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New Option in Advanced Non-Clear Cell Kidney Cancer

SAN FRANCISCO — First-line pembrolizumab (Keytruda) in advanced non-clear cell renal cell carcinoma (RCC) yielded promising antitumor activity and should be considered an option for these patients, according to researchers here.

In cohort B of the KEYNOTE-427 trial, the confirmed overall response rate (ORR) with the anti-PD-1 checkpoint inhibitor was 24.8% (95% CI 18.5%-32.2%), reported David McDermott, MD, of Beth Israel Deaconess Medical Center in Boston, at the Genitourinary Cancers Symposium.

Among the 165 patients in the single-arm trial, eight achieved a complete response (4.8%), 33 had partial responses (20.0%), and the disease control rate was 40.6%.

“We think the results here support further evaluation of pembrolizumab in patients with advanced non-clear cell kidney cancer,” McDermott said during his presentation.

Most tumor responses occurred early (median 2.8 months), and 81.5% of responses lasted 6 months or longer. Some remained durable even after treatment cessation. Median duration of response was not reached. In all, 12.1% of patients had tumor reductions of 80% or more.

Bernard Escudier, MD, of Gustave Roussy Cancer Campus in Villejuif, France, commented from the audience that for him, the study has set a “new bar” in non-clear cell RCC, and asked what the next path forward would be for pembrolizumab in this setting.

“Do we do need a randomized trial to get pembro approved for our patients with non-clear cell kidney cancer? I would argue that we don’t,” McDermott responded.

“I think pembro should become available,” he said. “If not approved, then certainly through the guidelines.”

“I think it’s now an option for non-clear cell kidney cancers,” said discussant Tracy Rose, MD, MPH, of the University of North Carolina at Chapel Hill. “PD-L1 staining as well as subtype may be predictive of response, although I do not think we can use either to dictate therapy at this point.”

An exploratory analysis found that expression of PD-L1 (the protein to which PD-1 attaches) was associated with better responses. The ORR was 33.3% for patients in the PD-L1–high group (≥1%) compared with 10.3% in the PD-L1–low group (<1%). As most patients in the trial were PD-L1–positive (62%), Rose said clinicians can assume that the majority of their patients are in this higher-responding group.

With regard to histology, ORRs were 25.4% among the 118 patients with papillary subtype, 9.5% in the 21 patients with chromophobe RCC, and 24.6% in the 26 patients with unclassified histology, as defined by World Health Organization criteria. Complete responses were seen in all three groups.

Rose highlighted that even within the lowest-performing group — the chromophobe subtype — the disease control rate was 33%, a “histology which has been historically very hard for us to treat and very unresponsive to pretty much any of the treatments that we have available to us.”

Roughly 15% to 20% of kidney cancers are non-clear cell histology, and trial data in this space are limited as patients are often excluded from clear cell RCC trials. Guidelines from the National Comprehensive Cancer Network (NCCN) currently recommend enrollment in clinical trials for those with advanced disease.

Two recent but small randomized trials in non-clear cell kidney cancer showed a slight advantage with the VEGF receptor inhibitor sunitinib (Sutent) over mTOR inhibitor everolimus (Afinitor), according to Rose, though the activity was only modest. In the 108-patient ASPEN trial, for instance, the rate of response was 18% and 10%, respectively.

“Sunitinib represents the current standard of care for first-line non-clear cell RCC,” she said.

The ORRs in KEYNOTE-427 were similar between International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable- and poor-risk groups (28.3% vs 23.2%, respectively), and complete responses were seen in both (9.4% vs 2.7%). Rose noted that the 9% complete response rate in the favorable-risk group is not a number “to sneeze at.”

The study administered 200-mg pembrolizumab every 3 weeks in non-clear cell RCC patients with recurrent or metastatic disease not previously treated systematically. The agent was administered until progression or unacceptable toxicity.

Baseline characteristics for the cohort were typical for a late-stage kidney cancer trial, said McDermott. Most patients were white (88%), two-thirds were men, and 68% had intermediate- or poor-risk disease. Patients were required to have Karnofsky performance status ≥70%, though three-fourths were ≥90%.

At a median follow-up of 11.1 months, progression-free survival in the trial was 4.1 months but median overall survival was not reached — 72% patients were alive at 1 year.

Most patients experienced a treatment-related adverse event (AE, 64%), with pruritus (18%), hypothyroidism (13%), fatigue (13%), and diarrhea (12%) being the most common. Grade 3-5 treatment-related AEs occurred in 11%, and two patient deaths were deemed related to treatment. Immune-related AEs were consistent with previous experience with the anti-PD-1 therapy in other tumor types, said McDermott.

Rose said it’s “very clear” that pembrolizumab is more tolerable than sunitinib in the first-line setting, and pointed to the fact that 6% of pembrolizumab-treated patients in this trial discontinued due to toxicity compared with 14% of sunitinib-treated patients in the ASPEN trial.

The study was funded by Merck.

McDermott reported relationships with Array BioPharma, Bristol-Myers Squibb, Exelixis, Genentech/Roche, Merck, Novartis, Pfizer, and X4 Pharma. Co-authors disclosed various relevant relationships with industry.

Rose disclosed relationships with Bristol-Myers Squibb, GeneCentric Therapeutics, Genentech/Roche, and X4 Pharma.