Innate Pharma’s new checkpoint inhibitor, monalizumab, currently in development for solid tumours, is now being discontinued in head and neck squamous cell carcinoma (HNSCC). Monalizumab failed to meet a pre-defined threshold of efficacy during a planned futility interim analysis of the INTERLINK-1 Phase III study, which has led AstraZeneca, the drug’s co-developer, to terminate the study.

Monalizumab is an anti-NKG2A monoclonal antibody that aims to promote cancer cell killing mediated by NKG2A-expressing immune cells. NKG2A is considered to be a novel checkpoint in solid tumours. Monalizumab’s pivotal clinical trial in HNSCC, INTERLINK-1, was in combination with Eli Lilly’s EGFR antibody, Erbitux (cetuximab). The combination had previously demonstrated a 32.5 overall response rate in a Phase I/II study, with a very unclear benefit over Erbitux alone. As such, the Phase III failure was not a complete surprise to investors.

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In non-small cell lung cancer (NSCLC), AstraZeneca and Innate are following a slightly different strategy with the pivotal PACIFIC-9 trial by targeting a population where AstraZeneca’s Imfinzi (durvalumab) is the current market leader. This population consists of Stage III unresectable patients following concurrent chemoradiation; monalizumab is being investigated in combination with Imfinzi, or with the novel anti-CD70 antibody oleclumab, versus Imfinzi as a single agent. Previous Phase II data from the COAST trial showed that both oleclumab and monalizumab can prolong progression-free survival (PFS) compared to Imfinzi alone. Specifically, the 12-month PFS for Imfinzi monotherapy was 33.9%, while for the combination with oleclumab, it was 62.6%, and for the combination with monalizumab, it was 72.7%. If these results hold up in the PACIFIC-9 study, a monalizumab combination could see very high clinical uptake in the Stage III unresectable setting.

While Innate and AstraZeneca are making an admirable effort to investigate novel checkpoint inhibitors, this is a high-risk, high-reward approach, especially considering the numerous recent failures of novel checkpoint molecules. Despite this, the failure of monalizumab in HNSCC is viewed as a temporary setback. According to previous GlobalData estimates, Imfinzi could become a blockbuster in the NSCLC unresectable setting, meaning that both oleclumab and monalizumab have a good chance of generating very lucrative combined revenue. Monalizumab is also being investigated in a Phase II study in the neoadjuvant and adjuvant NSCLC settings, which can be highly lucrative. PD-1 and PD-L1 inhibitors have, however, already started to infiltrate this area, making monalizumab a late-mover in this setting. Consensus analyst forecasts predict revenues for monalizumab to surpass $200m worldwide by 2028.

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