ASCO GU 2019: Phase III KEYNOTE-426 Study: Pembrolizumab plus Axitinib versus Sunitinib as First-Line Therapy for Locally Advanced or Metastatic Renal Cell Carcinoma

San Francisco, CA (UroToday.com) Combination vascular endothelial growth factor (VEGF) inhibition with immunotherapy has shown promising results in several phase I/II studies. During ASCO 2018, Dr. Lee et al presented a study of 30 patients with metastatic renal cell carcinoma (mRCC) who were treated with Pembrolizumab and Levantinib, and this combination yielded an overall response rate of 66.7% by RECIST v1.1 and irRECIST with a median duration of response of 18.4 months.1 97% of patients experienced some tumor size reduction from baseline. A phase II study of Avelumab plus axitinib was presented at 2017 ASCO and this combination achieved an ORR of 58.20%.2 Preliminary data regarding the combination of pembrolizumab and axitinib was initially presented at GU ASCO 2018, and out of 52 patients, 73.1% of patients had an objective response with a median PFS of 20.9 months.3 This abstract provides the phase III update to that data.
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This global phase III study enrolled patients with untreated metastatic clear cell RCC and randomized patients to receive either pembrolizumab plus axitinib (PA) or sunitinib. Pembrolizumab was given in standard fashion at a dose of 200 mg every 3 weeks and axitinib was given at a dose of 5 mg twice a day. Sunitinib was dosed at 50 mg daily, 4 weeks on, 2 weeks off schedule.

A total of 861 patients were enrolled in the study. The median age was 62 in the pembrolizumab arm and 61 in the sunitinib arm. The majority of patients were men (71%) and had intermediate or poor risk disease by IMDC criteria. This cohort also contained a high percentage of patients who were deemed PD-L1 positive, based on a CPS ≥1 (roughly 60% in both arms). Also, unlike many patients in the post-CARMENA era, the majority of patients had a previous nephrectomy (82%).
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At the time of data cutoff, 59% of patients on pembro/axi remain on therapy, compared with 43% of patients on sunitinib. After a median follow up of 12.8 months, patients receiving PA had improved overall survival (HR 0.53 [95% CI 0.38-0.74]; P< 0.0001), progression-free survival (HR 0.69 [95% CI 0.57-0.84]; P = 0.0001), and objective response rates (59.3% vs 35.7%; P< 0.0001). The median progression-free survival was 15.1 months in the PA arm and 11. Month in the sunitinib arm.
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The benefit of PA over sunitinib was observed in all IMDB risk groups and PD-L1 expression subgroups. In terms of patient safety, 62.9% of patients had grade 3-5 treatment-related adverse events with PA compared to 58.1% with sunitinib. Patients receiving PA had a lower rate of discontinuation (6.3% vs 10.1%).
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In terms of objective responses, ORR of PA was 59.3% compared with 35.7% on sunitinib. In terms of safety, 0.9% of patients on PA had a treatment-related AE which led to death compared to 1.6% of patients on sunitinib. Overall, PA was well tolerated but did have greater grade 3-5 adverse events of interest than sunitinib (10.7% vs 1.9%). Patients receiving PA did have more dysphonia, diarrhea, and hypertension.
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Pembrolizumab plus axitinib is effective and safe for patients with clear cell mRCC, with an impressive 59% objective response rate. This compares favorably to the Ipi/Nivo data (ORR 42%) from CheckMate 214, which truly established immunotherapy as a front-line option for patients with mRCC. As more and more combination trials began reporting out data, the choice for front line therapy becomes increasingly difficult. Future biomarker work may be important to define which patient populations best respond to immunotherapy, combination immunotherapy with TKI, or TKI alone. PD-L1 is not a reliable biomarker for response to immunotherapy for mRCC and gene signatures may be a better option in the future.  An excellent review in the NEJM published at the same time as this oral presentation offers expert commentary comparing this combination therapy to avelumab/axi.4

Presented by: Thomas Powles, MD, PhD, FCRP, Professor of Genitourinary Oncology, Lead for Solid Tumour Research at Barts Cancer Institute, Director of Barts Cancer Centre

Written by: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University, @TheRealJasonZhu at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA

References:
  1. Lee C-H, Makker V, Rasco DW, et al. Lenvatinib+ pembrolizumab in patients with renal cell carcinoma: Updated results. American Society of Clinical Oncology; 2018.
  2. Choueiri TK, Larkin JMG, Oya M, et al. First-line avelumab + axitinib therapy in patients (pts) with advanced renal cell carcinoma (aRCC): Results from a phase Ib trial. Journal of Clinical Oncology 2017;35:4504-.
  3. Atkins MB, Plimack ER, Puzanov I, et al. Safety and efficacy of axitinib (axi) in combination with pembrolizumab (pembro) in patients (pts) with advanced renal cell cancer (aRCC). Journal of Clinical Oncology 2018;36:579-.
  4. Escudier B. Combination Therapy as First-Line Treatment in Metastatic Renal-Cell Carcinoma.0:null.
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