Adjuvant PD-1 Inhibition on Horizon in Melanoma

June 30, 2017

Paul Lorigan, MD

Several clinical trials are examining the use of adjuvant PD-1 inhibition for patients with melanoma, with a potential new standard of care on the horizon for those at high risk of recurrence following resection, according to Paul Lorigan, MD, at the 2017 European Post-Chicago Melanoma/Skin Cancer Meeting in Munich, Germany.

“It’s likely there will be a new standard of care for adjuvant therapy within the next 3 to 5 years,” said Lorigan, Professor of Medical Oncology, Melanoma, University of Manchester, Manchester, United Kingdom. “This might be PD-1 inhibitors alone, PD-1 combinations, or BRAF combinations.”

The PD-1 inhibitors, such as nivolumab (Opdivo) and pembrolizumab (Keytruda), have rapidly become the standard of care for metastatic melanoma, due to having a favorable ratio of activity to toxicity. It is intuitive to explore PD-1 inhibitors in the adjuvant setting, given the activity and FDA approval of the CTLA-4 inhibitor ipilimumab (Yervoy), Lorigan added.

Some of the challenges of assessing PD-1 inhibitors in the adjuvant setting include choosing a comparator arm, due to the standard of care being unclear, patient selection, unexpected toxicity, and deciding how long to treat the patient. Another challenge is presented by the selection of a meaningful primary endpoint, whether that be overall survival (OS) or recurrence-free survival (RFS). “OS was the gold standard until 2010 but now is increasingly difficult to show with the advent of potent new salvage therapies,” said Lorigan. Disease-free survival is another goal of adjuvant therapy as patients value their time without disease and also consider it a ‘bridge’ to better treatments in the future, he added.

Based on aggregated data, Lorigan said “for CTLA-4 inhibitors it is likely RFS predicts for OS. If you go for a leap of faith you might say that for immunotherapy treatment with checkpoint inhibitors there is a signal. But that remains to be seen of course.”

To potentially provide the answers to these questions, Lorigan highlighted 4 pivotal, phase III trials evaluating PD-1 inhibitors in the adjuvant setting:

SWOG S1404 is comparing pembrolizumab at 200 mg every 3 weeks for 1 year with physician’s choice, which could consist of ipilimumab at 10 mg/kg or high-dose interferon alfa-2b, for patients with high-risk resected melanoma that is stage IIIa (N2a), IIIb/c, or IV with no evidence of disease (NED) following surgery. The coprimary endpoints are OS and RFS in the overall population and in a PD-L1—positive subgroup (NCT02506153).
CheckMate 238 is comparing nivolumab with ipilimumab in patients with resected stage IIIb/c melanoma or stage IV with NED who are at high risk of recurrence. The primary endpoint is RFS (NCT02388906).
KEYNOTE-054 aims to address the question of whether adjuvant pembrolizumab is more effective than pembrolizumab in the metastatic setting in patients with resected stage III a/b/c melanoma. Co-primary endpoints are RFS in the overall study population and in patients with PD-L1—positive tumors (NCT02362594).
CheckMate-915 is exploring nivolumab plus ipilimumab versus ipilimumab alone or nivolumab alone for patients with completely resected stage IIIb/c/d or stage IV melanoma (NCT03068455).

PD-L1 testing has been incorporated into all current studies, suggesting there should be a substantial accumulation of data over the next few years on the effectiveness of this marker, Lorigan noted. Additionally, he added, molecular profiling has potential to provide a further level of discrimination. The most mature data for molecular testing in the adjuvant space come from the DecisionDX gene expression profile test, which is based on a panel of 31 genes; however, at this time, “there is no evidence yet that molecular profiling is predictive,” Lorigan noted. “Unlike the Oncotype DX test in breast cancer, molecular profiling in melanoma so far is purely prognostic.”

There have been signs that mutations play a role in outcomes. The adjuvant phase III AVAST-M study showed intriguing prognostic differences in outcomes for patients with various mutations. In this phase III trial, the VEGF inhibitor bevacizumab (Avastin) was compared with observation for patients with melanoma at high risk of recurrence. Patients received bevacizumab at a dose of 7.5 mg/kg every 3 weeks for 1 year.

In the final analysis, OS by BRAF and NRAS status was evaluated for those in the bevacizumab arm. Patients with BRAF-mutant melanoma tended to have a longer disease-free interval (DFI) and OS compared with wild-type individuals (DFI hazard ratio [HR], 0.79; 95% CI, 0.58-1.08; P = .14; OS HR, 0.79; 95% CI, 0.55-1.13; P = .20). However, patients with NRAS-mutant melanoma tended to have a shorter DFI (HR, 1.39; 95% CI, 1.03-1.88; P = .03) and OS (HR, 1.18; 95% CI, 0.88-1.62; P = .20), when compared with the NRAS wild type group.

In the future, Lorigan anticipates greater usage of circulating tumor DNA for molecular testing, with a focus on patient selection.

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Another challenge is being able to determine whether or not it is better to treat the patient in the adjuvant setting or to wait and administer the treatment as salvage therapy. “There’s a suggestion that due to the primed immune system you get more toxicity in the adjuvant setting than in the advanced disease setting,” said Lorigan.