Merck's Keytruda Secures Confirmatory Phase III Success in Second-Line Hepatocellular Carcinoma, Alleviating Withdrawal Concerns

On September 27, MSD announced that the Phase III KEYNOTE-394 study met its primary endpoint. In Asian patients with hepatocellular carcinoma previously treated with sorafenib, Keytruda plus best supportive care (BSC) demonstrated a statistically significant improvement in overall survival compared with placebo plus BSC.

Additionally, the KEYNOTE-394 trial met the key secondary endpoints of progression-free survival (PFS) and objective response rate (ORR). No new safety signals were identified, and detailed results will be presented at an upcoming medical conference.

With this announcement, a heavy weight was finally lifted off MSD's shoulders.

In November 2018, Keytruda received accelerated approval from the FDA for patients with hepatocellular carcinoma previously treated with sorafenib, based on ORR and DOR data from the KEYNOTE-224 study. However, the primary endpoints of OS and PFS were not met in the subsequent confirmatory KEYNOTE-240 study.

In late April this year, the FDA Oncologic Drugs Advisory Committee convened a three-day meeting specifically to review six indications for certain PD-1/PD-L1 inhibitors that were approved via the "accelerated approval" pathway but subsequently failed in confirmatory clinical trials, to determine whether they should remain on the market. These included three indications for Keytruda, two for Tecentriq, and one for Opdivo. The indications for second-line treatment of hepatocellular carcinoma for both Keytruda and Opdivo were not spared and were both included in the discussion.

On July 23, following communications with the FDA, BMS ultimately announced the voluntary withdrawal of the U.S. approval for Opdivo monotherapy for the indication of treating patients with hepatocellular carcinoma (HCC) who had previously received sorafenib. In contrast to Opdivo's disappointing outcome, Keytruda still retains a chance to maintain its approval for this indication. This is because the FDA Oncologic Drugs Advisory Committee (ODAC) had previously voted 8-to-0 to temporarily maintain Keytruda's approval status for this indication, while designating the KEYNOTE-394 study as the confirmatory trial to evaluate whether Keytruda provides clinical benefit to patients who have failed prior sorafenib therapy.

Regarding the liver cancer indication, following BMS's withdrawal of Opdivo monotherapy, the company still retains the Opdivo + Yervoy combination therapy as a strategic fallback. As a second-line therapy following sorafenib, it can continue to capture a share of the market. MSD, however, has only Keytruda to rely on; should it be withdrawn, the impact would undoubtedly be substantial. This is because liver cancer is one of the major indications for which MSD secured early regulatory approval, and it remains a crucial pillar supporting Keytruda's sales revenue in the U.S. market.

Liver cancer is the fourth leading cause of cancer-related mortality worldwide. Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the fastest-growing cause of cancer-related death in the United States, with an estimated 42,200 new cases and 30,300 deaths projected in 2021. HCC is typically diagnosed at an advanced stage, where effective treatment options are limited and the 5-year survival rate for first-line standard-of-care therapies is less than 15%. Treatment options for patients who experience disease progression following sorafenib therapy are extremely limited, representing an urgent unmet clinical need.

Prior to this, two indications for Keytruda had already been withdrawn. On March 1, MSD announced in the United States the voluntary withdrawal of the Keytruda indication for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy. On July 1, MSD announced in the United States the voluntary withdrawal of the Keytruda indication for the treatment of patients with PD-L1-positive (CPS ≥ 1) recurrent, locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma who have progressed on or after two or more prior lines of therapy, including fluoropyrimidine- and platinum-containing chemotherapy and HER2/neu-targeted therapy, as appropriate.

MSD stated that it will discuss this matter with regulatory authorities as soon as possible.

Note: The original text has been abridged.