RET fusions are oncogenic drivers of various tumors, including non-small cell lung cancers (NSCLC). The safety and antitumor activity of the multikinase RET inhibitor RXDX-105 were explored in a phase I/Ib trial. A recommended phase II dose of 275 mg fed daily was identifi ed. The most common treatment-related adverse events were fatigue (25%), diarrhea (24%), hypophosphatemia (18%), maculopapular rash (18%), and nonmaculopapular rash (17%). In the phase Ib cohort of RET inhibitor-naïve patients with RET fusion-positive NSCLCs, the objective response rate (ORR) was 19% (95% CI, 8%-38%, n = 6/31). Interestingly, the ORR varied signifi cantly by the gene fusion partner ( P < 0.001, Fisher exact test): 0% (95% CI, 0%-17%, n = 0/20) with KIF5B (the most common upstream partner for RET fusion-positive NSCLC), and 67% (95% CI, 30%-93%, n = 6/9) with non-KIF5B partners. The median duration of response in all RET fusion-positive NSCLCs was not reached (range, 5 to 18+ months). SIGNIFICANCE:Although KIF5B-RET is the most common RET fusion in NSCLCs, RET inhibition with RXDX-105 resulted in responses only in non-KIF5B-RET-containing cancers. Novel approaches to targeting KIF5B-RET-containing tumors are needed, along with a deeper understanding of the biology that underlies the differential responses observed. RESULTS PatientsA total of 152 patients were treated with RXDX-105; 55 were treated in the phase I dose-escalation portion of the study, and 97 were treated in the phase Ib dose-expansion portion of the study ( Table 1 and Supplementary Fig. S1). The median age was 63 (range, 27-90) years, and the majority (89%) of patients were pretreated and received one or more prior systemic therapies. The most common tumor type Research.on August 5, 2020.doses that ranged from 20 mg daily up to a dose of 275 mg daily without dietary restrictions. In the last two cohorts, RXDX-105 was administered at 275 mg daily and 350 mg daily in the fed state.

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Flavone acetic acid (FAA) is a new antitumor agent that has recently entered Phase I clinical trials. In preclinical studies, we have found that FAA was broadly active against a variety of transplantable solid tumors of mice (colon #51, #07, #10, #26; pancreatic ductal adenocarcinomas #02 and #03; mammary adenocarcinoma #16/C/Adr; M5076 reticulum cell sarcoma and Glasgow's osteosarcoma). FAA was curative for colon adenocarcinoma #10 and pancreatic ductal adenocarcinoma #03. Thus, for the first time an agent has been identified with very broad, perhaps nearly universal solid tumor activity. FAA was also found to be orally active and stable in solution at 37 degrees C for 48 h. FAA was selectively cytotoxic in vitro for solid tumors over leukemias L1210 and P388 (in a soft-agar colony formation assay), thus correlating cellular selectivity in vitro with in vivo antitumor activity. The finding that FAA was active in vitro, established that the agent did not need metabolism (activation) outside the tumor cell. The main drawback of FAA was an unusual 'threshold' behavior in which only a narrow range of doses were active and splitting the dose markedly decreased activity.

Introduction The PI3K/Akt/mTOR pathway is activated in a majority of malignant pleural mesotheliomas (MPM). We evaluated the activity of everolimus, an oral mTOR inhibitor, in patients with unresectable MPM. Methods MPM patients who had received at least one but no more than two prior chemotherapy regimens, which must have been platinum-based, were treated with 10 mg of everolimus daily. The primary endpoint was 4-month progression free survival (PFS) by RECIST 1.1. Results A total of 59 evaluable patients were included in the analysis. The median duration of treatment was 2 cycles (56 days). Overall response rate (ORR) was 2% (95%CI: 0%–12%) by RECIST 1.1 and 0% (0%–10%) by modified RECIST for MPM. The 4-month PFS rate was 29% (95% CI: 17%–41%) by RECIST 1.1 and 27% (95%CI: 16%–39%) by modified RECIST. The median PFS was 2.8 months (95%CI: 1.8–3.4) by RECIST 1.1. The median overall survival (OS) was 6.3 months (95%CI: 4.0–8.0). There was no difference in PFS among patients who received 1 or 2 prior chemotherapy regimens (p= 0.74). There was no difference in OS between patients with epithelioid histology versus other types (p = 0.47). The most common toxicities were fatigue (59%), hypertriglyceridemia (44%), anemia (42%), oral mucositis (34%), nausea (32%), and anorexia (32%). The most common grade 3–4 toxicities were fatigue (10.2%), anemia (6.8%), and lung infection (6.8%). Conclusion Everolimus has limited clinical activity in advanced MPM patients. Additional studies of single-agent everolimus in advanced MPM are not warranted.