Nivolumab plus radiotherapy with or without temozolomide in newly diagnosed glioblastoma: Results from exploratory phase I cohorts of CheckMate 143

Abstract

Background: The phase 1 cohorts (1c+1d) of CheckMate 143 (NCT02017717) evaluated the safety/tolerability and efficacy of nivolumab plus radiotherapy (RT) ± temozolomide (TMZ) in newly diagnosed glioblastoma.

Methods: In total, 136 patients were enrolled. In part A (safety lead-in), 31 patients (n = 15, methylated/unknown MGMT promoter; n = 16, unmethylated MGMT promoter) received nivolumab and RT+TMZ (NIVO+RT+TMZ) and 30 patients with unmethylated MGMT promoter received NIVO+RT. In part B (expansion), patients with unmethylated MGMT promoter were randomized to NIVO+RT+TMZ (n = 29) or NIVO+RT (n = 30). Primary endpoint was safety/tolerability; secondary endpoint was overall survival (OS).

Results: NIVO+RT±TMZ was tolerable; grade 3/4 treatment-related adverse events occurred in 51.6% (NIVO+RT+TMZ) and 30.0% (NIVO+RT) of patients in part A and 46.4% (NIVO+RT+TMZ) and 28.6% (NIVO+RT) in part B. No new safety signals were detected. In part A, median OS (mOS) with NIVO+RT+TMZ was 33.38 months (95% CI, 16.2 to not estimable) in patients with methylated MGMT promoter. In patients with unmethylated MGMT promoter, mOS was 16.49 months (12.94-22.08) with NIVO+RT+TMZ and 14.41 months (12.55-17.31) with NIVO+RT. In part B, mOS was 14.75 months (10.01-18.6) with NIVO+RT+TMZ and 13.96 months (10.81-18.14) with NIVO+RT in patients with unmethylated MGMT promoter.

Conclusions: CheckMate 143 was the first trial evaluating immune checkpoint inhibition with first-line treatment of glioblastoma. Results showed that NIVO can be safely combined with RT±TMZ, with no new safety signals. Toxicities, including lymphopenia, were more frequent with NIVO+RT+TMZ. OS was similar with or without TMZ in patients with unmethylated MGMT promoter, and differences by MGMT methylation status were observed.

Keywords: PD-1; newly diagnosed glioblastoma; nivolumab; radiotherapy; temozolomide.

Figure 1.

Study design. Abbreviations: 5/28 d, days 1–5 of every 28-day cycle; meth, methylated; MGMT, O⁶-methylguanine-DNA methyltransferase; Q2W, every 2 weeks; RT, radiotherapy; TMZ, temozolomide; unk, unknown; unmeth, unmethylated. ^aPatients in both cohorts had surgical resection prior to starting study treatment. ^bStandard RT (60 Gy; 2-Gy fractions 5 days per week for ≤7 weeks) was administered starting ≥7 days after the first dose of nivolumab.

Figure 2.

Kaplan-Meier estimates of OS, with insets demonstrating the number of events and median overall survival. (A) OS in cohort 1c (nivolumab + RT + TMZ, methylated/unknown or unmethylated MGMT promoter) and cohort 1d (nivolumab + RT, unmethylated MGMT promoter) in part A and in cohort 1c (nivolumab + RT + TMZ, unmethylated MGMT promoter) and cohort 1d (nivolumab + RT, unmethylated MGMT promoter) in part B. (B) OS in cohort 1c in part A (nivolumab + RT + TMZ, methylated/unknown MGMT promoter; nivolumab + RT + TMZ, unmethylated MGMT promoter). Symbols indicate censored observations. Abbreviations: meth, methylated; MGMT, O⁶-methylguanine-DNA methyltransferase; NE, not estimable; OS, overall survival; RT, radiotherapy; TMZ temozolomide; unk, unknown; unmeth, unmethylated.

Figure 3.

Kaplan-Meier estimates of PFS, with insets demonstrating the number of events and median PFS. (A) PFS in cohort 1c (nivolumab + RT + TMZ, methylated/unknown or unmethylated MGMT promoter) and cohort 1d (nivolumab + RT, unmethylated MGMT promoter) in part A and in cohort 1c (nivolumab + RT + TMZ, unmethylated MGMT promoter) and cohort 1d (nivolumab + RT, unmethylated MGMT promoter) in part B. (B) PFS in cohort 1c in part A (nivolumab + RT + TMZ, methylated/unknown MGMT promoter; nivolumab + RT + TMZ, unmethylated MGMT promoter). Symbols indicate censored observations. Abbreviations: meth, methylated; MGMT, O⁶-methylguanine-DNA methyltransferase; NE, not estimable; PFS, progression-free survival; RT, radiotherapy; TMZ, temozolomide; unk, unknown; unmeth, unmethylated.