BACKGROUND Fusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions. METHODS We enrolled patients with consecutively and prospectively identified TRK fusion–positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1–2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progression-free survival, and safety. RESULTS A total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion–positive tumor types. The overall response rate was 75% (95% confidence interval [CI], 61 to 85) according to independent review and 80% (95% CI, 67 to 90) according to investigator assessment. At 1 year, 71% of the responses were ongoing and 55% of the patients remained progression-free. The median duration of response and progression-free survival had not been reached. At a median follow-up of 9.4 months, 86% of the patients with a response (38 of 44 patients) were continuing treatment or had undergone surgery that was intended to be curative. Adverse events were predominantly of grade 1, and no adverse event of grade 3 or 4 that was considered by the investigators to be related to larotrectinib occurred in more than 5% of patients. No patient discontinued larotrectinib owing to drug-related adverse events. CONCLUSIONS Larotrectinib had marked and durable antitumor activity in patients with TRK fusion–positive cancer, regardless of the age of the patient or of the tumor type. (Funded by Loxo Oncology and others; ClinicalTrials.gov numbers, NCT02122913, NCT02637687, and NCT02576431.)

Background BRAF mutations act as an oncogenic driver via the mitogen-activated protein kinase (MAPK) pathway in non-small cell lung cancer (NSCLC). BRAF inhibition has demonstrated antitumor activity in patients with BRAF V600E (Val600Glu)–mutant NSCLC. Dual MAPK pathway inhibition with BRAF and MEK inhibitors in BRAF V600E–mutant NSCLC may improve efficacy over BRAF-inhibitor monotherapy based on observations in BRAF V600–mutant melanoma. Methods In this phase 2, multicenter, nonrandomized, open-label study of patients with pretreated metastatic BRAF V600E–mutant NSCLC, antitumor activity and safety of oral dabrafenib (150 mg twice daily) plus oral trametinib (2 mg once daily) were evaluated. Adult patients (≥ 18 years) with documented progression following at least one prior platinum-based chemotherapy and no more than three prior systemic anticancer therapies were enrolled. Patients with prior BRAF or MEK inhibitor treatment were ineligible. Patients with brain metastases were permitted to enroll only if the lesions were asymptomatic, untreated (or stable > 3 weeks after local therapy if treated), and measured < 1 cm. The primary endpoint was investigator-assessed overall response, which was assessed by intention-to-treat in the protocol-defined population (≥ second-line); safety was also assessed in this population. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT01336634. Findings Fifty-seven patients previously treated with systemic chemotherapy for metastatic BRAF V600E–mutant NSCLC were enrolled. The investigator-assessed overall response was 63·2% (36 of 57; 95% CI 49·3–75·6). Serious adverse events were reported in 32 (56%) of 57 patients and included pyrexia (16%; 9 of 57), anemia (5%; 3 of 57), confusional state (4%; 2 of 57), decreased appetite (4%; 2 of 57), hemoptysis (4%; 2 of 57), hypercalcemia (4%; 2 of 57), nausea (4%; 2 of 57), and cutaneous squamous cell carcinoma (4%; 2 of 57). Common grade 3/4 AEs included neutropenia (9%; 5 of 57), hyponatremia (7%; 4 of 57), and anemia (5%; 3 of 57). Interpretation Dabrafenib plus trametinib represents a new targeted therapy with robust antitumor activity and a manageable safety profile in patients with BRAF V600E–mutant NSCLC. Funding GlaxoSmithKline.

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There is an urgent need for blood-based, noninvasive molecular tests to assist in the detection and diagnosis of cancers in a cost-effective manner at an early stage, when curative interventions are still possible. Additionally, blood-based diagnostics can classify tumors into distinct molecular subtypes and monitor disease relapse and response to treatment. Increasingly, biomarker strategies are becoming critical to identify a specific patient subpopulation that is likely to respond to a new therapeutic agent. The improved understanding of the underlying molecular features of common cancers and the availability of a multitude of recently developed technologies to interrogate the genome, transcriptome, proteome and metabolome of tumors and biological fluids have made it possible to develop clinically applicable and cost-effective tests for many common cancers. Overall, the paradigm shift towards personalized and individualized medicine relies heavily on the increased use of diagnostic biomarkers and classifiers to improve diagnosis, management and treatment. International collaborations, involving both the private and public sector will be required to facilitate the development of clinical applications of biomarkers, using rigorous standardized assays. Here, we review the recent technological and scientific advances in this field.