Background: Anti-programmed cell death 1 antibodies (PD-1 Abs) are widely used for advanced melanoma, but information on the efficacy of anti-PD-1 Abs is limited in the Asian population. There remains an unmet need to improve the therapeutic effects of anti-PD-1 Ab-treatment, particularly in patients with melanoma who are refractory to anti-PD-1 Abs. The aim of this study was to evaluate anti-PD-1 Ab-treatment in combination with TM5614 (a plasminogen activator inhibitor-1 inhibitor) in patients with unresectable melanoma.
Methods: The TM5614-MM study was a multicentre, open-label, single-arm, phase II clinical trial to evaluate the efficacy and safety of nivolumab in combination with TM5614 in patients with advanced, unresectable malignant melanoma recruited at seven Japanese institutes between 13 September 2021 and 31 March 2023. Patients with metastatic or unresectable melanoma previously treated with anti-PD-1 Abs were enrolled. Nivolumab 480 mg was administered intravenously every 4 weeks for 8 weeks, while TM5614 was administered orally at a dose of 120 mg (0-4 weeks) and 180 mg once daily (5-8 weeks). The primary endpoint was the overall response rate after 8 weeks of concomitant use of TM5614.
Results: Thirty-nine patients were enrolled, and 34 patients were included in the anti-PD-1 Ab-refractory cohort. The overall response rate at 8 weeks was 25.9% (95% confidence interval 12.9-44.9%, P = 0.027) in 27 patients who were anti-PD-1 Ab-refractory based on investigator assessment in the protocol per set cohort. Seven patients discontinued treatment owing to progressive disease or adverse events. Treatment-related grade 3 or higher adverse events occurred in 3 of 39 patients (7.7%) in the intention-to-treat cohort.
Conclusions: TM5614 in combination with nivolumab is well tolerated and effective in anti-PD-1 Ab-refractory unresectable melanoma.
Types of antibody called ‘anti-programmed cell death 1 antibodies’ (also known as ‘anti-PD-1 Abs’) are commonly used to treat a range of different advanced cancers, including melanoma. However, less is known about the effectiveness of anti-PD-1 Abs, especially in Asian populations. There remains an unmet need to improve anti-PD-1 Ab-treatment, particularly in people with melanoma who are ‘refractory’ (or do not respond) to anti-PD-1 Abs in Japan. To evaluate anti-PD-1 Ab-treatment, we carried out a clinical trial called the ‘TM5614-MM study’ to investigate the safety and efficacy of using a combination of drugs (TM5614 and nivolumab). People with advanced and ‘unresectable’ (cannot be surgically removed) malignant melanoma were recruited from seven Japanese institutes between 13 September 2021 and 31 March 2023. Those with metastatic or unresectable melanoma who had received prior treatment with or without anti-PD-1 Abs were enrolled. The main result that we measured was the response rate after 8 weeks of treatment with TM5614. We found that the response rate at 8 weeks was 25.9% in 27 patients who were anti-PD-1-Ab-refractory (those who had received prior treatment with anti-PD-1 Abs) and 0% in four patients in the anti-PD-1 Ab-naïve group (those who had not previously received treatment with anti-PD-1 Abs). Treatment-related severe adverse events occurred in three of 39 patients (7.7%). Overall, our study findings suggest that TM5614 in combination with nivolumab is well tolerated and could be effective in anti-PD-1 Ab-refractory unresectable melanoma.
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