Pembrolizumab plus reduced-dose ipilimumab confers durable antitumor activity in advanced melanoma

CHICAGO — The combination of standard-dose pembrolizumab and low-dose ipilimumab led to robust and durable antitumor activity with a manageable safety profile in patients with advanced melanoma, according to mature data from KEYNOTE-029.

Perspective from Shailender Bhatia, MD

“The main question we asked was, ‘Can we get the efficacy of standard-dose ipilimumab [Yervoy, Bristol-Myers Squibb] with low-dose PD-1, but with less toxicity, by changing the ratios?’” Matteo S. Carlino, MBBS, PhD, clinical senior lecturer in Westmead Clinical School of The University of Sydney and oncologist in the department of medical oncology at Westmead Hospital, told HemOnc Today.

Earlier results from the trial showed standard-dose pembrolizumab (Keytruda, Merck) with reduced-dose ipilimumab was safe and effective in patients with advanced melanoma.

Carlino and colleagues conducted extended follow-up of KEYNOTE-029 and landmark 1-year OS and PFS analyses.

The analysis included 153 patients (median age, 60 years; 66% men) who received 2 mg/kg pembrolizumab and 1 mg/kg ipilimumab every 3 weeks for four doses, followed by pembrolizumab alone for up to 2 years. Safety served as the primary endpoint. Secondary endpoints included overall response rate, PFS and duration of response.

Fifty-six percent of patients had stage M1c disease and 36% harbored BRAF V600 mutations. Thirteen percent of patients at least one prior therapy.

Median follow-up was 17 months, at which time 64 patients (42%) remained on pembrolizumab.

Most patients (72%) received all four doses.

During the additional 7 months of follow-up, six more patients achieved a response for an ORR of 61% (95% CI, 53-69). The complete response rate increased from 10% to 15%.

Median duration of response had not been reached (range, 1.6+ to 18.1+ months).

Most responders (92%) remained alive without progressive disease, including all 23 patients with a complete response.

Sixty-nine percent of patients achieved 1-year PFS and 89% achieved 1-year OS; median PFS and OS had not been reached.

“The efficacy looks comparable to other doublets,” Carlino said. “However, it appears slightly less toxic than the other ratio of high-dose ipilimumab, low-dose pembrolizumab.”

No treatment-related deaths occurred.

All patients experienced a treatment-related adverse event, including 45% who experienced a grade 3 or grade 4 event. Adverse events led to discontinuation of the combination in 11% of patients, ipilimumab alone in 7%, and pembrolizumab alone in 12%. Four of 17 patients who discontinued the combination and one of 11 who discontinued ipilimumab alone experienced progressive disease.

PAGE BREAK

Immune-mediated adverse events occurred in 59% of patients, including 25% with grade 3 or grade 4 events.

“The next question we want to address is whether we can give even less ipilimumab,” Carlino said. “How far can you go without losing the efficacy? Next we are texting 15 mg/kg of ipilimumab every 6 weeks, or 100 mg/kg every 12 weeks. We hypothesize to see a response rate of 60% again, but with even less toxicity.” – by Alexandra Todak

Reference:

Carlino MS, et al. Abstract 9545. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.

Disclosure: Carlino reports honoraria from Bristol-Myers Squibb, Merck and Novartis, as well as consultant/advisory roles with Amgen, Bristol-Myers Squibb, Merck and Novartis. Please see the abstract for a list of all other researchers’ relevant financial disclosures.

Perspective

Shailender Bhatia, MD

The study results show that combining low-dose ipilimumab (Yervoy, Bristol-Myers Squibb) at 1 mg/kg with the standard dose of PD-1 blockade with pembrolizumab (Keytruda, Merck) has a manageable toxicity profile and robust activity. We know from the results of other trials that ipilimumab plus PD-1 blockade combination, specifically with nivolumab (Opdivo, Bristol-Myers Squibb), improves the response rate; however, the improved response rates come at the cost of significantly increased toxicity. The combination of ipilimumab plus nivolumab is already approved for melanoma but in the combination, ipilimumab is given at 3 mg/kg. This trial adds to the rapidly accumulating literature that perhaps a lower dose of ipilimumab at 1mg/kg may strike the right balance with enhanced immune activation and a somewhat better toxicity profile.

Shailender Bhatia, MD

Seattle Cancer Care Alliance

University of Washington

Disclosures: Bhatia reports institution research support from Bristol-Myers Squibb, EMD-Serono, Immune Design, Merck, NantKwest and Oncosec; an unpaid advisory board position for EMD-Serono; and honorarium from Genentech.