How Biologics Are Shaping Cancer and MS

Among the highlights of Cleveland Clinic’s Biologic Therapies VI Summit from spring 2015 was an unprecedented session titled “Biological Cross Fire: What Can We Learn From Each Other?” It brought together six expert physicians from diverse disciplines to spotlight how biologics are being used or studied in interesting ways in their specialties.

Consult QD recently recapped two of those experts’ talks — on rheumatoid arthritis and psoriasis — here . This post summarizes key points from two more of the session’s presentations, on biologics in cancer and multiple sclerosis (MS).

Free CME-certified webcasts of all six presentations are available at ccfcme.org/BioVIOnline.

Biologics in cancer: Immune checkpoint inhibitors boost survival

For patients with solid tumors, immunotherapeutic approaches appear to be among the brightest beacons of hope for longer survival, according to Vamsidhar Velcheti, MD, a specialist in solid tumor oncology in Cleveland Clinic’s Taussig Cancer Institute.

“Even with various personalized approaches, five-year survival for most metastatic solid tumors is very modest,” said Dr. Velcheti. “Novel immunotherapy approaches and combinations with targeted agents and/or chemotherapy may provide more effective and durable responses.”

One of the hottest areas of oncology research and drug development involves administration of antibodies that block immune inhibitory pathways, or “immune checkpoints,” with the aim of breaking tolerance and reactivating tumor immunity.

One such agent, ipilimumab, blocks the CTLA-4 checkpoint, which attenuates the early activation of naïve and memory cells in the lymph nodes. Ipilimumab is FDA-approved for treatment of melanoma and is being studied in combination with other agents for the treatment of lung cancer.

Two other FDA-approved biologics, nivolumab and pembrolizumab, block a different checkpoint, PD-1, which modulates the effector phase of T cell activity in peripheral tissues via interaction with PD-L1 and PD-L2. In clinical trials, nivolumab produced a 42 percent one-year survival rate, which Dr. Velcheti described as “quite remarkable.” Not only are these drugs more effective than cytotoxic chemotherapy, but they are much better tolerated with significantly lower rates of adverse events.

Dr. Velcheti cautioned, however, that these agents don’t work in all patients and there is currently no accurate biomarker test to predict response. Work on that is ongoing.

Biologics in MS: From inflammatory to progressive disease

Progressive advances in the potency and tolerability of biologic therapies for the inflammatory aspects of MS are spurring efforts to develop biologics for the challenging progressive stage of the disease. So observed Jeffrey A. Cohen, MD, Director of Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research.

Dr. Cohen noted that of the 12 drugs currently FDA-approved for treating MS (with two more expected to be available soon), none is 100 percent effective and none addresses the later progressive stage of the disease, when demyelination and axonal damage occur.

For that reason, Dr. Cohen said, the general treatment philosophy today is to begin treatment early, with a “treat to target” approach, aiming for no detectable disease activity while the patient is on therapy.

Newer, more potent agents are now replacing the older injectable interferon-beta and glatiramer acetate, which are inconvenient and work in only about one-third of patients. The newer agents have the advantage of improved convenience (oral dosing or less-frequent IV infusion) and are more potent than the older injectables, though they are costlier and currently have limited long-term data.

Oral agents and the infused monoclonal antibody natalizumab have become the “go-to” second-line agents for patients with early-stage disease or inadequate response to injectables, Dr. Cohen observed. Natalizumab is the most potent, but its use is hampered by the risk of progressive multifocal leukoencephalopathy. Oral agents such as fingolimod and dimethyl fumarate are alternatives for immunosuppressed patients and those who are seropositive for the JC virus.

Alemtuzumab, the most recently approved biologic for MS, is also highly potent and convenient, but its use is hampered by the development of secondary autoimmunity. Ocrelizumab, which is likely to be the next biologic approved for MS, may well serve as a replacement for it.

“We have a pretty good handle on the inflammatory aspect of MS,” Dr. Cohen concluded. “A few improvements could be made, but much of our intellectual effort is being shifted toward progressive disease, where we don’t have effective therapies. We’re going to attack that challenge from a number of directions.”

The online webcast activities discussed above have been approved for AMA PRA Category 1 credit™.