Phase 2 study of pembrolizumab (pembro) plus plinabulin (plin) and docetaxel (doc) for patients (pts) with metastatic NSCLC after progression on first-line immune checkpoint inhibitor alone or combination therapy: Initial efficacy and safety results on immune re-sensitization.

Abstract

8560 Background: Immune checkpoint inhibitor (ICI)-based treatment regimens have become the standard of care for first-line treatment of EGFR/ALK wild-type NSCLC. However, >60% pts inevitably develop progressive disease (PD) from acquired resistance (AR), which could be due to T cell exhaustion and antigen presenting cell (APC) pathway mutation. For patients with PD, the standard of care (SOC) is still doc, while the efficacy is limited with ~10% ORR, median PFS 3.7 months in TROPION-Lung01. Thus, there is a huge unmet need for this setting of patients. Plin is a selective immunomodulating microtubule-binding agent which promotes dendritic cell maturation and enhances anti-tumor T cell response. The mechanism of action has been validated via in vitro , in vivo models, and human trials, suggesting that plin may have the potential to overcome immunotherapy AR. This phase 2 study was aimed to evaluate the efficacy and safety of pembro combined with plin and doc in pts with metastatic NSCLC who had progressed after ICI. Methods: In this single-arm phase 2 trial, metastatic NSCLC pts who developed acquired resistance on immunotherapy alone or in combination with platinum-doublet chemotherapy were enrolled. Participants received pembro 200 mg, plin 30 mg/m 2 , and doc 75 mg/m 2 intravenously day 1 every 21days. The primary endpoint is investigator-based ORR per RECIST 1.1. The secondary endpoints included PFS, OS, DoR and safety. The sample size is 47 patients. The ORR and DOR was assessed in the evaluable set. Results: At of the 21 th Jan, 2025, data cutoff, 47 pts were enrolled, the median follow-up time was 8.7 months, median age of 67.5 (rang 44-83), 80.9%(n=38) were male, 68.1% had smoking history. Histology included 66% with non-squamous, 34% with squamous cell carcinoma. Efficacy and safety were analyzed in the 45 patients, 40 patients were evaluable. The ORR was 20% (confirmed ORR was 17.5%) and the median DoR was 9.4 m; the DCR was 81.6% (defined as PR and SD> 4 months), median PFS was 8.2 m (current 6 m PFS rate was 60.2%, 12 m PFS rate was 29.9%), OS had not been reached（6 death since the first patient enrollment of 02/2023）. G3 or higher treatment-related AEs (TRAEs) were reported by 37.8% of pts, ≥5% TRAEs include diarrhea (6.7%), myelosuppression (8.9%) and hypertension (8.9%). Conclusions: Pembro plus plin and doc in pts with metastatic NSCLC who developed PD on ICI shows promising efficacy, with doubling PFS and DCR compared with historical data of doc. The AEs of the triple combination treatment is manageable. Further investigations into which pts would benefit from continued ICI treatment after progression is warranted. Clinical trial information: NCT05599789 .