656MO - Phase I study of M6620 (VX-970, berzosertib) in combination with cisplatin and XRT in patients with locally advanced head and neck squamous cell carcinoma

Background

M6620 is a highly potent and selective ATP-competitive ATR inhibitor. It showed strong synergy with cisplatin and radiation in preclinical cancer models. The significant vulnerability to ATR inhibition by cancer cells harboring inactivating p53 mutations provided a rationale to test the safety of M6620 along with definitive chemoradiation in Head and Neck Squamous Cell Carcinoma (HNSCC) where such alterations are common.

Methods

Eligible patients with stage III or IV HNSCC not amenable to surgical resection were enrolled in defined dose cohorts using the Escalation with Overdose Control (EWOC) design. The optimal dose of cisplatin (40 or 30mg/m2 weekly) to combine with standard radiation (70Gy) and biologically relevant dose of M6620 (120mg/m2) was tested in stage I. The safety of escalating doses of M6620 across a range of 160 to 280mg/2 along with fixed dose cisplatin and XRT (70Gy) was planned in stage II of the study.

Results

We enrolled 43 patients; median age 60 years (range 45-76); 11.6% Black; 37.2% females. The most common treatment emergent adverse events (TEAE) in 39 evaluable patients were: Anemia (74%), Nausea (72%), Fatigue (69%), Dysphagia (69%), Lymphopenia (69%) and Leukopenia (67%) while the most frequent grade ≥3 TEAE occurring in ≥ 20% of patients were Lymphopenia (31%), Leukopenia (28%), Anemia (26%), Dysphagia (21%), and Neutropenia (21%). Dose limiting toxicities recorded on study included Dysphagia, neutropenia, thrombocytopenia, febrile neutropenia, intestinal hemorrhage, pseudogout and hypomagnesemia. M6620 was safely combined with cisplatin (40mg/m2) and XRT (70Gy) at doses of 120, 160 and 200mg/m². The highest dose of 200mg/m² plus standard chemoradiation was declared the recommended phase 2 dose. Unconfirmed best response in 20 evaluable patients by RECIST were complete response (30%), partial response (40%), stable disease (15%) and progressive disease (10%). Ongoing PK and tissue-based biomarker analysis will be presented at the meeting.

Conclusions

M6620 at the dose of 200mg/m² was safe and was declared the RP2D in combination with weekly cisplatin (40mg/m2) and standard XRT (70Gy) in locally advanced HNSCC with encouraging initial efficacy.

Clinical trial identification

NCT02567422.

Editorial acknowledgement

Legal entity responsible for the study

NCI CTEP.

Funding

US National Institutes of Health.

Disclosure

J.W. Riess, T.K. Owonikoko: Financial Interests, Personal, Advisory Board: EMD Serono. All other authors have declared no conflicts of interest.