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PurposeWe report the intracranial efficacy of selpercatinib, a highly potent and selective RET inhibitor, approved in the United States for RET fusion-positive non-small cell lung cancers (NSCLC).Patients and methodsIn the global phase 1/2 LIBRETTO-001 trial (NCT03157128) in advanced RET-altered solid tumors, selpercatinib was dosed orally (160 mg twice every day) in 28-day cycles. Patients with baseline intracranial metastases had MRI/CT scans every 8 weeks for 1 year (12 weeks thereafter). In this pre-planned analysis of patients with RET fusion-positive NSCLC with baseline intracranial metastases, the primary endpoint was independently assessed intracranial objective response rate (ORR) per RECIST 1.1. Secondary endpoints included intracranial disease control rate, intracranial duration of response, and intracranial progression-free survival (PFS) independently reviewed.ResultsEighty patients with NSCLC had brain metastases at baseline. Patients were heavily pretreated (median = 2 systemic therapies, range = 0-10); 56% of patients received ≥1 course of intracranial radiation (14% whole brain radiotherapy, 45% stereotactic radiosurgery). Among 22 patients with measurable intracranial disease at baseline, intracranial ORR was 82% [95% confidence interval (CI), 60-95], including 23% with complete responses. Among all intracranial responders (measurable and nonmeasurable, n = 38), median duration of intracranial response was not reached (95% CI, 9.3-NE) at a median duration of follow-up of 9.5 months (IQR = 5.7, 12.0). At 12 months, 55% of intracranial responses were ongoing. In all 80 patients, median intracranial PFS was 13.7 months (95% CI, 10.9-NE) at a median duration of follow-up of 11.0 months (IQR = 7.4, 16.5). No new safety signals were revealed in patients with brain metastases compared with the full NSCLC trial population.ConclusionsSelpercatinib has robust and durable intracranial efficacy in patients with RET fusion-positive NSCLC.

BACKGROUND: RET mutations occur in 70% of medullary thyroid cancers, and RET fusions occur rarely in other thyroid cancers. In patients with RET-altered thyroid cancers, the efficacy and safety of selective RET inhibition are unknown. METHODS: We enrolled patients with RET-mutant medullary thyroid cancer with or without previous vandetanib or cabozantinib treatment, as well as those with previously treated RET fusion-positive thyroid cancer, in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response), as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety. RESULTS: In the first 55 consecutively enrolled patients with RET-mutant medullary thyroid cancer who had previously received vandetanib, cabozantinib, or both, the percentage who had a response was 69% (95% confidence interval [CI], 55 to 81), and 1-year progression-free survival was 82% (95% CI, 69 to 90). In 88 patients with RET-mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the percentage who had a response was 73% (95% CI, 62 to 82), and 1-year progression-free survival was 92% (95% CI, 82 to 97). In 19 patients with previously treated RET fusion-positive thyroid cancer, the percentage who had a response was 79% (95% CI, 54 to 94), and 1-year progression-free survival was 64% (95% CI, 37 to 82). The most common adverse events of grade 3 or higher were hypertension (in 21% of the patients), increased alanine aminotransferase level (in 11%), increased aspartate aminotransferase level (in 9%), hyponatremia (in 8%), and diarrhea (in 6%). Of all 531 patients treated, 12 (2%) discontinued selpercatinib owing to drug-related adverse events. CONCLUSIONS: In this phase 1-2 trial, selpercatinib showed durable efficacy with mainly low-grade toxic effects in patients with medullary thyroid cancer with and without previous vandetanib or cabozantinib treatment. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).

BackgroundRET fusions are oncogenic drivers in 1 to 2% of non-small-cell lung cancers (NSCLCs). In patients with RET fusion-positive NSCLC, the efficacy and safety of selective RET inhibition are unknown.MethodsWe enrolled patients with advanced RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response) as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety.ResultsIn the first 105 consecutively enrolled patients with RET fusion-positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). The most common adverse events of grade 3 or higher were hypertension (in 14% of the patients), an increased alanine aminotransferase level (in 12%), an increased aspartate aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%). A total of 12 of 531 patients (2%) discontinued selpercatinib because of a drug-related adverse event.ConclusionsSelpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).

Non-small-cell lung cancer (NSCLC) is a heterogeneous disease. Front-line therapy may affect responses to subsequent treatment regimens, thus influencing second-line therapy decision making. In the randomised phase 3 REVEL study, second-line ramucirumab plus docetaxel (ram+doc) versus docetaxel (doc) improved survival of patients with metastatic NSCLC. We explore efficacy, safety and quality-of-life (QoL) in REVEL based on front-line therapy. Patients were grouped by specific front-line therapy received. Overall survival (OS), progression-free survival (PFS), objective response rate, safety and QoL were assessed descriptively. Kaplan-Meier estimation and Cox proportional hazards modelling were used; frequencies reported in percentages. Baseline characteristics of 1253 patients were generally well balanced between treatment arms within each front-line therapy subgroup. For patients with non-squamous disease (n=912), induction therapies included platinum-based chemotherapy plus a taxane (n=227; 25%) or pemetrexed (n=449; 49%), with (n=172; 19%) or without bevacizumab. For patients with squamous disease (n=328), induction therapies included platinum-based chemotherapy plus gemcitabine (n=176; 54%) or a taxane (n=69; 21%). A highly selected subgroup (n=127; 14%) received pemetrexed continuation maintenance therapy. Ram+doc improved median OS and PFS versus doc across front-line therapy subgroups, as reflected by HRs ranging from 0.78 to 0.91 and 0.66 to 0.92, respectively, similar to results in the overall intention-to-treat cohort (HRs: 0.86 and 0.76, respectively). High-grade treatment-emergent adverse events of special interest (including neutropenia, febrile neutropenia, leucopenia and hypertension) were generally higher in ram+doc-treated patients relative to doc-treated patients regardless of front-line therapy. No clear differences in safety or QoL were seen across front-line therapy subgroups; outcomes were consistent with those reported in the overall intention-to-treat cohort. Results of this exploratory analysis suggest that second-line ram+doc may be effective regardless of prior treatment with platinum-based chemotherapy plus a taxane, pemetrexed, gemcitabine or bevacizumab. Overall, ram+doc is clinically beneficial across a wide range of patients with metastatic NSCLC who have progressed after various front-line therapies. NCT01168973.

Oncogenic fusion events have been identified in a broad range of tumors. Among them, RET rearrangements represent distinct and potentially druggable targets that are recurrently found in lung adenocarcinomas. We provide further evidence that current anti-RET drugs may not be potent enough to induce durable responses in such tumors. We report that potent inhibitors, such as AD80 or ponatinib, that stably bind in the DFG-out conformation of RET may overcome these limitations and selectively kill RET-rearranged tumors. Using chemical genomics in conjunction with phosphoproteomic analyses in RET-rearranged cells, we identify the CCDC6-RETI788N mutation and drug-induced mitogen-activated protein kinase pathway reactivation as possible mechanisms by which tumors may escape the activity of RET inhibitors. Our data provide mechanistic insight into the druggability of RET kinase fusions that may be of help for the development of effective therapies targeting such tumors.