DUBLIN-3 Trial With Plinabulin in Advanced NSCLC to Continue Without Modifications

The Data and Safety Monitoring Board has advised that the phase 3 DUBLIN-3 trial of the antineoplastic agent plinabulin in patients with advanced or metastatic non–small cell lung cancer who have progressed on standard-of-care therapy can continue without any modifications.

The Data and Safety Monitoring Board has advised that the phase 3 DUBLIN-3 trial of the antineoplastic agent plinabulin in patients with advanced or metastatic non—small cell lung cancer (NSCLC) who have progressed on standard-of-care therapy can continue without any modifications, according to a press release issued by BeyondSpring, the developer of the agent.1

The recommendation follows intensive review of the safety and efficacy data at the second interim analysis of more than 500 patients and approximately 300 prespecified death events. In the DUBLIN-3 trial, investigators are evaluating the anticancer efficacy of plinabulin in combination with docetaxel versus docetaxel alone as second- or third-line systemic treatment in patients with EGFR-mutant, wild-type NSCLC. The primary end point of the trial is overall survival (OS).2

“The DUBLIN-3 study was designed to quantify the immune-enhancing potential of plinabulin. We selected tumors with a measurable lung lesion (per RECIST 1.1), which has more tumor mutation burden to prospectively test this population,” Ramon Mohanlal, MD, PhD, MBA, BeyondSpring’s chief medical officer and executive vice president of Research and Development, commented in a press release.

“This population—over 70% of EGFR wild-type NSCLC patients—represents new subclones with a higher probability of harboring antigens capable of stimulating the immune system,” Mohanlal added. “The DSMB’s green light is an encouraging step as we continue this trial without modifications following our second interim dataset review.”

Patients with EGFR wild-type NSCLC account for 85% of the entire NSCLC population, and those who are in need of later lines of treatment continue to be a significant unmet need, as limited treatment options are available. The progress made with immunotherapies and pemetrexed has led to the use of these approaches in the first-line treatment of these patients, thus leaving a void for those who experience disease progression.

Although docetaxel alone or in combination with ramucirumab (Cyramza) are remaining options in this space, but the benefit achieved with these approaches is limited. The combination offers a limited improvement in OS over docetaxel alone and both options are associated with high rates of neutropenia. In light of the COVID-19 pandemic, the avoidance of adverse events, such as neutropenia, in patients with NSCLC has become imperative.

“Combining standard docetaxel with something [such as plinabulin] that brings more punch like blocking the blood vessels makes sense,” Goetz H. Kloecker, MD, MBA, MSPH, FACP, an associate professor of medicine and director of the Thoracic Oncology Clinic at the University of Louisville James Graham Brown Cancer Center, told OncLive in a past interview. “You suffocate the cancer cells because there is no oxygen, and you make them stop replicating with the chemotherapy.”

Results from a prior phase 2 study showed that plinabulin plus docetaxel led to a median OS of 11.3 months in patients with advanced NSCLC with a measurable lesion versus 6.7 months with docetaxel alone.3 The median progression-free survival with the combination was 3.7 months with an objective response rate of 18% versus 2.9 months and 10.5%, respectively, with docetaxel alone. Moreover, the duration of response was 12.7 months in the combination arm compared with 1 month in the docetaxel-only arm (P <.05).

Findings from a post hoc analysis of the study indicated that those with larger tumors experienced a significant improvement with regard to median OS, and this improvement was greater as the tumor size increased.

With regard to safety, the 2 agents have not been found to have overlapping toxicities; overall, the combination appears to be well tolerated. Plinabulin plus docetaxel was not found to induce immune-related adverse events, and importantly, it was found to prevent docetaxel-inducted neutropenia.

“As a result of the current COVID-19 pandemic, patients with lung cancer who are infected by the virus have a 55% death rate. This population is already facing tremendously high odds, and the pandemic provides another proof point as to the need for additional treatment options,” Lan Huang, BeyondSpring’s CEO and founder stated in the press release. “The plinabulin/docetaxel combination may offer a favorable benefit/risk profile in the potential for extending patient survival and reducing severe neutropenia associated with docetaxel.”

Plinabulin is also being investigated in the prevention of chemotherapy-induced neutropenia. The agent is also being evaluated in combination with nivolumab (Opdivo) and with docetaxel in KRAS-mutant NSCLC.

References

  1. BeyondSpring announces Data & Safety Monitoring board recommendation for plinabulin to continue NSCLC phase 3 Dublin-3 study without modification. News release. June 3, 2020. Accessed June 3, 2020. bit.ly/2MqnIEf.
  2. Docetaxel + plinabulin compared to docetaxel + placebo in patients with advanced NSCLC (DUBLIN-3). Updated March 11, 2020. Accessed June 3, 2020. https://clinicaltrials.gov/ct2/show/NCT02504489
  3. Mohanlal RW, Lloyd K, Huang L, et al. Plinabulin as a novel small molecule clinical stage immuno-oncology agent for NSCLC. J Clin Oncol. 2017;35(suppl 7):139. doi:10.1200/JCO.2017.35.7_suppl.139