Immune-Related Adverse Events Predict Efficacy of Nivolumab in NSCLC


“While immunotherapy with programmed death receptor 1 (PD-1) inhibiting antibodies has revolutionized the treatment of non-small cell lung cancer (NSCLC), use of these agents comes at the cost of potential serious immune-related adverse events (irAEs). In melanoma, development of cutaneous irAEs, such as rash and vitiligo, during treatment with PD-1 inhibitors has been shown to be associated with survival benefit, suggesting that early onset of irAEs may predict treatment outcomes. However, in NSCLC, the predictive value of immunotherapy-related toxicity as a clinical marker for efficacy to PD-1 inhibition is unknown.  A multi-institution retrospective study investigated the relation between the development of irAEs and efficacy of PD-1 inhibitors in 134 patients with advanced or recurrent NSCLC who received second-line treatment with nivolumab. The primary outcome for this analysis was progression-free survival (PFS) according to the development of irAEs in a 6-week landmark analysis.”

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Melanoma Therapy Tied to Cutaneous Adverse Events

“Anti-programmed cell death (PD)-1 therapy for metastatic melanoma is associated with the development of immune-related cutaneous events, according to research published in the March issue of the Journal of the American Academy of Dermatology.

“Shelley Ji Eun Hwang, M.B.B.S., from the University of Sydney, and colleagues reviewed the clinical and histologic information of 82 patients treated with single-agent anti-PD-1 therapy for  at one institution from May 2012 to February 2015.”

Vitiligo Predicts Improved Survival in Patients Receiving Immunotherapy for Stage III or IV Melanoma

The gist: A recent study found that melanoma patients who develop a side effect called vitiligo during treatment with immunotherapy are more likely to have good survival outcomes. A patient with vitiligo experiences a loss of dark skin pigment and develops patches of lighter-colored skin. Immunotherapy is a type of treatment that boosts a patient’s own immune system to fight cancer. The study found that patients who develop vitiligo during immunotherapy treatment have longer survival times. They also experience a longer period of time without their cancer worsening after treatment.

“In a systematic review and meta-analysis reported in the Journal of Clinical Oncology, Teulings et al found that development of vitiligo in patients receiving immunotherapy for stage III or IV melanoma was a significant predictor of improved progression-free and overall survival.

“The study involved data from 5,737 patients in 137 studies on melanoma immunotherapy published between 1995 and 2013 that reported on autoimmune toxicity or vitiligo. The studies included a total of 139 treatment arms, including general immune stimulation in 11, vaccine in 84, antibody-based treatment in 28, and adoptive transfer in 16.

“The overall incidence of vitiligo was 3.4% (95% confidence interval = 2.5%–4.5%). In 27 studies reporting individual patient data, analysis adjusting for age and sex showed that development of vitiligo was associated with significantly improved progression-free survival (hazard ratio [HR] = 0.51, P = .005) and overall survival (HR = 0.25, P = .003).

“The investigators concluded: ‘Although vitiligo occurs only in a low percentage of patients with melanoma treated with immunotherapy, our findings suggest clear survival benefit in these patients. Awareness of vitiligo induction in patients with melanoma is important as an indicator of robust antimelanoma immunity and associated improved survival.’ ”

Inflammatory Monocytes are Potent Antitumor Effectors Controlled by Regulatory CD4+ T cells

“The present study evaluates the impact of immune cell populations on metastatic development in a model of spontaneous melanoma [mice expressing the human RET oncogene under the control of the metallothionein promoter (MT/ret mice)]. In this model, cancer cells disseminate early but remain dormant for several weeks. Then, MT/ret mice develop cutaneous metastases and, finally, distant metastases. A total of 35% of MT/ret mice develop a vitiligo, a skin depigmentation attributable to the lysis of normal melanocytes, associated with a delay in tumor progression. Here, we find that regulatory CD4+ T cells accumulate in the skin, the spleen, and tumor-draining lymph nodes of MT/ret mice not developing vitiligo. Regulatory T-cell depletion and IL-10 neutralization led to increased occurrence of vitiligo that correlated with a decreased incidence of melanoma metastases. In contrast, inflammatory monocytes/dendritic cells accumulate in the skin of MT/ret mice with active vitiligo. Moreover, they inhibit tumor cell proliferation in vitro through a reactive oxygen species-dependent mechanism, and both their depletion and reactive oxygen species neutralization in vivo increased tumor cell dissemination. Altogether, our data suggest that regulatory CD4+ T cells favor tumor progression, in part, by inhibiting recruitment and/or differentiation of inflammatory monocytes in the skin.”