.1093/annonc/mdx380


D.R. Gandara1, M. Kowanetz2, T.S.K. Mok3, A. Rittmeyer4, L. Fehrenbacher5, D. Fabrizio6, G. Otto7, C. Malboeuf8, D. Lieber7, S.M. Paul2, L. Amler2, T. Riehl9, E. Schleifman10, C.A. Cummings2, P.S. Hegde2, W. Zou11, A. Sandler12, M. Ballinger12, D.S. Shames10

Author affiliations

  • 1 Thoracic Oncology, UC Davis Comprehensive Cancer Center, 95817 - Sacramento/US
  • 2 Oncology Biomarker Development, Genentech, South San Francisco/US
  • 3 Clinical Oncology, Chinese University of Hong Kong, Hong Kong/CN
  • 4 Thoracic Oncology, Lungenfachklinik Immenhausen, Immenhausen/DE
  • 5 Oncology, Kaiser Permanente Medical Center, Vallejo/US
  • 6 Cancer Immunotherapy, Foundation Medicine Inc., Cambridge/US
  • 7 Product Development, Foundation Medicine Inc., Cambridge/US
  • 8 Molecular Biology And Sequencing, Foundation Medicine Inc., Cambridge/US
  • 9 Product Development Clinical (oncology), Genentech, South San Francisco/US
  • 10 Oncology Biology Development, Genentech, South San Francisco/US
  • 11 Biostatistics, Genentech, South San Francisco/US
  • 12 Product Development Oncology, Genentech, South San Francisco/US


Abstract 1979


Atezo (anti–PD-L1) was FDA approved for 2L+ NSCLC based on results from the randomized OAK and POPLAR trials, with atezo showing superior efficacy vs docetaxel (doc). We previously showed that TMB in tissue correlates with atezo efficacy in 1L+ NSCLC. To address the significant challenge of consistently obtaining sufficient tumor tissue for molecular testing, we developed a novel blood-based assay to measure bTMB. Here we analyzed plasma samples from OAK and POPLAR with the bTMB assay to correlate bTMB with atezo clinical activity.


The biomarker evaluable population (BEP) included 211 pts in POPLAR (ITT=287) and 583 pts in OAK (excludes pts with known EGFR/ALK mutations; ITT=850), with blood samples available for targeted genomic sequencing. The bTMB assay interrogates single nucleotide variants (SNVs) in 394 genes from cell-free DNA in plasma and reports a score based on the number of high-confidence SNVs identified. The BEP was grouped by bTMB cut points based on the minimum number of SNVs present.


In POPLAR, improved PFS and OS HRs with atezo vs doc were observed at a range of bTMB cut points compared with the ITT and BEP. In OAK, PFS benefit with atezo vs doc was observed at bTMB cut points ≥ 10 compared with BEP. (Table) Importantly, bTMB did not correlate with PD-L1 expression (SP142 or 22C3).


These exploratory analyses represent the first demonstration of a novel blood-based assay measuring bTMB that may predict atezo clinical efficacy in 2L+ NSCLC. Thus, the bTMB assay may provide a non-invasive biomarker to identify pts who may derive clinical benefit from single agent checkpoint inhibition. Prospective studies using bTMB are currently ongoing in pts with 1L NSCLC (B-F1RST/BFAST).Table:

1295O Clinical efficacy of atezo vs doc in bTMB subgroups

POPLAR study
ITT (N = 287)BEP (N = 211)
OS HR (95% CI)0.73 (0.53, 0.99)0.68 (0.50, 0.93)
PFS HR (95% CI)0.94 (0.72, 1.23)0.90 (0.68, 1.20)
bTMB subgroup≥ 10≥ 16≥ 20
No. of patients966342
OS HR0.590.560.51
PFS HR0.680.570.58
OAK study
ITT (N = 850)BEP (N = 583)
OS HR (95% CI)0.73 (0.62, 0.87)0.64 (0.53, 0.77)
PFS HR (95% CI)0.95 (0.82, 1.10)0.87 (0.73, 1.04)
bTMB subgroup≥ 10≥ 16≥ 20
No. of patients251158105
OS HR0.690.640.65
PFS HR0.730.650.61

BEP, biomarker-evaluable population; bTMB, tumor mutational burden in blood; ITT, intention to treat.

Clinical trial identification

NCT02008227; NCT01903993

Legal entity responsible for the study

F. Hoffmann - La Roche Ltd.


F. Hoffmann - La Roche Ltd.


D.R. Gandara: Consultant: Genentech Clinical trial grant: Genentech. M. Kowanetz, D.S. Shames: Genentech employee and Roche stock. T.S.K. Mok: Spt: AZ, BI, PFE, NV, SFJ, ROG, MSD, CLVS, BMS, Eisai, Taiho ROG/GNE, LLY, NV; Stock Sanomics AB: AZ, ROG/GNE, PFE, LLY, BI, CLVS, MSD, NV, SFJ, ACEA Bio, VRTX, BMS, GeneDecode, OGX, CELG, RXDX Bod: IASLC, CLCRF, CSCO, HKCTS. A. Rittmeyer: Grants as an advisor or speaker by: Astra Zeneca, BMS, Boehringer Ingelheim, Eli Lilly, Pfizer and Roche Genentech. D. Fabrizio, C. Malboeuf: Employee and stockholder of Foundation Medicine. G. Otto, D. Lieber: Employee and shareholder of Foundation Medicine. S.M. Paul: Genentech employee, Roche Stock, Travel, Accommodations, Expenses from Genentech. L. Amler, T. Riehl, E. Schleifman, C.A. Cummings, P.S. Hegde: Genentech employee. W. Zou: Genentech employee, Roche research funding. A. Sandler, M. Ballinger: Employee of Genentech, Roche stock. All other authors have declared no conflicts of interest.

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