Long-Term Follow-up Sustains Frontline Nivolumab/Ipilimumab Benefit in Melanoma

Jedd D. Wolchok, MD, PhD

At a minimum follow-up of 18 months, the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) reduced the risk of disease progression by 58% compared with ipilimumab alone, and single-agent nivolumab lowered the risk of progression by 45% versus ipilimumab monotherapy in patients with advanced melanoma.

In the long-term findings from the phase III CheckMate-067 trial, which were presented at the 2016 ASCO annual meeting, the 18-month progression-free survival (PFS) rates for the combination, single-agent nivolumab, and ipilimumab monotherapy regimens were 46%, 39%, and 14%, respectively.

“The combination of nivolumab plus ipilimumab and nivolumab alone each significantly improved progression-free survival and objective response rates compared with ipilimumab alone in patients with previously untreated metastatic melanoma,” lead author Jedd D. Wolchok, MD, PhD, said when presenting the data at ASCO.

“The combination resulted in numerically longer progression-free survival and a higher response rate when compared with nivolumab monotherapy in the intention to treat analysis, as well as in subgroups with poor prognostic factors,” added Wolchok, who is chief of the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center.

In the 3-arm, double blind phase III CheckMate-067 trial, 945 patients with untreated unresectable or metastatic melanoma were randomized to receive nivolumab (n = 316), ipilimumab (n = 315), or nivolumab plus ipilimumab followed by nivolumab alone (n = 314). In the monotherapy arms, nivolumab was administered at 3 mg/kg every 2 weeks and ipilimumab was administered at 3 mg/kg every 3 weeks. In the combination arm, nivolumab at 1 mg/kg was administered with 3 mg/kg of ipilimumab every 3 weeks for 4 doses followed by 3 mg/kg of nivolumab every 2 weeks.

Treatment was administered until progression or unacceptable toxicity. The coprimary endpoints of the trial were PFS and overall survival. Secondary outcome measures included objective response rate (ORR) and safety.

At a follow up of ≥18 months, the median PFS with nivolumab/ipilimumab was 11.5 months (95% CI, 8.9-16.7) versus 2.9 months (95% CI, 2.8-3.4) with single-agent ipilimumab (HR = 0.42; 99.5% CI, 0.31-0.57; P <.0001). The median PFS was 6.9 months (95% CI, 4.3-9.5) with single-agent nivolumab (HR versus ipilimumab monotherapy = 0.55; 99.5% CI, 0.43-0.76; P <.0001).

These median PFS data “Are not changed from the prior [CheckMate-067] analysis presented at ASCO 2015,” said Wolchok. The overall survival data are still immature.

The PFS benefit with the combination and single-agent nivolumab versus ipilimumab monotherapy was upheld across all patient subgroups. “Similar results were also observed with objective response rates across the same subgroups,” said Wolchok.

The ORR with the combination and nivolumab alone were 58% and 44%, respectively, versus 19% with ipilimumab monotherapy (P <.0001). The complete response rates were 12% (n = 38), 10% (n = 31), and 2% (n = 7), respectively. The partial response rates were 46% (n = 143), 34% (n = 107), and 17% (n = 53), respectively.

At a median follow-up of 20.7 months, the median duration of response had not yet been reached for the nivolumab/ipilimumab group, and was 22.3 and 14.4 months, respectively, for single-agent nivolumab and ipilimumab monotherapy arms. Tumor burden decreased by 51.9% and 34.5% in the combination and single-agent nivolumab arms, respectively, and increased by 5.9% with ipilimumab alone.

“While the response rates have not changed [since the previous data analysis], some partial responses have evolved into complete responses over time,” said Wolchok.

He also noted that in descriptive analyses, the risk of progression for the nivolumab plus ipilimumab combination group was reduced by 24% when compared with nivolumab alone, and the response rate for the combination was numerically higher than for the single-agent nivolumab group.

PD-L1 status was also assessed in CheckMate-067, with PD-L1 positivity defined as an expression level ≥5%. In patients with PD-L1 expressions levels <5%, the median PFS for the combination was 11.1 months compared with 5.3 months with single-agent nivolumab and 2.8 months with ipilimumab alone.

However, Wolchok noted that “In patients with at least 5% PD-L1 expression, PFS appeared comparable in the nivolumab alone and the nivolumab plus ipilimumab combination groups, with a hazard ratio of 0.87.” In the original analysis performed last year, the hazard ratio for this comparison was 0.96, with a 14-month median reported for both subgroups. With the current analysis, the median for the combination group has still not yet been reached, while the median is 22 months for nivolumab monotherapy. “This indicates the very dynamic nature of these curves, even with over 20 months of follow-up,” said Wolchok.

Unlike with the PFS results, Wolchok said, “It’s clear that treatment with the nivolumab plus ipilimumab combination resulted in a numerically higher objective response rate compared with nivolumab alone, regardless of PD-L1 expression.” In PD-L1&shy;—positive patients, the ORR was 72% with the combination compared with 57.5% in the single-agent nivolumab group.

At the long-term follow-up, the safety profile for the combination regimen was similar to previously reported adverse event (AE) data for nivolumab plus ipilimumab, with no new safety signals. Wolchok noted that “There is no common signature adverse event for this combination.”

The majority of AEs related to therapy were manageable with immune-modulating medications. “However, as observed in prior studies, most of the endocrine events did not resolve, and required hormone replacement,” said Wolchok.

The most frequently reported all-grade AEs with nivolumab/ipilimumab versus ipilimumab alone included increased ALT levels (17.9% vs 3.9%), increased AST levels (15.7% vs 3.9%), diarrhea (45.4 % vs 33.8%), colitis (11.5% vs 11.3%), rash (28.4% vs 21.2%), pruritus (35.1% vs 36.3%), hypothyroidism (16% vs 4.5%), hyperthyroidism (10.2% vs 1%), elevated creatinine (4.2% vs 1.6%), and pneumonitis (6.7% vs 1.6%).

The rate of grade 3/4 AEs was higher with the combination (56.5%) versus single-agent nivolumab (19.8%) and ipilimumab alone (27%). The rates of discontinuation due to treatment-related AEs were 38.7%, 10.5%, and

Treatment-related AEs of any grade led to discontinuation in 38.7% of patients treated with the combination regimen, 10.5% for patients treated with nivolumab monotherapy, and 15.4% of patients treated with ipilimumab alone.

“Interestingly, 68% of these patients who discontinued due to treatment-related AEs developed a response, and 50% of these responses occurred after treatment had ended. This is very important information for us as we talk with patients and their families about the difficulties of stopping treatment,” said Wolchok.

There were no treatment-related deaths among patients receiving the nivolumab/ipilimumab combination; however, there was 1 death reported for each of the single-agent arms.

The initial data from the CheckMate-067 trial formed the basis of the FDA’s January 2016 approval of the nivolumab/ipilimumab combination and nivolumab monotherapy for the first-line treatment of patients with advanced melanoma harboring BRAF V600 mutations. Prior to that indication, the FDA had approved the combination and single-agent nivolumab for BRAF V600 wild-type patients with advanced melanoma.

Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Updated results from a phase III trial of nivolumab (NIVO) combined with ipilimumab (IPI) in treatment-naïve patients (pts) with advanced melanoma (MEL) (CheckMate 067). J Clin Oncol 34, 2016 (suppl; abstr 9505).

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