Immune checkpoint therapy, specifically PD-1 blockade, has improved survival for patients with metastatic cancer, but not all patients respond to treatment. At the 2017 ASCO-SITC Clinical Immuno-Oncology Symposium, Robert L. [ Read More ]
Best Practices in Immunotherapy – June/July 2017 Vol 8
Plinabulin Improves Survival and Duration of Response in Advanced Non–Small Cell Lung Cancer
When added to treatment with docetaxel, the investigational drug plinabulin improved overall survival by 4.7 months in patients with advanced non–small cell lung cancer (NSCLC) with measurable lesions. Data from the phase 2 randomized trial also demonstrated durable responses, with median duration of response exceeding 1 year versus less than 2 months with docetaxel alone.
“We saw very encouraging activity for plinabulin in patients with measurable lung disease,” said Alain C. Mita, MD, of Cedars-Sinai Medical Center, Los Angeles, CA. “In addition to durable responses, there was an extended survival benefit of approximately 5 months in these patients.”
As Dr Mita reported at the 2017 ASCO-SITC Clinical Immuno-Oncology Symposium, plinabulin is a small molecule with tumor-inhibiting and immune-enhancing effects. For this phase 2 trial, investigators 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.
Although the combination of plinabulin plus docetaxel yielded only a modest benefit in the overall study population, in the subset of patients with measurable lesions, median duration of response improved from 1.5 months with docetaxel alone to 12.7 months with the addition of plinabulin. Furthermore, among the 76 patients with measurable disease, median overall survival increased to 11.3 months, compared with 6.7 months with docetaxel alone. Due to the small population size, the 4.6-month improvement in overall survival did not meet statistical significance (P = .26), but the nearly 1-year improvement in duration of response was statistically significant (P <.05), Dr Mita reported.
The addition of plinabulin appeared to exacerbate diarrhea, nausea, vomiting, headache, dizziness, and hypertension; however, the vast majority of these adverse events were “mild, transient, and responded to dose reduction to 20 mg/m2,” said Dr Mita.
Based on these findings, the global phase 3 DUBLIN-3 trial is underway to evaluate second- or third-line treatment with plinabulin and docetaxel in patients with at least 1 measurable lung lesion. At the same time, other NSCLC trials are examining plinabulin’s “potent immune-enhancing effects.” According to Dr Mita, preclinical research in colon and breast tumor models has suggested that plinabulin works in synergy with other immunotherapies to slow tumor growth by operating through mechanisms distinct from PD-1/PD-L1 inhibition. Two investigator-initiated phase 1/2 trials of plinabulin and nivolumab in combination will explore this interaction.
Discussant Heather L. McArthur, MD, MPH, Medical Director of Breast Oncology at Cedars-Sinai Medical Center, called the dramatic increase in overall survival and duration of response “provocative.” Nevertheless, said Dr McArthur, given plinabulin’s complicated mechanism of action, investigators still have “a lot to learn about this drug.”
“It will be important to tease apart the influence of bona fide antitumor effects of the agent from its neutrophil-protecting effects, as the latter may not be of much help when plinabulin is combined with noncytotoxic immunotherapies,” Dr McArthur observed.
When administered by intratumoral injection, oncolytic viruses have been shown to enhance the body’s immune response and be effective in combination with checkpoint antibodies. According to data presented at the [ Read More ]