July 8, 2020

Impact: High

  • FDA has issued a CRL (Complete Response Letter) in response to the sBLA for the combination of Keytruda/Lenvima (pembrolizumab/lenvatinib) to treat first-line (1L) unresectable HCC (hepatocellular carcinoma). This application was supported by Merck and Eisai.
  • The application was based on data from the phase 1b single-arm KEYNOTE-524 (Study 116; NCT03006926) trial. The combination had previously received Breakthrough Therapy Designation and the companies sought Accelerated Approval. Key efficacy data from -524 were presented at ASCO 2020 and included:
    • mOS: 22 months
    • ORR (Objective Response Rate): 36% (CR rate: 1%)
    • mDoR (median Duration of Response): 12.6 months
  • According to the press release, the main reason for the CRL was that Keytruda/Lenvima did not represent a meaningful advantage over currently available therapies in 1L HCC. Notably, the combination of Tecentriq/Avastin (atezolizumab/bevacizumab) in 1L HCC was approved 4 weeks earlier on the basis of benefits observed for mOS (median Overall Survival) and mPFS (median Progression-Free Survival) in a phase 3 active comparator study.
  • Merck/Eisai still plan to submit for a full approval of Keytruda/Lenvima based on the LEAP-002 trial in 1L HCC. This trial is fully enrolled.


BeiGene submits sNDA for tislelizumab in China for 2L+ HCC

  • BeiGene announced that the Center for Drug Evaluation (CDE) of the NMPA (China National Medical Products Administration) has accepted a sNDA of tislelizumab monotherapy for the treatment of patients with previously treated unresectable HCC.
  • The submission is based on a pivotal phase 2 trial (NCT03419897) which is anticipated to be presented at an upcoming medical conference.

inThought Analysis

The issuing of a CRL here is surprising. Of late, FDA has tended to take a more lenient stance that permits the availability of a greater number of approved treatment options for oncology patients and lets physicians decide which treatment option is best suited for their specific patients. Further, Keytruda/Lenvima represents a differentiated product option when compared to Tecentriq/Avastin. These key differentiators include PD-1 v. PD-L1 targeting and oral v. intravenous delivery of the VEGF inhibiting agent. Further, in a cross-trial comparison, the ORR for Keytruda/Lenvima in KEYNOTE-524 was higher than that included on the Tecentriq/Avastin label (36% v. 28% ORR). Yet, mOS comparison was less clear – 22.0 months for Keytruda/Lenvima v. not reached out to 17 months for Tecentriq/Avastin. Nonetheless, although a hardline stance, the CRL driven by a full approval (although just 4 weeks earlier) for a competing combination with a more robust dataset does align with traditional FDA protocols.

As a result of this Keytruda/Lenvima setback, Tecentriq/Avastin is now convincingly out ahead in the important frontline setting. Targeting of PD-1/PD-L1 and VEGF signaling remains a key approach in HCC. This strategy is also being pursued in China by Jiangsu HengRui via a phase 3 study of camrelizumab/apatinib and by Innovent/Lilly via a phase 3 study of sintilimab/IBI305. Other agents in phase 3 frontline HCC studies include BeiGene’s tislelizumab (global trial), AstraZeneca’s durvalumab/tremelimumab, and the Exelixis kinase inhibitor cabozantinib in combination with atezolizumab.

In June 2019, Bristol announced negative topline results from its phase 3 CheckMate-459 trial of Opdivo (nivolumab) in 1L unresectable HCC. A frontline trial exploring the Opdivo/Yervoy (ipilimumab) combination, CheckMate 9DW, is ongoing.

In 2L HCC, Keytruda, Opdivo, and Opdivo/Yervoy currently have Accelerated Approvals based on response rates.

Source: Merck Press Release, BeiGene Press Release