Expanding the Playing Field: Immune-Based Therapy Shows Potential for Lung, Other Cancers
Results from two early-phase clinical trials presented at the 2012 American Society of Clinical Oncology annual meeting provide further evidence that priming the immune system to attack tumors has potential as a treatment for certain cancers. The findings were also published June 2, 2012, in the New England Journal of Medicine (NEJM, here and here).
Although preliminary, the results are notable because, in both trials, the treatments produced substantial tumor shrinkage in some patients with non-small cell lung cancer, which has been extremely resistant to immune-based therapies thus far, the trial leaders explained. And in many of these patients, the tumor responses were maintained for a year or more.
"I think it's one of the most exciting things I've seen in recent years," said D. Ross Camidge, M.D., Ph.D., a lung cancer researcher at the University of Colorado Denver, who was not involved in either study. "A lot of the progress we've made recently has been about identifying molecular subtypes of lung cancer and having very specific targeted treatments. The promise of immunotherapy is something that actually cuts across some of those boundaries and may change every single treatment paradigm that we're currently developing."
Both studies tested investigational drugs that target molecules known as "checkpoint" molecules, which help restrain immune responses so they don't harm the body. Tumors can co-opt these checkpoint molecules, weakening the immune system's ability to eradicate the tumors.
Tumor shrinkage was also seen in patients with melanoma and kidney cancer. Previous studies have shown that these cancers can respond to immunotherapy, and the Food and Drug Administration (FDA) has approved immunotherapies for patients with these tumors. In addition, one of 17 patients with ovarian cancer who received one of the investigational drugs also had a tumor response.
Unleashing the Immune Response
The two drugs tested in the trials are monoclonal antibodies, one of which targets a receptor protein known as PD-1 on the surface of activated T cells. The other drug targets a binding partner (ligand) of PD-1, called PD-L1, which is expressed at higher than normal levels on many tumors and on cells in the tumor microenvironment in response to inflammatory stimuli.
Both agents are being developed by Bristol-Myers Squibb, which was the primary funder of both trials.
In 2011, the FDA approved the first checkpoint molecule inhibitor, ipilimumab (Yervoy™) to treat advanced melanoma. Ipilimumab, however, targets a different checkpoint molecule, CTLA-4, on the surface of activated T cells.
Patients in the trials also had stomach, breast, colorectal, castration-resistant prostate, or pancreatic tumors that grew despite multiple prior treatments. Nearly 300 patients were enrolled in the trial testing the PD-1 targeted agent, and slightly more than 200 were enrolled in the trial testing the PD-L1 targeted agent. Both trials tested escalating doses of the drugs, starting with a low dose. If no significant side effects were seen, the researchers incrementally increased the doses for patients who enrolled later.
The results are intriguing not only because of the number of the responses but also because of their durability, noted Suzanne Topalian, M.D., of the Johns Hopkins University School of Medicine, who led the trial testing the PD-1 targeted agent. Among 31 patients who responded to the PD-1 targeted agent and were followed for at least one year, 20 had responses that persisted for at least a year.
|Anti-PD-1 Trial||Anti-PD-L1 Trial|
|Melanoma||26 of 94 patients||9 of 52 patients|
|Kidney||9 of 33||2 of 17|
|Lung||14 of 76||5 of 49|
|Ovarian||n/a||1 of 17|
The most common side effects of treatment included fatigue, rash, and diarrhea. Other less-common side effects, such as fever, were consistent with the activation of the immune system. Five percent of patients in the trial targeting PD-1, and 6 percent in the trial targeting PD-L1, stopped receiving treatment because of severe side effects, and three patients who received the PD-1 targeted drug died of uncontrolled lung inflammation, called pneumonitis, caused by the treatment.
"The pneumonitis is a safety concern," said Dr. Camidge. And finding a method to predict which patients are most likely to benefit from these agents will be essential to justify both the risks and expected costs of any licensed immune therapy, he added.
In an attempt to address this issue, Dr. Topalian and her colleagues examined tumor samples collected before treatment from a subset of patients in the anti-PD-1 trial. They found that about one-third of the patients whose tumors expressed PD-L1 had measurable tumor responses, whereas no responses were observed in patients whose tumors did not express the protein. Much more work is needed, she stressed, before PD-L1 could be considered a predictive biomarker of response to treatment.
An Important Pathway
The trials' impact on immunotherapy research could be substantial, suggested Antoni Ribas, M.D., of UCLA's Jonsson Comprehensive Cancer Center, in an accompanying editorial in NEJM.
"These initial observations suggest that antibodies blocking PD-1 and PD-L1 are likely to provide a new benchmark for antitumor activity in immunotherapy," Dr. Ribas wrote.
Additional phase II trials of the PD-1 targeted agent are under way, and phase III trials involving patients with melanoma, non-small cell lung cancer, and kidney cancer are being planned. PD-1 pathway targeted agents are also top priority agents for clinical trials that will be conducted by researchers in NCI's Immunotherapy Clinical Trials Network.
"We've come to this point where we really understand the importance of these inhibitory pathways, which are holding the immune system back from recognizing cancer," said Dr. Topalian. "By blocking these pathways, we can then drive the immune system to recognize and destroy cancer cells.
"We feel that these findings, in addition to the findings reported in the past 2 years with ipilimumab, have established immunotherapy as a treatment for cancer," she added.