Opdivo-Yervoy Combo Shows Signs of Activity in CRPC Patients with Metastases

A combination of Bristol-Myers Squibb’s immune checkpoint inhibitors Opdivo (nivolumab) and Yervoy (ipilimumab) reduces tumor burden in castration-resistant prostate cancer patients whose tumors have spread, interim Phase 2 results show.

Findings from the CheckMate 650 trial (NCT02985957) were recently shared at the 2019 Genitourinary Cancers Symposium in San Francisco in a presentation titled, “Initial results from a phase II study of nivolumab (NIVO) plus ipilimumab (IPI) for the treatment of metastatic castration-resistant prostate cancer (mCRPC; CheckMate 650).”

“The results from CheckMate 650 provide strong rationale for the development of combination immune checkpoint therapy for the treatment of prostate cancer, which is considered a cold tumor with few tumor-infiltrating lymphocytes,” Padmanee Sharma, MD, PhD, professor of genitourinary medical oncology and immunology at The University of Texas MD Anderson Cancer Center, said in a press release.

“The clinical results from this study are encouraging and provide the foundation to test the combination strategy in a larger cohort of patients,” she said.

Generally, prostate cancer tumors have very little infiltration of immune cells in their environment, which has largely limited the use of immune checkpoint inhibitors as single agents.

These treatments counteract signals from cancer cells to suppress an immune anti-tumor response, thereby promoting the body’s own defenses against cancer cells. However, immune cells must penetrate the tumors to exert their function.

In some cancers, combinations of immune checkpoint inhibitors targeting different molecules have led to better responses than any of these treatments alone. This led Bristol-Myers Squibb to design a Phase 2 trial testing a combination of its two immune checkpoint inhibitors — the anti-PD-1 Opdivo and the anti-CTLA-4 Yervoy — in metastatic castration-resistant prostate cancer patients.

The trial included patients with asymptomatic or minimally symptomatic disease who had progressed after second-generation hormone therapy (castration-resistant). There were two groups of patients: those who had not received prior chemotherapy (group 1) and those whose tumors had progressed after a taxane-based chemotherapy (group 2).

In both groups, patients received the combo therapy — Opdivo at 1 mg/kg and Yervoy 3 mg/kg  — every three weeks for four doses, followed by Opdivo 480 mg every four weeks.

At the time of the analysis, 78 patients had been followed for at least six months. Of the 32 patients in group 1 with measurable disease at trial start, six (26%) saw their tumors decrease. Similarly, three of the 30 patients (10%) in group 2 with measurable disease responded to the combination.

For both groups, the highest response rates were seen in patients whose tumors produced the PD-L1 factor — a biomarker that often predicts responses to PD-L1 or PD-1 inhibitors — those with defective DNA repair, and those with a high rate of mutations.

The combination’s safety was consistent with prior studies testing this combination with the same dosing schedule. Serious adverse events occurred in 42% of patients in cohort 1 and 53% of patients in cohort 2. There was one death in each group.

“Assessing the effect of biomarkers on treatment outcomes is an important part of our ongoing multidisciplinary approach to research in translational medicine,” said Arvin Yang, MD, PhD at Bristol-Myers Squibb. “These interim results are exciting and reinforce our commitment to identifying the patient populations most likely to derive benefit from immuno-oncology-based regimens across tumor types and in hard-to-treat patient populations.”

An ongoing pilot trial, which is still recruiting participants at the Sidney Kimmel Cancer Center in Baltimore, Maryland, has shown similar benefits of the Opdivo-Yervoy combination in a subset of metastatic castration-resistant prostate cancer patients.