DUBLIN-3: Plinabulin–Docetaxel Improves Advanced NSCLC Outcomes

By Lynda Williams, Senior medwireNews Reporter 

medwireNews: The DUBLIN-3 trial findings demonstrate overall survival (OS), quality of life and neutropenia prevention benefits with the addition of plinabulin to docetaxel in advanced non-small-cell lung cancer (NSCLC) patients who have progressed on platinum-based chemotherapy. 

Trevor Feinstein, from the Piedmont Cancer Institute in Atlanta, Georgia, USA, presented the phase III trial results at the ESMO Congress 2021, saying that the combination “had a favourable benefit to risk ratio, and has the potential [to become] a preferred second- and third-line treatment for EGFR wild-type non-small-cell lung cancer.” 

He explained that plinabulin is a first-in-class, selective immunomodulating microtubule-binding agent – or SIMBA – that binds to beta-tubulin and releases the immune defence protein GEF-H1, thereby inducing dendritic cell maturation, “a key step in optimising immune oncology response.” 

For the trial, 278 patients with stage IIIB or IV nonsquamous or squamous NSCLC who had progressed after platinum-based chemotherapy and up to one other treatment were randomly assigned to receive plinabulin 30 mg/m2 plus docetaxel 75 mg/m2 on day 1 of a 21-day cycle, followed by a second dose of plinabulin on day 8. 

The investigated reported that the primary endpoint of OS was significantly longer for these patients than the 281 participants who instead were given docetaxel plus placebo, at a median of 10.5 months versus 9.4 months, and a hazard ratio (HR) for death of 0.82. 

“Plinabulin had a durable benefit”, commented Trevor Feinstein, noting that the combination “doubled” the OS rate at 24 months (22.13 vs 12.51%) and 36 months (11.73 vs 5.27%). At 48 months, 10.6% of patients given plinabulin plus docetaxel were alive versus none of the controls. 

Patients given plinabulin plus docetaxel also had significantly longer median progression-free survival than those given placebo plus docetaxel (3.6 vs 3.0 months, HR=0.76), with significantly higher rates at 6 and 12 months. And the overall response rate was “doubled”, at 12.23% versus 6.76%. 

Patients “equally benefited” in OS from receipt of plinabulin regardless of age, ECOG performance status, sex, smoking status and tumour stage, reported Trevor Feinstein. 

In addition, exploratory analysis indicated that patients given at least four cycles of plinabulin plus docetaxel achieved significantly longer median OS than controls (HR=0.634) but the benefit increased with more treatment, with a HR for death of 0.453 among those given eight or more cycles. 

The presenter explained that the DUBLIN-3 trial started in 2015 and treatment with a checkpoint inhibitor was not mandatory but as clinical practice changed, 23% of recruited patients had previously received PD-1 or PD-L1 inhibitor therapy.  

Exploratory analysis of this subgroup suggests “a long durable response” to plinabulin plus docetaxel among the 62 patients given the combination versus the 67 patients given placebo plus docetaxel, he added. Although the respective median OS durations of 12.3 and 12.1 months gave a HR of 0.682 that did not reach statistical significance, the presenter highlighted the significantly higher OS rate in the combination arm at 24 months (35.82 vs 11.88%), and the numerically higher rates at 36 months (12.54 vs 4.95%) and 48 months (12.54 vs 0%).  

Turning to the safety profile, Trevor Feinstein reported that rates of grade 4 neutropenia were significantly lower in the combination than the placebo plus docetaxel treatment arm at day 8 of cycle 1 (5.26 vs 27.80%) and on day 8 of all treatment cycles (5.13 vs 33.58%). 

“This is very similar to what was seen in the [PROTECTIVE]-2 trial, highlighting plinabulin’s effect on neutropenia”, he said. 

Overall, plinabulin plus docetaxel was “well tolerated” and was associated with a lower rate of grade 3–4 treatment-related adverse events than placebo plus docetaxel, albeit with “a transient increase in hypertension that resolved shortly after the infusion”, affecting 17.2% versus 1.1%. 

Recognising that patients given plinabulin plus docetaxel had more treatment cycles than controls, the researchers estimated the rate of grade 3–4 adverse events per year, giving a significantly lower per patient event rate with the combination, at 9.88 and 11.04, respectively. 

Finally, the presenter reported a “clinically meaningful” 18.43% improvement in quality-adjusted time without symptoms of disease and toxicity (Q-Twist) with the combination versus control regimens. 

This Q-Twist improvement is “very similar” to that described for advanced NSCLC with pembrolizumab in the KEYNOTE-10 and KEYNOTE-24 trials, he remarked. 

Reference  

LBA48 - Feinstein T, Han B, Shi Y, 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. Ann Oncol 2021;32(suppl_5):S1283–S1346. doi:10.1016/annonc/annonc741