A phase II trial to evaluate the epithelial-to-mesenchymal (EMT) inhibitor sotevtamab combined with docetaxel in patients with metastatic non-small cell lung cancer following failure of primary chemoimmunotherapy.

8577 Background: Sotevtamab is an investigational humanized monoclonal antibody that binds to tumor associated secreted clusterin (TA-sCLU). TA-sCLU is a potent inducer of the epithelial-to-mesenchymal transition (EMT), a process known to contribute to tumor invasion, metastasis, chemoresistance and immune evasion. Sotevtamab abrogates the EMT-promoting activity of TA-sCLU by inhibiting its ability to be internalized in cancer cells. Methods: An open-label, single-arm, multi-center Phase II clinical study of sotevtamab administered in combination with docetaxel was performed in subjects with metastatic non-small cell lung cancer who had experienced progression following frontline immunochemotherapy. 35 subjects were enrolled from March 2021 to November 2022 and the study was completed in December 2023. Sotevtamab was administered at a dose of 12 mg/kg once weekly on Days 1, 8 and 15 combined with docetaxel at a dose of 75 mg/m 2 once every 3 weeks on Day 1. One cycle of treatment consisted of 21 days. The primary objectives were to determine the objective response rate (ORR) and the safety and tolerability of the combination. Tumor biopsies were performed prior to study initiation and after two cycles of therapy for pharmacodynamicevaluation. Results: As per interim data obtained from a rolling database lock performed in February 2023, the mean subject age was 63 and 22 patients (63%) were female. Of the 35 subjects, 28 were diagnosed with adenocarcinoma, 6 with squamous cell carcinoma and 1 with adenosquamous carcinoma; 11 were ECOG 0, 22 ECOG 1 and 2 ECOG 2. Six subjects with adenocarcinoma had a partial response for an ORR of 17.1%. Stable disease (SD) was experienced in an additional 10 subjects (9 adenocarcinomas and one squamous cell carcinoma) for an SD rate of 28.6%. The observed responses were sustained with a median duration of over one year (405 days). The estimated one-year survival rate was 33.9%. The most frequent adverse events were fatigue, infusion related reaction (IRR), diarrhea, nausea and anemia. The incidence of IRR was significantly decreased following the implementation of a premedication protocol. Analysis of paired tumour biopsies revealed in certain patients that sotevtamab induced a strong intratumoral immune response with the formation of Tertiary Lymphoid Structures (TLS). Various pharmacodynamic evaluations are being performed to better define the profile of responding patients. Conclusions: This phase II study showed promising response and overall tumor control. Duration of response was particularly encouraging and relevant to further exploration. The sotevtamab and docetaxel combination may enhance immune-mediated anti-tumor response through induction of TLS. Data from the final database lock will be presented. Clinical trial information: NCT04364620 .