Encouraging Activity Seen With Pembrolizumab in Non-Clear Cell RCC

David McDermott, MD

First-line treatment with single-agent pembrolizumab (Keytruda) induced a 24.8% overall response rate (ORR) in patients with non-clear cell renal cell carcinoma (RCC), according to findings from cohort B of the phase II KEYNOTE-427 trial that were presented during the 2019 Genitourinary Cancers Symposium.

By confirmed histology, the confirmed ORR was 25.4% in the patients with papillary histology and 34.6% in those with unclassified histology, findings from the single-arm, open-label study (NCT01853344) showed.¹In those with chromophobe histology, the ORR was 9.5%, said lead study author David McDermott, MD, during the meeting.

At a median follow-up of 11.1 months, median progression-free survival was 4.1 months (95% CI, 2.8-5.6) and the estimate for 12-month overall survival was 72%.

“We think the results support further evaluation of pembrolizumab in patients with advanced non-clear cell RCC,” said McDermott, a hematologist/oncologist at Beth Israel Deaconess Medical Center.

Clinical trial data with non-clear cell RCC are limited, as up to 80% of RCCs are of clear cell histology “so patients with non-clear kidney cancer are often excluded from clinical trials, largely based on their historical lack of response to cytokine-based immune therapy,” said McDermott. Treatment guidelines for advanced non-clear cell RCC recommend enrollment in a clinical trial or use of the VEGF inhibitor sunitinib (Sutent), based on the latter’s efficacy in clear-cell RCC.

However, there are no therapies approved by the FDA for patients with non-clear cell histology, creating “a significant unmet medical need for safe and effective treatment options for these patients,” he added.

KEYNOTE-427 is a 2-cohort study of patients with recurrent or advanced metastatic RCC, measurable disease, and a Karnofsky performance status ≥70%. No prior systemic therapy was allowed. Cohort A consisted of 110 patients with clear-cell RCC. Results from that cohort were reported at ASCO 2018, and showed that single-agent pembrolizumab induced an ORR of 42%, with a complete response (CR) rate of 2.7% and a partial response (PR) rate of 35.5%.²

Data from the 165 patients with non-clear cell histology (cohort B) were presented at the 2019 Genitourinary Cancers Symposium. Patients received pembrolizumab at 200 mg intravenously every 3 weeks for 35 cycles, approximately 2 years, or until progressive disease, unacceptable toxicity, or withdrawal. Response was assessed at week 12 and then every 6 weeks until week 54, and every 12 weeks thereafter.

Among the 41 responders overall, 8 (8%) achieved a CR as best response and 33 (20.0%) had a PR. An additional 53 patients (32.1%) had stable disease. In addition, 55.2% of the overall cohort B experienced a reduction in tumor burden, with 12.1% having a reduction in tumor burden ≥80% and 4.2% having a 100% reduction in target lesions.

Most tumor responses occurred early in the course of therapy, said McDermott. The median response duration has not been reached (95% CI, 2.8-15.2+) and the median time to response was 2.8 months (95% CI, 0.1-8.3). Further, 81.5% of patients experienced a response duration of ≥6 months.

“Complete and durable responses were seen in all histologic subgroups,” he said. By confirmed RCC histology per blinded independent central review, the CR rate was 4.2% in those with papillary histology, 4.8% in those with chromophobe kidney cancer, and 7.7% in those with unclassified histology. The PR rates in these 3 groups were 21.2%, 4.8%, and 26.9%, respectively, and the rates of stable disease were 34.7%, 47.6%, and 7.7%, respectively.

Histology, as confirmed by a central pathologist, was as follows: 71% of specimens were papillary, 13% were chromophobe, and 16% were unclassified by WHO criteria. At baseline, 68% of patients were at intermediate/poor risk by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. Further, 62% of patients were positive for PD-L1, defined as a combined positive score (CPS) &ge;1, while 35% were PD-L1-negative (CPS <1). Tissue analysis for PD-L1 status was not available for 3% of patients.

In the 53 patients in the favorable IMDC risk category, the ORR with the single-agent was 28.3% (CR, 9.4%; PR, 18.9%) compared with an ORR of 23.2% (CR, 2.7%; PR, 20.5%) in the 112 patients in the intermediate/poor IMDC risk group.

By PD-L1 expression, the ORR was 33.3% (CR, 5.9%; PR, 27.5%) in the 102 patients with CPS &ge;1 versus 10.3% (CR, 3.4%; PR, 6.9%) in those with low PD-L1 expression (CPS <1).

As of the data cutoff of September 7, 2018, treatment is ongoing in 55 patients. A total of 110 patients discontinued pembrolizumab; 15 of which discontinued due to toxicity, 76 due to progressive disease, 16 due to clinical progression, 1 per the discretion of the treating physician, and 2 patients withdrew from the trial.

Ten patients (6%) discontinued due to a treatment-related adverse event (TRAE). A TRAE of any grade was experienced by 64% of patients, with pruritus (18%), hypothyroidism (13%), fatigue (13%), and diarrhea (12%) observed as the most common events. Eighteen (11%) patients experienced grade 3-5 TRAEs. Two patients had grade 5 TRAEs; 1 had pneumonia and the other had cardiac arrest. The most common immune-mediated adverse events of any grade included hypothyroidism (15%) and hyperthyroidism (7%).

&ldquo;Pembrolizumab clearly has activity with durable responses and is certainly worthy of further study,&rdquo; said discussant Tracy L. Rose, MD, MPH, assistant professor of Medical Oncology at the University of North Carolina, Chapel Hill. &ldquo;I think it&rsquo;s now an option for non-clear cell RCCs. Response rates, however, remain inferior to that seen in clear-cell kidney cancers. We really need randomized studies to know what to do.&rdquo; PD-L1 staining as well as subtype may be predictive of response, she added, &ldquo;Although I do not think that we can use either to dictate therapy at this point.&rdquo;

References:

1. McDermott DF, Lee J-L, Ziobro M, et al. First-line pembrolizumab (pembro) monotherapy for advanced non-clear cell renal cell carcinoma (nccRCC): Results from KEYNOTE-427 cohort B.J Clin Oncol. 2019;37(suppl; abstr 546).
2. McDermott DF, Lee J-L, Szczylik C, et al. Pembrolizumab monotherapy as first-line therapy in advanced clear cell renal cell carcinoma (accRCC): Results from cohort A of KEYNOTE-427.J Clin Oncol. 2018;36(suppl; abstract 4500). doi: 10.1200/JCO.2018.36.15_suppl.4500.