Nivolumab Delivers Enduring Benefits in Advanced Melanoma

Nivolumab, the most developed of an emerging class of PD-1-targeting cancer immunotherapy, has demonstrated an overall objective response rate (ORR) of 31% with a median duration of two years in patients with advanced melanoma, according to long-term clinical trial results presented Saturday at the American Society of Clinical Oncology (ASCO) Annual Meeting.

The ORR rate is higher than the 5%-15% rates typically achieved with immunotherapy agents in melanoma, said lead investigator Mario Sznol, MD, who discussed the trial results during a press briefing and interview.

The data help fuel continuing excitement over the potential of the PD-1 immune checkpoint anticancer strategy, which has shown evidence of activity in several tumor types. “PD1 blockade is a breakthrough strategy for the treatment of cancer,” said Sznol, a professor of Medical Oncology at the Yale Cancer Center in New Haven, Connecticut. “As time goes on, this will be a therapy that will be active in many diseases, or at least in a subset of patients in many different diseases.”

Bristol-Myers Squibb, which is developing nivolumab, said in a press release that promising phase I studies have prompted the company to accelerate its development program for the agent. The company said seven “potentially registrational” trials are under way in advanced melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC).

The data that Sznol described were follow-up findings from the CA209-003 phase I trial, presented at the 2012 ASCO Annual Meeting. That early-phase study found that nivolumab, then called BMS-936558, exhibited “substantial activity” in melanoma, RCC, and NSCLC, Sznol said.

Patients with melanoma who participated in the study had stage IV disease and had been heavily pretreated, with 25% having undergone three or more prior therapies and 63% experiencing two or more prior therapies.

In the follow-up results, 33 out of 107 (31%) patients with melanoma experienced tumor shrinkage of at least 30% as defined by RECIST criteria. There was evidence of clinical activity, including prolonged stable disease or unconventional response, in another 11% of patients, Sznol said.

Sznol also said there are indications that patients do not have to take the drug continuously to maintain a response. Of 17 trial participants who stopped taking nivolumab for reasons other than disease progression, 12 remained progression-free for at least 12 weeks. And, eight of those 12 patients have not relapsed.

There were five different doses of the drug evaluated in the trial, with patients receiving nivolumab intravenously every two weeks for up to two years (≤12 cycles at 4 doses/cycle) at doses ranging from 0.1 mg/kg though 10 mg/kg.

The median overall survival (OS) across all doses was 16.8 months; there was a higher OS of 20.3 months for the 3 mg/kg dose, which will be used in subsequent studies. The 1- and 2-year survival rates were estimated at 62% and 43%, respectively. Dr. Sznol Describes Nivolumab in Advanced Melanoma

In addition, Sznol said nivolumab is “one of the best-tolerated drugs I’ve given in the clinic.” He said the rate of grade 3/4 adverse events (AEs) overall was 14%, immune-specific AEs were limited to 5% of the patients, and that only 6% of the participants discontinued treatment due to toxicity. There were no new safety signals or drug-related pneumonitis deaths, Sznol said. He noted that there were 3 deaths in the CA209-003 study linked to pneumonitis, but that more vigilance and better side effect management had mitigated that concern.

“The bottom line is that durability of responses have held up,” said Sznol. He noted that the drug has not yet been evaluated in a randomized study but that “it makes us feel confident that when this goes to a phase III trial this will show real benefit for patients.”

Thus far, nivolumab’s potential to improve survival outcomes for patients compares favorably with other therapies for previously treated patients, Sznol indicated. He noted median survival is approximately 16 months for patients with BRAF-mutated melanoma treated with vemurafenib (Zelboraf),10 months for those treated with ipilimumab (Yervoy), and nine months for chemotherapy. Two-year survival rates range from 24% to 33%.

In the realm of immunotherapies, Sznol said the ORR is about 15% with interleukin-2 and from 5% to 15% with ipilimumab, depending on the study.

He added that about 10% of patients achieve long-term, durable responses with ipilimumab.

“There’s no question that nivolumab appears to be more active than either of those two immunotherapies, which were the best immunotherapies we had for melanoma up to this point in time,” Sznol said.

Sznol M, Kluger HM, Hodi FS. Survival and long-term follow-up of safety and response in patients (pts) with advanced melanoma (MEL) in a phase I trial of nivolumab (anti-PD-1; BMS-936558; ONO-4538). J Clin Oncol. 2013;31 (suppl; abstr CRA9006).