Pembrolizumab plus axitinib prolongs survival in advanced renal cell carcinoma
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First-line pembrolizumab plus axitinib extended survival among patients with advanced renal cell carcinoma, according to updated results of the randomized phase 3 KEYNOTE-426 study presented during the ASCO20 Virtual Scientific Program.
The benefit with pembrolizumab (Keytruda, Merck) and axitinib (Inlyta, Pfizer) compared with sunitinib (Sutent, Pfizer) persisted across all subgroups. Researchers observed no new safety signals with the combination.
“It is encouraging that, with longer follow-up, we see the patients who received the combination continue to achieve better PFS and OS,” Elizabeth R. 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 Healio. “We also looked at depth of response. In the combination group, the deeper the response, the longer patients tended to survive. That relationship did not hold true with sunitinib.”
VEGF inhibition and checkpoint inhibition are active in kidney cancer.
Many early combinations of checkpoint inhibitors and VEGF inhibitors were associated with unacceptable toxicity. However, a phase 1/phase 2 trial showed the combination of the PD-1 inhibitor pembrolizumab and the VEGF-targeted tyrosine kinase inhibitor axitinib could be an effective and safe option.
The phase 3 KEYNOTE-426 study compared the pembrolizumab-axitinib combination with sunitinib as first-line therapy for previously untreated advanced or metastatic clear-cell renal cell carcinoma.
The study included 861 patients (median age, 62 years; 73% men) who had Karnofsky performance scores of at least 70%.
Researchers randomly assigned 432 patients to 200 mg pembrolizumab IV every 3 weeks for a maximum 35 cycles plus 5 mg oral axitinib twice daily. The other 429 patients received 50 mg oral sunitinib daily in a 4-weeks-on, 2-weeks-off schedule. Treatment continued until disease progression, unacceptable toxicity or withdrawal.
Researchers stratified randomization by International Metastatic RCC Database Consortium (IMDC) risk (favorable vs. intermediate vs. poor) and geographic region (North America vs. Western Europe vs. the rest of the world).
OS and PFS served as co-primary endpoints. Secondary endpoints included overall response rate, duration of response and safety.
At last year’s Genitourinary Cancers Symposium, Plimack and colleagues presented results of the first preplanned interim analysis based on median follow-up of 12.8 months.
As Healio previously reported, the pembrolizumab-axitinib combination appeared associated with improvements in median PFS (15.1 months vs. 11.1 months; HR = 0.69; 95% CI, 0.57-0.84); 12-month PFS (59.6% vs. 46.2%), 18-month PFS (41.1% vs. 32.9%), 12-month OS (89.9% vs. 78.3%) and 18-month OS (82.3% vs. 72.1%). Median OS had not been reached in either group, but the early results showed a significant benefit with pembrolizumab-axitinib (HR = 0.53; 95% CI, 0.38-0.74).
The FDA approved the combination for first-line treatment in April 2019 based on these results.
At ASCO, Plimack presented updated analyses based on median follow-up of 27 months (range, 0.1-38.4).
Results continued to show a statistically significant benefit with pembrolizumab-axitinib with regard to median OS (not reached vs. 35.7 months; HR = 0.68; 95% CI, 0.55-0.85), 24-month OS (74% vs. 66%), median PFS (15.4 months vs. 11.1 months; HR = 0.71; 95% CI, 0.6-0.84) and 24-month PFS (38% vs. 27%).
“Some people mention how the HR [for OS] numerically changed — it was 0.53 [in the interim analysis] and now it is 0.68 — and how that seems to show the difference between the two groups is narrowing over time,” Plimack said. “I would say a couple things in response to that. First, to show an early benefit actually ends up helping more patients than showing a late benefit.
“Second, HR is one way to measure benefit, but another is to look at these landmarks and see how many people make it to 1 year or 2 years,” Plimack added. “Those results continue to impress with the combination and continue to be superior to sunitinib. These are landmark survivals that we haven’t really seen in kidney cancer to date.”
A higher percentage of patients assigned pembrolizumab-axitinib than sunitinib achieved objective response (60% vs. 40%; P < .0001) and complete response (9% vs. 3%). Median duration of response was 23.5 months (range, 1.4+ to 34.5+) with the combination vs. 15.9 months (2.3-31.8+) with sunitinib.
Researchers observed the benefit with the combination in all subgroups tested.
Plimack and colleagues performed a post-hoc exploratory analysis to evaluate the association between depth of response and OS.
This analysis included patients who survived at least 6 months. Investigators divided patients into cohorts based on depth of response.
Results showed depth of response correlated with survival in the combination group but not in the sunitinib group.
The toxicity profile of the pembrolizumab-axitinib combination has been consistent over time, with relatively low rates of individual immune-related adverse events and a collective rate of about 10% to 15%, Plimack said.
“We have known how active this regimen is since the early days of the phase 1 trial, so we are really grateful that the FDA acted quickly to approve it,” Plimack said. “Also, this trial represents a collaboration between two big drug companies. The phase 3 trial is a Merck trial, but the phase 1 trial was a Pfizer trial. I commend these two companies for working together to make sure we can devise the best treatments for patients. That’s something that may not have happened years ago when companies were more competitive.” – by Mark Leiser
Reference:
Plimack ER, et al. Abstract 5001. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
Disclosures: Merck Sharp & Dohme funded this study. Plimack reports research funding to her institution from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, Merck Sharp & Dohme, Peloton Therapeutics and Pfizer, and consultant/advisory roles with AstraZeneca, Bristol-Myers Squibb, Flatiron Health, Genentech/Roche, Incyte, Janssen, Merck, Pfizer and Seattle Genetics. Please see the abstract for all other researchers’ relevant financial disclosures.
Perspective
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Kai Tsao, MD
Two combination therapeutic approaches — one with checkpoint inhibitors ipilimumab (Yervoy, Bristol-Myers Squibb) and nivolumab (Opdivo, Bristol-Myers Squibb), and another with targeted therapy plus a checkpoint inhibitor, axitinib plus pembrolizumab — have become standards of care for the first-line treatment of patients with metastatic clear cell renal cell carcinoma after demonstrating definitive OS benefits in randomized phase 3 studies in comparison with sunitinib.
However, without studies directly comparing the two approaches, selection of treatment is based on cross-trial data comparison and personal experience. Some favor ipilimumab plus nivolumab, citing the high rate of complete response, favorable toxicity profile and quality of life, as well as the long duration response, with 38% of patients remaining on therapy at 42 months. Others favor axitinib plus pembrolizumab, citing a higher response rate and clinical benefit.
Given the first analysis of KEYNOTE-426 was based on median follow-up of only 18 months, the updated analysis has been long anticipated to help us better understand the long-term therapeutic effect with axitinib plus pembrolizumab.
In this updated analysis, with median follow-up of 27 months, axitinib plus pembrolizumab continued to demonstrate improved OS, PFS and ORR vs. sunitinib. Additionally, longer-follow-up showed a higher complete response rate with axitinib plus pembrolizumab compared with the initial analysis (9% vs. 5.8%), and median duration of response is impressive at 23.5 months.
No new safety signals were observed. Among patients with favorable-risk disease, ORR and PFS favored those treated with the combination. These findings underscore the durability of therapeutic efficacy and clinical benefit for patients treated with axitinib plus pembrolizumab.
Despite the favorable results in this updated analysis, it does not address the question of which is the better first-line treatment. Heterogeneity in clinical presentation, patient preferences, IMDC risk and concurrent medical comorbidities are among the factors to consider when clinicians select a treatment plan for a patient with intermediate- or poor-risk metastatic renal cell carcinoma. However, with the definitive clinical benefit seen among those with IMDC favorable-risk disease — and not seen in the CheckMate 214 trial of ipilimumab plus nivolumab — axitinib plus pembrolizumab should be considered the standard of care for this patient population. As we anticipate the results of additional phase 3 immunotherapy-plus-TKI combinations — such as cabozantanib (Cabometyx, Exelixis) plus nivolumab, or pembrolizumab plus lenvatinib (Lenvima, Eisai) — the evolving paradigm of first-line metastatic renal cell carcinoma treatment may once again shift in the near future.
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Plimack ER, et al. Abstract 5001. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
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