Pembrolizumab Continues to Demonstrate Long-Term Efficacy in Melanoma

Eric Whitman, MD

The PD-1 inhibitor pembrolizumab (Keytruda) continues to be a promising frontline immunotherapy option for patients with advanced melanoma, according to a presentation by Eric Whitman, MD, at the 14th Annual International Symposium on Melanoma and Other Cutaneous Malignancies.

Whitman, medical director of Atlantic Health System Cancer Care and director of the Atlantic Melanoma Center, cited the final results from the phase III KEYNOTE-006 study, which randomized 834 patients with unresectable stage III or stage IV advanced melanoma to 4 cycles of ipilimumab (Yervoy) at 3 mg/kg every 3 weeks (n = 278); 10 mg/kg of pembrolizumab every 3 weeks (n = 277); or 10 mg/kg of pembrolizumab every 2 weeks (n = 279).¹

Patients enrolled on the multicenter, open-label, randomized study previously received either 0 or 1 prior lines of therapy, excluding immunotherapy with CTLA-4, PD-1, or PD-L1 inhibitors. Of the overall patient population, 65.8% did not receive prior systemic treatment for their advanced melanoma. About 80% of the patients involved had positive PD-L1 staining, 18% had negative staining, and 2% of the population was unknown. Patients also had an ECOG performance status of 0 or 1.

Results from the trial showed that overall survival (OS)-which was a primary endpoint-was superior in both pembrolizumab arms compared with the ipilimumab arm. The 12-month OS rate was 74% for patients who had pembrolizumab every 2 weeks, 68% for patients who had pembrolizumab every 3 weeks, and 59% for patients receiving ipilimumab. At the 2-year mark, both pembrolizumab arms had a 55% OS rate versus 43% for those in the ipilimumab arm. The median OS at 2 years was not reached for either pembrolizumab treatment arm compared with 16 months for the ipilimumab arm (HR, 0.68; 95% CI, 0.53-0.87 for pembrolizumab every 2 weeks vs ipilimumab; P = .0009 and HR, 0.68; 0.53-0.86 for pembrolizumab every 3 weeks vs ipilimumab; P = .0008).

The overall response rate (ORR) was 37% for patients receiving pembrolizumab every 2 weeks, 36% for the every-3-week regimen, and 13% with ipilimumab (P <.001). The complete response (CR) rates were 12%, 13%, and 5%, respectively.

Based on the primary findings of this trial, the FDA approved pembrolizumab in December 2015 for the frontline treatment of patients with advanced melanoma, regardless of whether or not they harbor a BRAF mutation.

"The two different doses of [pembrolizumab] don't seem to matter," Whitman said, but added that this dosage information is essential for physicians to know when prescribing to their patients.

"There's an obvious survival benefit," Whitman added. "You can't underestimate this. When you're going to talk to a patient…there is nothing better than to be able to say, 'Statistics show that treating you with this is better than not treating you with this or treating you with the alternative examined in the trial. You have a reduced risk of dying. And, that is why they're sitting in your office-they're talking about how they want to live."

Aside from the efficacious outcomes with pembrolizumab, the safety profile is acceptable; however, Whitman emphasized commonly reported adverse events (AEs) such as diarrhea, colitis, and pneumonitis that are associated with the PD-1 inhibitor that need to be reported to physicians as early as possible.

"I tell patients they will get some side effects and likely be able to deal with them," Whitman said, referring to other side effects, such as fatigue and rash. "But there are side effects that they need to tell us about, because if you allow them to go on, patients will end up in the hospital-or worse, with one of my surgical colleagues."

Not only will early intervention help decrease the chance that the diarrhea, colitis, and pneumonitis will become grade 3/4 AEs, but also, treatment could be altered to stop the side effects, Whitman explained.

"Patients think that the worst thing that's going to happen to them is their treatment being stopped. If, for any reason treatment is stopped, they may think they're going to die," Whitman said. "However, by working with immunotherapy, we know that is not the case. It may only take 1 or 2 doses for the patient to live. The immune system will figure it out."

Moreover, according to findings from the KEYNOTE-006 trial, a greater exposure to pembrolizumab was not associated with higher toxicity. Grade 3/4 toxicities were seen in 17% of patients on the pembrolizumab arm compared with 20% on the ipilimumab arm.

Overall, Whitman said physicians must educate typical immune-related AEs to patients, which differ from those associated with chemotherapy as it has a very different mechanism of action.

"What we are really trying to do with this drug is teach your immune system to do what it failed to do: recognize and kill the melanoma," he said.

Pembrolizumab continues to be explored in other settings in melanoma. For example, the PD-1 inhibitor is being explored in combination with the IDO1 inhibitor epacadostat in the phase III (KEYNOTE-252 / ECHO-301) trial in patients with metastatic or unresectable melanoma. Phase I findings in the KEYNOTE-037 trial exploring this regimen showed that the combination demonstrated an ORR of 56% with a CR rate of 13%.²

Another combination involves pembrolizumab with talimogene laherparepvec (T-VEC; Imlygic), early results of which were seen from the phase I MASTERKEY-265 study. Here, the regimen had an ORR of 62% with a CR rate of 33%. The median PFS has not yet been reached.³ The KEYNOTE-034 trial continues to assess pembrolizumab and T-VEC (NCT02263508), along with a phase III expansion cohort of the MASTERKEY-265 trial (NCT02263508).

References

1. Schachter J, Ribas A, Long GV, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet Oncol. 2017;390(10105):1853-1862. doi: 10.1016/S0140-6736(17)31601-X.
2. Hamid O, Gajewski TF, Frankel AE, et al. Epacadostat plus pembrolizumab in patients with advanced melanoma: Phase 1 and 2 efficacy and safety results from ECHO-202/ KEYNOTE-037. In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract 1214O.
3. Ribas A, Dummer R, Puzanov I, et al. Oncolytic virotherapy promotes intramoral T cell infiltration and improved anti-PD-1 immunotherapy. Cell. 2017. doi: http://dx.doi.org/10.1016/j.cell.2017.08.027