Is it feasible to change the immunotherapy dose schedule for a patient in complete response?
Immunotherapy represents a novel form of therapy in many ways, and it may not need to be given continuously. Currently approved checkpoint inhibitors activate the patient’s immune system, allowing it to target the cancer.
The question is, do you need to keep giving the drug to continue that activation? With ipilimumab (Yervoy, Bristol-Myers Squibb), the first checkpoint inhibitor approved for melanoma, patients get four doses and then no further therapy. We now have long-term survival data for patients treated with ipilimumab suggesting that patients who have responded and still have disease control at 3 years are very unlikely to experience recurrence. With high-dose interleukin-2, one of the first immunotherapies, patients received a defined course and then no further therapy. With decades of follow-up for these patients, about 5% to 10% have long-term remissions.
PD-1 inhibitor trials were originally designed so that patients could be dosed long-term. However, the drugs are very expensive — at $10,000 to $15,000 per dose — adding up to hundreds of thousands of dollars when patients stay on these therapies for years. But, do they really need to? There are some data in melanoma looking at outcomes in patients who electively stopped therapy after 2 years, but we don’t know if patients with a complete response could stop even earlier. Alternative schedules could be possible, as well; these drugs have very long half-lives and a wide therapeutic index, making this more feasible than with other agents used to treat cancer. In March 2018, the FDA approved a dosing change from every-2-week dosing to every 4 weeks for nivolumab, which is meaningful, but clinical endpoints are still lacking.
Immunotherapy, in some ways, is changing how clinical trials are designed. Not everyone should change their immunotherapy regimens, but there’s a lot of suggestion that it could be feasible. This is a such an important area for investigation, because it has huge financial and quality-of-life implications for patients.
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April K.S. Salama, MD, is director of the melanoma disease group at Duke Cancer Institute. She can be reached at 20 Duke Medicine Circle, Durham, NC 27710; email: email@example.com. Disclosure: Salama reports research funding to her institution from Bristol-Myers Squibb, Celldex Therapeutics, Dynavax Technologies, Immunocore and Merck.
We are very early on in terms of the evidence basis for immunotherapy dose changes, mostly because a lot of immunotherapies are being approved for their first indications as we speak. Only recently have the dose schedules been able to be changed in a standardized fashion. For example, the method of giving nivolumab every 4 weeks instead of every 2 weeks was approved just last year. I don’t know of any good data that suggest that based on clinical response, reducing the dose of immunotherapy is a viable strategy, nor do I know of data that suggest this is something we should be doing routinely.
There are certainly data — especially in the melanoma literature, including 3-year OS data from Robert and colleagues published in Journal of Clinical Oncology — that suggest if the patient has a response to a drug like pembrolizumab, limited doses of immunotherapy could lead to a response that persists for quite a long time. So, it’s reasonable to think about adjusting the dosing regimen in the melanoma community. However, this usually entails stopping immunotherapy altogether and entering a surveillance period once there’s a good response or complete radiologic response.
For other patients in response, the decision should focus on whether to continue immunotherapy beyond a set time period, not necessarily to modify the dose schedule. For example, in the maintenance setting, based on data from Antonia and colleagues published in The New England Journal of Medicine, the duration of immunotherapy with durvalumab (Imfinzi, AstraZeneca) consolidation after concurrent chemotherapy and radiation for stage 3 non-small cell lung cancer is usually for a specific time period (typically up to 1 year).
Modifying dose schedules ad hoc in relation to response remains speculative until there is phase 3 evidence.
Antonia SJ, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1809697.
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Ravi B. Parikh, MD, MPP, is instructor of medical ethics and health policy at Perelman School of Medicine at University of Pennsylvania. He can be reached at 3401 Civic Center Blvd., Philadelphia, PA 19104; email: firstname.lastname@example.org. Disclosure: Parikh reports research funding from Conquer Cancer Foundation, Medical University of South Carolina, Penn Center for Precision Medicine, and VA Center for Health Equity Research and Promotion; a columnist stipend from Medscape; and consultant fees from GNS Healthcare.