Plinabulin Improves Survival in Subset of Patients With Non–Small Cell Lung Cancer




We saw very encouraging activity for plinabulin in patients with measurable lung disease. In addition to durable responses, there was an extended survival benefit of approximately 5 months in these patients.
— Alain Mita, MD

The investigational small-molecule plinabulin yielded some interesting benefits when added to docetaxel in previously treated patients with stage III/IV non–small cell lung cancer (NSCLC), in a phase II study.1 Although the benefit of the doublet was modest in the overall study population, the study’s findings were striking in two ways: the duration of response was 7 times that achieved with docetaxel alone, and patients with measurable disease had a 4.6-month improvement in survival.

The results of this randomized trial were presented at the 2017 ASCO-SITC Clinical Immuno-Oncology Symposium by Alain Mita, MD, of Cedars-Sinai Medical Center, Los Angeles.

Mechanism of Action

Plinabulin is a novel small molecule that destabilizes microtubule dynamics by adhering to the colchicine-binding site of tubulin. Although pairing plinabulin with docetaxel, a microtubule-stabilizing agent, may seem counterintuitive, plinabulin’s activity seems aimed at the tumor microenvironment for an immune-enhancing effect, Dr. Mita explained.

Plinabulin is believed to help induce tumor-cell apoptosis; stimulate the maturation of dendritic cells (thus promoting T-cell–mediated tumor-cell killing); and facilitate the release of cytokines, which protect neutrophils from apoptosis. Such immuno-oncologic effects have been demonstrated in tumor models, where the agent appears to be synergistic in combination with checkpoint inhibitors.

The phase II trial enrolled 163 patients with stage IIIB/IV NSCLC who had received 1 or 2 prior treatments. Patients were randomly assigned to treatment with plinabulin plus docetaxel or docetaxel alone. Docetaxel was dosed at 75 mg/m2 across all arms on day 1 of a 21-day cycle, and plinabulin (20 or 30 mg/m2) was administered on days 1 and 8.

Durable Responses

Efficacy was reported for the cohort of 105 patients randomized to receive plinabulin at 30 mg/m2 plus docetaxel or docetaxel alone. In this group, the doublet led to a median overall survival of 8.7 months, vs 7.5 months with docetaxel alone. The difference of 1.2 months failed to meet statistical significance.

In contrast to these modest outcomes, the median duration of response was greatly improved, from 1.5 months with docetaxel alone to 12.7 months with the addition of plinabulin—a statistically significant 11.2-month difference in response duration (P < .05).

“We saw very encouraging activity for plinabulin in patients with measurable lung disease,” Dr. Mita said. “In addition to durable responses, there was an extended survival benefit of approximately 5 months in these patients.”

In this subset of 76 patients, median overall survival was 11.3 months, vs 6.7 months with docetaxel alone, although the difference of 4.6 months did not meet statistical significance (P = .29) “due to small numbers,” suggested Dr. Mita. The duration of response was 12.7 months vs 1.0 months, respectively, which was statistically significant (P < .05). Objective response rates were 18.4% and 10.5%, respectively, and median progression-free survival was 3.7 and 2.9 months.

Toxicity

Adverse events that appeared to be exacerbated by plinabulin included diarrhea, nausea, vomiting, headache, dizziness, and hypertension. However, the vast majority of these side effects were mild, transient, and responded to dose reduction to 20 mg/m2.

“In addition, we’ve seen some transient hypertension [with plinabulin/docetaxel], with 20% of patients experiencing some grade 3/4 hypertension as well as some associated symptoms, such as headache and dizziness,” he said. This occurred primarily with the 30-mg/m2 dose, within hours of plinabulin administration, and “with patients recovering by the next day, without any complications,” Dr. Mita said. “We also saw no increase in immune-related adverse events, vs docetaxel alone.”

Unexpectedly, plinabulin appeared to protect against the development of docetaxel-induced neutropenia. Grade 4 neutropenia was observed in 33% of the docetaxel arm but in less than 5% of the plinabulin-treated patients (P < 0.0003). This finding translated to reduced rates of sepsis (3.6% vs 0%, respectively), severe infections (3.6% vs 0%, respectively), and docetaxel dose reductions due to toxicity (19.2% vs 6.7%, respectively). ■

Disclosure: Dr. Mita reported no potential conflicts of interest.

Reference

1. Mohanlal RW, et al: Plinabulin as a novel small molecule clinical stage immuno-oncology agent for NSCLC. 2017 ASCO-SITC Clinical Immuno-Oncology Symposium. Abstract 139. Presented February 23, 2017.


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