Overcoming MET-Dependent Resistance to Selective RET Inhibition in Patients with RET Fusion-Positive Lung Cancer by Combining Selpercatinib with Crizotinib.

PURPOSE: The RET proto-oncogene encodes a receptor tyrosine kinase that is activated by gene fusion in 1%-2% of non-small cell lung cancers (NSCLC) and rarely in other cancer types. Selpercatinib is a highly selective RET kinase inhibitor that has recently been approved by the FDA in lung and thyroid cancers with activating RET gene fusions and mutations. Molecular mechanisms of acquired resistance to selpercatinib are poorly understood. PATIENTS AND METHODS: We studied patients treated on the first-in-human clinical trial of selpercatinib (NCT03157129) who were found to have MET amplification associated with resistance to selpercatinib. We validated MET activation as a targetable mediator of resistance to RET-directed therapy, and combined selpercatinib with the MET/ALK/ROS1 inhibitor crizotinib in a series of single patient protocols (SPP). RESULTS: MET amplification was identified in posttreatment biopsies in 4 patients with RET fusion-positive NSCLC treated with selpercatinib. In at least one case, MET amplification was clearly evident prior to therapy with selpercatinib. We demonstrate that increased MET expression in RET fusion-positive tumor cells causes resistance to selpercatinib, and this can be overcome by combining selpercatinib with crizotinib. Using SPPs, selpercatinib with crizotinib were given together generating anecdotal evidence of clinical activity and tolerability, with one response lasting 10 months. CONCLUSIONS: Through the use of SPPs, we were able to offer combination therapy targeting MET-amplified resistance identified on the first-in-human study of selpercatinib. These data suggest that MET dependence is a recurring and potentially targetable mechanism of resistance to selective RET inhibition in advanced NSCLC.

Response to RET-Specific Therapy in RET Fusion-Positive Anaplastic Thyroid Carcinoma.

Background: Anaplastic thyroid carcinoma (ATC) remains one of the most challenging malignancies to treat in the modern era. Most patients present with or develop recurrent/metastatic incurable disease with poor response rates to conventional chemotherapy, and life expectancy is short. Next-generation sequencing (NGS) can be leveraged in ATC to identify oncogenic alterations that can be targeted with molecularly specific therapy, offering new effective treatment options to a subset of patients. Patient Findings: A 73-year-old man presenting with locally advanced papillary thyroid carcinoma containing a minor component of ATC was treated with surgery and iodine-131. He developed biopsy-confirmed ATC distant metastases that progressed on cytotoxic chemotherapy. NGS revealed several alterations, including a CCDC6-RET gene fusion. The patient enrolled in LIBRETTO-001, a phase I/II trial of the potent and specific RET inhibitor, LOXO-292. The patient tolerated LOXO-292 well and experienced a deep and durable partial response, ongoing beyond 19 months. Conclusion: This clinically significant response achieved with LOXO-292 in a patient with a CCDC6-RET fusion-positive ATC who had exhausted conventional treatment options highlights the importance of conducting tumor genomic profiling in patients with ATC to identify uncommon but actionable genomic alterations, such as RET gene fusions.

RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies.

INTRODUCTION: Novel rearranged in transfection (RET)-specific tyrosine kinase inhibitors (TKIs) such as selpercatinib (LOXO-292) have shown unprecedented efficacy in tumors positive for RET fusions or mutations, notably RET fusion-positive NSCLC and RET-mutated medullary thyroid cancer (MTC). However, the mechanisms of resistance to these agents have not yet been described. METHODS: Analysis was performed of circulating tumor DNA and tissue in patients with RET fusion-positive NSCLC and RET-mutation positive MTC who developed disease progression after an initial response to selpercatinib. Acquired resistance was modeled preclinically using a CCDC6-RET fusion-positive NSCLC patient-derived xenograft. The inhibitory activity of anti-RET multikinase inhibitors and selective RET TKIs was evaluated in enzyme and cell-based assays. RESULTS: After a dramatic initial response to selpercatinib in a patient with KIF5B-RET NSCLC, analysis of circulating tumor DNA revealed emergence of RET G810R, G810S, and G810C mutations in the RET solvent front before the emergence of clinical resistance. Postmortem biopsy studies reported intratumor and intertumor heterogeneity with distinct disease subclones containing G810S, G810R, and G810C mutations in multiple disease sites indicative of convergent evolution on the G810 residue resulting in a common mechanism of resistance. Acquired mutations in RET G810 were identified in tumor tissue from a second patient with CCDC6-RET fusion-positive NSCLC and in plasma from patients with additional RET fusion-positive NSCLC and RET-mutant MTC progressing on an ongoing phase 1 and 2 trial of selpercatinib. Preclinical studies reported the presence of RET G810R mutations in a CCDC6-RET patient-derived xenograft (from a patient with NSCLC) model of acquired resistance to selpercatinib. Structural modeling predicted that these mutations sterically hinder the binding of selpercatinib, and in vitro assays confirmed loss of activity for both anti-RET multikinase inhibitors and selective RET TKIs. CONCLUSIONS: RET G810 solvent front mutations represent the first described recurrent mechanism of resistance to selective RET inhibition with selpercatinib. Development of potent inhibitor of these mutations and maintaining activity against RET gatekeeper mutations could be an effective strategy to target resistance to selective RET inhibitors.

[A Case of Pediatric Soft Tissue Sarcoma with LMNA-NTRK1 Gene Fusion Treated with Larotrectinib under Single Patient Expanded Access System].

Tropomyosin-related kinase(TRK)fusion proteins are oncogenic drivers in multiple tumors in adults and children.Larotrectinib, an orally administered selective TRK inhibitor approved in the US, exhibits inhibitory activity against tumors harboring TRK fusions and is well tolerated.Here, we report the case of an 8-year-old female child with recurrence of an NTRK fusion low-grade sarcoma treated with larotrectinib monotherapy.The patient previously underwent resection of low-grade sarcoma in the right brachialis at 6 years of age, but local recurrence occurred after 16 months.As re-operation likely required amputation, larotrectinib was commenced at a dose of 100 mg BID.Complete radiographic remission was achieved after 3 months.There were no adverse events attributed to larotrectinib treatment.After dosing for 6 months, we performed local resection, confirming pathological complete remission.The drug was stopped, and the patient showed no evidence of relapse at 4 months after resection.In this case, larotrectinib was obtained using Single Patient Expanded Access under the FDA.In this paper, we also discuss the issues faced while accessing unapproved drugs in the precision medicine era in Japan.

Pharmacokinetics and Safety of Vilazodone in Hepatic Impairment.

Vilazodone, a selective serotonin reuptake inhibitor and 5-HT1A partial agonist approved for the treatment of major depressive disorder, is extensively hepatically metabolized. The pharmacokinetics, tolerability, and safety of vilazodone were investigated in 2 trials comparing participants with hepatic impairment with healthy controls. In these phase 1, open-label, parallel-group, single-dose pharmacokinetic studies, vilazodone (20 mg) was administered to participants with mild, moderate, or severe hepatic impairment or individually matched healthy controls. Vilazodone and M17 (the major metabolite) concentrations in plasma were analyzed using validated liquid chromatography with tandem mass spectrometry. Forty-eight participants (8 each in mild, moderate, and severe hepatic impairment groups with matched healthy controls) were evaluated for pharmacokinetic analyses. All pharmacokinetic parameters in participants with mild and moderate hepatic impairment were similar to those in healthy controls. Mean Cmax and AUC0-∞ were approximately 29% and 17% lower in participants with severe hepatic impairment compared with healthy participants; values for Tmax, and t1/2 were similar between groups. Diarrhea was experienced by more participants with hepatic impairment than controls (10 vs. 5, respectively), and vomiting (4 participants) occurred only in participants with severe hepatic impairment; other adverse events were roughly equivalent between groups. Following a single, 20-mg oral dose of vilazodone, pharmacokinetics were similar in participants with mild, moderate, or severe hepatic impairment and healthy controls. No dose adjustment is needed for patients with major depressive disorder who have mild, moderate, or severe hepatic impairment.