AstraZeneca's Imfinzi/Tremelimumab Combo Conquers HIMALAYA
Improves Overall Survival In Liver Cancer Patients
Executive Summary
After the combination's success in the non-small cell lung cancer POSEIDON study, AstraZeneca's Imfinzi and tremelimumab could now be on the way to approval as a first-line treatment for hepatocellular carcinoma.
A combination of AstraZeneca PLC's PD-L1 inhibitor Imfinzi and its much-maligned investigational CTLA-4 inhibitor tremelimumab has sprung a very pleasant surprise by improving survival rates in liver cancer patients.
The UK major has unveiled topline results from the closely watched HIMALAYA Phase III study which showed that a single, high-priming dose of tremelimumab added to Imfinzi (durvalumab) demonstrated a significant overall survival (OS) benefit versus Bayer AG/Amgen, Inc.’s long-time standard of care Nexavar (sorafenib) as a first-line treatment for patients with unresectable hepatocellular carcinoma (HCC). Observers will have to wait until detailed data are presented at a forthcoming medical meeting to see the extent of the benefit but the topline represents a somewhat surprising success for HIMALAYA, which enrolled 1,324 patients and was conducted in 190 centres across 16 countries.
The surprise principally lies with the benefit seen of adding tremelimumab which has failed to show any in a number of trials in other tumor types. The combination of the CTLA-4 agent with Imfinzi has had a poor track record, posting failures in small cell lung, head and neck and bladder cancer trials. (Also see "CASPIAN Proves Too Choppy For AZ Imfinzi/Tremelimumab Combo" - Scrip, 17 Mar, 2020.) (Also see "Imfinzi Racks Up Another Phase III Failure, But AZ Undeterred" - Scrip, 6 Mar, 2020.) (Also see "AstraZeneca’s Imfinzi Fails Again In Head And Neck Cancer" - Scrip, 5 Feb, 2021.)
The most high-profile flops were in non-small cell lung cancer. In 2019, the Imfinzi/tremelimumab combination failed to improve OS in metastatic NSCLC patients with a high tumor mutational burden in the Phase III NEPTUNE study, following another major disappointment for the combo in the MYSTIC first-line NSCLC trial in 2018. (Also see "Mystic Miss Not Make Or Break For Imfinzi" - Scrip, 16 Nov, 2018.) (Also see "AstraZeneca’s Imfinzi-Treme Checkpoint Inhibitor Combination Fails Again In NSCLC" - Scrip, 21 Aug, 2019.)
The combination did achieve an unexpected win in the POSEIDON trial where, used together with chemotherapy, it improved OS in first-line NSCLC. However, the data failed to match the performance of rival immunotherapies, especially Merck & Co., Inc.’s market leader Keytruda (pembrolizumab).
At face value, the HIMALAYA results suggest that AstraZeneca may have been right to persist with tremelimumab. The company noted that Imfinzi alone only managed to demonstrate non-inferior OS to Nexavar, although with a numerical trend in favor of Imfinzi and an improved tolerability profile compared with the Bayer/Amgen therapy, a multi-kinase inhibitor.
Susan Galbraith, head of oncology R&D at AstraZeneca, noted that inhibition of CTLA-4 "has shown the ability to drive benefit particularly in the tail of the survival curve in several settings." She said that "this is the first time a dual immunotherapy regimen has improved overall survival as a first-line treatment for patients with unresectable liver cancer for whom treatment options are limited and long-term outcomes are poor.”
The dosing regime, with tremelimumab 300mg added to Imfinzi 1500mg followed by Imfinzi every four weeks, could be key, and HIMALAYA's principal investigator Ghassan Abou-Alfa of Memorial Sloan Kettering Cancer Center, added that the study was the first Phase III trial to add a novel single priming dose of an anti-CTLA4 antibody to another checkpoint inhibitor. “This serves to boost the patient’s own immune system against their liver cancer, aiming to maximise long-term survival with minimal side effects,” he said.
Ready To Take On Roche's Combo
Securing a first-line HCC approval for the Imfinzi/tremelimumab combination would put AstraZeneca in a strong position to challenge its fellow immunotherapy player Roche Holding AG. In June 2020, the US Food and Drug Administration approved the Swiss firm's PD-L1 inhibitor Tecentriq (atezolizumab) in combination with Roche's own anti-VEGF blockbuster Avastin (bevacizumab) for people with unresectable or metastatic HCC who have not received prior systemic therapy. That green light was based on results from the IMbrave150 study, which was the first Phase III cancer immunotherapy trial to show an improvement in both OS and progression-free survival in that subset of patients compared with Nexavar. (Also see "ASCO 2020: Roche Highlights TIGIT As Tecentriq Bags Another Approval" - Scrip, 1 Jun, 2020.)
AstraZeneca's other rivals have fared less well in HCC. In July last year, the FDA issued a complete response letter for Merck and Eisai Co., Ltd.'s bid for accelerated approval of their Keytruda/Lenvima (lenvatinib) combination in first-line HCC, with the agency saying that the application, which was based on the Phase Ib KEYNOTE-524/Study 116 trial, did not provide evidence that the combo with the multiple kinase inhibitor represents a meaningful advantage over available therapies. (Also see "Keytruda/Lenvima CRL To Give Roche More Space In 1L HCC?" - Scrip, 10 Jul, 2020.)
Merck and Eisai have not given up, however. The LEAP-002 Phase III program comparing the combo with Lenvima monotherapy in first-line advanced HCC is scheduled to read out in the middle of 2022.
Bristol Myers Squibb Company’s combination of its PD-1 inhibitor Opdivo (nivolumab) plus the company's CTLA-4 inhibitor Yervoy (ipilimumab) is being evaluated for first-line HCC in the Checkmate-9DW trial, the results of which are expected in 2023. In 2017, Opdivo became the first drug in the PD-1/PD-L1 inhibitor class approved in the US for the treatment of advanced HCC patients who have progressed on Nexavar but the drug failed the confirmatory first-line Phase III CheckMate 459 trial and was withdrawn as a second-line treatment as well in July this year; the Opdivo/Yervoy combo is still on the market for second-line HCC. (Also see "BMS' Bid For Opdivo In First-Line HCC Stymied" - Scrip, 24 Jun, 2019.)