Phase 2 Study Evaluating the Safety and Efficacy of Pembrolizumab, Plinabulin, and Docetaxel in Patients With Metastatic NSCLC After Failure on First-Line Immune Checkpoint Inhibitors

Treatment regimens based on immune checkpoint inhibitors (ICIs) have established themselves as the standard first-line approach for non-small cell lung cancer (NSCLC). Upon disease progression, the continuation of ICI monotherapy is not advised, and the efficacy of chemotherapy is limited, with an overall response rate (ORR) of approximately 10% when using docetaxel. This situation highlights a significant unmet medical need. Plinabulin, a selective immunomodulating agent that binds to microtubules, facilitates the maturation of dendritic cells, and enhances the antitumor response of T cells, showing promise in overcoming resistance to immunotherapy. The objective of this phase 2 study (NCT05599789) was to assess the efficacy and safety of the combination of pembrolizumab, plinabulin, and docetaxel in patients with metastatic NSCLC who have experienced progression following ICI treatment.

KeyPemls-004 is an ongoing investigator-initiated, single-arm, open-label phase 2 trial evaluating patients with metastatic NSCLC who have developed resistance to ICIs. Participants were administered pembrolizumab at a dosage of 200 mg on day 1, plinabulin at 30 mg/m² on day 1, and docetaxel at 75 mg/m² on day 1, delivered intravenously over a 21-day cycle. The primary end point of the trial was the ORR as evaluated by the investigator using RECIST v1.1 criteria. Secondary end points include progression-free survival (PFS), overall survival (OS), duration of response (DOR), and assessment of toxicity. The study plans to enroll 47 patients, with an interim analysis scheduled after 19 patients have been enrolled.

A total of 29 patients were enrolled in the study, with 19 patients analyzed during the initial stage at the database cutoff on April 29, 2024. The median follow-up duration was 8.67 months, and the median age of participants was 66.0 years. The cohort comprised 68.4% males and 31.6% females, with 57.9% identified as current or former smokers. Histological analysis revealed that 57.9% of the patients had nonsquamous cell carcinoma, while 42.1% had squamous cell carcinoma. The confirmed ORR was 21.1%, and the disease control rate (DCR), defined as partial response and stable disease lasting more than 4 months, was 89.5%. The median PFS was recorded at 8.63 months, with current PFS rates of 67.1% at 6 months and 49.2% at 12 months. OS data had not yet been reached, as no deaths were reported. The median DOR was 11.40 months, and 52.6% of patients experienced grade ≥3 treatment-related adverse events, with no treatment-related fatalities.

The combination of pembrolizumab, plinabulin, and docetaxel in patients with metastatic NSCLC who demonstrated progressive disease following clinical benefit from ICIs was linked to an extended PFS and DCR when compared with historical chemotherapy controls, while maintaining an acceptable safety profile. There is a need for more in-depth investigation to determine which patients are likely to benefit from the sustained use of ICIs after their disease has progressed.

Source: Xu Y, Gao X, Chen M, et al. Phase II study of pembrolizumab (pemb) plus plinabulin (plin) and docetaxel (doc) for patients (pts) with metastatic NSCLC after failure on first-line immune checkpoint inhibitor alone or combination therapy: initial efficacy and safety results on immune re-sensitization. Barcelona, Spain, & online: presented at ESMO Congress 2024; abstract 1330P.