Plinabulin Plus Docetaxel Combination Succeeds in Improving OS in NSCLC With EGFR Wild Type

The combination of plinabulin with docetaxel showed improvement in overall survival (OS) compared with docetaxel alone as treatment of patients with second- and third-line non –small cell lung cancer with EGFR wild type, meeting the primary end point of the phase 3 DUBLIN-3 clinical trial (NCT02504489), according to a press release from BeyondSpring, Inc.

Topline results from the study show an increase in the mean OS with plinabulin plus docetaxel compared with docetaxel monotherapy (P =.03; OS log-rank, P <.04). Further multiple secondary end points of the study were also achieved including the objective response rate (ORR), the progression-free survival (PFS) and OS rates at 24 months and 36 months reduction in grade 4 neutropenia.

“The treatment of 2nd and 3rd line NSCLC, especially with EGFR wild type where tyrosine kinase inhibitors do not work, is an area of severe unmet medical needs. Now that checkpoint inhibitor immunotherapy has moved into the first line, there is a vacuum in this indication, where treatment is heavily centered around docetaxel. Currently, docetaxel-based therapies have limited survival benefit and >40% severe neutropenia,” said Trevor M. Feinstein, MD, of the Piedmont Cancer Institute, and the study’s principal investigator, in the press release. “In DUBLIN-3, a prolonged survival benefit, characterized by a long-tailed OS curve, was observed with plinabulin that represents an immune-associated anti-cancer benefit. The opportunity that plinabulin offers to these patients is not only to live longer, but also with significantly reduced severe neutropenia, which are both meaningful for these very sick patients.”

The ORR favored the combination of plinabulin and docetaxel over docetaxel alone (P <.03), as did the PFS rate (P <.01). The 24 months OS rate observed with the experimental combination was 22.1% compared with 12.5% in the patients who received docetaxel alone (P <.01). The 36-month OS rate observed with plinabulin plus docetaxel was 11.7% versus 5.3% (P =.04), and the 48-month OS rate was 10.6% versus 0%, respectively with a P-value that could not be determined.

In terms of safety the incidence of grade 3 neutropenia at cycle 1 day 8 was 5.3% in the combination arm compared with 27.8% in the monotherapy arm (P <.0001), showing a clear decrease with the addition of plinabulin. The topline safety data also showed a lower grade 3 adverse event (AE) occurrence and a shift to lower grade AE. There were no unexpected AES observed in the study.

“DUBLIN-3 is a pivotal study which succeeded in demonstrating OS benefit for the first agent with a novel mechanism – plinabulin – since the 2015 nivolumab approval. It was very rewarding to be the global principal investigator throughout the 6 years for the DUBLIN-3 trial that serves to address this severe unmet medical need. In the DUBLIN-3 study, it is especially gratifying to see the doubling of 24- and 36-month OS rate with a favorable safety profile in the plinabulin combination arm; this profile not only significantly advances NSCLC patients’ care, but also signals plinabulin’s profound immune anti-cancer benefit. The success of the DUBLIN-3 study is the gateway of plinabulin into multiple tumor indications within IO combinations, said Yan Sun, MD, the co-founder and former Chairman of Chinese Society of Clinical Oncology, Chairman of NCCN Guidelines of NSCLC in China, and Director of GCP Center at Cancer Hospital of Chinese Academy of Medical Sciences, in a statement.

DUBLIN-3 is an ongoing randomized, single-blind active-controlled, global study of 559 patients with second- or third-line NSCLC and EGFR wild-type disease and a measurable lung lesion. In both treatment arms, patients receive docetaxel 75 mg/m2 on day 1 for a 21-day cycle and the combination arm receive plinabulin 30 mg/m2 on day 1 and 8.

Plinabulin is a first-in-class, selective immunomodulating microtubule-binding agent, which has been shown to help prevent chemotherapy-induced neutropenia. The agent was granted breakthrough therapy designation by the FDA for this indication.

“The success of the DUBLIN-3 study represents proof-of-concept of plinabulin’s immune-enhancing mechanism of action that is complementary to that of checkpoint inhibitors, and which is the rationale for it to be combined as triple IO combinations in multiple tumor indications. These programs are already in Phase 1/2 stage and preliminary positive results were reported at American Society of Clinical Oncology Annual Meeting 2021,” stated Mohanlal, chief medical officer and executive vice president of Research & Development at BeyondSpring, in the press release.

_Reference:

_{BeyondSpring announces positive topline results from its DUBLIN-3 registrational trial of plinabulin in combination with docetaxel for the treatment of 2nd/3rd line non-small cell lung cancer (NSCLC) with EGFR wild type. News release. August 4, 2021. Accessed August 4, 2021. https://bit.ly/3xnoEyq}