Nick Mulcahy

June 01, 2013

CHICAGO, Illinois — New longer-term data from an early trial of the immunotherapy nivolumab (Bristol-Myers Squibb) continue to indicate that this experimental agent provides unprecedented response rates in patients with metastatic melanoma.

Overall, 33 of 107 (31%) pretreated patients with melanoma had an objective response (tumor shrinkage of at least one third). The responses were seen at all 5 doses tested in the phase 1 trial.

These and other findings from this study will be presented here today at the 2013 Annual Meeting of the American Society of Clinical Oncology (ASCO®).

In an analysis of less mature data with fewer patients from the same study, which was presented last year at the ASCO meeting, objective responses were seen in 28% of patients with melanoma.

Dr. Mario Sznol

In both cases, these rates compare favorably with the response rates of 5% to 10% seen with earlier immunotherapy drugs in patients with advanced melanoma.

"I think nivolumab is a real breakthrough drug for patients with metastatic melanoma, and probably for other diseases, too," said lead author Mario Sznol, MD, from the Yale Cancer Center in New Haven, Connecticut, in a press statement. He was referring to response rates seen with nivolumab in other solid tumors.

An expert not involved with the study believes only time will tell if nivolumab is truly a breakthrough.

The duration of survival is longer than expected.

Nivolumab and other experimental agents in the same class, known as immune checkpoint blockade, are definitely improving survival in patients with advanced melanoma, said Giuseppe Giaconne, MD, PhD, from the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC. "The duration of survival is longer than expected," he told Medscape Medical News in an interview.

In the current trial, median overall survival across all doses was 16.8 months; for the second-highest dose (3 kg/mg), it was 20.3 months. Both median survivals compare favorably with historic data, the study authors say. The 3 kg/mg dose will be studied in a phase 3 clinical trial in patients with metastatic melanoma.

However, it is too early to determine the implications of these data, Dr. Giaconne noted. "If these responses are sustained for a long time, it would be a big breakthrough," although he noted that there is no strong evidence of that yet.

In the current trial, 61% of 50 evaluable patients survived to 1 year, according to a Kaplan–Meier estimate. Overall survival rates were estimated to be 44% at 2 years and 40% at 3 years.

However, the 2- and 3-year survival estimates were calculated using small numbers of patients, Dr. Giaconne pointed out.

Larger patient cohorts in a randomized trial and more follow-up are needed, said Dr. Giaconne, who was chief of the Medical Oncology Branch of the Center for Cancer Research at the National Cancer Institute before joining Georgetown.

He suggested that the term breakthrough should be reserved for circumstances in which a notable proportion of patients have complete remissions.

Only 1 of the responses seen with nivolumab was a complete remission/response; the others were all partial responses. "By definition, a partial remission is not a cure," Dr. Giaconne explained.

However, at a meeting press conference today, Dr. Sznol revealed that out of 5 responders in the trial from his center, Yale, there were 4 "near complete responses." The trial criteria called for any evidence of a tumor on radiographic images, no matter how small, to be classified as a partial response. "The data underestimate, I think, the complete eradification of disease," he told an audience of reporters.

Neither Dr. Sznol nor another melanoma expert participating in the press conference, F. Stephen Hodi, MD, from the Dana-Farber Cancer Institute in Boston, Massachusetts, was willing to say that there was evidence of a patient being cured in these early data. However, Dr. Sznol said that 2 of his 4 patients have been virtually disease-free for 2 years, which, in other cases, has meant that the disease will not return. Dr. Hodi remarked that it is remarkable that the "C word" — cure — was even being discussed with regard to metastatic melanoma.

Curing advanced cancer is a very tall order for any drug, Dr. Giaconne added. "There are not many examples of being able to cure an advanced solid tumor with systemic therapy."

Other clinicians have been less reticent than Dr. Giaconne when evaluating nivolumab. "The results confirm that revving up the immune system is a powerful approach to shrinking melanoma. Melanoma patients are living longer and better with these new treatments. Truly remarkable," said ASCO spokesperson Lynn Schuchter, MD, in a meeting press statement. She is a melanoma expert from the University of Pennsylvania's Abramson Cancer Center in Philadelphia.

Fewer Adverse Events Than Ipilimumab

Nivolumab is a monoclonal antibody that neutralizes the programmed death 1 (PD-1) protein, which is an element of tumors that enables them to evade their nemesis, the immune system. Nivolumab is one of a number of new immune checkpoint blockade agents being evaluated in melanoma.

The first and only drug in that class to be approved by the US Food and Drug Administration is ipilimumab (Yervoy, Bristol-Myers Squib), which is indicated for metastatic melanoma but has a different target. It had a response rate of about 10% in its pivotal clinical trial.

However, ipilimumab, in addition to having a low response rate, is plagued with a high rate of serious adverse events.

In the current study, patients received 4 doses of nivolumab per cycle, and received 12 or fewer cycles of treatment. Cohorts of melanoma patients were expanded to include 5 doses (0.1, 0.3, 1, 3, and 10 mg/kg).

Drug-related adverse events (any grade) occurred in 82% of patients, but the grade 3/4 drug-related adverse events occurred in only 21%. The most common adverse events were lymphopenia (3%), fatigue, and increased lipase (2%).

Grade 3/4 drug-related events were diarrhea (2%), endocrine disorders (2%), and hepatitis (1%). No serious drug-related pneumonitis was observed in the cohort, and there were no treatment-related deaths.

The study patients were heavily pretreated, with 63% receiving 2 or more pervious therapies and 25% receiving 3 or more.

The study was supported by Bristol-Myers Squibb. Dr. Sznol and some of his coauthors report serving as consultants or advisors for Bristol-Myers Squibb. Some of his coauthors are employees of the company.

2013 Annual Meeting of the American Society of Clinical Oncology: Abstract CRA9006. Presented June 1, 2013.


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