Bristol Myers Squibb is gunning for newly diagnosed unresectable liver cancer—again—after an immunotherapy setback five years ago.

The dual immunotherapy combination of Opdivo and Yervoy showed it can prolong the lives of patients with previously untreated advanced hepatocellular carcinoma compared with either Bayer’s Nexavar or Eisai’s Lenvima, BMS said Wednesday.

The overall survival win came from the phase 3 CheckMate-9DW trial. BMS said it’ll evaluate the data in full and share the results with the scientific community and drug regulators.

The front-line CheckMate-9DW study serves as the confirmatory trial for Opdivo and Yervoy’s accelerated approval in the second-line, post-Nexavar setting, which was granted by the FDA in 2020.

If the FDA eventually gives the combo its go-ahead in the first-line setting, the Opdivo-Yervoy regimen will compete with Roche’s and AstraZeneca’s PD-L1 regimens. Besides those two companies, other immunotherapy players are eyeing the same field.

The positive first-line readout comes nearly three years after BMS, under pressure from the FDA, voluntarily pulled Opdivo monotherapy as a post-Nexavar liver cancer treatment from the U.S. market. The decision followed Opdivo’s failure as a first-line treatment in the CheckMate-459 trial. Data released in 2019 showed that Opdivo alone only reduced the risk of death by a nonstatistically significant 15% versus Nexavar.

Since that trial flop, Roche’s Tecentriq and Avastin in 2020 became the first immunotherapy-based treatment to be approved in previously untreated advanced liver cancer. In the IMbrave150 study, the Tecentriq-Avastin regimen slashed the risk of death by 42% versus Nexavar. In Roche’s most recent quarterly report, first-line liver cancer was cited as one of the two main growth drivers for Tecentriq.

AstraZeneca joined the first-line club in 2022 with its dual immunotherapy combo Imfinzi and Imjudo. In the phase 3 HIMALAYA trial, the AZ combo cut the risk of death by 22% against Nexavar, as the British pharma touted a 30.7% three-year survival rate for its regimen. With first-line approvals in liver cancer and non-small cell lung cancer, Imjudo collected $218 million in sales last year.

But the competitive picture isn’t complete just yet. Elevar Therapeutics and Hengrui Pharma’s applications for their China-approved combination of the VEGFR inhibitor rivoceranib (also known as apatinib) and the PD-1 inhibitor camrelizumab in first-line liver cancer are awaiting an FDA decision expected in May. During an interim analysis of an international phase 3 study coded CARES-310, rivoceranib and camrelizumab significantly cut the risk of death by 38% versus Nexavar.

And last year, Roche reported what some analysts viewed as very encouraging phase 1/2 data for its triple combination of Tecentriq, Avastin and the TIGIT inhibitor tiragolumab in first-line liver cancer. Roche in September advanced that triplet regimen into a phase 3 study called SKYSCRAPER-14, or IMbrave152.

Meanwhile, Merck in 2022 surprisingly found that its combination of Keytruda and Lenvima couldn’t top Lenvima alone at extending patients’ lives in first-line liver cancer. The New Jersey pharma is also exploring the possibility of adding its anti-TIGIT candidate vibostolimab to Keytruda in phase 2.