Atezolizumab Treatment of Tumors with High Tumor Mutational Burden from MyPathway, a Multicenter, Open-Label, Phase IIa Multiple Basket Study

Abstract

High tumor mutational burden (TMB-H) correlates with improved immunotherapy response. We assessed atezolizumab 1,200 mg every 3 weeks for TMB-H tumors from MyPathway (NCT02091141), a phase IIa multibasket study. One hundred twenty-one patients had advanced solid tumors with TMB ≥10 mut/Mb by any Clinical Laboratory Improvement Amendments (CLIA)-certified assay. The preplanned primary endpoint was objective response rate (ORR) in patients with TMB ≥16 mut/Mb tumors by FoundationOne TMB testing [F1(CDx)]. Patients with F1(CDx) TMB ≥10 and <16 mut/Mb were also evaluated. Ninety patients with 19 tumor types and F1(CDx) TMB ≥10 mut/Mb were efficacy evaluable. In 42 patients with F1(CDx) TMB ≥16 mut/Mb, confirmed ORR was 38.1% [16/42; 95% confidence interval (CI), 23.6-54.4], and disease control rate was 61.9% (26/42; 95% CI, 45.6-76.4) versus 2.1% (1/48; 95% CI, 0.1-11.1) and 22.9% (11/48; 95% CI, 12.0-37.3) for 48 patients with TMB ≥10 and <16 mut/Mb. Responses were observed in nine different tumor types (47%; 9/19).

Significance: Atezolizumab monotherapy had promising, durable clinical activity across a variety of advanced solid tumor types in patients with TMB ≥16 mut/Mb tumors lacking other suitable treatment options and who were immunotherapy-naïve at enrollment, regardless of microsatellite instability status. Limited activity was observed in tumors with TMB ≥10 and <16 mut/Mb. See related commentary by Maron and Klempner, p. 602. This article is highlighted in the In This Issue feature, p. 587.

Figure 1.

TMB local and central testing. One hundred and twenty-one patients treated with atezolizumab in MyPathway were included in the safety population. Among these patients, one with TMB ≥10 and <16 mut/Mb did not have a tumor evaluation by the data cutoff and was not included in the efficacy analysis. Based on local or central F1(CDx) TMB testing, 42 patients had tumors with TMB ≥16 mut/Mb and comprised the primary efficacy population, and 48 patients had tumors with TMB ≥10 and <16 mut/Mb. Thirty patients had TMB <10 mut/Mb upon retrospective F1(CDx) testing or did not have an F1(CDx) testing result, and were not included in the F1(CDx) efficacy-evaluable population. ^aPatient had TMB ≥10 and <16 mut/Mb by any CLIA-certified and F1(CDx) testing. CDx, Companion Diagnostic; CLIA, Clinical Laboratory Improvement Amendments; F1, FoundationOne.

Figure 2.

Time on treatment in patients with F1(CDx) TMB testing. A, Patients with TMB ≥16 mut/Mb tumors (n = 42). B, Patients with TMB ≥10 and <16 mut/Mb tumors (n = 49). Patients with ongoing treatment at data cutoff and timepoints for first response, disease progression, and death are shown. Termination points of the treatment bars represent three weeks after the date of the last drug administration. ^aPOLE/POLD1 mutations refer to mutations in the exonuclease domains only. ^bPatient had a tumor proportion score <1 and no combined positive score. ^cPatients 72, 114, and 119 discontinued treatment without a tumor assessment and were considered to be nonresponders. Patient 121 did not have an efficacy evaluation reported by the data cutoff date and was not included in the efficacy population. CDx, Companion Diagnostic; CUP, carcinoma of unknown primary; MND, mutation not detected; MUT, mutated; NE, not evaluable; PD, progressive disease.

Figure 3.

PFS and OS in efficacy-evaluable patients with F1(CDx) TMB testing (n = 90). A, PFS in patients with TMB ≥16 mut/Mb versus TMB ≥10 and <16 mut/Mb tumors. B, OS in patients with TMB ≥16 mut/Mb versus TMB ≥10 and <16 mut/Mb tumors. CDx, Companion Diagnostic; CI, confidence interval; F1, FoundationOne; TMB, tumor mutational burden.

Figure 4.

Tumor groups in efficacy-evaluable patients with F1(CDx) TMB. Tumor types from (A) all patients with F1(CDx) TMB ≥10 mut/Mb (n = 90) and (B) F1(CDx) TMB ≥16 mut/Mb (n = 42). Nineteen different tumor types for all patients with F1(CDx) TMB testing and 16 different tumor types for F1(CDx) TMB ≥16 mut/Mb were represented among efficacy-evaluable patients, with the largest groups comprised of patients with breast and colorectal cancers. CDx, Companion Diagnostic; CUP, carcinoma of unknown primary; F1, FoundationOne; TMB, tumor mutational burden.