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.

Patient-Reported Outcomes with Selpercatinib Treatment Among Patients with RET-Mutant Medullary Thyroid Cancer in the Phase I/II LIBRETTO-001 Trial.

BACKGROUND: Medullary thyroid cancer (MTC) standard of care includes multikinase inhibitors (MKIs), which can exacerbate disease-related diarrhea, primarily because of non-RET kinase inhibition. We report diarrhea and other patient-reported outcomes (PROs) with selpercatinib, a highly selective RET inhibitor, among patients with RET-mutant MTC in the ongoing, phase I/II LIBRETTO-001 trial. MATERIALS AND METHODS: Instrument completion time points were baseline (cycle 1, day 1) and approximately every other 28-day cycle until cycle 13 (every 12 weeks thereafter) for the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, and baseline, weekly during cycle 1, and day 1 of every cycle for the modified Systemic Therapy-Induced Diarrhea Assessment Tool (mSTIDAT). A ≥10-point change from baseline in domain score was considered clinically meaningful. PROs were summarized through cycle 13 in all patients and by subgroups with or without prior exposure to MKIs vandetanib and/or cabozantinib (V/C). RESULTS: Among the overall MTC population (n = 226), 88 (39%) and 124 (55%) patients comprised the V/C-naïve and previous V/C subgroups, respectively. Compliance was >85% for both instruments at each time point. Most patients maintained/improved in all health-related quality of life (HRQoL) subscales throughout treatment. Improvements in diarrhea were clinically meaningful in 43.5% of patients overall and in 36.8% and 51.3% of V/C-naïve and previous V/C subgroups, respectively. At baseline, 80.4% of all patients reported diarrhea on mSTIDAT. The percentage of patients who reported diarrhea was reduced to less than half of all patients (range: 33.3%-48.3%) after cycle 2. CONCLUSION: These interim results demonstrate that patients with RET-mutant MTC improved/remained stable on all domains of HRQoL during treatment with selpercatinib. Future analyses will be conducted as the data mature.

Patient-Reported Outcomes with Selpercatinib Among Patients with RET Fusion-Positive Non-Small Cell Lung Cancer in the Phase I/II LIBRETTO-001 Trial.

BACKGROUND: LIBRETTO-001 is an ongoing, global, open-label, phase I/II study of selpercatinib in patients with advanced or metastatic solid tumors. We report interim patient-reported outcomes in patients with RET fusion-positive non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) version 3.0 at baseline (cycle 1, day 1), approximately every other 28-day cycle until cycle 13, and every 12 weeks thereafter. Data were evaluated through cycle 13 as few patients had reached later time points. A change of ≥10 points from baseline in domain scores was considered clinically meaningful. RESULTS: Among 253 selpercatinib-treated patients, 239 were categorized into subgroups by prior therapy: treatment-naïve (n = 39), one prior line of therapy (n = 64), or two or more prior lines of therapy (n = 136). The QLQ-C30 was completed by >85% of patients at each time point. Most patients overall and in each subgroup maintained or improved in all health-related quality of life (HRQoL) domains during treatment. The percentage of patients who experienced clinically meaningful improvements ranged from 61.1% to 66.7% for global health status, 33.3% to 61.1% for dyspnea, and 46.2% to 63.0% for pain. The 61.1% of patients with improved dyspnea had two or more prior lines of therapy; median time to first improvement was 3.4 months. At the first postbaseline evaluation (cycle 3), 45.9% of all patients reported a ≥10-point reduction in pain. CONCLUSION: In this interim analysis, the majority of patients with RET fusion-positive NSCLC remained stable or improved on all QLQ-C30 subscales at each study visit, demonstrating favorable HRQoL as measured by the QLQ-C30 during treatment with selpercatinib.

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.

Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer.

BACKGROUND: RET 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. METHODS: We 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. RESULTS: In 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. CONCLUSIONS: Selpercatinib 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.).

Pharmacokinetics and safety of neratinib during co-administration with loperamide in healthy subjects.

PURPOSE: To evaluate the effects of multiple doses of loperamide on the pharmacokinetics and safety of a single oral dose of neratinib. METHODS: This was an open-label, two-period, fixed-sequence study. Twenty healthy adult subjects received an oral dose of neratinib 240 mg daily on Days 1-4 of Period 1 followed by a 7-day washout. In Period 2, oral neratinib 240 mg was administered with loperamide 4 mg followed by two further doses of loperamide 2 mg 8 and 16 h later on Days 1-4. Pharmacokinetic sampling was performed for 72 h following each neratinib dose. Safety was monitored throughout the study. RESULTS: A median tmax of ~ 6 h was observed for neratinib during both periods. Apparent clearance and volume of distribution were similar for Periods 1 and 2: mean CLss/F 308.2 and 322.1 L/h; mean Vzτ/F 7995 and 10,318 L, respectively. The half-life of neratinib increased in the presence of loperamide from 18.0 to 22.2 h. Mean exposure was within the same range without and with loperamide administration: Cmax 61.2 ng/mL and 49.5 ng/mL; AUClast 1086 ng h/mL and 1153 ng h/mL, and AUCtau 779 ng h/mL and 745 ng h/mL, respectively. Treatment-emergent adverse events were mainly mild in intensity, with the most frequent events being diarrhea (45%) and constipation (35%). CONCLUSIONS: Neratinib administered alone and concomitantly with multiple oral doses of loperamide is generally safe and well tolerated. Loperamide has minimal effects on neratinib pharmacokinetic parameters.

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.

The characterization, management, and future considerations for ErbB-family TKI-associated diarrhea.

PURPOSE: Diarrhea is recognized as a common adverse event associated with tyrosine kinase inhibitors (TKIs), with those targeting the ErbB family of receptors being associated with the highest rate of diarrhea. METHODS: This paper reviews data on the incidence, timing, and duration of diarrhea associated with US Food and Drug Administration-approved ErbB family-targeted TKIs from the published literature, and sets forth recommendations for management. RESULTS: In the absence of anti-diarrheal prophylaxis the incidence of any-grade diarrhea varies and typically occurs early during the course of treatment. Although it is difficult to determine if the incidence and severity of diarrhea is related to inhibition of a particular kinase target because of the multi-targeted and overlapping activity of many agents, evidence suggests that second-generation TKIs with broader target profiles (i.e., afatinib, lapatinib, neratinib) result in a higher incidence of diarrhea compared with highly specific first- (erlotinib, gefitinib) or third- (osimertinib) generation agents. The mechanisms responsible for TKI-associated diarrhea are not fully understood and are likely multi-factorial, involving dysregulated ion transport, inflammation, and mucosal injury. Management strategies have been developed-and continue to be refined-to prevent and reduce the severity and duration of TKI-associated diarrhea. For agents associated with more significant symptoms, anti-diarrheal prophylaxis reduces the incidence and severity of diarrhea, and ongoing studies are evaluating specific strategies to further reduce incidence and duration of TKI-associated diarrhea. CONCLUSIONS: Continued investigations into risk factors and pharmacogenomic markers for diarrhea may further improve management of this common toxicity.

Targeting neratinib-induced diarrhea with budesonide and colesevelam in a rat model.

PURPOSE: Neratinib is an irreversible pan-ErbB tyrosine kinase inhibitor used for the extended adjuvant treatment of early-stage HER2-positive breast cancer. Its use is associated with the development of severe diarrhea in up to 40% of patients in the absence of proactive management. We previously developed a rat model of neratinib-induced diarrhea and found inflammation and anatomical disruption in the ileum and colon. Here we tested whether anti-diarrheal interventions, budesonide and colesevelam, can reduce neratinib-induced diarrhea and intestinal pathology. METHODS: Rats were treated with 50 mg/kg neratinib via oral gavage for 14 or 28 days (total n = 64). Body weight and diarrhea severity were recorded daily. Apoptosis was measured using immunohistochemistry for caspase-3. Inflammation was measured via a multiplex cytokine/chemokine assay. ErbB levels were measured using PCR and Western Blot. RESULTS: Budesonide co-treatment caused rats to gain significantly less weight than neratinib alone from day 4 of treatment (P = 0.0418). Budesonide (P = 0.027) and colesevelam (P = 0.033) each reduced the amount of days with moderate diarrhea compared to neratinib alone. In the proximal colon, rats treated with neratinib had higher levels of apoptosis compared to controls (P = 0.0035). Budesonide reduced histopathological injury in the proximal (P = 0.0401) and distal colon (P = 0.027) and increased anti-inflammatory IL-4 tissue concentration (ileum; P = 0.0026, colon; P = 0.031) compared to rats treated with neratinib alone. In the distal ileum, while budesonide decreased ErbB1 mRNA expression compared to controls (P = 0.018) (PCR), an increase in total ErbB1 protein was detected (P = 0.0021) (Western Blot). CONCLUSION: Both budesonide and colesevelam show potential as effective interventions against neratinib-induced diarrhea.

Rapid and sharp decline in HCV upon monotherapy with NS3 protease inhibitor, ACH-1625.

BACKGROUND: ACH-1625 is a linear peptidomimetic inhibitor that non-covalently binds to HCV NS3 protease with high potency and specificity. Short-term monotherapy of HCV genotype-1 infection with ACH-1625 was found to be safe and resulted in ≥3.3 log(10) IU/ml mean viral load reduction. These viral load decay data were analysed to compare HCV dynamics with prior reports and estimate the antiviral efficiency of ACH-1625. METHODS: Drug efficiency was estimated by analysing the viral decay following initiation of up to 5 days of monotherapy with ACH-1625 in 36 chronically infected HCV genotype-1 patients. During this monotherapy study, ACH-1625 was administered either twice-a-day for 4.5 days or once daily for 5 days at 5 different dose levels in 36 patients. RESULTS: A sharp viral decay during the first 48 h following the initiation of ACH-1625 treatment afforded high drug efficiency estimates (≥0.9934). In addition, an increase in the estimated drug efficiency was observed with increasing ACH-1625 dose. The observed anti-HCV response was fairly uniform in this proof-of-concept study across the population of 36 patients. CONCLUSIONS: Estimates of the treatment-independent viral kinetics parameters were consistent with prior reports and the estimated drug efficiency of ACH-1625 monotherapy was very high (≥0.9934) in fasted and fed states.

A multicenter study of recombinant human interleukin 12 for the treatment of chronic hepatitis C virus infection in patients nonresponsive to previous therapy.

Recombinant human interleukin 12 (IL-12) is an immunomodulatory cytokine that is active against several viruses. Treatment options in patients with chronic hepatitis C with nonresponse to interferon (IFN)-based therapy are limited. Prior dose-ranging studies have indicated drug tolerability and transient suppression of hepatitis C virus (HCV) RNA by IL-12. The aim of this study was to determine the safety and efficacy of prolonged IL-12 therapy in patients who have failed treatment with IFN-alpha +/- ribavirin. A total of 225 patients at 21 U.S. sites who had a history of nonresponse to IFN-alpha or combination IFN-alpha plus ribavirin for treatment of HCV were randomized to 500 ng/kg IL-12 or placebo subcutaneously twice weekly for 12 weeks. The groups were then unblinded; patients receiving IL-12 continued for another 36 weeks, and the placebo group received 48 weeks of treatment with IL-12 in an open-label fashion. HCV RNA, serum alanine aminotransferase (ALT) level, and a repeat liver biopsy were assessed at 24 weeks following therapy. Approximately 1% (2 of 160) of nonresponsive patients enrolled for treatment had a sustained virologic response to IL-12 therapy, but 3% (7 of 225) developed severe adverse events probably related to treatment, resulting in early termination of the trial. Common adverse effects reported by most patients included chills, fever, fatigue, headache, and arthralgia. At termination of the study, 160 patients had received at least 8 weeks of treatment with IL-12. Paired liver biopsy specimens were available for evaluation in 54 patients, but there were no significant changes in Knodell fibrosis or histologic activity index (HAI) scores. In conclusion, IL-12 as monotherapy at the doses used in this trial for chronic hepatitis C has low efficacy, was poorly tolerated, and is unlikely to provide an alternative to conventional IFN-based therapy.