Breast Cancer Tumors Respond to Sorafenib, Pemetrexed Combination Therapy

A new combination therapy is showing promise for treating advanced solid tumors and may especially be beneficial in patients with recurrent or metastatic triple-negative breast cancer.  A phase I clinical trial testing a novel combination therapy of sorafenib (Nexavar) and pemetrexed (Alimta) slowed the growth of cancer in the majority of patients with advanced solid tumors. This study was recently published in the journal Oncotarget.

Approximately 61% of the patients experienced some degree of tumor growth delay, with multiple partial responses and one complete response. A phase II study testing the same combination in patients with recurrent or metastatic triple-negative breast cancer is now underway. Pemetrexed is a first-line therapy for non-small cell lung cancer (NSCLC) and mesothelioma. Currently, sorafenib is used to treat liver, kidney, and thyroid cancer.

“Though phase I studies are designed to evaluate the safety of a new therapy, we had strong preclinical evidence suggesting this novel drug combination could work against a variety of cancers, so we hoped that we would see a response in our patients in this early phase trial,” said lead study investigator Andrew Poklepovic, MD, who is with Virginia Commonwealth University Massey Cancer Center, in a news release. “With this trial, we established a safe dosing schedule, and we will now be testing the efficacy of the therapy in the phase II study.”

The study enrolled 37 patients between October 2011 and December 2014. Of those patients, 36 received treatment and 33 were evaluated for response. One patient had a complete response, and four patients had a partial response. The therapy stabilized disease progression in an additional 15 patients, with some of these patients responding for up to a year. The therapy was found to be particularly active in breast cancer patients.

Dr. Poklepovic said some dose-limiting toxicities associated with pemetrexed were observed in one cohort of patients. However, those who were eligible were switched to the dosing schedule of the second cohort, which was found to be safe and tolerable.

A new investigation is now underway to evaluate whether adding a third drug may act to further enhance the anticancer properties of the pemetrexed and sorafenib combination. A preliminary finding is suggesting that this two-drug combination therapy could be enhanced even further by a class of drugs known as ERBB1/2/4 inhibitors. The investigators found that in mouse models of breast cancer both lapatinib (Tykerb) and vandetanib (Caprelsa) significantly enhanced the antitumor effect of the pemetrexed and sorafenib therapy without any apparent toxicity to normal tissue. In addition, the team made a nearly identical observation when adding the drug afatinib (Gilotrif) in experiments involving NSCLC.

Preclinical work conducted by a team led by Paul Dent, PhD, Universal Corporation Chair in Cancer Cell Signaling and a member of the Cancer Cell Signaling research program at Massey, used a screening tool called a multiplex assay which simultaneously examined the levels of multiple hormones in the blood and determined the activities of enzymes in the cancer cells. Using this technology, the researchers discovered that the enzyme ERBB1 was activated in response to the pemetrexed and sorafenib therapy.  The investigators report that the multiplex assay could potentially provide a molecular “fingerprint” of the point at which tumors develop resistance to therapy.