Axitinib/Pembrolizumab Combination Improves Survival in Metastatic RCC, But Only Marginally


A real-world survival analysis showed that patients with metastatic RCC treated with axitinib plus pembrolizumab did not experience significantly improved survival outcomes compared with patients treated with ipilimumab plus nivolumab.

A real-world analysis presented at the 2021 Kidney Cancer Research Summit (KCRS) showed that axitinib (Inlyta) plus pembrolizumab (Keytruda) didnot induce clinically meaningful survival rates in patients with metastatic renal cell carcinoma (RCC) compared with ipilimumab (Yervoy) plus nivolumab (Opdivo). 1

The median progression-free survival in the intent-to-treat (ITT) population was 9.0 months with axitinib plus pembrolizumab vs 6.9 months with ipilimumab plus nivolumab (P = .20). In the patients with a favorable International Metastatic RCC Database Consortium (IMDC) risk, the real-world PFS was not reached with axitinib/pembrolizumab vs 6.9 months with ipilimumab plus nivolumab; however, this was not determined to be clinically significant, and the sample size was small. In those with intermediate/poor risk, the PFS was 9.0 months with axitinib plus pembrolizumab vs 6.0 months with ipilimumab plus nivolumab.

The median overall survival (OS) in the ITT population was not yet reached with axitinib/pembrolizumab vs 23.7 months with ipilimumab/nivolumab (P = .10). In those with favorable risk, the median OS had not yet been reached with either regimen. In those with intermediate/poor risk, the median OS was not reached with axitinib plus pembrolizumab vs 22.0 months (95% CI, 18.2-26.4) with ipilimumab plus nivolumab.

“When we look at landmark 18-month survival, you can appreciate that as the IMDC risk goes from favorable to intermediate/poor, survival decreases,” Kevin Zarrabi, lead study author and hematology/oncology fellow at Fox Chase Cancer Center, said in a presentation on the data. “However, there is absolutely no discernible difference between the [patients treated with] axitinib/pembrolizumab vs ipilimumab/nivolumab. Survival seems almost identical.”

Data from the phase 3 CheckMate-214 trial (NCT02231749) showed that in a sample size of 1096 patients, ipilimumab plus nivolumab improved OS and objective response rates (ORR) vs sunitinib (Sutent) in previously untreated patients with intermediate- and poor-risk advanced RCC.2

The median PFS with the doublet was 11.6 months (95% CI, 8.7-15.5) vs 8.4 months (95% CI, 7.0-10.8) with the monotherapy. The landmark 12-month OS rates in the investigative and control arms in IMDC all-risk patients were 83% (95% CI, 80%-86%) and 77% (95% CI, 74%-81%), respectively. The ORRs in IMDC all-risk patients were 39% (95% CI, 35%-43%) and 32% (95% CI, 28%-36%), respectively. Data from the trial resulted in the April 2018 FDA approval of the combination for use in patients with intermediate- or poor-risk, previously untreated advanced RCC.3

The combination of axitinib plus pembrolizumab was found to prolong OS and PFS in a sample size of 861 patients with advanced RCC, as well as elicit a higher ORR compared with sunitinib, according to data from the phase 3 KEYNOTE-426 trial (NCT02853331).4

Results showed that the median PFS with the doublet vs the monotherapy was 15.1 months (95% CI, 12.6-17.7) and 11.1 months (95% CI, 8.7-12.5), respectively. The median PFS in the intermediate- and poor-risk patients in the investigative and control arms was 12.6 months and 8.2 months, respectively. The landmark 12-month OS rates in the all-risk population were 89.9% and 78.3%, respectively; the ORRs were 59.3% (95% CI, 54.5%-63.9%) and 35.7% (95% CI, 31.1%-40.4%), respectively. Findings from this trial supported the April 2019 FDA approval for axitinib/pembrolizumab for use in the frontline treatment of patients with advanced RCC.5

“Although these were remarkable advances in terms of treatment options for [our patients with] clear cell RCC, we don’t have head-to-head prospective data to help guide us in treatment choice,” Zarrabi explained. “When looking at the IMDC criteria and survival we do know that in the intermediate- and poor-risk patient population, there’s no real clear signal advantage in terms of either treatment option.”

Common practice, with respect to practitioner comfort with combination therapies as well as patient preference and goals, is to tailor treatment, according to Zarrabi. However, a gap in knowledge exists due to lack of data; as such, it is difficult to discern whether an advantage exists with either regimen in this population.

To fill this gap, Zarrabi and colleagues partnered with Flatiron Health to look at survival data on 9940 treatment-naïve patients with metastatic RCC stored in the electronic health record database, which houses healthcare information for over 3 million patients treated at 280 community and academic sites.

Investigators looked at information from 2018, when ipilimumab plus nivolumab emerged in the treatment landscape, through March 2021, a total of 1045 patients with clear cell RCC were identified for inclusion in the analysis. “This is a fairly large sample size compared with what is already in the literature,” Zarrabi said.

Of the 1045 patients included in the final cohort, 698 had received treatment with ipilimumab plus nivolumab and 347 received axitinib plus pembrolizumab.

The patient demographic and clinical characteristics were well balanced, with no real preference for one combination regimen over another, according to Zarrabi.

The median age of patients who received axitinib/pembrolizumab was 68.0 years (range, 21-85) vs 66.0 years (range, 29-84) with ipilimumab/nivolumab. Most patients were male (70.6% and 75.6%, respectively), White (70.0% and 63.6%), intermediate/poor risk (80.5% and 84.9%), had stage IV disease at diagnosis (56.2% and 60.06%), and received treatment in community settings (92.8% and 90.3%).

“In 2018, when the ipilimumab/nivolumab data were released, more patients were receiving that combination,” Zarrabi noted. “However, over the ensuing 3.5 years, there seems to be provider preference to move toward axitinib/pembrolizumab.”

Longer-term survival outcomes have recently been reported for both CheckMate-2146 and KEYNOTE-426 and survival benefit was found to be sustained.7 In CheckMate-214, the median PFS with ipilimumab/nivolumab in patients with intermediate/poor risk RCC was 11.6 months and the median OS was 47.0 months. In the real-world dataset, the median PFS and OS was 6.9 months and 22.0 months, respectively. The 18-month landmark survival rate was 77% in the ITT population vs 58.8% in the real-world dataset.

In KEYNOTE-426, the median PFS with axitinib/pembrolizumab was 15.7 months and the median OS was 45.7 months. In the real-world dataset, the median PFS was 9.0 months and the median OS had not yet been reached. The 18-month landmark survival rate in the ITT population was 81.0%; this rate was 58.2% in the real-world dataset.

“Not surprisingly, we see a significantly lower survival [in terms of both] PFS and OS in our real-world population compared with the trial population,” Zarrabi noted.

In the absence of prospective studies, retrospective analyses such as the report shared during the 2021 KCRS are utilized to guide decision making when it comes to frontline treatment choice for this patient population, according to Zarrabi.

“Longer follow-up time will be necessary to discern any clinically significant difference in survival,” Zarrabi concluded. “Future studies may include data on newly approved frontline combination therapies, including lenvatinib [Lenvima]/pembrolizumab and cabozantinib [Cabometyx]/nivolumab.”


  1. Zarrabi K, Handorf EA, Miron B, et al. Real-world outcomes of front-line axitinib plus pembrolizumab versus ipilimumab plus nivolumab for metastatic clear cell renal cell carcinoma: landmark 18-month survival analysis. Presented at: 2021 Kidney Cancer Research Summit; October 7-8, 2021; Philadelphia, PA.
  2. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal cell carcinoma. N Engl J Med. 2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126
  3. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. News release. FDA. April 16, 2018. Accessed October 12, 2021.
  4. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1116-1127. doi:10.1056/NEJMoa1816714
  5. FDA approves pembrolizumab plus axitinib for advanced renal cell carcinoma. News release. FDA. April 19, 2019. Accessed October 12, 2021.
  6. Motzer RJ, Escudier B, McDermott DF, et al. Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial. J Immunother Cancer. 2020;8(2):e000891. Doi:10.1136/jitc-2020-000891
  7. Powles T, Plimack ER, Soulières D, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020;21(12):1563-1573. doi:10.1016/S1470-2045(20)30436-8

This article was originally published on OncLive as “Analysis Examines Real-World Survival Outcomes With Frontline Combos in Metastatic RCC”

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