Expanded Long-Term Phase I Results Show Promise for Nivolumab in Advanced Melanoma

Mario Sznol, MD

The anti-PD-1 therapy nivolumab demonstrated an overall objective response rate (ORR) of 31%, with a median duration of 2 years in patients with advanced melanoma, according to long-term results of a phase I study presented at ASCO 2013.

The data were follow-up findings from the CA209-003 phase I trial, presented at the 2012 ASCO Annual Meeting. That earlyphase study found that nivolumab, then called BMS-936558, exhibited substantial activity in melanoma, renal cell carcinoma (RCC), and non-small cell lung cancer (NSCLC).

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. The trial evaluated five dosages, with patients receiving nivolumab intravenously every 2 weeks for up to 2 years (≤12 cycles at 4 doses/cycle) at doses ranging from 0.1 mg/kg to 10 mg/kg.

In the follow-up results presented at ASCO 2013, 33 out of 107 (31%) patients with melanoma experienced tumor shrinkage of at least 30% as defined by RECIST. The median overall survival (OS) across all dosages was 16.8 months, and 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.

Of 17 trial participants who stopped taking nivolumab for reasons other than disease progression, 12 remained progression- free for at least 12 weeks. Eight of those 12 patients have not relapsed.

The rate of grade 3/4 adverse events (AEs) overall was 14%, immune-specific AEs were limited to 5% of patients, and only 6% of the participants discontinued treatment due to toxicity, according to lead author Mario Sznol, MD, professor of Medical Oncology at the Yale Cancer Center in New Haven, Connecticut. There were no new safety signals or drug-related pneumonitis deaths. Sznol 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. Although nivolumab has not yet been evaluated in a randomized study, “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 said, noting that median survival is approximately 16 months for patients with BRAF-mutated melanoma treated with vemurafenib, 10 months for those treated with ipilimumab, and 9 months for chemotherapy.

The data help fuel continuing excitement over the potential of the PD-1 immune checkpoint blockade strategy, which has shown evidence of activity in several tumor types. “PD-1 blockade is a breakthrough strategy for the treatment of cancer,” Sznol said. “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, with seven potentially registrational trials under way in advanced melanoma, NSCLC, and RCC.

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