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Do enough data exist to properly screen and monitor patients for toxicities associated with immunotherapies?
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Yes.
Immune checkpoint inhibitors have changed the landscape of cancer treatment since first coming on the scene a decade ago. Ipilimumab, a CTLA-4 inhibitor, was the first of these drugs to be FDA approved for the treatment of advanced melanoma in 2011. Since then, pembrolizumab and nivolumab — both PD-1 inhibitors — as well as atezolizumab, avelumab and durvalumab, all PD-L1 inhibitors, have been approved for the treatment of a variety of solid and hematologic malignancies, improving survival outcomes for our patients.
These drugs work on different inhibitory receptor proteins with a common mechanistic goal to improve the immune system’s T-cell response to cancer antigens. Treatment is therefore associated with a unique spectrum of autoimmune side effects not previously seen with cancer chemotherapy and targeted therapy agents. Additionally, there may not be a temporal association with use of these agents, as toxicities are known to develop several weeks and months after last dose.
Oncologists at tertiary care centers who accrued patients to early trials with immunotherapies are certainly developing familiarity with diagnosing and managing these toxicities. With more rampant use of these drugs and the media attention surrounding them, first responders such as ED physicians and hospitalists are also more sensitized to at least including them in the differential diagnosis for a patient’s clinical presentation.
Drug manufacturing companies have developed and distributed user-friendly manuals to clinics for the identification and management of immune-related side effects. For several years now, international oncology conferences have held educational sessions around this topic for early-career and community physicians, providing annual updates based on postmarketing data. Most importantly, oncology societies such as ESMO, Society for Immunotherapy of Cancer, ASCO and NCCN have published or announced the development of consensus guidelines that would make management of immune-mediated toxicities more uniform.
Through joint community endeavors, and as we gain greater experience with these novel therapies, we can hope to get better in our practice so as to make this a safe and effective treatment option for our patients.
References:
C Granier, et al. ESMO Open. 2017;doi:10.1136/esmoopen-2017-000213.
Haanen J, et al. Ann Oncol. 2017;doi:10.1093/annonc/mdx225.
Puzanov I, et al. J Immunother Cancer. 2017;doi:10.1186/s40425-017-0300-z.
Aarti Bhatia, MD, MPH, is assistant professor of medical oncology at Yale School of Medicine at Yale Comprehensive Cancer Center. She can be reached at aarti.bhatia@yale.edu. Disclosure: Bhatia reports no relevant financial disclosures.
No.
No one can dispute the significant improvements in OS achieved by immunotherapies — specifically checkpoint inhibitors — for a wide variety of solid tumors. Unfortunately, with the introduction of these therapies, physicians also have been introduced to a wide variety of toxicities with different mechanisms, treatment and times of occurrence. The same pathway that leads to improved antitumor T-cell response and T-cell disinhibition also reduces T-cell tolerance to self-antigens, which leads to autoimmunity.
Not enough data currently exist to monitor our patients appropriately and expectantly. The best approach for now is to educate patients and colleagues to appropriately identify and treat the toxicities. Communication is the best tool. At our clinic, patients are told to call with any new symptom and to have their other physicians call us in cases of emergency. We see patients with immune-related diabetes, myositis, colitis and endocrinopathy, which either have been unidentified or suboptimally treated, resulting in significant risks for morbidity and mortality. ED physicians, local consultants and community oncologists are slowly being introduced to the benefits of the therapy; mastery of the toxicities must follow.
The current focus of immuno-oncology is identifying predictive biomarkers to select patients who will respond to immunotherapy and differentiate those who will need single-agent or combination therapy. These biomarkers also potentially could elucidate the right therapeutic path in the event of resistance to therapy. Predictive markers for immune checkpoint inhibitor toxicity have yet to be discovered. Early work has focused on pretreatment serum samples and evaluation for autoantibodies, which could lead to site-specific toxicities and evaluation of the microbiome. The significant array of organs affected, however, makes this task daunting. Current paradigms of the time course of immune-related adverse events exist in the literature as a guide, but remain rudimentary at best. Combination therapies result in increased incidence of disease and earlier occurrences; sequenced therapies do the same. Our experience has shown that these toxicities can occur days, weeks and even months after the last dose of therapy. No chemotherapy or targeted therapy ever did this.
References:
Gowen, M, et al. J Clin Oncol. 2017;doi:10.1200/JCO.2017.35.15_suppl.9559.
J Weber, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2014.60.0379.
Zhong S, et al. Proc Natl Acad Sci USA. 2013;doi:10.1073/pnas.1221609110.
Omid Hamid, MD, is chief of research in immuno-oncology at The Angeles Clinic & Research Institute, an affiliate of Cedars-Sinai, and co-director of cutaneous malignancy at Cedars-Sinai. He also is a HemOnc Today Editorial Board Member. He can be reached at ohamid@theangelesclinic.org. Disclosure: Hamid reports no relevant financial disclosures.