Researchers at UCLA’s Jonsson Comprehensive Cancer Center (JCCC) are reporting exciting dual discoveries in the treatment of non-small-cell lung cancer (NSCLC), which accounts for about 85 percent of all lung cancers, the leading cause of cancer deaths in the United States. Two new experimental drugs, ramucirumab and CO-1868, developed for use in patients with advanced NSCLC, are showing great promise in UCLA clinical trials in a type of cancer that historically has had very poor outcomes.
The findings were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting 2014 in Chicago.
Ramucirumab: A New Second-Line Defense
Lung cancer is expected to cause over 150,000 deaths in the United States this year alone. The usual standard therapy for patients when disease worsens during or after initial therapy is chemotherapy with a single drug. This is a patient population for whom an overall survival of approximately six to nine months is usual, with less than 10 percent of patients responding to therapy, and even then, responses are generally of short duration.
Dr. Edward Garon, assistant professor in hematology-oncology and JCCC member, conducted an extensive multi-year phase 3 clinical trial of 1,253 patients with NSCLC who had their cancer progress during or after a first-line treatment of chemotherapy. Ramucirumab, an investigational drug being developed by Eli Lilly and Company, is an antibody that targets the extracellular domain of VEGFR-2, an important protein in the formation of blood vessels that support cancer cells. Patients were given the experimental drug in combination with docetexal, a clinically approved therapy that is considered the cornerstone of second-line treatment in advanced NSCLC.
Response to ramucirumab was 23 percent at the time the study was analyzed. The drug is the first new therapy for previously treated NSCLC to improve overall survival, with findings showing a progression-free survival (PFS) rate of 4.5 months, and median 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,” Garon said. “Although adverse effects were experienced by patients, most commonly neutropenia, fatigue and hypertension, toxicities were largely manageable with appropriate dose reductions and supportive care, and without substantial reduction in planned dose intensity.”
The study was published in the June edition of The Lancet.
Combating the T790M Mutation with CO-1686
One of the major advances in the understanding of lung cancer has been the identification of specific mutations that drive the disease, and are presumed to be the initial genetic event that triggers cells to become cancerous. Of note, 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 JCCC 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.
A first example of targetable mutations in lung cancer was the identification of the EGFR mutation. This has resulted in a new class of targeted therapeutic agents called EGFR tyrosine kinase inhibitors (TKIs). Though TKIs have delivered promising results, the duration of benefit to patients still remains relatively short with progressive disease generally occurring about a year after the start of treatment. TKI treatment is also complicated by side effects such as diarrhea and skin rash.
Recent studies have 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. Currently, there are no targeted therapies approved for the treatment of the T790M mutation.
CO-1686 is an oral investigational drug discovered and being developed 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 in a cohort of 88 patients with EGFR-mutated, advanced NSCLC who were previously treated with an EGFR inhibitor and subsequently developed resistant disease. In a phase 1 trial, CO-1686 was administered continuously to patients in 21-day cycles.
Response to the drug, meaning those patients whose tumors shrank significantly, was seen in 58 percent of the patients. The benefit has been durable, with more than 75 percent of patients still on the drug at the time the study was analyzed. Treatment-related side effects, including elevated blood sugar levels, were for the most part mild and manageable.
“The results we’ve seen with CO-1686 are very promising,” said Goldman. “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.”
Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial, Dr Edward B Garon MD et al., The Lancet, DOI:10.1016/S0140-6736(14)60845-X, published online 2 June 2014.