Nivolumab May 'Raise Expectations' in Metastatic Cancer, Say NCI Docs

Fran Lowry

March 04, 2014

Emerging data on the immune therapy nivolumab (Bristol-Myers Squibb) "may allow medical oncologists to have raised expectations for patients with metastatic cancer," according to Geraldine O'Sullivan Coyne, MD, and colleagues from the National Cancer Institute, Bethesda, Maryland, in an editorial published this week.

The essay accompanies a new report on the use of nivolumab in patients with metastatic melanoma, which is published online in the Journal of Clinical Oncology.

The immune-based therapy nivolumab continues to produce durable and persistent remission out to 2 years in some patients with previously treated advanced melanoma.

The remissions have taken place in the context of a phase 1 study of the experimental agent, which produced "unprecedented response rates" among patients with metastatic melanoma.

The data, which were first presented at the American Society of Clinical Oncology (ASCO) in June 2013, are now more mature.

"This report is a longer follow up so we have a longer safety analysis and now we can present survival curves for these patients," lead author Suzanne L. Topalian, MD, professor of surgery and oncology, Johns Hopkins University School of Medicine, and director of the Melanoma Program, Kimmel Cancer Center, Baltimore, Maryland, told Medscape Medical News.

The nivolumab-treated cohort had a median estimated overall survival of 16.8 months, a result Dr. Topalian calls "notable."

"This is a heavily pretreated group. The majority of these patients had at least 2 other systemic treatments for melanoma and had not responded, and three fourths of them had visceral metastases, so this is a high risk, relatively poor prognosis group of melanoma patients."

Nivolumab, a programmed cell death 1 (PD-1) inhibitor, blocks an immune suppressive pathway that creates a shield for cancer cells against the immune system. It interrupts that pathway and reactivates immune responses against cancer, allowing the immune cells that have percolated into the tumor to do their job and destroy the cancer cells, the editorialists explain.

In their editorial, Dr. Coyne and colleagues write that perhaps immune checkpoint inhibitors such as nivolumab can be part of a strategy to enhance the number of patients with metastatic solid tumors who can enjoy sustained, durable responses.

"The data presented by Topalian et al suggest that nivolumab could have clinical benefits similar to those of ipilimumab, but with less toxicity. A limited [adverse effects] profile could be critical to deploying immunotherapy earlier in the adjuvant setting (perhaps in combination with antigen-specific vaccines)," they write.

"Initiating an ongoing, dynamic immune response with minimal tumor burden early in the disease course could allow for a sustained antitumor immune response long after treatment is discontinued, perhaps magnifying the proportion of durable responses seen in the metastatic setting. If future clinical trials validate the findings that have been seen in recent years, perhaps immunotherapy will not just raise expectations, but the all-important survival tail of Kaplan-Meier curves as well."

Promising Results Raise Expectations

In the study, the 107 patients with advanced melanoma were enrolled between 2008 and 2012 and received intravenous nivolumab in an outpatient setting in 8-week treatment cycles.

Treatment continued up to 96 weeks (12 cycles) until patients had a confirmed complete response, developed unacceptable toxicity, experienced disease progression, or withdrew consent.

Almost two thirds (62%) of the patients had received 2 to 5 prior systemic treatments for melanoma, 78% had a visceral metastatic lesion, and 36% had an increased lactate dehydrogenase level in the blood, which indicates an adverse prognosis in these patients.

The researchers report that the survival rate was 62% for 1 year and 43% for 2 years.

Among the 33 patients with objective tumor regressions (31%) the estimated median response duration was 2 years. An additional 7% (7 of 107) of patients experienced stable disease lasting 2 years or more.

In addition, 17 patients discontinued therapy for reasons that were not due to disease progression, and 12 (71%) of 17 patients continued to show response to the treatment when nivolumab was stopped for at least 16 weeks and up to 56 weeks thereafter.

With longer observation time since the initial ASCO report (median time on treatment, 22 weeks; range, 2 to 122 weeks), adverse events remained stable. The most common were fatigue, rash, and diarrhea, most of which occurred in the first 6 months of therapy. Prolonged exposure to nivolumab did not produce cumulative negative effects.

Nivolumab Compares Favorably With Other Agents

The overall survival rates of 62% at 1 year and 43% at 2 years, with a median overall survival of 16.8 months, compare favorably with results seen in trials with both immunotherapy and nonimmunotherapy drugs available now for patients with advanced melanoma, Dr. Topalian said.

For example, ipilimumab, a drug similar to nivolumab approved by the US Food and Drug Administration in 2011, produced an overall survival of 10.1 months in a similar patient population of previously treated advanced melanoma, she noted.

BRAF and MEK inhibitors are other powerful drugs that are used in various cancers that have certain mutations but treatment with these agents is limited to patients with mutation-positive melanomas.

"These drugs are very powerful but they tend to have limited durability in their effects, so even though over 50% of all patients respond to kinase inhibitors in melanoma, those responses last an average of 7 or 8 months and then the tumor recurs, because of the genetic complexity of melanoma where there are many bypass molecular pathways that can overcome blockade of one signalling pathway," Dr. Topalian said.

For example, the overall survival in studies of BRAF inhibitors was about 16 months, which is comparable to the results reported for nivolumab. However, the big difference is that the response duration was relatively short, only 7 months, she said.

Any patient can get nivolumab and in this study, patients were enrolled regardless of mutational status, she added.

Booster Shots With Nivolumab?

Why the duration of response to nivolumab is so much longer is not yet known, but Dr. Topalian offered this explanation.

"This treatment is directed at the immune system and it works by a completely different mechanism than the kinase inhibitors which target molecular signalling pathways in melanoma and in general cancer cells. Nivolumab can amplify immune responses against cancer and enhance immunity against cancer cells with many different kinds of mutations and are not limited to people who have one particular mutation. They are very broad-based therapies. The immune system has memory and is adaptable, so theoretically it can adapt and evolve to keep pace with the evolution of the cancer.

"In this study, even after the treatment was stopped, these responses continued. The maximum time the patients could get treatment was 2 years of continuous therapy and then everyone had to stop and be observed in the clinic. And without any further therapy, most of the patients remained in response for a very long time. In fact, one patient's tumor continued to shrink after the drug was stopped," she said.

These results suggest that nivolumab may turn out to be used as a kind of booster vaccine, where patients come back to get their immune system boosted.

"We don't know yet the best way to give drugs that block PD-1 or PDL-1, and it is possible that we should build in some kind of booster regimen, but we really don't know that yet. But in one melanoma patient, she did very well for a while but after she went off drug, about a year and a half later, she developed tumor progression, so we treated her with nivolumab and she re-responded. That does open the question about boosting the regimen and the best way to give this drug, so we still have a lot of work ahead of us," Dr. Topalian said.

Dr. Topalian reports a consultant or advisory relationship with Bristol-Myers Squibb, Jounce Therapeutics, Amplimmune, and sanofi-aventis. Dr. Coyne and coeditorialists report no relevant financial relationships.

J Clin Oncol. 2014. Abstract, Editorial

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