The Severe Immunotherapy Complications (SIC) Service and Clinical-Translational Research Effort at Mass General Cancer Center is working to address the urgent need to understand how and why immune-related adverse events (irAEs) occur. SIC's multidisciplinary team comprises more than 50 individuals across 19 areas of the hospital, and this unique group of clinicians and researchers are involved in the care of every patient admitted with a suspected irAE after checkpoint blockade immunotherapy.

In this new interview series, Kerry Reynolds, MD, director of the SIC program, sits down with a SIC team member for a deeper-dive into their work. This month we meet Yevgeniy (Eugene) Semenov, MD, a board-certified dermatologist at Mass General Hospital with extensive experience in working with large data sets. He is interested in cutaneous oncology with a focus on skin cancers and characterizing cutaneous immune-related adverse events.

Kerry Reynolds, MD
Kerry Reynolds, MD

Kerry: Eugene, thank you so much for joining us today. We look forward to your talk Examining the Landscape of Immune Checkpoint Inhibitor Toxicities: Epidemiology to Germline Correlates that you will be giving to the Severe Immunotherapy Complications Service this month. You and your research team have been doing very interesting work. The recent paper in JAAD April 2021 looking at the epidemiology and risk factors for the development of cutaneous toxicities is fascinating. Can you tell us more about it?

Eugene: Thank you for having me Kerry. It is truly a pleasure to work with you and the rest of the Severe Immunotherapy Complications team in caring for our patients. Since joining the faculty here, my group has been largely focused on investigating the epidemiology and risk factors for the development of cutaneous immune-related adverse events. As you know, cutaneous eruptions are the most common presentation of immune-related adverse events. Unfortunately, much like with other organ systems, there is a lack of definitional standards of what constitutes a cutaneous irAE with different definitions and approaches to diagnosis across the country. To date, there has been no concerted effort to examine the nationwide incidence of these events as well as risk factors for their development.

Yevgeniy Semenov, MD
Yevgeniy (Eugene) Semenov, MD

Our JAAD paper was the first such study and demonstrated that only 10 of more than 40 dermatoses previously linked to ICIs actually occurred at a significantly higher incidence in the ICI population by comparison to age, gender, comorbidity, and cancer-matched controls. Interestingly, the median time to onset of these events was 113 days, which was significantly delayed from the 4-6 weeks observed in clinic trials. We further identified several important risk factors for the development of these toxicities, including melanoma and RCC diagnosis, younger age at ICI initiation, and use of combination immunotherapy. Lastly, we observed that approximately 5.0% of patients developing cutaneous irAEs required systemic immunosuppression for the management of these toxicities, which was at the higher end of what was previously reported in clinical trials.

Kerry: How do you think this work informs the field moving forward? What should we do differently when thinking about cutaneous irAEs?

Eugene: These findings are of particular clinical relevance to both dermatologists and oncologists caring for patients receiving immune checkpoint inhibitors. For example, clinicians should be on the lookout for the 10 conditions identified in this analysis as patients continue taking these medications. The real-world delays in the time to presentation of many of these conditions should also revise clinicians’ understanding of when to expect patients to present with these toxicities and not to rule out a delayed onset of symptoms as being unrelated to immunotherapy. These delays in presentation also suggest an opportunity for improving patient care. Dermatologists can work with oncologists to educate patients and facilitate earlier evaluations of these vulnerable patients so that they can take steps to prevent progression to more severe toxicities. Having identified the cutaneous morphologies most strongly linked to ICIs, we are now exploring the prognostic implications of these morphologies individually and as a class on cancer outcomes. Additionally, since many of these toxicities mimic cutaneous autoimmune disorders occurring outside of ICI settings, we are exploring the role of germline autoimmunity predisposition for the risk of developing these toxicities.

Kerry: What is the most pressing need, in your opinion, in the field of immune-related adverse events. In short, where do we go from here?

Eugene: The most pressing need is for us to utilize the observations from our study and other ongoing investigations to come together as a community and agree on standardized definitions for immune-related adverse events. This should be done in collaboration with oncologists and disease-specific experts for each organ system. These definitions, in turn, will facilitate further clinical care and research in this domain. The next step after that would be to try to develop robust risk prediction models for the development of these toxicities. We certainly have enough observational data from the last 10 years of experience with ICIs to do this now, it’s mostly a matter of pooling together the disparate data sources from across our institution and available national/public repositories. The risk prediction models would not only help identify patients at highest risk of toxicity, thereby allowing for earlier and more rigorous clinical monitoring, but also help elucidate mechanisms of immunotherapy response for which these toxicities are often a favorable prognostic marker.

Kerry: Is there any paper in press that we should know about? When/where will it be coming out?

Eugene: We have several manuscripts in submission and in press in this domain. One such manuscript was recently published in JITC investigating the nationwide epidemiology and risk factors for the development of severe irAEs of all organ systems. This was the first such effort in this space and provides an algorithmic approach to identifying these patients using claims data. Another interesting study, which is currently under review investigated the impact of race and ethnicity on development of cutaneous irAEs. In this study, we found that Asians and Hispanics were more likely to develop cutaneous toxicities by comparison to whites and that blacks were less likely. We also identified that some of the decreased incidence of cutaneous irAEs among blacks was caused by an observational bias in identifying inflammatory conditions in darker pigmented skin. We are hoping this manuscript will be published in the next several months. Other ongoing investigations are exploring the differential impact of various morphologies of cutaneous irAEs on cancer outcomes. I am looking forward to giving a sneak peek to this work in my upcoming talk.


Wongvibulsin S, Pahalyants V, Kalinich M, et al. Epidemiology and risk factors for the development of cutaneous toxicities in patients treated with immune checkpoint inhibitors: A United States population-level analysis [published online ahead of print, 2021 Apr 2]. J Am Acad Dermatol. 2021;S0190-9622(21)00661-7. doi:10.1016/j.jaad.2021.03.094

Kalinich M, Murphy W, Wongvibulsin S, et al. Prediction of severe immune-related adverse events requiring hospital admission in patients on immune checkpoint inhibitors: study of a population level insurance claims database from the USA. Journal for ImmunoTherapy of Cancer 2021;9:e001935. doi: 10.1136/jitc-2020-001935