Conclusions: IrAEs were associated with improved efficacy in advanced NSCLC patients when a landmark analysis was applied. Patients receiving corticosteroids had significantly poorer outcomes when they were used for cancer-related symptoms.

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mTOR inhibitors are used to treat renal cell carcinoma (RCC). Treatment response is variable and appears to correlate with genetic alterations that activate mTOR signaling. Recently, everolimus was suggested to be more effective than sunitinib in chromophobe RCC (chRCC), a tumor with frequent mTOR pathway defects. This report presents the genomic and functional characterization of a metastatic chRCC that showed complete response at metastatic sites and 80% reduction in primary tumor size upon temsirolimus treatment. After surgery, the patient remained disease-free for 8 years after temsirolimus therapy. Whole-exome sequencing (WES) revealed 2 somatic variants in , a critical negative regulator of mTOR: a splicing defect (c.5069-1G>C) and a novel missense variant [c.3200_3201delinsAA; p.(V1067E)]. In vitro functional assessment demonstrated that the V1067E substitution disrupted TSC2 function. Immunohistochemistry in the tumor tissues revealed increased phosphorylated S6 ribosomal protein, indicating mTOR pathway activation. In conclusion, WES revealed inactivation as the likely mechanism for this extraordinary response to temsirolimus. These findings support high efficacy of mTOR inhibitors in a subset of patients with chRCC and propose sequencing of mTOR pathway genes to help guide therapy.

Availability of multiple trials is associated with higher odds of ODAC recommendation and drug approval. Availability of randomized data appears less important. Declaration of FCOIs among ODAC members was frequent during the time period of interest but has decreased significantly over time. There is no apparent association between FCOIs and ODAC recommendations and subsequent FDA approval.