Lung cancer is the leading cause of cancer deaths in Los Angeles as well as the rest of the nation; 85% of these cancers are advanced non-small-cell lung cancers (NSCLCs), which most often have a poor prognosis. Two new experimental drugs for NSCLC have undergone clinical trials at UCL; these trials are showing great promise for treatment of this type of cancer. Ramucirumab is a medication that blocks blood vessel formation, improves overall survival in a phase three trial of patients whose condition deteriorated after standard therapy. CO-1686 has been found to shrink tumors with prolonged responses in patients whose tumors carry a specific mutation that prevents tumors from responding to available EGFR inhibitors (EGFR T790M mutation). The findings were published in the June edition of the journal The Lancet and were presented on June 2 at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.
Researchers at UCLA’s Jonsson Comprehensive Cancer Center (JCCC) explain that lung cancer is expected to cause more than 150,000 deaths in the US this year alone. Overall, the survival of lung cancer patients after diagnosis is usually from six to nine months; less than 10% of patients respond to therapy, and even if they do respond, responses are usually short-lived. The standard therapy for patients when disease worsens during or after initial therapy is single-drug chemotherapy.
An extensive, multi-year clinical trial was conducted by a UCLA research team led by Dr. Edward Garon, assistant professor in hematology-oncology and JCCC member. The study group comprised 1,253 NSCLC patients whose cancer progressed during or after a first-line treatment of chemotherapy. Ramucirumab is an investigational drug being developed by Eli Lilly and Company; it is an antibody that targets the extracellular domain of VEGFR-2, which is an important protein involved in the formation of blood vessels that support cancer cells. The patients were given the experimental drug in combination with docetexal, which is a clinically approved medication that is considered the foundation of second-line treatment for advanced NSCLC.
When the study was analyzed, the researchers found that the response to ramucirumab was 23%. They note that the drug is the first new therapy for previously treated NSCLC to improve overall survival; they found a progression-free survival (PFS) rate of 4.5 months, and an average overall survival of 10.5 months. “We are excited to have a drug that lengthens survival time in lung cancer patients, who often have few options,” explained Dr. Garon, He added, “Although adverse effects were experienced by patients, most commonly neutropenia [low white blood cell count], fatigue and hypertension [low blood pressure], toxicities were largely manageable with appropriate dose reductions and supportive care, and without substantial reduction in planned dose intensity.”
The study authors explain that one of the major advances in the understanding of lung cancer has been the identification of specific mutations that advanced the disease; these mutations are believed to be the initial genetic event that triggers cells to become malignant. They note that the results of the Lung Cancer Mutation Consortium were published in the Journal of the American Medical Association (JAMA) within the last two weeks. The UCLA cancer center was one of a group of leading institutions who participated in this collaborative project that showed that personalized therapies could be directed at a large percentage of non-small cell lung cancer patients.
The first example of targetable mutations in lung cancer was the identification of the EGFR mutation. This discovery has resulted in a new class of targeted therapeutic agents known as EGFR tyrosine kinase inhibitors (TKIs). TKIs have been found to have promising results; however, the duration of benefit to patients currently remains relatively short with progressive disease generally occurring about a year after the start of treatment. TKI treatment also has side-effects such as diarrhea and skin rash.
Recent research has shown that when resistance to EGFR inhibitors occurs, more than half the time it is due to the emergence of a new “gatekeeper” mutation, called T790M. At present, there are no targeted therapies approved for the treatment of the T790M mutation. CO-1686 is an oral investigational drug that was discovered and is under development by Clovis Oncology to selectively target both the initial EGFR mutations and the T790M resistance mutation. Dr. Jonathan Goldman, assistant professor in hematology-oncology and JCCC member, was one of the leaders of a study comprised of 88 patients with EGFR-mutated, advanced NSCLC who were previously treated with an EGFR inhibitor and later developed resistant disease. In a phase 1 trial, CO-1686 was administered continuously to patients in 21-day cycles.
Response to the drug was measured by significant tumor shrinkage; this occurred in 58% of the patients. The benefit has been long-lasting; more than 75% of patients were still on the medication at the time the study was analyzed. Treatment-related side effects, including elevated blood sugar levels, were, in most cases, mild and manageable. Dr. Goldman explained, “The results we’ve seen with CO-1686 are very promising. Many of these responses are very dramatic, and the result is that patients can feel better and live longer, often with fewer side effects than chemotherapy.”