Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment for the 25% of patients who experience response. ICIs are now FDA-approved for the treatment of 8 different cancers.
“Along with the good news, we have seen an emergence of a spectrum of immune-related adverse events [AEs]. The common mechanism is that when these drugs ‘release the brakes’ on the immune system, then the immune system can also attack normal tissue,” said John A. Thompson, MD, Professor of Medicine, University of Washington; Co-Director, Melanoma Clinic, Seattle Cancer Care Alliance; and Chair of the NCCN Guidelines Panel for Management of Immunotherapy-Related Toxicities.
NCCN in collaboration with ASCO developed a standardized approach for the recognition, management, and education of ICI-related toxicity. ASCO published its Practice Guideline in the Journal of Clinical Oncology on February 14, 2018,1 with NCCN releasing theirs the same day (available at NCCN.org). At the 23rd NCCN Annual Conference, Dr. Thompson presented key points from the new NCCN Guidelines.
Dr. Thompson emphasized that the NCCN Guidelines are based on expert opinion and there are no prospective trials on treatment of immunotherapy-related AEs. He pointed out that grades 3–5 immunotherapy-related AEs occur with greater frequency with CTLA-4 inhibitors than with PD-1 or PD-L1 inhibitors. Toxicity is also more severe with combinations of CTLA-4 with PD-1 or PD-L1 inhibitors than with either class of agent alone. “Physicians have to be alert for these effects, and we have to educate our patients to be prepared,” he stated.
The pattern of onset of immunotherapy-related toxicity varies. Some toxicities may occur early, some later, and some even after completion of treatment, he noted. “In general, when a patient encounters a serious toxicity, the checkpoint inhibitor should be stopped until the toxicity resolves. Patients may fear that they will lose the antitumor effect, but studies of outcomes in patients who discontinue therapy due to AEs show no statistically significant difference in progression-free and overall survival. This provides some reassurance that stopping therapy due to AEs does not jeopardize the anticancer effect of immunotherapy,” Dr. Thompson elaborated.
ICI therapy is effective in approximately 25% of patients, and the drugs are expensive, so research is being conducted to find a biomarker for response. Thus far, results have been limited. Recent studies suggest that tumor mutational burden plus PD-L1 expression may select patients for therapy with an anti–PD-1 or anti–PD-L1 drug. The presence of high tumor mutation burden and high PD-L1 expression suggest that durable clinical benefit is more likely (Figure 1).2
Brahmer JR, Lacchetti C, Schneider BJ et al.. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Practice Guideline [published online February 14, 2018]. J Clin Oncol. doi: 10.1200/JCO.2017.77.6385
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. Brahmer JR Lacchetti C Schneider BJ Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Practice Guideline [published online February 14, 2018]. J Clin Oncol. doi: 10.1200/JCO.2017.77.6385
Rizvi H, Sanchez-Vega F, La K et al.. Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed cell death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing. J Clin Oncol 2018;36:633–641.
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. Rizvi H Sanchez-Vega F La K Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed cell death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing. J Clin Oncol 2018; 36: 633– 641.
Pollack MH, Betof A, Dearden H et al.. Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma. Ann Oncol 2018;29:250–255.