Novel Drug Combination Hits Non-Small Cell Lung Cancer With Double Punch

A NEW DRUG COMBINATION in testing could hit non-small cell lung cancer (NSCLC) with a one-two punch: simultaneously suffocating tumor cells and preventing new ones from forming.

Plinabulin, an angiogenesis inhibitor that prevents growth of new blood vessels, is being tested in combination with the chemotherapy drug Taxotere (docetaxel) as an option for patients with advanced stage 4 NSCLC who have progressed after treatment with standard-of-care therapy. The investigators intend to determine the overall survival (OS) benefit of plinabulin for patients receiving second- or third-line chemotherapy.

For patients treated solely with chemotherapy, OS is often very short, with a median survival of 7 to 8 months, according to Goetz H. Kloecker, M.D., M.S.P.H., MBA, FACP, an associate professor of medicine and director of the Thoracic Oncology and Hematology/Oncology Fellowship programs at the University of Louisville in Kentucky. “In the initial trials, [for patients who had] larger tumors — more than 3 centimeters — 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,” Kloecker said.

This drug could represent a big step forward in helping patients with lung cancer who have received standard-of-care therapies in the first- or second-line setting. There are currently two approved antiangiogenetic therapies for this patient population — Avastin (bevacizumab) and Cyramza (ramucirumab) — and adding another option to be combined with Taxotere could lead to treating more patients for a longer period.

“Tumors need a lot of blood, since they live on oxygen,” Kloecker said. “Plinabulin blocks blood vessels from growing and kills tumor blood vessels. It does this by blocking the inner microtubules of the blood vessels, killing them and depriving the tumor cells of oxygen, causing cell death.” Adding Taxotere, which blocks the mitosis of cancer cells, creates a “double hit” to the tumor’s system, he said, and the cancer cells can no longer replicate.

The combination thus targets the environment surrounding the cancer, the blood vessels and the cells all at the same time. “Combining standard docetaxel with something that brings more punch, like blocking the blood vessels, makes sense,” Kloecker said. “You suffocate the cancer cells because there is no oxygen, and you make them stop replicating with the chemotherapy.”

The trial will randomize approximately 550 participants to receive either the combination of plinabulin and Taxotere, or Taxotere alone with a placebo. Eligible patients will have metastatic, stage 4 NSCLC and have progressed after initial treatment with standard therapy, including chemotherapy or immunotherapy, with no severe heart problems or brain metastases. Patients also must have an Eastern Cooperative Oncology Group performance status of zero to 2, and at least one lesion larger than 3 centimeters in diameter in the lung parenchyma. Since it is a large phase 3 trial, the investigators will be assessing OS, PFS and duration of response (DoR).

In a previous phase 2 study of plinabulin and Taxotere in patients with advanced NSCLC, the median OS was 11.3 months, with a PFS of 3.7 months, compared with 6.7 months and 2.9 months, respectively, with Taxotere alone. The DoR of the combination was 12.7 months versus 1 month. The investigators concluded that adding plinabulin to Taxotere improves the efficacy versus Taxotere alone.

The two drugs do not have overlapping toxicities or side effects and it tends to be well tolerated.

Notably, lesion size does seem to matter in terms of plinabulin’s efficacy.

Although this drug is not a “sure thing,” Kloecker said, he added that patients tend to do better when enrolled in clinical trials and encourages people with NSCLC to ask their physicians if a trial center is near their area. U.S. trial locations are in California, Colorado, Georgia, Illinois, Kentucky, Mississippi, Ohio and Tennessee. The majority of the enrollment is taking place in China.