A phase Ib expansion cohort of the Keynote-029 trial found that a combined regimen of pembrolizumab (Keytruda) at the standard dose (2 mg/kg) and ipilimumab (Yervoy) at a reduced dose (1 mg/kg) was safe and effective for patients with advanced melanoma.
Georgina V. Long, PhD, MBBS
A phase Ib expansion cohort of the Keynote-029 trial found that a combined regimen of pembrolizumab (Keytruda) at the standard dose (2 mg/kg) and ipilimumab (Yervoy) at a reduced dose (1 mg/kg) was safe and effective for patients with advanced melanoma. Lead investigator Georgina V. Long, PhD, MBBS, Melanoma Institute Australia and the University of Sydney, North Sydney, Australia, presented the results at the 2016 ASCO Annual Meeting.
“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 Oncol34, 2016 (suppl; abstr 9506).