Combos Mark Next Step in Melanoma Immunotherapy

Gina Columbus @ginacolumbusonc | February 27, 2017
Tara C.
Gangadhar, MD

Tara C. Gangadhar, MD

Evidence continues to build for the long-term efficacy of PD-1–targeting immunotherapies in melanoma, including fresh data indicating when patients can stop taking the drugs and still maintain a response, according to Tara C. Gangadhar, MD. The future will bring an increased focus on novel combinations and more informative biomarkers.

Those insights were among the observations that Gangadhar made during a presentation at the 13th Annual International Symposium on Melanoma and Other Cutaneous Malignancies® that Physicians’ Education Resource® (PER®) hosted in Sunny Isles Beach, Florida, on February 11.

Single-agent PD-1 blockade with nivolumab (Opdivo) or pembrolizumab (Keytruda) has become a standard- of-care first-line option for patients with metastatic or unresectable melanoma in the National Comprehensive Cancer Network guidelines, noted Gangadhar.

“Ongoing clinical trials will likely lead to improved combination regimens with improved toxicity profiles and, most importantly, individualizing combination therapy remains a challenge and an area of active research,” said Gangadhar, an assistant professor of medicine at Abramson Cancer Center at the University of Pennsylvania.

Reflecting on 2016 clinical findings and FDA approvals, Gangadhar said that pembrolizumab, nivolumab, the PD-L1 inhibitor atezolizumab (Tecentriq), the oncolytic virus talimogene laherparepvec (T-VEC; Imlygic), and the CTLA-4 inhibitor ipilimumab (Yervoy), have all demonstrated encouraging and durable responses, which have been confirmed with longer follow-up. The question is where the field will go next.

Single-Agent PD-1 Inhibitor Efficacy

Long-term follow-up from the phase I KEYNOTE- 001 trial, in which patients were randomly assigned to receive pembrolizumab or ipilimumab, demonstrated that those who received pembrolizumab had an improvement in survival versus those who had treatment with the CTLA-4 inhibitor.1

“We’ve had the opportunity to get longer survival data on these single agents since the first drugs entered clinical trials in 2010 and 2011,” Gangadhar said. “Going back to the phase I study of pembrolizumab that accrued 655 patients, we saw in 2016 that the 2-year survival was 50% and the 3-year survival was 40%. These patients treated with pembrolizumab were patients either with or without prior therapy.”

“In the subset of 152 patients who were treatment- naïve, there was a 2-year overall survival [OS] rate of 61% and a 3-year OS rate of 45%,” she added. “The big question, in our clinical practice, is: can we stop therapy?”

Additionally, Gangadhar noted that patients enrolled on the initial pembrolizumab trial achieved a complete response (CR), with the majority of patients responding at the 9- or 12-week mark of their first imaging assessment. “In all of the patients except for 2, the response was ongoing after stopping pembrolizumab,” said Gangadhar. “We now know we can stop PD-1 blockade after a confirmed CR. In this case, 97% of patients will have an ongoing CR that is durable after stopping therapy.“

Dual Checkpoint Therapy

Immunotherapy combination regimens for patients with melanoma were investigated as frontline treatment in the randomized, doubleblind, multicenter, phase III CheckMate-067 trial.2 Here, nivolumab and ipilimumab were explored as monotherapy and in combination in a 1:1:1 ratio in a total 945 patients. They were treated with nivolumab alone (n = 316), nivolumab plus ipilimumab followed by nivolumab alone (n = 314), or ipilimumab alone (n = 315), with the co-primary endpoints being progression-free survival (PFS) and OS.

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, the agency approved the combination and single-agent nivolumab for BRAF V600 wild-type patients with advanced melanoma.

Eighteen-month follow-up results of the CheckMate-067 study were presented during the 2016 ASCO Annual Meeting.3 Findings showed that the combination arm led to a 58% reduction in the risk of disease progression compared with ipilimumab monotherapy in advanced melanoma. Additionally, single-agent nivolumab lowered the risk of progression by 45% compared with ipilimumab alone.

Moreover, the 18-month PFS rates were 46% for the combination arm, 39% for the nivolumab-alone arm, and 14% for the ipilimumab-alone arm. The overall response rates (ORR) with the combination and nivolumab alone were 58% and 44%, respectively, versus 19% with ipilimumab monotherapy (P <.0001). The CR rates were 12% (n = 38), 10% (n = 31), and 2% (n = 7), respectively.


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