Frontline Nivolumab Regimens Significantly Improve PFS Versus Ipilimumab in Melanoma

Jedd D. Wolchok, MD, PhD

Frontline nivolumab as monotherapy and in combination with ipilimumab more than doubled progression-free survival (PFS) versus ipilimumab alone in patients with advanced melanoma, according to results from the phase III CheckMate-067 trial. The greatest benefit was seen with the combination regimen, which reduced the risk of progression by 58% and 26% (nonsignificant) compared with single-agent ipilimumab and nivolumab, respectively. The results also showed that the combination is more effective than either agent alone in PD-L1—negative patients.

“Nivolumab alone and nivolumab with ipilimumab significantly improved progression-free survival compared to ipilimumab alone in patients with previously untreated melanoma. The combination resulted in a numerically higher progression-free survival and a higher overall response rate versus nivolumab alone,” lead author Jedd Wolchok, MD, PhD, chief of the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center, said in a press briefing at the 2015 ASCO Annual Meeting. The results were simultaneously published in The New England Journal of Medicine.

The double-blind CheckMate-067 trial randomized 945 previously treated patients equally to placebo plus either 3 mg/kg of nivolumab every 2 weeks (n = 316) or 3 mg/kg of ipilimumab every 3 weeks (n = 315) for 4 doses, or combination PD-1/CTLA-4 inhibition with 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab every 3 weeks for 4 doses followed by 3 mg/kg of nivolumab every 2 weeks (n = 314). Treatments were administered until disease progression or unacceptable toxicity.

Patients were stratified by M-stage, PD-L1 status, and BRAF mutation status. Overall survival and PFS were the primary outcome measures, with ORR (RECIST v1.1) and safety as secondary endpoints.

At ≥9 months’ follow-up, median PFS with nivolumab/ipilimumab was 11.5 months versus 2.9 months with ipilimumab alone (HR = 0.42; 95% CI, 0.31-0.57; P = <.00001). With a median PFS of 6.9 months, single-agent nivolumab also significantly delayed disease progression versus ipilimumab monotherapy (HR = 0.57; 95% CI, 0.43-0.76; P = <.00001).

The results also suggested that dual checkpoint inhibition with nivolumab/ipilimumab improved PFS versus nivolumab monotherapy (HR = 0.74; 95% CI, 0.60-0.92); however, the trial was not statistically powered for this comparison.

ORR was 57.6% and 43.7% for the nivolumab combination and single-agent arms, respectively, and 19% for the ipilimumab arm. Complete/partial response rates were 11.5%/46.2%, 8.9%/34.8%, and 2.2%/16.8%, respectively. Stable disease rates were 13% and 10.8% in the combination and single-agent nivolumab arms, and 21.9% in the ipilimumab arm.

Depth of response (median reduction in tumor burden) was -52% and -34% in the combination and single-agent nivolumab groups, and 5% with ipilimumab. The duration of response had not yet been reached in any of the three arms, which Wolchock noted was very characteristic of immunotherapy.

Regarding overall survival, Wolchok said the data are “not expected to be reported until 22 months of follow-up, so we’re quite a ways away from that.”

PD-L1 status was measured using a validated PD-L1 assay, with PD-L1—positive tumors defined as those with expression levels ≥5%. In PD-L1–positive patients, the ligand was not a biomarker for outcomes, with a PFS of 14 months in both nivolumab arms, and 3.9 months with ipilimumab. However, PD-L1–negative patients benefitted more from combination versus single-agent therapy, with a PFS of 11.2 months versus 5.3 and 2.8 months in the single-agent nivolumab and ipilimumab arms, respectively.

Discussing ORR and PD-L1 status, Wolchok said, “In general the response rates are higher for patients who have >5% PD-L1 expression. The highest response rate was 72% for the combination in patients who had >5% PD-L1 expression. Even though the two groups—nivolumab and nivolumab plus ipilimumab&mdash;had similar progression-free survival in the PD-L1 >5% subgroup, the response rate was still higher for the combination within that subgroup compared to nivolumab alone.”

Response rates were also higher with the combination compared with either monotherapy in PD-L1—negative patients, according to Wolchok.

When asked about the significance of the PD-L1 data, Wolchok said, “It is the first effort to try and introduce a precision aspect to immunotherapy and I think that in this study we see that it is a way to initiate meaningful conversations between patients and clinicians about whether a combination is the right fit for them versus nivolumab alone.”

He added that OS data are ultimately needed. “Response rate and progression-free survival are both surrogates for overall survival, and until we have that we will continue to have these discussions with each patient to find out what therapy is optimal for them.”

The safety data were consistent with outcomes previously reported for the drugs. All grade adverse-events (AEs) were 95.5%, 82.1%, and 86.2%, in the combination, nivolumab, and ipilimumab arms, respectively. The most common any-grade AEs in the combination arm versus the nivolumab and ipilimumab arms were diarrhea (44.1%, 19.2%, 33.1%), rash (40.3%, 25.9%, 32.8%), fatigue (35.1%, 34.2%, 28.0%), pruritus (33.2%, 18.8%, 35.4%), and nausea (25.9%, 13.1%, 16.1%)

Grade 3/4 AEs were reported in 55%, 16.3%, and 27.3% of the combination, nivolumab, and ipilimumab groups, respectively. The most frequent grade 3/4 toxicities reported in the ipilimumab/nivolumab arm compared with nivolumab and ipilimumab were diarrhea (9.3%, 2.2%, 6.1%) colitis (7.7%, 0.6%, 8.7%), increased lipase (8.6%, 3.5%, 3.9%), increased ALT levels (8.3%, 1.3%, and 1.6%) and increased AST levels (6.1%, 1.0%, 1.6%).

Rates of treatment-related discontinuations with the combination and single-agent nivolumab and ipilimumab arms were 36.4%, 7.7%, and 14.8%, respectively. Wolchok noted that there was a 68% response rate among the group of patients who discontinued the combination regimen, with half of those responses occurring after the patient stopped receiving treatment.

There was one drug-related death in each of the monotherapy arms compared with zero for those receiving the combination. “Importantly for safety, we saw no drug-related deaths with the combination, which I think is a very important point because this trial was conducted at 137 sites globally, and the safety guidelines that have been put in place along the way during the development of both ipilimumab and nivolumab clearly were able to handle the side effects as were investigators in a variety of different venues. So this treatment can be safely applied in a global setting,” said Wolchok.

At this point, ipilimumab is the only one of the two drugs with an FDA approval in the frontline melanoma setting. Nivolumab’s melanoma indication is for the treatment of patients with unresectable or metastatic melanoma following treatment with ipilimumab or a BRAF inhibitor.

At the press briefing, ASCO expert Steven J. O’Day, MD, discussed the significance of the CheckMate-067 results. “The message here is that both PD-1 monotherapy as well as the combination are doing extraordinarily well compared with ipilimumab, which was the benchmark. I think the response differences between the combo are relatively modest, but what strikes us is the progression-free survival difference between monotherapy and the combination of almost 5 months. Historically, that has correlated well with survival,” said O’Day, who is director of Clinical Research at the Beverly Hills Cancer Institute.

Asked about where the PD-1 revolution has left the CTLA-4 inhibitor ipilimumab, O’Day said, “It’s a very important target and drug in the field of melanoma and it’s not going away. I think it works differently than PD-1s…so together, they are synergistic approaches. Both will be active, the question is what sequence or combination is the best. And this combination in melanoma is incredibly promising.”

Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Efficacy and safety results from a phase III trial of nivolumab (NIVO) alone or combined with ipilimumab (IPI) versus IPI alone in treatment-naive patients (pts) with advanced melanoma (MEL) (CheckMate 067). J Clin Oncol. 2015;33 (suppl; abstr LBA1).

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