Abstract LB012: Efficacy of atezolizumab in the treatment of solid tumors with high tumor mutational burden (TMB): A MyPathway study cohort
Authors: Hainsworth John , Friedman Claire F. , Kurzrock Razelle , Spigel David R. , Burris Howard , Sweeney Christopher J. , Meric-Bernstam Funda , Wang Yong , Levy Jonathan , Shames David , Schulze Katja , Patel Arisha , Swanton Charles 
Published: July 2021

Abstract
Purpose Data suggest that TMB is correlated with response to checkpoint blockade. We present an analysis of atezolizumab treatment of patients (pts) with advanced solid tumors and high TMB from MyPathway (NCT02091141), a multi-basket study assessing activity of FDA-approved therapies in non-indicated tumors with targetable alterations.
Methods Eligible pts were ≥18 years old with previously treated advanced solid tumors with TMB ≥10 mut/Mb by any CLIA-certified assay. Pts received atezolizumab 1200 mg IV q3w. The pre-planned primary endpoint was objective response rate (ORR) in pts with TMB ≥16 mut/Mb by FoundationOne CDx (F1CDx), a threshold determined by a retrospective study that showed TMB ≥16 mut/Mb is associated with improved ORR and duration of response (DOR) for various tumor types. Other endpoints in this group included disease control rate (DCR), DOR, progression-free survival (PFS), and overall survival (OS). Separate analyses were performed in pts with TMB ≥10 and &lt;16 mut/Mb by F1CDx, and TMB by any CLIA assay.
Results Enrollment closed on 7-9-20. By the 12-11-20 data cutoff, 118 pts with 20 tumor types and TMB ≥10 mut/Mb by any CLIA assay were evaluable for efficacy. In the primary efficacy population of 42 pts with TMB ≥16 mut/Mb by F1CDx, confirmed investigator-assessed ORR was 38.1% vs 2.1% in 48 pts with TMB ≥10 mut/Mb and &lt;16 mut/Mb; median DOR was not reached in either group. DCR was 61.9% vs 22.9%, respectively; median PFS was 5.7 vs 1.8 mos; and median OS was 13.7 vs 11.4 mos. In pts with TMB ≥16 mut/Mb by any CLIA assay, ORR was 28.6% and DCR was 55.4%. Responses were observed in diverse tumor types. In pts with TMB ≥16 mut/Mb tumors by F1CDx, those with high microsatellite instability (MSI) had an ORR of 54.5% vs 30.0% for microsatellite stable/low tumors.
Conclusions Atezolizumab had durable activity against diverse solid tumor types with TMB ≥16 mut/Mb, independent of MSI status. Limited activity was observed in tumors with TMB ≥10 and &lt;16 mut/Mb.
Clinical outcomesSubgroupORRaDCRbDORPFSOSn (%)n (%)Median mosMedian mosMedian mos95% CI95% CI95% CI95% CI95% CITMB by F1CDx assayc≥16 mut/Mb (n=42)16d (38.1)26 (61.9)Not reachede5.713.723.6-54.445.6-76.42.7-9.911.9-NA≥10 and &lt;16 mut/Mb (n=48)1 (2.1)11 (22.9)Not reached1.811.40.1-11.112.0-37.31.4-2.65.3-15.7TMB by any CLIA assayf≥16 mut/Mb (n=56)16d (28.6)31 (55.4)12.24.813.717.3-42.241.5-68.74.4-NA2.6-5.811.9-NA≥10 and &lt;16 mut/Mb (n=62)2 (3.2)13 (21.0)3.51.410.70.4-11.211.7-33.20.7-3.51.4-2.65.3-14.9TMB by F1CDx + MSI statusgTMB ≥16 mut/Mb + MSI-H (n=11)6h (54.5)8 (72.7)Not reached8.3Not reached23.4-83.339.0-94.06.9-NA1.3-NA10.4-NATMB ≥16 mut/Mb + MSS/Li (n=30)9j (30.0)17 (56.7)8.45.612.614.7-49.437.4-74.52.0-NA1.4-8.511.1-NATMB ≥10 and &lt;16 mut/Mb + MSS/Li (n=45)1 (2.2)10 (22.2)Not reached1.811.40.1-11.811.2-37.11.9-NA1.4-2.65.3-15.7Tumor types represented in the safety population with any TMB CLIA assay (n=119) were colon (n=31), breast (n=29), biliary tract (n=6), uterine (n=6), gastroesophageal (n=5), ovarian (n=5), head and neck (n=5), cervical (n=4), prostate (n=4), sarcoma (n=3), urothelial (n=3), lung (n=3), pancreatic (n=3), small bowel (n=3), carcinoma of unknown primary (n=3), pancreatic endocrine (n=2), adrenocortical (n=1), central nervous system (n=1), liver (n=1), and skin (n=1).aIncludes patients with complete or partial response.bIncludes patients with complete or partial response, or stable disease &gt;4 months.cIncludes local F1CDx (n=68) and central F1CDx (n=39); upon central retesting, 17 patients fell below the TMB threshold of 10 mut/Mb required for inclusion in the efficacy analysis.dIncludes three patients with a complete response.eDOR was &gt;15 months in &gt;50% of responders.fIncludes local F1CDx (n=68) and other local CLIA assays (n=51) from the safety population. One patient had no tumor assessment and was not included in the efficacy analysis population.gMSI status was missing for one patient with TMB ≥16 mut/Mb and two patients with TMB ≥10 and &lt;16 mut/Mb. One additional patient with TMB ≥10 and &lt;16 mut/Mb + MSI-H is not shown.hIncludes one patient with a complete response.iMSS/L includes microsatellite stable, low, or intermediate tumors, which were classified as “not high”.jIncludes two patients with a complete response.CI, confidence interval; CLIA, Clinical Laboratory Improvement Amendments; DCR, disease control rate; DOR, duration of response; F1CDx, FoundationOne CDx; MSI-H, high microsatellite instability; MSS/L, microsatellite stable/low; NA, not available; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; TMB, tumor mutational burden.JH and CL contributed equally to this work.
Citation Format: John Hainsworth, Claire F. Friedman, Razelle Kurzrock, David R. Spigel, Howard Burris, Christopher J. Sweeney, Funda Meric-Bernstam, Yong Wang, Jonathan Levy, David Shames, Katja Schulze, Arisha Patel, Charles Swanton. Efficacy of atezolizumab in the treatment of solid tumors with high tumor mutational burden (TMB): A MyPathway study cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB012.