One-third of a group of heavily pretreated patients with advanced melanoma who received nivolumab monotherapy were alive 5 years after starting the drug, a phase I trial showed. Survival plateaued at 34% by 48 months, after which time disease control was maintained.

“What it does demonstrate is the importance of the durability of clinical benefit to patients [who] now we’re measuring in terms of years, as well as the memory aspect of how the immunologic memory can translate into benefit,” said Dr. Stephen Hodi, director of the melanoma center at Dana-Farber Cancer Institute in Boston during a news conference at the annual meeting of the American Association for Cancer Research.

Nivolumab is an immune checkpoint inhibitor that blocks PD-1, allowing enhanced antitumor immune responses. It is approved as a first-line agent for advanced melanoma, alone or in combination with ipilimumab. The approved dose for monotherapy is 3 mg/kg every 2 weeks.

The study randomized 107 patients (median age, 61 years; 67% male) to one of five doses ranging from 0.1 mg/kg to 10 mg/kg IV given every 2 weeks for up to 96 weeks. The patients had advanced melanoma at any site and had been on one to five lines of systemic therapy prior to entering the trial but could not have received any immune checkpoint inhibitors. They had treated and stable brain metastases and an ECOG (Eastern Cooperative Oncology Group) performance status of 0, 1, or 2. The minimum follow-up was 45 months.

Among all the patients, the median overall survival was 17.3 months (95% confidence interval, 12.5-37.8 months), and for those patients receiving 3-mg/kg doses, the median survival was 20.3 months (95% CI, 7.2 months and no upper confidence level reached). The Kaplan-Meier survival curves for all patients and those receiving the 3-mg/kg dose began to level off at about 36 months, and were essentially flat at 34% for all patients as a group from 48 months out to 5 years.

Five patients who achieved disease control but later had progressive disease were retreated with their original doses of nivolumab after being off the drug for more than 100 days. “In all five patients, disease control was obtained again, and this disease control was again durable,” Dr. Hodi reported.

Nivolumab monotherapy was safe and well tolerated. No study deaths or new safety signals were observed. The most common drug-related adverse effects were any grade of fatigue (29.9% of all patients; 47.1% of patients at the 3-mg/kg dose) and any grade of rash (23.4% and 11.8%, respectively). Although there were some grade 3-4 adverse events, adverse reactions led to study discontinuation for only 10.3% of the total patient group and 5.9% of patients on the 3-mg/kg dose.

Calling the study findings “very compelling,” conference moderator Dr. Louis Weiner, director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C., identified what he said is a key point of the study – the length of benefit. “What distinguishes immunotherapy at this point when it’s effective from other forms of cancer treatment is the durability of the benefit,” he said. “People who have good responses really seem to be protected against the disease returning in many cases.”

He asked Dr. Hodi if he would expect even better disease control results if nivolumab were combined with a different checkpoint inhibitor, such as ipilimumab. Dr. Hodi replied that it is reasonable to think that agents working through different mechanisms of action should produce even better results.

A reporter in the audience asked if it was Dr. Hodi’s practice to test tumors for PD-1 expression before using nivolumab. He replied that he and his colleagues do not routinely test for PD-1 because there have been observations that some tumors that test negative for the biomarker do respond to the drug.


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