Pfizer and Merck Collaborate on ALK-Positive NSCLC

Crizotinib is an anti-cancer drug acting as an ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) inhibitor, approved for treatment of some non-small cell lung carcinoma (NSCLC) Crizotinib is currently thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells. Other studies suggest that crizotinib might also act via inhibition of angiogenesis in malignant tumors. Pembrolizumab (also known as MK-3475) is a drug in marketted by Merck that targets the programmed cell death 1 (PD-1) receptor. The drug is intended for use in treating metastatic melanoma.

Pfizer and Merck announced that they have entered into an agreement to explore the therapeutic potential of the combination of Pfizer’s crizotinib with Merck’s investigational anti-PD-1 antibody pembrolizumab. A clinical study evaluate the safety and tolerability of the combination in patients with ALK-positive advanced or metastatic non-small cell lung cancer (NSCLC). This collaboration between Pfizer and Merck is just one example of the willingness of sponsors to work together in an effort to accelerate progress against some of the most difficult-to-treat cancers. The effects of combining one drug, crizotinib, which inhibits an abnormally activated enzyme in patients with ALK-positive metastatic lung cancer, with the investigational drug, pembrolizumab, which harnesses the body’s immune system to fight cancer.

This multi-center, open-label clinical study is expected to begin in 2015. Pfizer will conduct the study. Both companies previously announced plans to evaluate the safety and efficacy of pembrolizumab in combination with Pfizer’s small molecule kinase inhibitor axitinib in patients with renal cell carcinoma. Separately, pembrolizumab plus Pfizer’s PF-05082566 (PF-2566), an investigational immuno-oncology agent that targets the human 4-1BB receptor, will be evaluated in multiple cancer types. These studies are expected to begin enrollment later this year.

Last week in Nature Medicine, a study led by Christine, assistant professor of Medicine and Cancer Biology, was published online. The work was based on an intriguing clinical observation of a female patient with advanced lung cancer who had an unexpected response to a monoclonal antibody that targets the insulin-like growth factor receptor (IGF-1R). IGF-1R helps cancer cells survive and evade anti-cancer therapies.

Remarkably, the patient remained on the IGF-1R therapy for 17 months — far longer than any other patient on the clinical trial. The researchers became interested in why this particular patient’s tumor responded to the experimental therapy so dramatically. Investigators decided to test for gene mutations and found an unexpected result — the patient’s tumor was positive for an ALK gene fusion. Only about 5 percent of lung cancer patients have this gene fusion in their tumor.

With this new information, the patient was enrolled in another clinical trial testing crizotinib, a drug that targets ALK rearrangements, and her cancer stopped progressing for several more months. This patient’s surprising response to different forms of therapy sparked a new line of research to identify and explain the biological mechanisms at work. Researchers from medical centers in the United States, Germany and Australia tested the ability of IGF-1R inhibitor therapies alone or in combination with ALK inhibitors to impede the growth of ALK+ lung cancer and to overcome acquired resistance to ALK inhibitor therapies.

Working in cell lines, mouse models and patient lung tumor cells, they tested the two types of drugs and found that the combination therapy enhanced the ability to slow down the growth of ALK+ lung cancer cells. They found similar results in cell lines from ALK+ lymphoma, a different form of cancer harboring the same tumor genetic alteration.

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