Plinabulin Combo With Docetaxel Aimed at Delivering a "Double Hit" in NSCLC Trial

Goetz H. Kloecker, MD, MBA, MSPH, FACP

Plinabulin, an antineoplastic agent that activates an immune response, is being investigated as a treatment option for patients with advanced or metastatic non-small cell lung cancer (NSCLC) who have progressed after standard-of-care therapy. The drug is being tested in combination with docetaxel in the phase III DUBLIN-3 trial for patients receiving second- or third-line chemotherapy (NCT02504489).

Investigators are seeking to significantly improve survival for a patient population with a particularly poor prognosis. Despite the introduction of tyrosine kinase inhibitors and PD-1—targeting immunotherapy, many patients in this disease setting are treated with docetaxel alone. The median survival for patients who are treated with chemotherapy alone is about 7 to 8 months, according to Goetz H. Kloecker, MD, MBA, MSPH, FACP, associate professor of medicine and director of the Thoracic Oncology Clinic at the University of Louisville James Graham Brown Cancer Center in Kentucky.

Kloecker, who is the principal investigator for the trial at the University of Louisville, said the addition of plinabulin to standard chemotherapy has improved outcomes compared with docetaxel alone in initial studies. “Overall survival [OS] and progression-free survival [PFS] was significantly improved, and significant for lung cancer means the median survival was improved by more than 2 months.”

It may not sound like much, but for lung cancer, a median of 2 months often translates that there are more people alive 1 or 2 years later,” said Kloecker. Plinabulin works by destabilizing microtubule networks in the cell’s cytoskeleton through the activation of guanine nucleotide exchange factor GEF-H1, which results in inhibition of angiogenesis and activation of the JNK pathway.^1,2 Additionally, plinabulin has been shown in in vitro and in vivo studies to generate an immune response by inducing dendritic cell (DC) maturation and releasing interleukins.² Administered intravenously, plinabulin’s mechanism of action is unique in its ability to induce DC maturation and prevent neutropenia, according to BeyondSpring Pharmaceuticals, which is developing the drug.¹

Kloecker said the combination of plinabulin and docetaxel causes a “double hit” by targeting the tumor microenvironment, including the blood vessels, and directly killing tumor cells at the same time. “Combining standard docetaxel with something that brings more punch like blocking the blood vessels makes sense,” said Kloecker. “You suffocate the cancer cells because there is no oxygen, and you make them stop replicating with the chemotherapy.”

The DUBLIN-3 trial is seeking to randomize approximately 550 participants in a 1:1 ratio to receive either the combination of plinabulin and docetaxel, or docetaxel alone with a placebo (Figure). There are limited trial areas for the United States, with locations in California, Colorado, Georgia, Illinois, Kentucky, Mississippi, Ohio, and Tennessee. The majority of the enrollment for the trial is taking place in China.

Figure. Plinabulin in Metastatic NSCLC

Eligible patients will have advanced or metastatic NSCLC who have progressed after initial treatment with standard therapy, including chemotherapy or immunotherapy, with no severe heart problems. Patients with active brain metastasis or leptomeningeal involvement with brain metastases who are asymptomatic or stable may be candidates for enrollment. Participants must also have an ECOG performance status of 0 or 2, and must have at least 1 lesion that is larger than 1 cm in diameter in the lung parenchyma. The primary endpoint is OS.

In a previous phase II study, patients with advanced NSCLC with a measurable lesion who received plinabulin plus docetaxel (n = 38) achieved median OS of 11.3 months compared with 6.7 months for those who were treated with docetaxel alone (n = 38).³ The median PFS was 3.7 months and the objective response rate was 18% with the combination versus 2.9 months and 10.5%, respectively, for docetaxel. Additionally, the duration of response was 12.7 months with the combination versus 1 month in the docetaxel-only arm (P <.05).

Notably, lesion size does seem to matter in terms of plinabulin’s efficacy. “In the posthoc analysis of the phase II study, they found that the larger tumors had a significant improvement in median OS,” said Kloecker. Additionally, the improvement in OS was greater as the tumor size increased, he said.

The 2 drugs do not have overlapping toxicities or adverse events (AEs), and the combination tends to be well tolerated. In the phase II trial, the combination did not induce immune-related AEs, and prevented docetaxel-induced neutropenia,3 giving further credence to plinabulin’s tolerability overall. Plinabulin is also being investigated in preventing chemotherapy-induced neutropenia, due to its evident effect on the AE. It is also being studied in combination with nivolumab (Opdivo) in NSCLC and with docetaxel in KRAS-mutant NSCLC.⁴

Article and figure were updated on January 12, 2018, to clarify the lesion size requirement for inclusion in the clinical trial.

References

1. Plinabulin’s MOA. BeyondSpring Pharmaceuticals website. beyondspringpharma.com/en/plinabulin/moa/. Accessed November 17, 2017.
2. Lloyd GK, Mueller P, Zippelius A, Huang L. Plinabulin: evidence for an immune-mediated mechanism of action. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; Jan 7-10, 2016; San Diego, CA. Cancer Res. 2016;76(suppl 15; abstr A07). doi: 10.1158/1538-7445.TME16-A07.
3. Mohanlal RW, Lloyd K, Huang L, Bazhenova L. Plinabulin as a novel small molecule clinical stage immune-oncology agent for NSCLC. Presented at: 2017 ASCO-SITC Clinical Immuno-Oncology Symposium; February 23-25, 2017; Orlando, FL. J Clin Oncol. 2017;35(suppl 7S; abstr 139). meetinglibrary.asco.org/record/144489/abstract.
4. Broadening our development pipeline. BeyondSpring Pharmaceuticals website. beyondspringpharma.com/en/pipeline/. Updated May 2017. Accessed November 17, 2017.