Pembrolizumab/Ipilimumab Combo is Safe in Advanced Melanoma
Published Online: 6:20 PM, Tue June 14, 2016
"This combination has robust antitumor activity, as shown by a 57% overall response rate, a rate that was similar across key subgroups. Of the responding patients, 98% remained in response and 70% were progression free at 6 months."
—Georgina V. Long, PhD, MBBS
—Georgina V. Long, PhD, MBBS
Georgina V. Long, PhD, MBBS
“This combination has robust antitumor activity, as shown by a 57% overall response rate, a rate that was similar across key subgroups,” Long said. “Of the responding patients, 98% remained in response and 70% were progression free at 6 months.”
The dose expansion cohort of Keynote-029 included patients with advanced melanoma (n = 153) who could have received any number of prior therapies, but patients must not have received any prior anti-CTLA-4, PD-1, or PD-L1 therapies. The study’s primary endpoint was safety. Secondary endpoints included objective response rate (ORR), duration of response (DOR), progression free survival (PFS), and overall survival (OS).
The median follow-up, as of data cutoff on March 17, 2016, was 10.0 months (range 0.8-14.1) and the minimum follow-up was 6.0 months. Seventy-two percent of patients (n = 110) received all 4 planned ipilimumab doses. At data cutoff, pembrolizumab treatment was ongoing in about half the patients (n = 86, 56%).
Sixty-seven patients (44%) had discontinued all treatment by the time of data cutoff. The 2 main reasons included adverse events (AEs) (n = 31) and disease progression (n = 29). Three patients discontinued treatment because they achieved a complete response (CR).
At baseline, the median age of study participants was 60 (range 22-82), nearly two-thirds of the patients were men (n = 101, 66%), and about one-fourth (n = 37, 24%) had elevated lactate dehydrogenase (LDH) levels. The group was largely treatment naïve, with only 20 patients (13%) having received prior therapy. The vast majority of patients were PD-L1-positive (n = 127, 83%), while 55 patients (36%) had a BRAF-V600 mutation.
Long and her colleagues analyzed both treatment-related and immune-mediated AEs. Nearly all patients (n = 145, 95%) experienced a treatment-related AE of any grade, while just over half (n = 89, 56%) experienced an immune-related AE. Sixty-four patients (42%) had a grade 3/4 treatment-related AE, and 38 patients (25%) experienced a comparable immune-related AE. No adverse events of any kind led to patient death.
Some AEs led to ipilimumab discontinuation (treatment-related: n= 16, 10%; immune-related: n = 12, 8%). Pembrolizumab had a lower discontinuation rate with 11 patients (7%) discontinuing due to treatment-related AEs and 6 patients (4%) stopping due to immune-related AEs. Sixteen patients (10%) discontinued the combined regimen due to treatment-related AEs and 11 patients (7%) due to immune-related AEs.
In all, 9 treatment-related AEs affected 15% or more of the study population. Fatigue was the most common AE (n = 70, 46%), followed by both pruritus and rash (n = 59, 39% each). About one-fourth of patients (n = 36, 24%) had diarrhea, but only 1 patient had severe diarrhea. “However, 14% of patients experienced a grade 3/4 raise in their lipase. This was asymptomatic in a majority of cases, with no sequelae,” Long noted.
Regarding immune-mediated AEs, 58% of patients experienced at least one, while 25% had a grade 3/4 AE. As expected, hyperthyroidism, hypothyroidism, and hypophysitis were the most common, though nearly all cases were grade 1/2. Hepatitis, colitis, and skin reactions had lower incidence rates, but they also had the highest percentage of grade 3/4 immune-related AEs.
In looking at the number of immune-mediated events per patient of any grade, Long shared the following distribution: 42% experienced 0 immune events, 31% had 1 immune-related events, 19% had 2 events, 7% had 3 events, and only 1% had 4 AEs. Additionally, 75% of patients did not experience any grade 3/4 immune-mediated events. Twenty-two percent of patients experienced 1 grade 3/4 immune-mediated event, 2% had 2 and less than 1% had 4 serious immune-related AEs.
Out of 145 total immune-mediated AEs, 57% were treated with systemic corticosteroids, 7% with infliximab, and 4% with other immunosuppressants. Three quarters (76%) of any grade immune-mediated AEs had resolved at data cutoff, as did 81% of serious AEs. Long emphasized that these data referred to the total number of events, not the number of patients.
Despite the adverse events, the combination of standard-dose pembrolizumab and lower-dose ipilimumab appeared tolerable. Of the total study population (n = 153), the ORR was 57% (95% CI, 49%-65%) according to RECIST v1.1, independent central review. The disease control rate, or the rate of complete responses, partial responses (PR), and stable diseases (SD), was 78% (95% CI, 71%-85%). Overall, 15 patients (10%) had CR, 72 (47%) had PR, 33 (22%) had SD, and 30 (20%) had progressive disease. Post-baseline scans were not performed on 3 of the patients (2%).
“Eighty-five of the 87 responders, that’s 98% of patients who had responded, had maintained their response at the time of data cut,” Long said. “And 81% of patients experienced some tumor size reduction with a median change of -54.5%.”
The Kaplan-Meier PFS curve demonstrated that 70% of patients were progression free at 6 months. With 49 events (32%) the median has not been reached. The Kaplan-Meier OS curve showed that 93% of patients were alive at 6 months. With 16 events (10%), the median has not been reached.
Long GV, Atkinson V, Cebon JS, et al. Pembrolizumab (pembro) plus ipilimumab (ipi) for advanced melanoma: Results of the KEYNOTE-029 expansion cohort. J Clin Oncol 34, 2016 (suppl; abstr 9506).