A substantial proportion of MET exon 14-altered lung cancers express PD-L1, but the median TMB is lower compared with unselected NSCLCs. Occasional responses to PD-1 blockade can be achieved, but overall clinical efficacy is modest.

Brain metastases occur frequently in RET-rearranged lung cancers, and outcomes with multikinase inhibitor therapy in general are suboptimal. Novel RET-directed targeted therapy strategies are needed.

Summary Background No standard therapy exists for refractory or relapsed, advanced thymic epithelial tumors (TETs). We investigated the efficacy of cixutumumab, a fully human, IgG1 monoclonal antibody targeting the insulin-like growth factor-1 receptor, in TETs after failure of prior chemotherapy. Methods In this multicentre, open-label, phase 2 trial we enrolled patients aged 18 years or older with histologically confirmed recurrent or refractory TETs, who had progressed after at least one prior platinum-containing chemotherapy regimen, had Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease and adequate organ function. Eligible patients received cixutumumab (20 mg/kg, intravenous) every three weeks until disease progression or development of intolerable toxicity. The primary endpoint was response rate, analyzed on an intention-to-treat basis. Multiple pharmacodynamic studies were performed. This trial has completed enrollment and is registered with ClinicalTrials.gov, number NCT00965250. Findings Between August 25, 2009, and March 27, 2012, 49 patients were enrolled (37 thymomas; 12 thymic carcinomas) and received a median of six cycles of cixutumumab (range 1–46). At final analysis median potential follow-up was 24 months (IQR 17·3–36·9). In the thymoma cohort five (14%) of 37 patients (95% CI 5–29%) achieved a partial response, 28 had stable disease and four had progressive disease. Corresponding numbers for the thymic carcinoma cohort were zero of 12 patients (95% CI 0–26%), five and seven. The most common grade 3–4 adverse events in both cohorts combined were hyperglycemia (5 [10%] of 49 patients), lipase elevation (3 [6%]), weight loss, tumor pain, and hyperuricemia (2 each [4%]). Nine (24%) of 37 patients with thymoma developed autoimmune conditions (five new-onset) during treatment, the most common of which was pure red cell aplasia. Two (4%) of 49 treated patients died while on study. One case was attributed to disease progression and the other to disease–related complications (respiratory failure, myositis, and an acute coronary event), which could have been precipitated by treatment with cixutumumab. Interpretation Cixutumumab monotherapy is well tolerated and active in relapsed thymoma. Development of autoimmunity during treatment needs further investigation. Funding Division of Cancer Treatment and Diagnosis, National Cancer Institute/National Institutes of Health and ImClone Systems.

Durable benefits with pemetrexed-based therapies in RET-rearranged lung cancers are comparable with ALK- and ROS1-rearranged lung cancers. When selecting therapies for patients with RET-rearranged lung cancers, pemetrexed-containing regimens should be considered.