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Taking the Brakes off the Immune System to Fight Deadly Cancers
Posted Date: 6/3/2014 4:30 AM

STORY HIGHLIGHTS

  • Experimental drug MK-3475 had estimated overall survival rates of 69 percent at one year and 62 percent at 18 months, in 411 patients with advanced melanoma
  • MK-3475 response rate was 20 percent overall in 217 patients with advanced non-small cell lung cancer
  • Reponses were durable with tolerable side effects across doses

Researchers at UCLA’s Jonsson Comprehensive Cancer Center (JCCC) are reporting exciting treatment milestones for patients with deadly cancers who are being treated with an experimental drug called MK-3475. The drug is an antibody that targets a protein expressed by immune cells called PD-1. In the body, PD-1 acts as an immune checkpoint, turning down the immune system’s T cells that otherwise would attack cancer cells as invaders. MK-3475 takes the brakes off the immune system and allows T cells to identify and attack cancer cells.

The U.S. Food and Drug Administration (FDA) granted breakthrough therapy designation to MK-3475 for unresectable or metastatic melanoma in May 2013 under its Accelerated Approval program.

In UCLA clinical trials, doctors are seeing unprecedented treatment success with MK-3475 in two types of cancer that have historically had very low survival rates. The first is metastatic melanoma, a malignant skin cancer that spreads (metastasizes) aggressively beyond the initial tumor to invade other vital organs, such as brain, lungs or liver. The other is lung cancer, the cause of the highest number of cancer deaths in the U.S. year after year.

Metastatic Melanoma

Dr. Antoni Ribas, professor of hematology-oncology and JCCC member, led what is probably the largest phase 1 study ever conducted in cancer, with 411 patients who had metastatic melanoma. In a disease with an average five-year survival rate of less than five percent, the one-year overall survival rate was 69 percent for all patient subgroups. Response to the drug, meaning those patients whose tumors shrank, was continuing in 88 percent of patients at the time the study was analyzed, after an average 12-month follow-up. Tumors responded in patients from all the different dose regimens and in various patient subgroups, including those whose cancers had worsened after having received the drug ipilimumab. There are currently no treatment options with proven activity for those patients.

“We are seeing unprecedented durable responses with this drug,” Ribas said. “MK-3475 is working in patients that had not been treated, as well as those who had been given ipilimumab and other therapies. These are early data, but response rates of this magnitude in such a large sample, with only four percent of patients discontinuing because of drug-related side effects, indicate the importance of moving forward quickly with this drug.”

Overall, 34 percent of patients had responses to MK-3475, including 40 percent not treated with ipilimumab and 28 percent whose cancer worsened despite ipilimumab treatment. Treatment-related side effects were mild and reversible for the most part. Eight percent of patients had serious side effects.

Dr. Antoni Ribas Dr. Edward Garon
Dr. Antoni Ribas Dr. Edward Garon

Non-Small Cell Lung Cancer (NSCLC)

Dr. Edward Garon, assistant professor of hematology-oncology and JCCC member led a cohort of 217 metastatic non-small cell lung cancer (NSCLC) patients whose disease worsened during or after at least one prior therapy as part of the same MK-3475 study. This was the largest report of lung cancer patients being treated with this approach of inhibiting PD-1.

The usual standard therapy for patients in this situation is chemotherapy with a single drug. After one prior therapy, 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. Outcomes are typically worse in patients who have received two or more therapies, as was often the case in this study.

For the majority of lung cancer patients whose tumors expressed PD-L1, a target of PD-1, 23 percent had a response to this therapy, and the responses were often durable.

“We are very excited about the preliminary results we are seeing with MK-3475 in these advanced lung cancer patients,” Garon said. “It is a very well tolerated drug, so the benefits are enhanced by the fact that it generally has very little negative effect on patient quality of life. We are conducting additional trials with MK-3475, and based on our work, we hope the drug will soon be available to patients throughout the world.”

About the Jonsson Comprehensive Cancer Center

UCLA's Jonsson Comprehensive Cancer Center has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation's largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2013, the Jonsson Cancer Center was named among the top 12 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 14 consecutive years. For more information on the Jonsson Cancer Center, visit our website at http://www.cancer.ucla.edu

 

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