Hypersensitivity Reactions to Selpercatinib Treatment With or Without Prior Immune Checkpoint Inhibitor Therapy in Patients With NSCLC in LIBRETTO-001.

INTRODUCTION: Immune checkpoint inhibitor (ICI) therapy has been found to increase the risk/severity of immune-mediated adverse events with subsequent kinase inhibitor treatment in oncogenically driven cancers. We explored the risk for hypersensitivity with selpercatinib, a first-in-class highly selective and potent, central nervous system-active RET inhibitor, in prior ICI-treated patients with RET fusion-positive NSCLC compared with their ICI-naive counterparts. METHODS: Data from patients enrolled by December 16, 2019, in the ongoing phase 1/2 LIBRETTO-001 (NCT03157128) trial were analyzed for hypersensitivity reactions reported using preferred terms of hypersensitivity/drug hypersensitivity and defined as a constellation of symptoms/findings characterized by maculopapular rash, often preceded by fever with arthralgias/myalgias, followed by greater than or equal to 1 of the following signs/symptoms: thrombocytopenia, increased aspartate aminotransferase or alanine aminotransferase, hypotension, tachycardia, or increased creatinine. RESULTS: Of 329 patients, 22 (7%) who experienced a grade 1 to 3 hypersensitivity reaction that met the defined constellation of events were attributed to selpercatinib by investigators, and more often in prior ICI-treated (n = 17, 77%) than ICI-naive (n = 5, 23%) patients. There were 19 patients with selpercatinib-related hypersensitivity who resumed selpercatinib post-hypersensitivity with dose modification/supportive care. Furthermore, 17 patients, of whom 14 received prior ICI therapy, were still on treatment at twice daily doses of 40 mg (n = 5), 80 mg (n = 4), 120 mg (n = 4), and 160 mg (n = 4). CONCLUSIONS: Rates of selpercatinib-related hypersensitivity were low overall and, as with other kinase inhibitors, occurred predominantly in prior ICI-treated patients. Hypersensitivity to selpercatinib can be managed with supportive care measures regardless of prior ICI status and is reversible.

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.

The calcium-sensing receptor: A novel target for treatment and prophylaxis of neratinib-induced diarrhea.

Diarrhea is one of the most commonly reported adverse effect of hemotherapy and targeted cancer therapies, such as tyrosine kinase inhibitors (TKI), which often significantly impact patient quality of life, morbidity, and mortality. Neratinib is an oral, irreversible pan-HER tyrosine kinase inhibitor, which is clinically active in HER2-positive breast cancer. Diarrhea is the most common side effect of this potent anticancer drug and the reasons for this adverse effect are still largely unclear. We have recently shown that activation of the calcium-sensing Receptor (CaSR) can inhibit secretagogue-induced diarrhea in the colon, therefore we hypothesized that CaSR activation may also mitigate neratinib-induced diarrhea. Using an established ex vivo model of isolated intestinal segments, we investigated neratinib-induced fluid secretion and the ability of CaSR activation to abate the secretion. In our study, individual segments of the rat intestine (proximal, middle, distal small intestine, and colon) were procured and perfused intraluminally with various concentrations of neratinib (10, 50, 100 nmol L-1). In a second set of comparison experiments, intraluminal calcium concentration was modulated (from 1.0 to 5.0 or 7.0 mmol L-1), both pre- and during neratinib exposure. In a separate series of experiments R-568, a known calcimimetic was used CaSR activation and effect was compared to elevated Ca2+ concentration (5.0 and 7.0 mmol L-1). As a result, CaSR activation with elevated Ca2+ concentration (5.0 and 7.0 mmol L-1) or R-568 markedly reduced neratinib-induced fluid secretion in a dose-dependent manner. Pre-exposure to elevated luminal calcium solutions (5.0 and 7.0 mmol L-1) also prevented neratinib-induced fluid secretion. In conclusion, exposure to luminal neratinib resulted in a pronounced elevation in fluid secretion in the rat intestine. Increasing luminal calcium inhibits the neratinib-associated fluid secretion in a dose-dependent manner. These results suggest that CaSR activation may be a potent therapeutic target to reduce chemotherapy-associated diarrhea.