Pembrolizumab plus axitinib new standard first-line treatment for advanced kidney cancer

Elizabeth Plimack

The combination of pembrolizumab and axitinib extended OS and PFS compared with sunitinib as first-line treatment for patients with previously untreated advanced or metastatic clear-cell renal cell carcinoma, according to results of the randomized phase 3 KEYNOTE-426 clinical trial scheduled for presentation at Genitourinary Cancers Symposium.

These data suggest the combination of the PD-1 inhibitor pembrolizumab (Keytruda, Merck) with the VEGF-targeted tyrosine kinase inhibitor axitinib (Inlyta, Pfizer) should be a new standard of care for this patient population, according to the researchers.

“Both VEGF inhibition and checkpoint inhibition are very active in kidney cancer,” study author Elizabeth Plimack, MD, MS, chief of the division of genitourinary medical oncology, associate professor in the department of hematology/oncology and director of genitourinary clinical research at Fox Chase Cancer Center, told HemOnc Today. “We previously tested checkpoint inhibitors with VEGF inhibitors with nivolumab [Opdivo, Bristol-Myers Squibb] and pazopanib [Votrient, Novartis], pembrolizumab and pazopanib, and nivolumab and sunitinib [Sutent, Pfizer]. All of those were characterized by toxicity that precluded moving forward with those combinations.”

However, a phase 1/phase 2 trial — led by Plimack, Michael B. Atkins, MD, and Toni Choueiri, MD, — of pembrolizumab plus axitinib in untreated patients with renal cell showed a “better partnership,” Plimack said.

“Pembrolizumab and axitinib combined safely in this group; we didn’t see a lot of liver toxicity like we did for the other combinations,” she said. “We also started to see really dramatic efficacy. Almost every patient in that early-phase study had tumor shrinkage. The vast majority of people in that trial, even now years later, are still alive. That parlayed excited into running the phase 3 trial, which accrued really rapidly.”

The analysis included 861 patients with metastatic clear-cell renal cell carcinoma (median age, 62 years; 73% men) who had not received previous systemic therapy and who had a Karnofsky performance score of at least 70%.

Researchers randomly assigned patients 1:1 to received 200 mg IV pembrolizumab every 3 weeks for a maximum for 35 cycles plus 5 mg oral axitinib twice daily (n = 432) or 50 mg oral sunitinib daily in a 4-week-on, 2-week-off schedule (n = 429).

OS and PFS served as co-primary endpoints. Overall response rate served as a key secondary endpoint.

After a median follow-up of 12.8 months, 59% of the pembrolizumab-axitinib group and 43.1% of the sunitinib group remained on treatment.

Results showed more patients assigned pembrolizumab-axitinib achieved 12-months OS (89.9% vs. 78.3%) and 18-month OS (82.3% vs. 72.1%). Median OS was not reached in either arm, but the data showed pembrolizumab-axitinib significantly improved OS (HR = 0.53; 95% CI, 0.38-0.74).

PFS also significantly improved with the pembrolizumab-axitinib combination, with a median PFS of 15.1 months in that group compared with 11.1 months with sunitinib (HR = 0.69; 95% CI, 0.57-0.84).

“It is important to note that 11.1-month [median PFS] for sunitinib is quite normal for the control arm, so there is nothing from these data to suggest that the sunitinib arm underperformed in this trial,”study author Thomas Powles, MD, PhD, FRCP, professor of urology oncology at Barts Cancer Institute in London, said during a press cast.

A greater proportion of patients assigned pembrolizumab-axitinib achieved PFS at 12 months (59.6% vs. 46.2%) and 18 months (41.1% vs. 32.9%).

“It is impressive that both endpoints of PFS and OS were met at the first interim analysis, where the bar is typically higher,” Plimack told HemOnc Today. “We were delighted, but also a little surprised to see the split that early. It’s quite a dramatic benefit, and one of the best data sets in renal cell that we’ve ever seen.”

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Researchers reported a higher ORR with pembrolizumab-axitinib than sunitinib (59.3% vs. 35.7%; P < .0001). Median duration of response was not reached (95% CI, 1.4+ to 18.2+) with the combination vs. 15.2 months (95% CI, 1.1+ to 15.4+) with sunitinib.

Researchers observed the benefit of the pembrolizumab-axitinib combination across patient subgroups, including for PD-L1 expression and International Metastatic Renal Cell Carcinoma Database Consortium risk group.

Grade 3 to grade 5 treatment-related adverse events occurred among 62.9% of patients assigned the combination compared with 58.1% of patients assigned sunitinib.

Adverse events led to discontinuation of any treatment among 25.9% of the combination group — with 8.2% discontinuing both pembrolizumab and axitinib — and 10.1% of the sunitinib group.

“The risk for death was reduced by 47% with pembrolizumab plus axitinib,” Powles said. “Pembrolizumab and axitinib should be a standard of care in this setting, in my opinion.”

The need for biomarkers to predict response is among the unanswered questions that remain, Powles added.

“PD-L1 levels, which have been markers for immunotherapy success in other cancers, remain unproven in renal cancer,” he said in a press release. “It is possible that by combining pembrolizumab with axitinib, the predictive value of PD-L1 is being masked.

In addition, it’s not yet known how long this treatment should be continued, Plimack told HemOnc Today.

“When drugs work as well as these do and patients are on them as long as they have been, we don’t know when to stop or which to stop, and what to do if there is growth afterward,” she said. “Right now in the study, pembrolizumab ends at 2 years and axitinib can continue. Is that the right thing to do? I don’t think we know, yet.”

Long-term toxicity is another remain question, she added, especially if patients are on VEGF inhibition for 5 to 10 years.

“Overall, we have not previously seen a renal cancer study which has improved response, PFS and OS,” Powles said. “This is, therefore, a major step forward in renal cancer.” – by Alexandra Todak

Reference:

Powles T, et al. Abstract 543. Scheduled for presentation at: Genitourinary Cancers Symposium; Feb. 14-16, 2019; San Francisco.

Disclosures: Merck funded this study. Powles reports consultant/advisory roles with AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, Merck and Novartis; honoraria or research funding from AstraZeneca/MedImmune, Bristol-Myers Squibb, Merck and Roche/Genentech; and other relationships with Bristol-Myers Squibb and Ipsen. Please see the abstract for all other authors’ relevant financial disclosures.