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Added Plinabulin Boosts OS as Later-Line Treatment for EGFR Wild-Type NSCLC

— However, plinabulin plus docetaxel still "not ready for prime time," expert says

MedpageToday

Adding the investigational agent plinabulin to docetaxel in the second and third line of treatment significantly improved overall survival (OS) in patients with advanced or metastatic EGFR wild-type non-small cell cancer (NSCLC), the phase III DUBLIN-3 trial showed.

Among 559 patients, the median OS was 10.5 months with plinabulin plus docetaxel compared with 9.4 months with docetaxel plus placebo (stratified HR 0.82, 95% CI 0.68-0.99, P=0.0399), reported Trevor Feinstein, MD, of the Piedmont Cancer Institute in Atlanta, at the World Conference on Lung Cancer in San Diego.

The study, which was published simultaneously in , also showed that mean OS was 15.1 months with added plinabulin versus 12.8 months with docetaxel (P=0.0332), 2-year OS rates were 22.1% and 12.5%, respectively, and 3-year OS rates more than doubled with plinabulin (11.7% vs 5.3%).

Progression-free survival was 3.3 months in the combination group versus 2.8 months in the docetaxel group (HR 0.79, 95% CI 0.66-0.96, P=0.0174), while overall response rates were 14% and 9% in the two groups, respectively (P=0.0404).

"The addition of plinabulin as a single agent to docetaxel improved anti-cancer efficacy in terms of OS, progression-free survival, and overall response, and did enhance safety by reducing docetaxel-induced neutropenia," Feinstein said, adding that the combination represents a potential practice-changing treatment for second- or third-line treatment of NSCLC with no driver mutation.

However, invited discussant Saiama Waqar, MD, of the Washington University School of Medicine in St. Louis, noted that the vast majority of patients in the study were Asian, and had not received anti-PD-1/PD-L1 therapy -- the current standard of care.

Thus, "my conclusion right now is that this regimen is not ready for prime time," she said. "We still need more data -- a global study confirming these results, especially after receiving immunotherapy."

In explaining the rationale behind the trial, Feinstein said that since nivolumab (Opdivo) was approved in 2015, no agent with a novel mechanism has been approved by the FDA for the second- or third-line treatment of NSCLC without driver mutations, and there is an unmet need for new therapies that are effective and tolerable in this setting.

Plinabulin is a unique tubulin binder with a binding site distinct from other classes of tubulin-binding agents, such as tubulin-stabilizing taxanes and tubulin-destabilizing vinca alkaloids and colchicine.

"Plinabulin prevents polymerization of tubulin, and liberates an immune defense protein GEF-H1, [which] has a downstream field effect causing dendritic cell maturation and T-cell activation," he explained.

In , Rafael Rosell, MD, PhD, of Hospital Quiron-Dexeus in Barcelona, and colleagues pointed out that DUBLIN-3 began in 2015 when the use of targeted next-generation sequencing (NGS) to identify actionable oncogenic driver alterations was still in its early stages, and that since then, the implementation of predictive molecular testing using large-panel NGS "is growing in relevance in NSCLC."

"At present, for tailored treatment of advanced and metastatic NSCLC, especially in lung adenocarcinoma, the use of NGS is a highly recommended prerequisite for selecting the most suitable treatment," they wrote. "This applies at any stage of the disease, whether for first-line therapy or consecutive lines of therapy following serial recurrences."

DUBLIN-3 was a single-blind, parallel-group trial conducted at 58 centers in the U.S., China, and Australia. Eligible patients were adults with EGFR wild-type NSCLC who had progressed after first-line platinum-based therapy.

Patients were randomized to receive intravenous docetaxel on day 1 and either plinabulin or placebo on days 1 and 8 in 21-day cycles until progression, unacceptable toxic effects, withdrawal, or death.

Across the two groups, median age was 60-61, 72-74% were men, and 87% were Asian. More patients in the combination arm had squamous histology, and about 20% of patients had received prior anti-PD-1/PD-L1 therapy.

The authors noted that the OS benefit observed with added plinabulin increased with more treatment cycles. For example, at 4 or more cycles of treatment, median OS in the combination group (133 patients) was 18.3 months, compared with 13.5 months in the control group (127 patients), while at 10 cycles or more of treatment, median OS among 27 patients in the combination group was 35.5 months compared with 19.2 months among 18 patients in the control group.

They also pointed out that treatment with docetaxel has been associated with a high (about 40%) incidence of severe neutropenia, and that plinabulin induces progenitor cell growth in bone marrow and helps prevent a decrease in neutrophil levels resulting from chemotherapy.

"As a result, plinabulin reduces chemotherapy-induced neutropenia and could thereby increase docetaxel tolerability," they suggested.

In DUBLIN-3, docetaxel-induced neutropenia was significantly reduced. Specifically, grade 4 neutropenia at cycle 1, day 8, fell from 28% with docetaxel and placebo to 5% with docetaxel and plinabulin.

Treatment-emergent adverse events (TEAEs) occurred in all but one patient in the combination group and all but two patients in the control group. Grade 3 or 4 gastrointestinal disorders occurred more frequently in the combination group than in the control group, with the most frequent being diarrhea and vomiting.

Feinstein also reported that there was an increase in grade 3 hypertension in the combination group (18% vs 3%), but this was transient, lasting just 4 to 6 hours after plinabulin was administered.

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    Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.

Disclosures

The study was funded by BeyondSpring Pharmaceuticals.

Feinstein reported receiving research funding from BeyondSpring Pharmaceuticals to conduct this trial and is a speaker for Sanofi and Sobi.

Several co-authors also reported relationships with industry.

Waqar had no disclosures.

The editorialists had no disclosures.

Primary Source

Lancet Respiratory Medicine

Han B, et al "Plinabulin plus docetaxel versus docetaxel in patients with non-small-cell lung cancer after disease progression on platinum-based regimen (DUBLIN-3): a phase 3, international, multicentre, single-blind, parallel group, randomised controlled trial" Lancet Respir Med 2024; DOI: 10.1016/S2213-2600(24)00178-4.

Secondary Source

Lancet Respiratory Medicine

Rosell R, et al "Plinabulin, a microtubule destabilising agent, in non-small-cell lung cancer: lessons from the DUBLIN-3 trial" Lancet Respir Med 2024; DOI: 10.1016/S2213-2600(24)00191-7.