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Nivolumab-based treatments slow progression of melanoma
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CHICAGO — Initial treatment with nivolumab alone or in combination with ipilimumab more than doubled the average time to disease progression for patients with melanoma compared with ipilimumab alone, according to results from a phase 3 trial presented during the plenary session at the ASCO Annual Meeting.
Nivolumab (Opdivo, Bristol-Myers Squibb) — a programmed cell death-1 (PD-1) inhibitor — and ipilimumab (Yervoy, Bristol-Myers Squibb), a CTLA-4 inhibitor, are immunotherapeutic monoclonal antibodies that are both FDA-approved for single-agent use in patients with unresectable or metastatic melanoma that no longer responds to other agents.
Results from a phase 1 study suggested complementary clinical activity between the two drugs, which prompted Jedd D. Wolchok, MD, PhD, chief of melanoma and immunotherapeutics service and the Lloyd J. Old Chair for Clinical Investigation at Memorial Sloan Kettering Cancer Center and a HemOnc Today Editorial Board member, and colleagues to conduct this study.
Jedd D. Wolchhok
“We’ve seen evidence of efficacy across the spectrum of tumor burden in these patients, so, if you can imagine that the symptomatology is related to the amount of tumor a patient has, this type of therapy has efficacy in patients who have a very small tumor burden in addition to patients who have more widespread, advanced disease,” Wolchok said during a press briefing. “Melanoma is a notoriously heterogeneous and quirky disease in terms of rate of progression. The sites of progression are also somewhat unpredictable.
“In the past, before the development of ipilimumab, BRAF inhibitors and nivolumab, median life expectancy for patients with melanoma in the U.S. was 7 or 8 months. Now we’re talking about PFS that’s 14 months in some subsets of patients, so you can see how much progress there has been recently across certain subsets.”
The current analysis included 945 treatment-naive patients. Researchers randomly assigned patients 1:1:1 to one of three treatment arms:
- 1 mg/kg nivolumab bi-weekly and 3 mg/kg ipilimumab every 3 weeks for four doses followed by 3 mg/kg nivolumab bi-weekly
- 3 mg/kg nivolumab bi-weekly plus placebo
- 3 mg/kg ipilimumab every 3 weeks for four doses plus placebo
Patients received the regimens in all three arms until progression or unacceptable toxicity.
PFS and OS served as the study’s primary endpoints; however, OS results were not yet mature at the time of this analysis. Secondary endpoints included objective response rate (ORR) and safety.
At a minimum follow-up of 9 months, the median PFS for ipilimumab alone was 2.9 months (95% CI, 2.8-3.4), whereas nivolumab alone conferred a 6.9-month median PFS (95% CI, 4.3-9.5). The combination of the two agents yielded the highest median PFS 11.5 months (95% CI, 8.9-16.7).
Researchers also observed a significant difference in ORR. Patients who received the combination therapy achieved a 57.6% response rate (95% CI, 52.0-63.2), which was higher than the ORR associated with nivolumab alone (43.7%; 95% CI, 38.1-49.3) and ipilimumab alone (19%; 95% CI, 14.9-23.8).
The average reduction in tumor burden was 52% in the combination arm compared with 34% in the nivolumab alone arm. However, patients in the ipilimumab alone arm experienced a 5% increase in tumor burden.
The highest rate of grade 3 to grade 4 adverse events occurred in the combination arm (55%) compared with the nivolumab alone arm (16.3%) and ipilimumab alone arm (27.3%). Further, 36.4% of patients in this arm discontinued treatment due to adverse events.
The most common events in the combination arm were diarrhea (9.3%), increased lipase (8.6%), increased alanine aminotransferase (8.3%) and colitis (7.7%); however, colitis was more common in the ipilimumab alone group (8.7%).
No drug-related deaths occurred in the combination arm, whereas one death occurred due to toxicity in each the other arms.
“Clearly these guidelines for when to stop treatment and how to manage the side effects were very effective in establishing a good risk–benefit profile,” Wolchok said at the press briefing.
Wolchok added that many patients who have to stop immunotherapy early still continue to do well because the immune system has been activated to fight the disease.
Additional biomarker analyses of PD-L1, which is sometimes found on the surface of tumor cells, indicated that nivolumab alone was as effective as the combination in patients with PD-L1–positive tumors. However, patients with PD-L1–negative tumors demonstrated a greater benefit from the combination than nivolumab alone.
"In my opinion, this study shows ipilimumab [alone] should no longer be considered a front-line treatment for patients with advanced melanoma,” plenary discussant Michael B. Atkins, MD, deputy director of the Georgetown-Lombardi Comprehensive Cancer Center in Washington and professor of oncology and medicine (hematology/oncology) at Georgetown University School of Medicine, said during the plenary session. – by Anthony SanFilippo
Reference:
Wolchok JD, et al. Abstract LBA1. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.
Disclosure: The study was funded by Bristol-Myers Squibb. Wolchok reported honoraria from, consulting/advisory roles with, travel expenses and accommodations from, stock or other ownership interests in and research funding from Bristol-Myers Squibb, EMD Serono, GlaxoSmithKline, Janssen Oncology, Jounce Therapeutics, MedImmune, Merck, Polaris, Polynoma, Potenza Therapeutics, Vesuvius Phamaceuticals and ZIOPHARM Oncology. See the full study for a complete list of relevant financial disclosures from the other researchers.
Perspective
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Steven J. O’Day, MD
The message here is that both PD-1 monotherapies and the combination are performing extremely well in comparison to ipilimumab alone, which was the benchmark. The response differences between the combination arm and the other arms are relatively modest, but what strikes us is this 5-month PFS difference between monotherapy and the combination arms. Historically, that has correlated with survival. Right now, in PD-L1–positive patients, we can be assured that their PFS will be very similar, and the real question is going to be, “What is the survival going to be at 2 or 3 years?” If it holds up in comparison to monotherapy, then it will be really obvious what we need to do.
In the short term, though, this is an incredibly encouraging combination. I will reemphasize that toxicity has been a big issue with this combination, but, we have spent a lot of time educating physicians on the management of toxicity and providing guidelines. This was a global trial with no toxic deaths on trial. So clearly, the melanoma physicians who participated in this trial followed guidelines and these toxicities can be managed and reversed relatively rapidly.
Ipilimumab is still a very important targeted drug in the field of melanoma and it’s not going to go away. It works differently than the PD-1 antibodies. Ipilimumab tends to generate an army of T cells to go into battle, whereas PD-1 therapy is more about activating or resurrecting the tired T cells in the tumor microenvironment. Together they fulfill different but potentially additive and synergistic approaches. Both will be active, and the question is what sequence or combination is the best. This combination in melanoma is incredibly promising.
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