A recent publication in Lung Cancer Journal details the results of the Big Ten Cancer Research Consortium (Big Ten CRC) study BTCRC-LUN17-127, a Phase I/II trial investigating the combination of plinabulin with nivolumab and ipilimumab for patients with recurrent small cell lung cancer (SCLC). While the study did not meet its primary efficacy endpoint, it demonstrated the tolerability of the combination and highlighted instances of durable responses in a subset of patients.
The multicenter trial, identified as NCT03575793, enrolled patients between September 2018 and February 2023. The Phase I portion utilized a 3+3 design to determine the recommended Phase 2 dose (RP2D) of plinabulin when administered with nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) on day 1 of each 21-day cycle for four cycles, followed by maintenance with plinabulin and nivolumab. Phase II focused on patients with recurrent PD(L)1 inhibitor-resistant SCLC, with the primary objective being median progression-free survival (PFS).
Study Findings
A total of 39 patients were enrolled, with 36 receiving treatment and being evaluable for safety (16 in Phase I, 20 in Phase II). In Phase I, two dose-limiting toxicities (DLTs) were observed: grade 3 altered mental status lasting less than 24 hours and grade 3 infusion reaction. The RP2D for plinabulin was established at 30 mg/m². Common treatment-related adverse events (TRAEs) included vomiting (44%), nausea (42%), and infusion reactions (36%). Six percent of patients experienced a grade 3 or higher TRAE, while 14% had grade 3 or higher immune-related adverse events (irAEs); notably, no cases of immune-related pneumonitis were reported.
Efficacy analysis in 27 patients revealed a median PFS of 1.6 months (95% CI: 1.2 to 2.7), falling short of the pre-specified target of 3.5 months. However, four patients treated at the 30 mg/m² dose achieved partial responses (one confirmed, three unconfirmed), and five patients had stable disease, resulting in a clinical benefit rate (CBR) of 33%. Interestingly, two of eight patients treated in Phase I at a lower dose of 20 mg/m² had confirmed partial responses, with one patient remaining on the regimen for over 90 cycles. The median overall survival (OS) was 5.5 months, with a median follow-up time of 2.5 months.
Clinical Implications
The study's authors, including Jyoti Malhotra from City of Hope National Medical Center and Alberto Chiappori from H. Lee Moffitt Cancer Center and Research Institute, concluded that plinabulin in combination with nivolumab and ipilimumab was tolerable at 30 mg/m². While the clinical responses in PD-1 resistant SCLC were limited, the observation of long-duration responses in some patients warrants further investigation. The lower-than-expected rate of grade 3 or higher irAEs with the combination is also a noteworthy finding.
This research provides valuable insights into the potential of plinabulin-based combination therapies in SCLC, particularly in the context of PD-1 resistance. Further studies may explore predictive biomarkers for response and strategies to optimize the combination regimen for improved efficacy.
