April 25, 2019
Impact level: High
- According to an updated label, FDA has granted accelerated approval to use of Keytruda (pembrolizumab; PD-1) in combination with Inlyta (axitinib; TKI) in 1L renal cell carcinoma (RCC).
In October 2018, Merck announced that the combination of Keytruda/Inlyta (KEYNOTE-426) had demonstrated significant improvements in OS, PFS, and ORR when compared to Sutent (sunitinib). The revised FDA label shows that the overall survival hazard ratio was 0.53 (p<0.0001) for the Keytruda/Inlyta arm, compared to the Sutent control. At a median follow-up of 12.8 months, mOS was not reached in either arm. Additionally, the Keytruda/Inlyta combination demonstrated a 4-month improvement in mPFS (15.1 vs 11.1 mon; HR=0.69, p=0.0001). ORR, a secondary endpoint, was 59% vs 36% (p<0.0001).
Despite the clear OS and PFS benefit, FDA has granted an accelerated approval, based on “tumor response rate and durability of response.” Conversion to regular approval status seems likely once the survival data are mature.
This approval came well before the June 20, 2019 PDUFA date. FDA is also reviewing a 1L RCC Bavencio/Inlyta filing from Merck KGaA and Pfizer (PDUFA date in June 2019). At last report, OS results from the Bavencio/Inlyta registrational trial, JAVELIN Renal 101, were immature. Given the impressive OS benefit in KEYNOTE-426, Merck appears to have the edge in this evolving PD-1 axis inhibitor/Inlyta combination showdown. Merck now also has a first mover advantage, although if FDA acts on the Bavencio/Inlyta filing in a similarly expeditious manner, Merck’s head start could be minimal. Pfizer markets Inlyta and this could help in promotion of the Bavencio/Inlyta combo if it is approved. Both of these PD-1/PD-L1 combination therapies will also compete with Bristol’s Opdivo/Yervoy, which is already labeled for the 1L RCC setting.
Keytruda as a monotherapy (KEYNOTE-564) and in combination with Lenvima (lenvatinib) (KEYNOTE-581) is being advanced in additional Phase 3 studies for RCC subsets.
Source: Updated Keytruda label