Yervoy-Opdivo Combination May Not Improve Outcomes Versus Opdivo Alone for Some Patients With High-Risk Melanoma

Combination treatment with two PD-1 inhibitors — Yervoy and Opdivo — did not improve survival without cancer recurrence compared with Opdivo alone in patients with high-risk melanoma, a type of skin cancer.

Patients with high-risk resected melanoma had no significant improvement in survival without cancer recurrence when treated with Yervoy (ipilimumab) plus Opdivo (nivolumab) as opposed to Opdivo alone, according to results from a phase 3 trial.

“(Patients can) be reassured that PD-1 alone is an adequate adjuvant regimen,” said study author Dr. Jeffrey S. Weber, deputy director of the Perlmutter Cancer Center at NYU Langone in New York, in an interview with CURE®. “(Also, Yervoy) does not necessarily add to the benefit seen with (Opdivo) alone, and … (Keytruda [pembrolizumab]) neoadjuvant therapy (before surgery) should be added to adjuvant PD-1 blockade.”

Current Treatment Options

Weber noted that current treatment options for patients with resected (previously surgically removed) stage 3 melanoma include observation or Opdivo, with several other choices for patients with particular genetic mutations. Although Opdivo is often given on its own to patients with high-risk resected melanoma, recent study findings and preliminary data demonstrate that combining Yervoy and Opdivo may be effective as an adjuvant therapy (after surgery).

The combination of immune therapies is intended to help shrink tumors while improving recurrence-free survival rates (the length of time after cancer treatment when a patient survives without symptoms or signs of cancer), as each individual therapy has demonstrated a benefit in unresectable and advanced-stage melanoma.

In the CheckMate 915 trial, a total of 1,833 patients with high-risk resected melanoma were assigned treatment, with 916 patients treated with Opdivo and Yervoy and 917 patients treated with Opdivo alone. Of note, only patients diagnosed with stage 3B-D or stage 4 resected melanoma were included in this trial.

Of the patients in the combination therapy group, 39.7% continued treatment for a full year compared with 61.2% of those in the single therapy group.

Median recurrence-free survival was not reached for either study group. In other words, less than half of patients in the study achieved recurrence-free survival at the time researchers assessed this factor. The most common recurrence for both groups was the development of distant metastases. Patients who received combination Yervoy and Opdivo did see marginally lower recurrences than those treated with Opdivo (35.5% versus 37.6%).

Weber noted that the lack of effect that Yervoy had on relapse-free survival may be due to its dosing frequency.

“The choice of (Yervoy) so infrequently at every six (weeks) instead of every three weeks was likely an error (in the study) and was actually based on lung cancer data,” he told CURE®.

Those treated with combination Yervoy/Opdivo did see a shorter median duration of therapy (7.6 months to 11.1 months) and, therefore, a lower overall Opdivo dose. However, the combination was also associated with higher toxicity.

Patients With PD-L1 Expression

Some patients in the study had a PD-L1 expression, meaning their melanoma is particularly responsive to immunotherapies like Yervoy and Opdivo. Of these patients, recurrence events occurred in 45.6% of the combination group and 47.3% of the Opdivo group. Median recurrence-free survival was 33.2 months in the combination group versus 25.3 months in the single therapy group. At 24-months, recurrence-free survival was 53.6% with Yervoy and Opdivo and 52.4% with Opdivo alone.

Nearly three times as many patients treated with the combination Yervoy and Opdivo discontinued treatment due to side effects compared with Opdivo alone (34.6% versus 11.3%).

Four patients (0.4%) in the combination therapy group died as a result of side effects compared with no patients in the single therapy group.

“Combination dosing in the adjuvant setting requires further refinement and investigation to determine the optimal balance between benefit and toxicity,” the researchers wrote in the study published in the Journal of Clinical Oncology.

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