Opdivo Safe, Effective in Early Stage Glioblastoma

Single-agent Opdivo (nivolumab) demonstrated encouraging signs of activity with a mild adverse event (AE) profile for patients with recurrent glioblastoma multiforme (GBM), according to findings from the open-label CheckMate-143 trial presented at the 2016 Annual Meeting of the American Society of Clinical Oncology (ASCO), a gathering of 30,000 oncology professionals in Chicago.

In the multi-cohort study, which also explored the combination of Opdivo and Yervoy (ipilimumab), the 12-month overall survival (OS) rate was 40 percent with Opdivo monotherapy. Median OS was 10.5 months and there were no grade 3/4 adverse events (AEs).

Based on these findings, a phase 3 cohort has been opened within CheckMate-143 that will compare single-agent Opdivo with Avastin (bevacizumab) for patients with recurrent GBM. This cohort of the study could serve as a registration study for the PD-1 inhibitor in GBM, according to lead investigator David Reardon.

"These data, although preliminary, are highly encouraging," said Reardon, clinical director, Center for Neuro-Oncology, Dana-Farber Cancer Institute. “This is a very complex study with many arms, including a registration phase 3 of Opdivo versus Avastin. At ASCO 2016 we are reporting on the two Yervoy plus Opdivo arms and Opdivo monotherapy from the original phase 2 part of the study.”

At the time of the analysis, the study had enrolled patients with recurrent or progressive GBM across two study cohorts looking at Opdivo alone or in combination with Yervoy, both at various doses and schedules. Treatment was continued until disease progression or unacceptable toxicity.

All patients had grade 4 glioma and were in their first recurrence following radiation and Temodar (temozolomide). Ages ranged from a median of 57 years in cohort 1 to 60 years in cohort 1b. The median Karnofsky performance status was 90. MGMT was unmethylated for half of the study participants in each cohort. PD-L1 status was determined using immunohistochemistry, with 60 percent and 77 percent of evaluable patients testing positive on one percent or greater of cells in cohort 1 and 1b, respectively.

There was one partial response by RANO criteria in the single-agent Opdivo arm, and 50 percent of patients had stable disease. In the N1/I3 and N3/I1 groups, 40 percent and 50 percent of patients had stable disease, respectively; however, responses were not recorded.

In the N1/I3 arm, the median OS was 9.3 months and the 12-month OS rate was 30 percent. In the N3/I1 arm, the median OS was 7.3 months and the 12-month OS rate was 35 percent.

In the single-agent Opdivo arm, the median progression-free survival (PFS) was 1.9 months. The median PFS was 2.1 months with N1/I3 and 2.4 months with N3/I1.

"The efficacy results are very limited due to very small sample size. In fairness it is not appropriate to draw firm conclusions due to this," Reardon noted. "That being said, there is concern that the toxicity of the original Yervoy/Opdivo dosing may contribute to lower efficacy with time. The revised dosing schedule is better tolerated and likely to have better efficacy due to enhanced compliance."

Grade 1/2 treatment-related AEs occurred in 90 percent of patients treated with single-agent Opdivo. There were no grade 3-5 events in the monotherapy arm. Serious treatment-related AEs occurred in 20 percent of patients in the single agent arm.

All patients treated with the Opdivo/Yervoy combination experienced treatment-related AEs. Grade 3/4 treatment-related AEs occurred in 90 percent of patients treated in the N1/I3 arm and in 25 percent of those treated with N3/I1 dose. Serious treatment-related AEs were seen in 70 percent and 10 percent of those treated with the N1/I3 and N3/I1 arms, respectively.

In cohort 1, none of the patients in the single-agent Opdivo arm discontinued due to toxicity. In the combination arm, three patients stopped the drug following AEs. In cohort 1b, just one patient stopped the combination from AEs.

The median treatment durations were 2.3, 2.2 and 2.5 months, with single-agent Opdivo, N1/I3 and N3/I1, respectively. The median Yervoy treatment duration was nearly doubled with the lower dose of Yervoy compared to the higher dose.

"The results we are reporting show that the combination with lower dose Yervoy plus standard Opdivo is well tolerated," said Reardon. "Modification of Yervoy dosing appears to significantly improve tolerability when administered with anti-PD-1 therapy. Further follow-up and additional testing of the combination appear warranted for glioblastoma patients." The phase 3 cohort of the CheckMate-143 study, known as cohort 2, is utilizing the same dosing for single-agent Opdivo as was administered in cohort 1. In this randomized portion of the study, Avastin will be administered every two weeks. The phase 3 study cohort has a primary endpoint of OS and plans to enroll 440 total participants. The estimated primary completion date for the study is April 2017.