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August 11, 2022

Novel checkpoint inhibitors hit by another setback, but opportunities remain

A trial of novel checkpoint inhibitor monalizumab has been terminated after the drug failed to meet the efficacy threshold.

By GlobalData Healthcare

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.

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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