BMS Submits sBLA for Opdivo plus Yervoy Combination Therapy in Previously Treated Advanced Hepatocellular Carcinoma

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On November 11, Bristol-Myers Squibb (BMS) announced that the U.S. FDA had accepted its supplemental Biologics License Application (sBLA) and granted Breakthrough Therapy Designation to the Opdivo and Yervoy immunotherapy combination (hereinafter referred to as the “OY” combination) for the treatment of patients with advanced hepatocellular carcinoma (HCC) who had previously received sorafenib therapy. The FDA has granted priority review to this sBLA, with a PDUFA target action date of March 10, 2020.

Liver cancer is the fourth leading cause of cancer-related deaths worldwide, and hepatocellular carcinoma (HCC) is the most common type of liver cancer, as well as the fastest-rising cause of cancer-related mortality. Sorafenib, an oral kinase inhibitor developed by Bayer, was approved by the U.S. FDA in November 2007 and currently serves as the first-line standard-of-care treatment for HCC. In April 2017, Bayer’s another oral multi-kinase inhibitor, Stivarga, received FDA approval, becoming the first new drug for liver cancer in the U.S. market in nearly a decade. It is indicated for the second-line treatment of HCC patients who have previously undergone sorafenib therapy (sorafenib-treated).

Currently, liver cancer has become a hotspot in new drug development. According to search results from the FDA’s new drug database, six drugs were approved for the treatment of hepatocellular carcinoma (HCC) between 2017 and 2019. In addition to Stivarga, these include Opdivo (September 2017, for patients previously treated with sorafenib), Lenvima (June 2018, first-line treatment), Keytruda (November 2018, for patients previously treated with sorafenib), Cabometyx (January 2019, for patients previously treated with sorafenib), and Cyramza (May 2019, for sorafenib-pretreated patients with elevated alpha-fetoprotein levels). Among these drugs, Stivarga, Lenvima, and Cabometyx are kinase inhibitors; Opdivo and Keytruda are PD-(L)1 immune checkpoint inhibitors; and Cyramza is a monoclonal antibody-based angiogenesis inhibitor.

Both drugs in the OY combination are cancer immunotherapies that leverage the body’s own immune system to fight tumors by targeting distinct regulatory components within the immune system. Opdivo targets and blocks the PD-1/PD-L1 pathway, while Yervoy targets and blocks CTLA-4. The OY combination is the most important therapeutic regimen in Bristol-Myers Squibb’s oncology pipeline. In addition to hepatocellular carcinoma (HCC), the company is evaluating this combination for use in multiple other tumor types.

This sBLA is based on the results from the OY cohort of the Phase I/II CheckMate-040 study (NCT01658878). This is an ongoing, open-label, multi-cohort study evaluating the efficacy and safety of Opdivo or Opdivo-based combination therapies in patients with advanced hepatocellular carcinoma (HCC), who are either sorafenib-naïve, intolerant to sorafenib, or have experienced disease progression during sorafenib treatment, regardless of viral hepatitis status. The OY cohort is assessing three dosing regimens:

Group A: Opdivo 1 mg/kg in combination with Yervoy 3 mg/kg (O1Y3) administered once every 3 weeks (Q3W) for 4 cycles, followed by Opdivo 240 mg administered once every 2 weeks (Q2W);

Group B: Combination regimen of Opdivo 3 mg/kg and Yervoy 1 mg/kg (O3Y1) administered every 3 weeks for 4 cycles, followed by Opdivo 240 mg every 2 weeks;

Group C: Opdivo 3 mg/kg Q2W and Yervoy 1 mg/kg every 6 weeks (Q6W).

The initial data from the study were presented at the 2019 ASCO Annual Meeting. The data showed that, with a minimum follow-up of 28 months, the objective response rate (ORR) assessed by blinded independent central review was 31%, and the median duration of response at the data cutoff was 17.5 months (95% CI: 11.1–N/A). Meaningful responses were observed in all three treatment groups. Among them, patients in Group A experienced the longest median overall survival (OS) in the cohort, at 22.8 months (95% CI: 9.4–N/A), with a 30-month OS rate of 44% (95% CI: 29.5–57).

Efficacy was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The disease control rates for the three groups were 54%, 43%, and 49%, respectively. In the overall cohort, 5% of patients achieved a complete response and 26% achieved a partial response; response was independent of baseline tumor PD-L1 status. The OY combination demonstrated an acceptable safety profile, with no new safety signals identified in any treatment group.

Reference Source: U.S. Food and Drug Administration Accepts for Priority Review Bristol-Myers Squibb’s Application for Opdivo (nivolumab) Plus Yervoy (ipilimumab) Combination for Patients with Previously Treated Advanced Hepatocellular Carcinoma