While immunotherapy has made quite an impact on the treatment of renal cell carcinoma, most of these tumors are have a clear cell histology, and patients with non-clear cell renal cell carcinoma (nccRCC) are often excluded from clinical trials.
Now, one of the first trials in this specific patient population has shown promising activity with monotherapy with pembrolizumab (Keytruda, Merck).
"The overall response rate was approximately 25%, and for those with papillary disease it was also 25%, while with unclassified histology, it was slightly higher at 35%," said lead author David F. McDermott, MD, director of the Biologic Therapy Program at Beth Israel Deaconess Medical Center, Boston, Massachusetts. "The safety profile was generally as expected, based on previously described safety profiles of pembrolizumab in other tumor types."
McDermott presented the results of the study here at the Genitourinary Cancers Symposium (GUCS) 2019.
He noted that as most renal cell carcinomas are clear cell in origin, study data directing treatment for other histologies are limited, and patients with nccRCC are often excluded from clinical trials.
"FDA-approved therapies for this population are limited, and there is a significant unmet need for safe and effective therapies for patients with non-clear cell renal cell carcinoma," he commented.
Antitumor Activity in Clear Cell RCC
The new results come from the KEYNOTE-427, a single-arm, open-label, two-cohort, phase 2 study in advanced treatment-naïve RCC.
Cohort A comprised 110 patients with clear cell RCC, and here single agent pembrolizumab demonstrated promising antitumor activity when used first line. These results were reported at the 2018 annual meeting of the American Society of Clinical Oncology, and showed an objective response rate (ORR) of 42%, with a complete response rate of 2.7% and a partial response rate of 35.5%. (J Clin Oncol.2018;36:suppl; abstract 4500).
At this meeting, McDermott presented the results from cohort B, which enrolled 165 patients with histologically confirmed nccRCC.
Of this group, 71% had papillary RCC, 13% were chromophobe, and 16% were unclassified by WHO criteria; about one third (32%) had favorable risk disease while 68% were intermediate/poor. Of the patients who had tumor tissue available for testing PD-L1 status, 62% of patients were positive for PD-L1 (CPS ≥1) and 35% were PD-L1-negative (CPS <1 p="">
At a median follow up of 11.1 months, the ORR was 24.8% for the overall cohort, with eight complete responses (4.8%), and 33 partial responses (20%). The median duration of response has not been reached.
When categorized by histology, the ORR for papillary RCC was 25.4% (95% confidence interval [CI], 17.9 -34.3), 9.5% with chromophobe, and 34.6% for unclassified nccRCC.
Among patients with favorable risk, the ORR was 28.3%; among patients with intermediate/poor IMDC risk, ORR was 23.2%; and among patients with CPS≥1 and CPS<1 10.3="" 33.3="" and="" orr="" p="" respectively.="" was="">
"The median progression-free survival was 4.1 months in the cohort and the median overall survival has not been reached," said McDermott. "In addition, 55% experienced a reduction in tumor burden, and 12% experienced a reduction of 80% or more, and 4.2% had a reduction in tumor burden of 100%."
As of the data cutoff of September 7, 2018, treatment is ongoing in 55 patients.
Almost two thirds (64%) of patients experienced treatment-related adverse events of any grade and the most common grade 3 to 5 events were colitis; hepatitis and fatigue; and type 1 diabetes mellitus. The most common immune-mediated adverse events of any grade included hypothyroidism (15%) and hyperthyroidism (7%). Two patients experienced grade 5 events, pneumonia and cardiac arrest.
"These results support further evaluation of pembrolizumab in patients with advanced non-clear cell RCC," McDermott concluded.
Randomized Trials Needed
In a discussion of the paper, Tracy L. Rose, MD, assistant professor of medical oncology at the University of North Carolina, Chapel Hill, noted that "this is the first prospective data that we have of immune checkpoint inhibition in non-clear cell RCC."
"Pembrolizumab clearly has activity with durable responses and is certainly worthy of further study," she said, "And [it] is now an option for non-clear cell RCCs."
Rose pointed out, however, that the response rates are inferior to those seen in clear cell kidney cancers. "We really need randomized studies to know what to do," she added. "PD-L1 staining as well as subtype may be predictive of response, although I don't think that we can use either to dictate therapy at this point."
The study was funded by Merck Sharp & Dohme Corp. McDermott has disclosed consulting or advisory roles with Array BioPharma, Bristol-Myers Squibb, Exelixis, Genentech/Roche, Merck, Novartis, Pfizer, and X4 Pharma. McDermott has also disclosed research funding from Bristol-Myers Squibb and Prometheus Laboratories (Inst). Rose has disclosed relationships with BMS, Genentech/Roche, GeneCentric, and X4 Pharmaceuticals.
Genitourinary Cancers Symposium (GUCS) 2019: Abstract 546. Presented February 16, 2019.
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