Plinabulin Plus Docetaxel Boosts OS in Pretreated EGFR Wild-Type NSCLC

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Second- or third-line treatment with plinabulin combined with docetaxel improved overall survival (OS) vs docetaxel plus placebo in patients with advanced or metastatic EGFR wild-type non–small cell lung cancer (NSCLC), according to data from the phase 3 DUBLIN-3 trial (NCT02504489) presented at the 2024 IASLC World Conference on Lung Cancer.¹

Results demonstrated that the combination of plinabulin and docetaxel reduced the risk of death by 18% compared with docetaxel plus placebo (HR, 0.82; 95% CI, 0.68-0.99; P = .0399). Patients treated with the combination (n = 278) achieved a median OS of 10.5 months (95% CI, 9.3-11.9) vs 9.4 months (95% CI, 8.4-10.7) for those in the control group (n = 281). Using a restricted mean survival time analysis, the mean OS was 15.05 months (standard error [SE], 0.848) in the plinabulin arm compared with 12.77 months (SE, 0.676) in the placebo arm.

In the experimental arm, the 2- and 3-year OS rates were 22.1% and 11.7%, respectively. These respective rates were 12.5% (P = .0072) and 5.3% (P = .0393) in the placebo arm.

“The data from DUBLIN-3 study demonstrates that the addition and proper sequencing of plinabulin to docetaxel has a favorable benefit/risk ratio compared with docetaxel alone and may have broad utility. This combination could be considered as a new treatment option for this population with high unmet medical needs,” lead study author Trevor Feinstein, MD, of Piedmont Cancer Center in Atlanta, Georgia, stated in a news release.²

Plinabulin is a unique tubulin binder intended to free GER-H1 from microtubules, inducing dendritic cell maturation, M1 polarization, and T-cell activation.¹

DUBLIN-3 was a global, randomized, patient-blinded study that enrolled patients with stage IIIB/IV, EGFR wild-type, squamous or nonsquamous NSCLC who experienced disease progression during or after 1 or 2 prior platinum-based chemotherapy regimens. Prior treatment with an immune checkpoint inhibitor was permitted. Patients were required to have an ECOG performance status of 0 to 2 and at least 1 measurable lung lesion.

A total of 559 patients were randomly assigned 1:1 to receive intravenous docetaxel at 75 mg/m² on day 1 plus plinabulin at 30 mg/m² on days 1 and 8 of each 21-day cycle, or the same docetaxel regimen plus placebo. Stratification factors included region (Asia vs non-Asia), line of therapy (second line vs third line), ECOG performance status (0-1 vs 2), and prior immune checkpoint inhibitor exposure (yes vs no).

The primary endpoint of the trial was OS. Key secondary end points included overall response rate (ORR), progression-free survival (PFS), duration of response, safety, and quality of life.

At baseline, the median age was 61 years (range, 37-82) in the plinabulin arm and 60 years (range, 25-85) in the placebo arm. The majority of patients were male (plinabulin arm, 71.6%; placebo arm, 73.7%), had nonsquamous histology (55.4%; 63.3%), had an ECOG performance status of 1 (82.4%; 80.1%), were from Asia (87.4%; 87.2%), had stage IV disease (80.6%; 84.0%), did not receive a prior immune checkpoint inhibitor (82.4%; 79.7%), and received study treatment as second-line therapy (73.4%; 75.4%).

The OS benefit was consistent for the experimental regimen across prespecified subgroups. An OS improvement with the plinabulin regimen was also observed after 24 months of follow-up after a database lock in both the intention-to-treat population (HR, 0.81; 95% CO, 0.68-0.98; P = .0270) and the subgroup of patients with nonsquamous NSCLC (HR, 0.72; 95% CI, 0.57-0.92; P = .0078).

Notably, among patients who received at least 4 cycles of docetaxel, the median OS was 18.3 months (95% CI, 14.96-22.88) for those in the plinabulin arm (n = 133) vs 13.5 months (95% CI, 10.68-16.54) for those in the placebo arm (n = 128; HR, 0.634; P = .0022). Notably, 5.8% of patients in the experimental arm received more than 12 cycles of docetaxel compared with 3.2% of patients in the placebo arm.

Additional data demonstrated that plinabulin plus docetaxel elicited a median PFS of 3.3 months (95% CI, 2.89-3.88) vs 2.8 months (95% CI, 2.76-2.93) for the placebo regimen (HR, 0.79; 95% CI, 0.66-0.96; P = .0174). The ORR was 14% for docetaxel plus plinabulin vs 9% for docetaxel plus placebo (P = .0404).

Any-grade treatment-emergent adverse effects (TEAEs) were reported in 99.6% of patients in the plinabulin arm and 99.3% of patients in the placebo arm. The respective rates of grade 3 TEAEs were 51.5% and 30.6%; the rates of grade 4 TEAEs were 19.0% and 42.8%, respectively.

The most common any-grade TEAEs included anemia (plinabulin arm, 50.0%; placebo arm, 43.5%), decreased white blood cell count (58.4%; 68.0%), decreased neutrophil count (51.8%; 70.5%), decreased platelet count (28.1%; 17.3%), diarrhea (43.1%; 22.3%), constipation (34.7%; 28.8%), nausea (36.5%; 24.1%), vomiting (29.9%; 14.0%), abdominal pain (15.3%; 8.3%), abdominal distension (10.6%; 4.7%), lung infection (11.3%; 15.1%), increased blood pressure (33.9%; 5.8%), increased hepatic enzyme (17.2%; 16.2%), decreased weight (11.7%; 8.6%), cough (23.4%), 27.7%), dyspnea (13.9%; 16.9%), and hemoptysis (11.3%; 9.7%).

Notably, grade 4 neutropenia at cycle 1, day 8 was reported in 5% of patients in the experimental arm vs 28% of patients in the placebo arm (P < .0001).

References

1. Feinstein T, Han B, Sun Y. Plinabulin/docetaxel vs. docetaxel in 2L/3L NSCLC after platinum regimens (DUBLIN-3): a phase 3 randomized controlled trial. Presented at: 2024 IASLC World Conference on Lung Cancer; September 7-10, 2024; San Diego, CA. Abstract OA08.04.
2. BeyondSpring delivers oral presentation at IASLC 2024 World Conference on Lung Cancer of its lead anti-cancer asset plinabulin showcasing positive final phase 3 data in 2L/3L NSCLC EGFR wild-type with concurrent publication in the Lancet Respiratory Medicine. News release. BeyondSpring. September 10, 2024. Accessed September 12, 2024. https://beyondspringpharma.com/beyondspring-delivers-oral-presentation-at-islac-2024-world-conference-on-lung-cancer-of-its-lead-anti-cancer-asset-plinabulin-showcasing-positive-final-phase-3-data-in-2l-3l-nsclc-egfr-wild-type-with/