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Upside to Immune-Related Toxicity in Cancer Immunotherapy?

Autoimmune skin effects may predict better outcomes in immunotherapy-treated cancer patients, and rates of high-grade adverse events (AEs) might be worse with PD-1 versus PD-L1 inhibitors, according to a pair of studies in JAMA Oncology.

In a prospective study of 73 non-small cell lung cancer (NSCLC) patients treated with anti-PD-1 therapy, autoimmune skin toxic effects were far more common in patients who achieved complete or partial remissions compared with those with progressive or stable disease as their best response (68.2% vs 19.6%), reported Lukas Flatz, MD, of University Hospital Zurich in Switzerland, and colleagues.

Autoimmune skin toxic effects occurred in roughly one-third of patients (34.2%), and the researchers identified nine T-cell antigens shared between tumor tissue and skin, suggesting that “during checkpoint inhibitor therapy, T cells recognizing shared lung tumor and skin antigens simultaneously target both organs,” they wrote.

Separately, a meta-analysis that included more than 20,000 patients with varying tumor types found that treatment with PD-1 inhibitors was associated with a 58% increase in incidence of grade ≥3 AEs compared with PD-L1 inhibitors (OR 1.58, 95% CI 1.00-2.54), Michael L. Wang, MD, PhD, of MD Anderson Cancer Center in Houston, and colleagues reported.

Overall, 66% of patients across the trials in this review — all on single-agent PD-1 and PD-L1 inhibitors — developed at least one AE of any grade, and while immune-related AEs were less common (hypothyroidism topped the list at 6.1%), they were typically severe when they did occur.

Together, these “disparate” studies begin to shed light on the “true spectrum of immune-related AE incidence across clinical trials and the mechanisms by which these events unfold,” said Diwakar Davar, MD, and John M. Kirkwood, MD, of UPMC Hillman Cancer Center in Pittsburgh, in an accompanying editorial.

Although the meta-analysis could not correlate immune-related AEs to response or survival, it did clarify that “most grade 3 or higher AEs are immune related and while PD-1/PD-L1 blockade is unlikely to cause grade 5 events, pneumonitis is the leading cause of death.” Both critical findings, according to Davar and Kirkwood.

Together, these two studies “raise the question of whether the identification of immunogenic tumor antigens may enable more effective immunotherapy while avoiding self-directed immune responses,” they concluded.

Skin Effects and Outcomes

For their study, Flatz and colleagues recruited 73 patients with NSCLC from four centers in Switzerland and took biopsies from sites of autoimmune skin toxic effects during a 2-year period to examine effects induced by anti-PD-1 treatment.

Patients who experienced skin toxic effects had significantly improved overall survival (HR 0.29, 95% CI 0.12-0.71) and progression-free survival (HR 0.22, 95% CI 0.09-0.49) compared to those that did not. Autoimmune skin toxic effects were over five times more likely to occur in patients who responded to therapy than in those who did not (OR 5.28, 95% CI 1.78-15.67, P=0.003).

The findings confirm results of other studies “suggesting that autoimmune adverse effects are associated with response to therapy,” Flatz and colleagues wrote.


The large meta-analysis included data from 125 clinical trials of PD-1 and PD-L1 inhibitors published from October 2017 to December 2018, and was designed to evaluate the incidence of treatment-related AEs and any differences between drugs and cancer types.

Compared with pembrolizumab (Keytruda), nivolumab (Opdivo) was associated with a 28% increase in incidence of all-grade AEs (OR 1.28, 95% CI 0.97-1.79) and a 30% increase in grade ≥3 AEs (OR 1.30, 95% CI 0.89-2.00).

Fatigue (18.26%), diarrhea (9.47%), and pruritus (10.61%) were the most common all-grade AEs. The most common grade ≥3 AEs were fatigue (0.89%), anemia (0.78%), and aspartate aminotransferase increase (0.75%).

The most common endocrine-related all-grade immune-related AEs were hypothyroidism (6.07%), hyperthyroidism (2.82%), hyperglycemia (1.20%), thyroiditis (0.75%), and adrenal insufficiency (0.69%).

Hypothyroidism and hyperthyroidism tended to be mild, according to the data, but other immune-related AEs tended to be more severe as reflected by a high risk ratio (RR) for grade ≥3 compared with all-grade incidence, including pneumonitis (RR 24.01%), hepatitis (RR 50.59%), lipase elevation (RR 42.01%), γ-glutamyltransferase elevation (RR 41.96%), and diabetes (RR 41.86%).

“A comprehensive analysis of all common treatment-related adverse events reported in clinical trials is critical, as the results constitute an important reference for clinicians,” Wang and colleagues wrote. “Such a global overview of immune checkpoint inhibitor adverse event incidences is complementary to American Society of Clinical Oncology and National Comprehensive Cancer Network guidelines on management of immune-related AEs and informs clinical practice guidelines.”

Wang disclosed relevant relationships with Acerta Pharma, AstraZeneca, and Celgene. Co-authors reported relationships with Agios, ArQule, ARRAY, Bayer, Boston Medical, Bristol-Myers Squibb, Celgene, Daiichi, Genentech, Ipsen, Merck, Thermo Fisher Scientific, and other industry entities.

The study by Berner, et al. was supported in part by a grant from the Swiss National Science Foundation and the Swiss Cancer League.

Berner reported no conflicts of interest. Co-authors reported grants from Krebsliga Beider Basel, the Gebert Ruef Foundation, Swiss National Science and Foundation and personal fees from AstraZeneca/MedImmune, Boehringer Ingelheim, Bristol-Myers Squibb, Merck, Novartis, Pfizer, Roche/Genentech, and other industry entities.

Daver reported grants and nonfinancial support from Amgen, Bristol-Myers Squibb, Checkmate Pharmaceuticals, Incyte, and Merck. Kirkwood reported personal fees from Amgen, Array Biopharma, Bristol-Myers Squibb, Novartis, and Roche, and grants from Immunocore, Merck, and Prometheus.