Center for Cancer Research plays key role in first FDA-approved drug for treatment of Merkel cell carcinoma

Merkel cell carcinoma cells

Merkel cell carcinoma, shown above, is a rare, aggressive form of skin cancer. In this photo, the tumor cells are stained green and the blood vessels stained red. The FDA just approved the immunotherapy drug avelumab for treatment of the aggressive disease thanks to collaboration between basic and clinical researchers at the Center for Cancer Research.

Photo credit: Isaac Brownell, M.D., Ph.D., Investigator, Dermatology Branch, CCR

The U.S. Food and Drug Administration on March 23 approved the immunotherapy drug avelumab for metastatic Merkel cell carcinoma (MCC) — a rare, aggressive form of skin cancer — for adults and patients 12 years of age and older. Avelumab, marketed as Bavencio, is the first FDA-approved treatment for MCC. Trials based at the Center for Cancer Research (CCR), whose infrastructure allows unparalleled, seamless collaboration between basic and clinical researchers, were instrumental in streamlining avelumab’s approval.

Avelumab is an antibody that targets programmed death-ligand 1 (PD-L1), a protein found on several types of tumors. PD-L1 binds T cells, white blood cells that defend against disease. This inactivates the T cells and allows tumor cells to avoid immune attack. Avelumab binds to PD-L1, preventing the T cells from being switched off so they can still attack tumor cells. Unlike existing anti-PD-1/PD-L1 immunotherapies, high concentrations of avelumab bound to PD-L1 on tumor cells can also trigger tumor killing by natural killer (NK) cells – netting “two shots on the goal,” explains James Gulley, M.D., Ph.D., Chief, Genitourinary Malignancies Branch.

The FDA’s approval of avelumab stems from a collaboration between CCR and EMD Serono Inc. to clinically develop the antibody. Preclinical research at CCR demonstrated that avelumab allows T cells to efficiently kill a variety of tumor cells and can enlist the help of NK cells. Based on these findings, Gulley and Jeffrey Schlom, Ph.D., Chief, Laboratory of Tumor Immunology and Biology, led the first human trials of avelumab in a dose-escalation study at CCR. This type of study begins with a small group of patients that receives the drug at a very low dose. Once it’s shown to be safe, the next group of patients gets a higher dose, and so on.

After only eight months, CCR investigators had enrolled four cohorts and established safety and pharmacokinetic data on avelumab, allowing rapid enrollment of 16 additional cohorts worldwide. This also allowed initiation of the trial of 88 patients with metastatic MCC that led to the FDA approval. Of the 88 patients, who had also previously undergone chemotherapy, 33 percent showed complete or partial decrease in the size of their tumors. The tumor shrinkage lasted six months or more in 86 percent of patients and a year or more in 45 percent of responders.

The question of whether avelumab induces side effects to the immune system still remained. To find out, CCR investigators led by Gulley and Schlom analyzed 123 subsets of immune cells from the study participants before and after treatment. They saw no significant decrease in the defensive cells after treatment, evidence that avelumab does not have harmful effects on the immune system.

The process leading to FDA approval embodies CCR’s unique bench-to-bedside-to-bench model. At CCR, where research labs spanning multiple disciplines neighbor world-class clinical facilities, investigators could rapidly translate preclinical findings on avelumab into human trials and confirm in those same patients that avelumab does not destroy immune cells, all within a few corridors. The CCR’s funding structure also allows researchers the flexibility to quickly respond to new opportunities.

The CCR is committed to finding cures for all types of cancer, including rare, neglected cancers. Having rare patient populations, such as MCC, allows CCR to expedite the testing of novel treatment approaches, such as avelumab. For trial participants who previously had few other treatment options, “it’s just completely a new age,” Gulley says. “It’s certainly a huge impact on the patient and their ability to get out there and go to their kids’ wedding or their grandkids’ graduation. … This is a real success story.”

To read more about avelumab, click here:

Posted on Tue, 04/18/2017