Pembrolizumab monotherapy showed promising antitumor activity in clear cell RCC in the phase II KEYNOTE-427 trial.
Pembrolizumab shows promising antitumor activity among patients with previously untreated advanced clear cell renal cell carcinoma (RCC), suggest findings from the first cohort of the single-arm, two-cohort, open-label, phase II KEYNOTE-427 study (abstract 4500). The findings were presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 1–5 in Chicago.
“Pembrolizumab showed antitumor activity as monotherapy in first-line clear cell RCC across IMDC [International Metastatic RCC Database Consortium] risk groups, with an overall response rate [ORR] of 38%,” reported lead study author David F. McDermott, MD, of the Beth Israel Deaconess Medical Center in Boston.
“The safety profile in KEYNOTE-427 was similar to the previously described safety profile for pembrolizumab in other tumor types,” he said. “Encouraging activity was also observed in key subgroups, such as IMDC intermediate- and poor-risk patients.”
IMDC favorable-risk patients saw an ORR of 32%, he noted.
The findings offer support for efforts like the currently enrolling KEYNOTE-564 trial to explore the benefits of pembrolizumab in the adjuvant setting.
KEYNOTE-427 was initiated to assess the safety and efficacy of first-line pembrolizumab monotherapy (200 mg intravenously administered every 3 weeks until progression, for up to 24 months) in previously untreated patients with histologically confirmed advanced RCC and a Karnofsky Performance Status score of at least 70%.
The study enrolled 110 patients with clear cell RCC into cohort A, of whom 49 were continuing treatment as of the database cutoff date of March 12, at a median follow-up of 12.1 months.
Sixty-one patients had discontinued participation in the trial, including 12 (10.9%) because of drug-related adverse events and 33 because of progressive disease.
Confirmed ORR by blinded independent central review was 38.2% overall (95% CI, 29.1%–47.9%) for cohort A, with best response being complete response in only 3 patients (2.7%), although 74 (67%) experienced some reduction in tumor burden, and 16 patients (14.5%) saw tumor burden reductions of at least 80%. Thirty-five patients (32%) had stable disease.
“Most responses occurred early,” McDermott said. “The median response duration has not yet been reached.”
ORR was higher in patients with programmed death ligand 1 (PD-L1)–positive tumors and tumor microenvironment cells (n = 46; ORR, 50%) compared with those with PD-L1–negative disease (n = 53; ORR, 26.4%). PD-L1 expression was unavailable for 11 patients.
The median progression-free survival (PFS) was 8.7 months, and the median overall survival was not reached.
One patient died of treatment-related pneumonitis. Nonfatal treatment-related adverse events included pruritis (any grade, 27%), fatigue (25%), diarrhea (19%), rash (15.5%), arthralgia (12.7%), and hyperthyroidism (10%). Grade 3 and 4 treatment-related toxicities included diarrhea (3.6%); colitis (2.7%); and asthenia, hepatitis, increased aspartate aminotransferase levels, hyponatremia, and hypophosphatemia (1.8% each).
The study demonstrated “very intriguing single-agent activity in clear cell RCC, especially in PD-L1–positive cases, and across all risk groups,” commented Toni K. Choueiri, MD, of the Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston.
Combining nivolumab plus ipilimumab for treatment of clear cell RCC has a longer reported median PFS (12.4 months vs 8.7 months for pembrolizumab monotherapy), Choueiri noted. “But that comes at the cost of higher rates of treatment discontinuations due to adverse events,” he pointed out.
“The study has had relatively short follow-up and some patients had tumors shrink by 80%, so some of these might become complete responses,” Choueiri noted of KEYNOTE-427.
Several other investigational immunotherapy combinations that are in phase I and II clinical testing appear to have impressive objective response rates, such as pembrolizumab plus axitinib (ORR, 73%).