Plinabulin/Docetaxel Demonstrates Durable Antitumor Benefit in EGFR Wild-Type NSCLC

The addition of plinabulin to docetaxel significantly improved overall survival (OS) when used in the second- or third-line treatment of patients with EGFR wild-type non–small cell lung cancer (NSCLC) who had progressed on a prior platinum-based regimen, meeting the primary end point of the phase 3 DUBLIN-3 trial (NCT02504489).¹

Results, which were presented during the 2021 ESMO Congress, showed that the combination resulted in a median overall survival (OS) of 10.5 months (95% CI, 9.3-11.9) vs 9.4 months (95% CI, 8.4-10.7) with docetaxel alone (HR, 0.82; 95% CI, 0.68-0.99; P = .0399).

The combination had sustained OS benefit vs docetaxel alone. At 12 months, the OS rates in the investigative and control arms were 43.48% vs 40.47%, respectively (P = .4862), and at 18 months, these rates were 31.11% and 23.75%, respectively (P = .0645). At 24 months the OS rates were 22.13% vs 12.51%, respectively (P = .0072), and at 36 months, these with were 11.73% vs 5.27%, respectively (P = .0393). Notably, at 48 months, the OS rate for the combination was 10.6% vs 0% with docetaxel alone.

“Plinabulin plus docetaxel has a favorable benefit/risk ratio, and has the potential of preferred second-/third-line treatment for NSCLC with EGFR wild-type,” lead study author Trevor M. Feinstein, MD, a medical oncologist at the Piedmont Cancer Institute, said in a presentation on the data.

A significant unmet need exists with respect to second- and third-line treatment options for patients with EGFR wild-type NSCLC, a subgroup that accounts for approximately 85% of patients with NSCLC in Western countries, and approximately 70% in Asian countries. With many immunotherapy options moved to the first-line setting, docetaxel-based combinations have become the standard of care, although they have limited efficacy and have been associated with severe neutropenia.

Plinabulin is a first-in-class, selective immunomodulating microtubule-binding agent that induces dendritic cell mutation, which is a key step in initiating durable anticancer response. The agent was first studied in a phase 1a dose-escalation trial (study 100; NCT00322608), in which 30 mg/m2 was selected as the appropriate dose. These results were sustained in the phase 1b portion of the phase 1b/2 trial (study 101; NCT00630110), which examined the agent in the second- or third-line treatment of patients with NSCLC.

In the phase 2 trial, results showed that the 30-mg/m² dose of plinabulin had better efficacy than a 20-mg/m² dose, and that the duration of response (DOR) was superior with docetaxel plus plinabulin compared with docetaxel alone.

The global, phase 3 DUBLIN-3 trial enrolled patients with nonsquamous or squamous stage IIIB or IV NSCLC, who had an ECOG performance status of 2 or less, and a least 1 measurable lung lesion. Patients must have progressed during, or after, treatment with 1 or 2 platinum-containing regimens. Prior checkpoint inhibitor therapy was permitted.

A total of 559 patients were randomized 1:1. Those in the investigative arm (n = 278) received plinabulin at a dose of 30 mg/m² plus docetaxel at a dose of 75 mg/m² on day 1, and plinabulin again at a dose of 30 mg/m² on day 8. Those on the control arm (n = 281) were given docetaxel at a dose of 75 mg/m² on day 1 and placebo on day 8. Patients continued the treatment until disease progression.

The primary end point of the study was OS. Secondary end points included overall response rate (ORR), progression-free survival (PFS), percent of patients with grade 4 neutropenia on day 8 of cycle 1, 24- and 36-month OS rates, DOR, Q-TWIST, quality of life (QoL), and the percentage of patients who received more than 8, 10, and 12 cycles of docetaxel.

The primary end point of OS from randomization was based on the intent-to-treat population. Additionally, a planned sample size of approximately 439 deaths was required to provide 85% power to detect a treatment difference at a 2-sided significance level of 0.05 with 2 planned intern analyses. The first interim analysis would occur after 33% of death events were reported, and the second would occur after 67% death events occurred. A final analysis would occur after 439 death events were reported.

Among the study participants, the median age was 61 years (range, 25-85). The majority of patients were male (72.6%), had a nonsquamous tumor histology (59.2%), an ECOG performance status of 1 (81.2%), had received prior first-line treatment (75.1%), and were geographically located in China (87.3%).

Additional findings showed that the median PFS with the combination was 3.6 months (95% CI, 3.0-4.4) vs 3.0 months (95% CI, 2.8-3.7) with docetaxel alone. The 6-month PFS rates in the investigative and control arms were 30.3% vs 17.8%, respectively (P = .004); at 12 months, these rates were 17.1% and 4.7%, respectively (P = .0004), and at 18 months, these rates were 5.0% vs 1.6%, respectively (P = .1634).

Moreover, the ORR was 12.23% with the combination compared with 6.76% with docetaxel alone (P = .0275).

For patients who received 4 or more treatment cycles, the median OS with the combination was 18.3 months (95% CI, 14.96-22.88) vs 13.5 months (95% CI, 10.68-16.54) with docetaxel alone (HR, 0.635; P = .0022). Similarly, the median OS was 28.2 months (95% CI, 12.99–not evaluable) vs 19.3 months (95% CI, 13.77-24.85), respectively, in those who received 8 cycles or more treatment cycles (HR, 0.453; P = .0121).

Among patients who were PD-1/PD-L1 exposed, the median OS was 12.3 months (95% CI, 9.34-22.88) with the combination vs 12.1 months (95% CI, 9.76-13.77) with docetaxel alone (HR, 0.682; 95% CI, 0.454-1.025; P = .0620). Consistent long-term survival benefit was observed in Western patients in the ITT population (P = .2681).

QoL was evaluated with validated tools like the EORTC QLQ C30 and QLQ-LC13. The Q-TWiST analysis integrated efficacy, safety, and QoL inputs, including EQ-5D Hu QoL. An improvement of higher than 18% in Q-twist, or time with good QoL, was reported with the combination; this was determined to be clinically meaningful.

In terms of safety, the addition of plinabulin significantly reduced the rate of grade 4 neutropenia. On day 8 of cycle 1, the rate of grade 4 neutropenia was 5.26% with the combination vs 27.80% with docetaxel alone (P < .0001). Additionally, at day 8 of all cycles, the rate of grade 4 neutropenia was 5.13% with the combination vs 33.58% with docetaxel alone (P < .0001).

Additionally, the most common grade 3/4 AEs reported with the combination included decreased white blood cell count (27.4%), decreased neutrophil count (29.6%), hypertension (17.2%), diarrhea (8.4%), and nausea (1.1%).

Reference

1. Han B, Shi Y-K, Feng D, et al. DUBLIN-3 (BPI-2358-103): A global phase (Ph) III trial with the plinabulin/docetaxel (Plin/Doc) combination vs. Doc in 2nd/3rd Line NSCLC patients (pts) with EGFR-wild type (wt) progressing on a prior platinum-based regimen. Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract LBA48.