ASCO 2019: Pembro plus Axitinib vs Sunitinib as First-Line Therapy for mRCC: Outcomes in the Combined IMDC Intermediate/Poor Risk and Sarcomatoid Subgroups of the Phase 3 KEYNOTE-426 Study - Medical Oncologist Perspective

Chicago, IL (UroToday.com)  During GU ASCO 2019, data from KEYNOTE-426 was released showing that combination pembrolizumab + axitinib was superior to sunitinib in terms of median progression-free survival (HR 0.69, P = .0001) and longer overall survival (OS) (HR 0.53, P < .0001).1 In this open-label, phase 3 trial which randomly assigned patients to either pembrolizumab+axitinib vs sunitinib alone, the median progression-free survival was 15.1 months in the combination therapy group, vs. 11.1 months in the sunitinib group.   The hazard ratio for overall survival was 0.53. The majority of patients were intermediate or poor IMDC risk (68%) and about 18% of patients in both arms had sarcomatoid features. In this analysis, the authors describe the outcomes in these subgroups.
ASCO 2019 KEYNOTE 426 study design

This abstract provides data on 592 patients who were classified as IMDC intermediate or poor risk. This accounted for 68.8% of all patients in this study. In terms of the objective response rate (ORR), 55.8% of patients responded to pembro+axi, compared with 29.5% of patients receiving sunitinib. The complete response (CR) rate was 4.8% in the intermediate/poor risk cohort, significantly higher than the 0.7% CR rate with sunitinib. Lastly, pembro+axi improved OS (HR 0.52, 95% CI 0.37-0.74; 12-mo rate 87.3% vs 71.3%) and progression-free survival (PFS) (HR 0.67, 95% CI 0.53-0.85; median 12.6 vs 8.2 mo) with similar outcomes as the data on the entire cohort reported at GU ASCO 2019.

The authors also describe the results of the patients with favorable risk disease with respect to OS, PFS, and ORR. These results here are quite different than the results of CheckMate214. Here, pembro/axi improved OS, PFS, and ORR as shown below.
ASCO 2019 KEYNOTE 426 IMDS favorable risk

For patients with sarcomatoid features (n=105), the CR rate was twice as high (11.8%), with maintained benefits in OS (HR 0.58, 95% CI 0.21-1.59; 12-mo rate 83.4% vs 79.5%) and PFS (HR 0.54, 95% CI 0.29-1.00; median not reached vs 8.4 mo) over sunitinib.
ASCO 2019 KEYNOTE 426 sarcomatoid features

Data from KEYNOTE-426 clearly demonstrate that pembrolizumab plus axitinib is superior to sunitinib in the front-line setting for patients with mRCC.1 This new data presented today on the sarcomatoid patients show that pembro/axi may be able to achieve the same CR rate as the combination of ipilimumab/nivolumab as was seen in CheckMate214 (9%).2 For patients with intermediate/poor-risk disease, the choice between front-line therapy for patients is becoming more challenging given the promising CR rates in both these therapies, and review of toxicity data will be important in defining the best options for our patients. For favorable risk disease, data presented today show consistent improvement over sunitinib with improvement in OS, PFS, and ORR. Thus, pembro/axi appears to be a very good option for all patients with mRCC who do not have contraindications to other therapy. Lastly, it will be important to review data on how avelumab/axitinib performs in the same cohorts of patients as this may also represent another promising front line option.3
ASCO 2019 KEYNOTE 426 summary and conclusions

Presented by: Brian I. Rini, MD, FACP, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio

Written by: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University, @TheRealJasonZhu, at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA

References:
  1. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. New England Journal of Medicine 2019;380:1116-27.
  2. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. New England Journal of Medicine 2018;378:1277-90.
  3. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. New England Journal of Medicine 2019;380:1103-15.
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