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Pembrolizumab/Axitinib Combination Improves Outcomes vs Sunitinib in Kidney Cancer


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The checkpoint inhibitor pembrolizumab plus the vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor axitinib significantly improved overall survival, progression-free survival, and objective response rates vs sunitinib as first-line therapy for clear cell metastatic renal cell carcinoma, according to the results of the randomized, phase III KEYNOTE-426 trial presented at the 2019 Genitourinary Cancers Symposium.1 Treatment with the pembrolizumab/axitinib combination led to a significant 47% reduction in the risk of death vs sunitinib (P < .0001).


By adding pembrolizumab to a VEGF-targeted tyrosine kinase inhibitor, we are seeing powerful anticancer responses, including improved survival, and, importantly, results are seen across broad subgroups of patients.
— Thomas Powles, MD

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“These results are exciting. By adding pembrolizumab to a VEGF-targeted tyrosine kinase inhibitor, we are seeing powerful anticancer responses, including improved survival, and, importantly, results are seen across broad subgroups of patients. These data suggest that pembrolizumab plus axitinib should be a new standard of care for this population, in my opinion,” said lead author Thomas Powles, MD, Professor of Urology Oncology, Barts Cancer Institute, London.

Sunitinib has been the standard of care for the first-line therapy for metastatic renal cell carcinoma. At the European Society for Medical Oncology (ESMO) 2018 Congress, the JAVELIN 101 study demonstrated that a similar combination of checkpoint inhibitor plus a VEGF tyrosine kinase inhibitor (avelumab plus axitinib) achieved superior progression-free survival vs sunitinib in a similar patient population, but there was no survival benefit at the time the data were presented.2 The benefits of the combination were found regardless of the level of programmed cell death ligand 1 (PD-L1) expression.

KEYNOTE-426 results are especially noteworthy compared with JAVELIN-101, because the investigators were able to show an overall survival benefit in a relatively short amount of time. This benefit was observed regardless of PD-L1 expression level or risk group (ie, favorable, intermediate, or poor risk).

Study Details

Earlier results of a phase Ib study showed that the combination of pembrolizumab and axitinib had superior antitumor activity compared with either agent alone in treatment-naive metastatic renal cell carcinoma.3 The combination was tolerable and yielded a 73% objective response rate.

After the promising results from the phase Ib study, the open-label phase III KEYNOTE-426 trial enrolled 861 patients with clear cell metastatic renal cell carcinoma and no previous systemic therapy for metastatic disease. Patients randomly assigned 1:1 to receive pembrolizu-mab at 200 mg intravenously every 3 weeks for a maximum of 35 cycles plus oral axitinib at 5 mg twice daily vs oral sunitinib at 50 mg every day on a 4 week on/2 week off schedule. Patients were treated until disease progression, unacceptable toxicity, or investigator’s decision.

Patients were stratified by risk group according to the International Metastatic Renal Cell Carcinoma Database Consortium as favorable-, intermediate-, or poor-risk disease and according to geographic region. About 31% had favorable-risk, 56% had intermediate-risk, and 13% had poor-risk disease. A total of 82% had prior nephrectomy, and 75% had metastases in 2 or more organs.

Clinical Outcomes

At a median follow-up of 12.8 months, the combination of pembrolizumab plus axitinib showed significant improvements in overall survival (hazard ratio = 0.53), progression-free survival, and objective response rate. The 12-month overall survival was 89.9% for the combination vs 78.3% for sunitinib (P = .0001); the 18-month overall survival rates were 82.3% vs 72.1%, respectively.

Pembrolizumab Plus Axitinib in Kidney Cancer

  • KEYNOTE-426 is the first phase III trial to establish a survival benefit for a checkpoint inhibitor plus axitinib compared with sunitinib in the first-line treatment of metastatic renal cell carcinoma.
  • The benefits for the combination of pembrolizumab plus axitinib vs sunitinib were observed across the board in all risk groups and subgroups regardless of PD-L1 expression level.
  • For more on the first-line use of pembrolizumab plus axitinib vs sunitinib in advanced renal cell carcinoma, see an interview with Thomas Powles, MD, on The ASCO Post Newsreels at www.ascopost.com/videos.

The 12-month progression-free survival was 59.6% with the combination vs 41.1%. The median progression-free survival was 15.1 months vs 11.1 months (P = .0001), respectively, and the objective response rate was 59.3% vs 35.7%, respectively (P < .0001). The duration of response was not yet reached for the combination therapy arm vs a median of 15.2 months for the sunitinib arm. Treatment is ongoing for 59% of the combination arm and 43.1% of the sunitinib arm.

The incidence of treatment-related adverse events of any grade was similar between the two treatment arms: about 96%. Treatment-related grades 3 to 5 adverse events were higher with the combination than with sunitinib: 62.9% vs 58.1%, respectively. Treatment-related adverse events leading to death were reported in 0.9% and 1.6%, respectively.

A total of 25.9% of patients discontinued either drug vs 10.1% of patients in the sunitinib arm. Discontinuation of both pembrolizumab and axitinib was reported in 8.2%.

Additional Commentary

“This is a very significant trial,” said Robert Dreicer, MD, of the University of Virginia Cancer Center, who moderated a premeeting press cast. “It is going to have an impact on patient management going forward, as it works through the regulatory process. Patients with metastatic kidney cancer have poor survival, and there have been few significant advances in treating this advanced type of the disease. These findings may help provide an important new option for patients with metastatic renal cell carcinoma.”

“The combination of pembrolizumab/axitinib appears to be superior to that of avelumab/axitinib, as reported in JAVELIN-101 at the 2019 European Society for Medical Oncology Congress,” commented ASCO expert Sumanta Pal, MD, of the City of Hope, in Duarte, California. “Both studies are almost identical in design. It’s mystifying that the same targeted therapy base of axitinib with a slightly different checkpoint inhibitor shows different results. KEYNOTE-426 already shows a 47% improvement in survival, whereas the survival data in JAVELIN with avelumab are still immature,” Dr. Pal continued.

“Both combinations are seeking U.S. Food and Drug Administration (FDA) approval, but in my view, it will be difficult for axitinib/avelumab to establish a role because of the more striking overall survival results with KEYNOTE-426. If approval is granted, this would be the first FDA labeling for avelumab or pembrolizumab for the first-line treatment of metastatic kidney cancer,” Dr. Pal stated. 

DISCLOSURE: Dr. Powles has received honoraria from Bristol-Myers Squibb, Merck, and Roche/Genentech; is a consultant/advisor for AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, Merck, and Novartis; has received research funding from AstraZeneca/MedImmune and Roche/Genentech; and has other relationships with Bristol-Myers Squibb and Ipsen. Dr. Dreicer is a consultant/advisor for Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, EMD Serono, Incyte, and Pfizer and has received institutional research funding from Genentech, Seattle Genetics, Janssen Oncology, Merck and BioClin Therapeutics. Dr. Pal is a consultant for Pfizer, Novartis, Aveo, Myriad, Genentech, Exelixis, Bristol-Myers Squibb, Astellas Pharma, Ipsen, and Eisai.

REFERENCES

1. Powles T, Plimack ER, Stus V, et al: Pembrolizumab plus axitinib vs sunitinib as first-line therapy for advanced renal cell carcinoma: Phase III KEYNOTE-426 study. 2019 Genitourinary Cancers Symposium. Abstract 543. Presented February 16, 2019.

2. Motzer RJ, Penkov K, Haanen JBAG, et al: JAVELIN Renal 101: A randomized, phase 3 study of avelumab + axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma. ESMO 2018 Congress. Abstract LBA6_PR. Presented October 21, 2018.

3. Atkins MB, Plimack ER, Puzanov I, et al: Safety and efficacy of axitinib in combination with pembrolizumab in patients with advanced renal cell cancer. 2018 Genitourinary Cancers Symposium. Abstract 579. Presented February 10, 2018.


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