BeiGene, Novartis' tislelizumab stages comeback with broader stomach cancer trial win

When BeiGene and Novartis announced a partial trial win for tislelizumab in stomach cancer, doubts started to circulate around the PD-1 inhibitor’s potential. Now, the partners have come back with broader success.

Tislelizumab’s ability to extend lives in newly diagnosed advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma now covers all patients with or without PD-L1 expression in their tumors, BeiGene said Thursday.

Pending detailed data, the new revelation from the RATIONALE 305 trial could vindicate tislelizumab in stomach cancer, a PD-1/L1 niche where BeiGene hopes to gain a foothold. Previously, at an interim analysis, only patients with PD-L1-positive tumors in the trial experienced a statistically significant improvement in overall survival.

In that analysis, tislelizumab and chemotherapy cut the risk of death by 26% compared with chemo alone in PD-L1-positive stomach cancer after a median follow-up of about 12 months, according to data presented at the ASCO Gastrointestinal Cancers Symposium in January. Patients on the tislelizumab regimen lived a median 17.2 months versus 12.6 months in the control group.

At that time, study presenter Markus Moehler, M.D., Ph.D., from the Johannes Gutenberg University Clinic in Germany, said the team will have additional data on all trialed patients later this year.

But the lack of a showing then in a broader patient population came in contrast with PD-L1-agnostic wins posted by Merck & Co.’s Keytruda and Bristol Myers Squibb’s Opdivo.

In its own phase 3 trial, Keytruda, used on top of chemo, reduced the risk of death by 22% in gastric or GEJ cancers regardless of PD-L1 expression. Opdivo in 2021 became the first PD-1/L1 drug approved in stomach cancer after showing its addition to chemo pared down death risks by 20% in gastric cancer, GEJ cancer and esophageal adenocarcinoma.

That’s not to say Keytruda and Opdivo are extremely powerful in PD-L1-negative patients. In both cases, the two market-leading PD-1 inhibitors only mounted an 8% death risk reduction in PD-L1-negative disease.

Based on the RATIONALE 305 data, Chinese authorities recently approved tislizumab as a first-line treatment for advanced gastric or GEJ adenocarcinoma, but only for PD-L1 expressers.

Opdivo is currently the only PD-1 drug approved for stomach cancer—Keytruda has a separate approval for HER2-positive disease—so tislelizumab may be able to gain a foothold in this field, BeiGene’s R&D head, Lai Wang, Ph.D., told Fierce Biotech last year.

Meanwhile, Novartis and BeiGene are awaiting a long-delayed FDA decision on tislelizumab’s first indication. Thanks to COVID-related travel restrictions, the FDA only recently scheduled a manufacturing inspection in China for tislelizumab’s application in previously treated esophageal squamous cell carcinoma for the second quarter, about a year after the original target decision date.

A follow-up submission in gastric cancer, along with some other indications, is planned for this year, Novartis said in its most recent earnings report.