Plinabulin Plus Docetaxel Significantly Improves OS in EGFR Wild-Type NSCLC

Trevor M. Feinstein, MD

The combination of plinabulin plus docetaxel resulted in a statistically significant improvement in overall survival (OS) vs docetaxel alone when used in the second- or third-line treatment of patients with EGFR wild-type, non–small cell lung cancer and measurable lung lesions, meeting the primary end point of the phase 3 DUBLIN-3 trial (NCT02504489).¹

Additional top-line data from the trial revealed that the addition of the first-in-class, selective immunomodulating microtubule-binding agent to docetaxel also significantly improved overall response rate (ORR; P < .03), progression-free survival (PFS; P < .01), 24- and 36-month OS rates, and resulted in a significant reduction in the incidence of grade 4 neutropenia, thus meeting key secondary end points of the trial.

“The treatment of second- and third-line NSCLC, especially with EGFR wild-type where TKIs do not work, is an area of severe unmet medical needs,” Trevor M. Feinstein, MD, of the Piedmont Cancer Institute and principal investigator for DUBLIN-3, stated in a 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 anticancer 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 active-controlled, global phase 3 trial, which was single blind to patients, enrolled a total of 559 patients with EGFR wild-type, NSCLC who required treatment in the second- or third-line setting.

To be eligible for participation, patients needed to be at least 18 years of age, have an ECOG performance status of 0 to 2, have histopathologically or cytologically confirmed nonsquamous or squamous disease, at least 1 measurable lung lesion of 10 mm or bigger, and a life expectancy of more than 12 weeks.²

If patients received chemotherapy, immunotherapy, biological, targeted, radiation therapy, or an investigational agent within 3 weeks before the administration of the study medication, they were excluded. Other key exclusion criteria comprised having significant cardiac history, having previously received docetaxel, experiencing a transient ischemic attack or cerebrovascular accident within the past year, or having a history of hemorrhagic diarrhea, inflammatory bowel disease, or active uncontrolled peptic ulcer disease.

Study participants randomized to the investigative arm (n = 278) of the trial were given an infusion of docetaxel at a dose of 75 mg/m2 on day 1 of a 21-day treatment cycle plus plinabulin at a dose of 30 mg/m2 on days 1 and 8. Those in the control arm (n = 281) received docetaxel alone, at the same dose of 75 mg/m2 on day 1.

The primary end point of the research was OS (mean OS: P = .03; OS log rank, P < .04). Important secondary end points comprised ORR; PFS; incidence of grade 4 neutropenia in cycle 1 day 8 of treatment; 24-, 36-, and 48-month OS rates, and safety.

Additional data showed that the OS rates at 24 months in the investigative and control arms were 22.1% vs 12.5%, respectively (P < .01); at 36 months, these rates were 11.7% vs 5.3% (P = .04), respectively. Moreover, the 48-month OS rate in the plinabulin/docetaxel arm was 10.6% vs 0% in the docetaxel-alone arm.

Regarding safety, the incidence of grade 4 neutropenia with the plinabulin combination was 5.3% vs 27.8% with docetaxel alone (P < .0001). Notably, no new safety concerns with the regimen were observed.

BeyondSpring Pharmaceuticals, the developer of plinabulin, shared that a pre–new drug application (NDA) meeting will be scheduled with the FDA this year to discuss what is needed for an NDA to support a NSCLC indication. The goal is to submit the application in the first half of 2022.

Previously, in April 2021, an NDA was submitted to both the FDA and the China National Medical Products Administration for the use of plinabulin in combination with granulocyte colony-stimulating factor for the prevention of chemotherapy-induced neutropenia (CIN).³

The application was based on data from the phase 3 PROTECTIVE-2 trial (Study 106; NCT03294577), in which plinabulin plus pegfilgrastim (Neulasta) proved to be 53% more effective in reducing the incidence of CIN vs pegfilgrastim alone in patients who were undergoing chemotherapy.⁴

Moreover, profound neutropenia occurred in 21.6% and 46.4% of patients in the investigative and control arms, respectively (P = .0001), in patients with breast cancer who were undergoing a chemotherapy regimen that consisted of docetaxel, doxorubicin, and cyclophosphamide. The plinabulin combination also reduced the risk of febrile neutropenia by 41% vs pegfilgrastim alone. A 50% reduction in the mean duration of profound neutropenia was also observed with the plinabulin regimen vs single-agent pegfilgrastim, at 0.3 days vs 0.6 days, respectively (P = .0004).

References

1. 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. BeyondSpring Pharmaceuticals. August 4, 2021. Accessed August 4, 2021. https://bit.ly/3jrC3k5
2. Docetaxel + plinabulin compared to docetaxel + placebo in patients with advanced NSCLC (DUBLIN-3). ClinicalTrials.gov. Updated May 21, 2021. Accessed August 4, 2021. https://clinicaltrials.gov/ct2/show/NCT02504489
3. BeyondSpring announces submission of new drug application to US FDA and China NMPA for plinabulin and G-CSF combination for the prevention of chemotherapy-induced neutropenia (CIN). News release. BeyondSpring, Inc. March 31, 2021. Accessed August 4, 2021. https://bit.ly/39vpShF
4. Blayney DW, Huang L, Mohanlal R. Superior and clinically meaningful protection against profound neutropenia with the plinabulin/pegfilgrastim (Plin/Peg) combination versus peg in breast cancer patients receiving TAC chemotherapy: phase 3 results from Protective-2 (BPI-2358-106). Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Abstract PS13-53-01.