AstraZeneca climbs a Himalaya to find ill-fated treme a place alongside Imfinzi in liver cancer

AstraZeneca’s star-crossed cancer immunotherapy tremelimumab all but looked like a dud until recently. Now, the British pharma has a win that shows the drug has at least some worth in liver cancer.

A combination of tremelimumab and AstraZeneca’s Imfinzi extended the lives of newly diagnosed patients with unresectable hepatocellular carcinoma—the most common type of liver cancer—compared with Bayer’s Nexavar. The risk of death was 22% lower for the AZ combo versus the aging standard of care in a phase 3 study, according to data unveiled at the 2022 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers symposium.

The latest win came after a string of trememliumab-Imfinzi trial flops that only recently ended with a modest success in lung cancer. However, a detailed look at the data still leaves some questions about treme’s strength and the AZ regimen’s place in an increasingly competitive indication for immuno-oncology agents.

For the phase 3 HIMALAYA trial in front-line liver cancer, AZ used a novel approach called Stride, which involves a single dose of CTLA-4 inhibitor treme at 300 mg and PD-L1 agent Imfinzi at its regular 1,500 mg to prime a patient, followed by Imfinzi alone every four weeks. That regimen that cut the death risk by 22% over Nexavar. Patients lived a median 16.4 months on the AZ therapy versus 13.8 months for the Bayer med.

Treme seemed to have pulled its weight; Imfinzi monotherapy only matched up to Nexavar in extending patients’ lives, with a death risk reduction of just 14%. Meanwhile, recruitment in another arm of the study that used four doses of treme at 75 mg plus Imfinzi stopped early after a phase 2 trial found the regimen didn’t differ meaningfully from Imfinzi monotherapy.

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Still, the successful treme-Imfinzi arm has its own problem. For starters, Imfinzi-treme’s 22% death risk reduction over Nexavar, while statistically significant, isn’t a big improvement from Imfinzi monotherapy’s 14%, although the trial wasn’t designed to make that comparison. In addition, patients on solo Imfinzi lived a median 16.6 months, which is also similar to the combo’s showing.

The difference between the trial’s Imfinzi treatment arms started to show the third year into treatment. While the two regimens’ two-year survival rates were similar at around 40%, the three-year number was 30.7% for the group that also got treme, versus 24.7% for Imfinzi monotherapy. The dual-drug regimen also shrunk tumors slightly better and showed longer duration of response.

The three-year overall survival rate for the combo is unprecedented, AZ said in a statement. 

But with the addition of treme comes more side effects: Grade 3/4 treatment-related side effects happened in 25.8% of patients in the combo arm, higher than the 12.9% rate for Imfinzi alone. The number was highest for Nexavar, at 36.9%.

“The three-year overall survival rate and favorable safety profile seen with the Stride regimen set a new benchmark in this setting,” said Ghassan Abou-Alfa, M.D., of Memorial Sloan Kettering Cancer Center and principal investigator in the HIMALAYA trial, in a statement.

In another weak showing, Imfinzi and treme failed to deliver a significant benefit on slowing tumor progression. The finding deserves further discussion, Cathy Eng, M.D., an ASCO expert in gastrointestinal cancers, said in a statement.

With all these caveats, industry watchers and doctors might still question treme’s strength despite HIMALAYA being a positive trial result. The drug’s past failures in non-small cell lung cancer (NSCLC), bladder cancer and head and neck cancer certainly won’t help. The CTLA-4 drug’s first success, in a cocktail with Imfinzi and chemotherapy, only pared down the risk of death by 23% over chemo alone in previously untreated NSCLC, an efficacy figure that looks not only inferior to Merck’s market-leading Keytruda but also to Bristol Myers Squibb’s rival combo of Opdivo, Yervoy and chemo. At least treme also came to rescue in that indication, as Imfinzi’s sole addition to chemo didn’t move the needle on survival.

RELATED: Roche's Tecentriq gets a green light to challenge Bayer with first-in-class liver cancer nod

The current AZ regimen’s 22% risk reduction is also no match to Roche’s pairing of PD-L1 inhibitor Tecentriq with VEGF inhibitor Avastin. As the first FDA approval for a PD-1/L1 inhibitor in front-line liver cancer, that Roche regimen slashed the risk of death by 42% and the risk of disease progression or death by 41% compared with Nexavar in the phase 3 Imbrave150 study.

Merck is also chasing closely with the formidable Keytruda in a combo with Eisai-partnered TKI Lenvima, which has its own frontline liver cancer nod in 2018 based on noninferior survival data with Nexavar. The phase 3 LEAP-002 trial testing that combo is expected to read out later this year.

At this point, AZ could argue that treme and Imfinzi offer a pure I-O option and could fit with patients who can’t tolerate a TKI. But Bristol Myers isn’t too far behind with its own PD-1/CTLA-4 combo of Opdivo and Yervoy, as the phase 3 CheckMate-9DW trial testing that theory could read out in 2023. If positive, the regimen would be a more direct threat to AZ.

Editor's Note: The story has been updated with additional comments from AstraZeneca and Ghassan Abou-Alfa, M.D.