16 ABBV-CLS-484: A Novel Oral PTPN2/1 Inhibitor for Cancer Immunotherapy

Vollständiger Abstract

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Abstract Background ABBV-CLS-484 is a first-in-class oral PTPN2/N1 inhibitor with a dual mechanism of action that both increases the immunogenicity of tumor cells and augments the antitumor T cell response. It has monotherapy efficacy in multiple preclinical tumor models, with comparable activity to anti-PD-1 in many cases. Notably, it has good antitumor activity in combination with PD-1 specific antibodies in syngeneic animal models known to be refractory to PD-1 blockade. Methods M20-431 is a first-in-human Phase 1 clinical trial testing the safety and preliminary clinical activity of ABBV-CLS-484 alone and with pembrolizumab in patients with advanced solid tumors whose disease has progressed on standard therapies (NCT04777994). Results To date, ABBV-CLS-484 was tolerable, with transient inflammatory adverse events that rapidly resolve off therapy. Durable anti-tumor activity was observed in dose escalation across several tumor types, including clear cell renal cell carcinoma (ccRCC). In 22 patients with anti-PD-1 exposed, >2nd line ccRCC treated with ABBV-CLS-484 alone or combined with pembrolizumab, the ORR was 18% and the DCR was 41%, with 1 durable CR for >2 years. Preliminary biomarker evaluation demonstrated target binding. Conclusions ABBV-CLS-484 is tolerable, with preliminary evidence of clinical activity in dose escalation. Dose expansion cohorts are now accruing to evaluate efficacy in I/O-experienced ccRCC. In tandem with these clinical cohorts, additional strategies that combine ABBV-CLS-484 with VEGF TKIs, CAR-T therapy, and T cell engagers are being tested in preclinical models.