Dorsal Fins and Immune-Mediated Adverse Reactions

by Dr. Terence Rhodes

It is no small secret that I have galeophobia. It is a moderate case. It doesn’t keep me from the beach.  My top choice for vacation is the beach. Sun, slumber, sand, and the sound of the crashing waves is a recipe for relaxation. Venturing into the ocean water, however, is a concoction for anxiety. What lurks beneath the waves? 

The phobia of sharks likely comes from my over-consumption of news and media. From “Jaws” to the latest “Sharknado (Sharknado 5: Global Swarming),” sharks have terrorized movie characters and moviegoers alike for decades. 

For those of us with galeophobia, reviewing shark attack facts does little to calm our anxiety.  Repeating in our minds that the odds of a shark attack are 1 in 3,748,067 does little to squelch panic. However, if we can believe the same media responsible for our galeophobia, there is, more often than not, a warning before shark attacks. 

If there is such a warning, then there is also a chance of avoiding a life-threatening ordeal. That warning is most often the dorsal fin. Stuck in our collective psyche is the slow approaching, or circling perhaps, shark’s dorsal fin. Seeing that dorsal fin, circling slowly, equals an impending doom.

Cancer immunotherapy has been a revolution in cancer treatment. Unfortunately, our immune system cannot be manipulated without risks. The sentinel paper investigating the CTLA-4 inhibitor, ipilimumab, in metastatic melanoma ushered in modern immunotherapy¹. This article also reported seven patient deaths of the 14 deaths in the study that were directly related to immune-mediated adverse events. These deaths represent 1.4% of the patients who received ipilimumab, highlighting the small but real risk of life-threatening reactions from immunotherapies. 

Other immunotherapies have shown a decrease in risk, but not total elimination of, immune-mediated adverse events. Clinical trials proving the efficacy of single-agent PD-1 and PD-L1 inhibitors in a number of different cancer types have immune-mediated adverse event rates ranging from less than 1% to 30%, depending upon the measured grade of toxicity²⁻⁶. Combination immunotherapy agents have shown, and hold the promise of, higher efficacy, but this comes at the cost of higher toxicity.  

One example is that of the combination nivolumab and ipilimumab for metastatic melanoma⁷. Three-year overall survival for patients who received the combination was 58% (it should be noted here that the average overall survival before 2010 for patients with metastatic melanoma was approximately six months). Major immune-mediated adverse events, for any grade, range from 7% to 17%.

Immune-mediated adverse events rarely occur without some warning. The “dorsal shark fins” of the common adverse events allow us as providers the chance to avoid impending doom and life-threatening consequences for our patients. New onset shortness of breath could herald pneumonitis. Persistent, lasting headache could signal a swelling of the pituitary. Profound diarrhea could be a result of colitis. 

The responsibility to look for these “dorsal fins” falls upon the cancer care team, in partnership with patients who should report symptoms. Vast educational resources for the providers, cancer center staff, and patients are available from various organizations including SITC⁸. As the excitement regarding cancer immunotherapies continues, so too is the growing recognition of the toxicities as illustrated by a recent article in The Washington Post. 

As the cancer care team carefully watches our patients wade into the ocean waters of immunotherapy we should always be wary of and watchful for the “dorsal fins” of immune-mediated adverse reactions in order to save them from a possible life-threatening attack.

Reference:

1. Hodi FS, O’Day SJ, McDermott DF, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363, 2010
2. Rosenberg JE, Hoffman-Censits J, Powles T, et al: Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387:1909-20, 2016
3. Gettinger S, Rizvi NA, Chow LQ, et al: Nivolumab Monotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 34:2980-7, 2016
4. Reck M, Rodriguez-Abreu D, Robinson AG, et al: Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 375:1823-1833, 2016
5. Antonia SJ, Villegas A, Daniel D, et al: Durvalumab after Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer. New England Journal of Medicine 0:null
6. Kaufman HL, Russell J, Hamid O, et al: Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol 17:1374-1385, 2016
7. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al: Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med 377:1345-1356, 2017
8. Puzanov I, Diab A, Abdallah K, et al: Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer 5:95, 2017

Terence Rhodes, MD, PhD, is a medical oncologist and Director of Immuno-Oncology for Intermountain Healthcare in Utah. You can follow him on Twitter @erencerhodes_.