From the Journals

Pembrolizumab plus axitinib continues to outshine sunitinib for advanced RCC



Pembrolizumab plus axitinib continued to top sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (RCC) in an extended follow-up of the phase 3 KEYNOTE-426 trial.

The trial’s initial results, published in The New England Journal of Medicine in 2019, showed superior efficacy with the combination. Pembrolizumab plus axitinib was subsequently approved in the United States and elsewhere as first-line treatment for advanced RCC.

The latest results from KEYNOTE-426, published in The Lancet Oncology, show a continued survival benefit with pembrolizumab plus axitinib.

“Overall, the results of this study continue to support pembrolizumab plus axitinib as standard of care in patients with previously untreated advanced renal cell carcinoma,” wrote study author Thomas Powles, MD, of the Queen Mary University and Barts Cancer Centre, London, and colleagues.

However, the new findings “must be read and interpreted together with the existing published literature,” they added. This includes trials of nivolumab plus ipilimumab, avelumab plus axitinib, and atezolizumab plus bevacizumab for advanced RCC, all versus sunitinib.

“Given the impossibility of making direct comparisons between the different combinations ... clinical experience and knowledge of the disease and of our patients will be vital to optimize this new therapeutic arsenal and to be able to reach goals that, until a few years ago, were considered unattainable,” wrote authors of a related editorial in The Lancet Oncology.

Trial details and results

KEYNOTE-426 included 861 patients with newly diagnosed stage IV or recurrent metastatic RCC with clear cell histology.

Patients were randomized to sunitinib monotherapy (n = 429) or pembrolizumab plus axitinib (n = 432). Pembrolizumab was given at 200 mg intravenously every 3 weeks for up to 35 cycles, and axitinib was given at 5 mg orally twice daily. Sunitinib was given at 50 mg orally once daily for 4 weeks per 6-week cycle.

Baseline characteristics were similar between the treatment arms. The median age was 62 years in the combination arm and 61 years in the sunitinib arm. Most patients were men (71% and 75%, respectively).

At a median follow-up of 30.6 months, the median overall survival (OS) was 35.7 months in the sunitinib arm but not yet reached in the pembrolizumab-axitinib arm (hazard ratio, 0.68, 95% confidence interval, 0.55-0.85, P = .0003).

The updated hazard ratio for OS with the combination wasn’t as robust as the hazard ratio in the initial analysis (0.53), likely in part because 48% of patients in the sunitinib group subsequently received immunotherapy, according to Dr. Powles and colleagues.

The median progression free survival (PFS) was 11.1 months with sunitinib and 15.4 months with the combination (HR, 0.71, 95% CI, 0.60-0.84, P < .0001). The objective response rate was 60% with pembrolizumab plus axitinib and 40% in the sunitinib group (P < .0001).

Risk groups and response criteria

Although patients in the combination arm had better objective response rates and PFS across all risk categories, there was no OS benefit in the favorable-risk subgroup, perhaps because favorable-risk patients have more indolent disease, Dr. Powles and colleagues noted.

Even so, “the pembrolizumab plus axitinib combination achieved a nonnegligible rate of 11% complete responses in favorable-risk cases, suggesting a potential curative role in this setting,” the editorialists wrote.

Dr. Powles and colleagues raised the question of whether RECIST-defined response is adequate to capture the full benefit of the combination.

In a post hoc analysis, the researchers found that change in tumor size was prognostic for OS. Patients in the pembrolizumab-axitinib group with an “at least 80% reduction in target lesions within 6 months of randomization had a durable subsequent overall survival benefit (i.e., 36 months survival), similar to patients who had RECIST-defined complete response,” Dr. Powles and colleagues wrote.

“These data support a hypothesis that durable benefit to an immunotherapy-containing regimen in renal cell cancer is not limited to the subset of complete responders,” the researchers added. “Because RECIST categories might not classify all patients who achieve durable benefit, depth of response might also supplement objective response as an important clinical endpoint.”

Safety and discontinuation

There were no new safety signals and no new treatment-related deaths.

The most frequent grade 3 or higher adverse events (in the combination and sunitinib arms, respectively) were hypertension (22% and 20%), alanine aminotransferase elevations (13% and 3%), and diarrhea (11% and 5%).

Treatment-related adverse events led to pembrolizumab interruption in 44% of patients, axitinib interruption in 62%, and interruption of both in 30%. Treatment-related adverse events led to discontinuation of one or the other drug in about 20% of subjects and both in 7%.

The number of discontinuations and interruptions suggests “caution in optimizing the therapeutic choice in real-world patients,” the editorialists wrote.

“New treatment modalities, including intermittent administrations or an induction phase followed by single-agent maintenance, could be explored in future adaptive clinical trials, with undeniable advantages in terms of reducing clinical and financial toxicity,” they added.

The KEYNOTE-426 study was funded by Merck, maker of pembrolizumab. The investigators and the editorialists disclosed ties to Merck and other companies.

SOURCE: Powles T et al. Lancet Oncol. 2020 Oct. 23. doi: 10.1016/S1470-2045(20)30436-8.

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