Prolonged complete response to adjuvant tepotinib in a patient with newly diagnosed disseminated glioblastoma harboring mesenchymal-epithelial transition fusion.

The prognosis of patients with glioblastoma (GBM) remains poor despite current treatments. Targeted therapy in GBM has been the subject of intense investigation but has not been successful in clinical trials. The reasons for the failure of targeted therapy in GBM are multifold and include a lack of patient selection in trials, the failure to identify driver mutations, and poor blood-brain barrier penetration of investigational drugs. Here, we describe a case of a durable complete response in a newly diagnosed patient with GBM with leptomeningeal dissemination and PTPRZ1-MET fusion who was treated with tepotinib, a brain-penetrant MET inhibitor. This case of successful targeted therapy in a patient with GBM demonstrates that early molecular testing, identification of driver molecular alterations, and treatment with brain-penetrant small molecule inhibitors have the potential to change the outcome in select patients with GBM.

Plain language summary of the development of tepotinib: a treatment for a subtype of non-small cell lung cancer called MET exon 14 skipping.

WHAT IS THIS SUMMARY ABOUT?: This plain language summary provides an overview of two of the main clinical studies that led to tepotinib's approval, the phase I first-in-human study and the phase II VISION study. WHAT IS TEPOTINIB?: Tepotinib is a targeted anti-cancer treatment taken orally (by mouth). It is available in many countries for people with advanced or metastatic non-small cell lung cancer (NSCLC), where the tumor contains a genetic mutation (alteration) called 'MET exon 14 skipping'. Tumor cells rely on this mutation to grow and survive, so targeted blocking of the effect of this mutation is an important treatment approach. MET exon 14 skipping occurs in approximately 3-4% of people with NSCLC. These people are usually of older age. This subtype of NSCLC is associated with poor outcomes. Before treatments that specifically target this MET mutation were developed, only general treatments such as chemotherapy were available for this type of cancer. Because chemotherapy attacks all rapidly dividing cells in a person's body and is administered intravenously (through a vein), it can often cause unwanted side effects. Cancer cells grow and divide rapidly because of defects, often involving proteins called 'tyrosine kinases'. Specific tyrosine kinase inhibitors (TKIs) were therefore developed to slow or stop cancer growth by targeting these proteins. Tepotinib is a MET TKI. This means that it blocks the activity of the MET pathway that is overactive in MET exon 14 skipping NSCLC. Doing this, may slow down cancer growth. WHAT WERE THE RESULTS FROM THE CLINICAL STUDIES OF TEPOTINIB?: In the studies summarized here, people with MET exon 14 skipping NSCLC who took tepotinib had their tumor growth stopped or their tumor shrunk for a period of time, and they mostly experienced side effects that they could tolerate. Clinical Trial Registration: NCT01014936 (tepotinib first-in-human), NCT02864992 (VISION), NCT03940703 (INSIGHT 2) (ClinicalTrials.gov).

Tepotinib: Management of Adverse Events in Patients With MET Exon 14 Skipping Non-Small Cell Lung Cancer.

BACKGROUND: Tepotinib, a highly selective, oral, once-daily MET inhibitor, has been approved for treatment of metastatic MET exon 14 skipping non-small cell lung cancer. OBJECTIVES: This article provides nurse-specific recommendations for identification and management of tepotinib adverse events (AEs). METHODS: Guidance on monitoring and proactive/reactive AE management was developed based on published literature and real-world nursing experience. Case studies of VISION trial participants were summarized to illustrate key principles. FINDINGS: Tepotinib AEs are generally mild to moderate and manageable, and can include peripheral edema, hypoalbuminemia, nausea, diarrhea, and creatinine increase. Alongside supportive care, tepotinib interruption and dose reduction is recommended for grade 3 AEs. For peripheral edema, proactive monitoring is crucial, and treatment interruption (including frequent, short treatment holidays) should be considered early. Nursing management of tepotinib AEs includes proactive monitoring, patient education, and interprofessional team coordination.

Safety of MET Tyrosine Kinase Inhibitors in Patients With MET Exon 14 Skipping Non-small Cell Lung Cancer: A Clinical Review.

MET exon 14 (METex14) skipping mutations occur in 3% to 4% of non-small cell lung cancer (NSCLC) cases. Currently, four oral MET tyrosine kinase inhibitors (TKIs) are in use for the treatment of patients with METex14 skipping NSCLC (tepotinib, capmatinib, savolitinib, and crizotinib). To support optimal management of METex14 skipping NSCLC in this typically older patient population, the safety profiles of these treatment options are reviewed here. Published safety data from prospective clinical trials with MET TKIs in patients with METex14 skipping NSCLC were reviewed. Treatment-related adverse events (TRAEs) occurring in ≥ 10% of patients were reported where feasible. Guidance on clinical monitoring and management of key MET TKI TRAEs and drug-drug interactions is provided. Across the clinical trials, safety data for MET TKIs were reported for 442 patients with METex14 skipping. Peripheral edema was the most reported TRAE (50%-63% of patients; grade ≥ 3: 1%-11%), followed by nausea (26%-46% of patients; grade ≥ 3: 0%-1%). TRAEs led to dose reductions in 33% to 38% of patients and to discontinuation in 7% to 14% of patients, across the MET TKIs. Considerations on interpreting available safety data are provided, along with insights into monitoring and managing specific MET TKI TRAEs of interest and drug-drug interactions. Overall, MET TKIs are tolerable treatment options for patients with METex14 skipping NSCLC, an older population for whom chemo- or immuno-therapy may not be an effective nor tolerable option. More data regarding the effectiveness of safety interventions and management strategies are needed.

Evaluation of EGFR inhibitor-mediated acneiform skin toxicity within the double-blind randomized EVITA trial: A thorough gender-specific analysis using the WoMo score.

Acne-like skin reactions frequently occur in patients undergoing treatment with drugs inhibiting the epidermal growth factor receptor. Recently, the effects of vitamin K1 containing cream (Reconval K1) as prophylactic skin treatment in addition to doxycycline were explored in a double-blind randomized phase II trial (EVITA) in patients with metastatic colorectal cancer receiving cetuximab. EVITA demonstrated a trend towards less severe skin rash in Reconval K1-treated patients using the tripartite WoMo skin reaction grading score as a thorough tool for quantification of drug related skin reactions. This gender-specific analysis of the EVITA trial evaluated the application of the WoMo score for assessment of epidermal growth factor receptor (EGFR)-related skin toxicities according to treatment arm and gender. To show the robustness of results parametric and non-parametric statistical analyses were conducted. All three parts of the WoMo score independently demonstrated the superiority of the treatment arm (Reconval K1) regarding a significant reduction in acneiform skin reactions in women. Men did not benefit from Reconval K1 cream at any time point in none of the WoMo score analyses. The treatment effect in women was confirmed by the use of skin rash categories based on the final WoMo overall score and mixed effect longitudinal multiple linear regression analysis. The WoMo score represents a sensitive tool for studies exploiting treatments against EGFR mediated acne-like skin rash. Part C of the WoMo score seems to be sufficient for quantification of drug related skin toxicities in further studies. Standard WoMo skin reaction score values for future studies are provided.

Intrapatient cetuximab dose escalation in metastatic colorectal cancer according to the grade of early skin reactions: the randomized EVEREST study.

PURPOSE: Skin toxicity in patients receiving cetuximab has been associated positively with clinical outcome in several tumor types. This study investigated the effect of cetuximab dose escalation in patients with irinotecan-refractory metastatic colorectal cancer who had developed no or mild skin reactions after 21 days of treatment at the standard dose. This article reports clinical and pharmacokinetic (PK) data. PATIENTS AND METHODS: After 21 days of standard-dose cetuximab (400 mg/m(2) initial dose, then 250 mg/m(2) per week) plus irinotecan, patients with ≤ grade 1 skin reactions were randomly assigned to standard-dose (group A) or dose-escalated (to 500 mg/m(2) per week; group B) cetuximab. Patients with ≥ grade 2 skin reactions continued on standard-dose cetuximab plus irinotecan (group C). RESULTS: The intent-to-treat population comprised 157 patients. PK profiles reflected the dose increase and were predictable across the dose range investigated. Weekly cetuximab doses of up to 500 mg/m(2) were well tolerated, and grade 3 and 4 adverse events were generally comparable between treatment groups. Dose escalation (n = 44) was associated with an increase in skin reactions ≥ grade 2 compared with standard (n = 45) dosing (59% v 38%, respectively). Dose escalation, compared with standard dosing, showed some evidence for improved response rate (30% v 16%, respectively) and disease control rate (70% v 58%, respectively) but no indication of benefit in relation to overall survival. In an exploratory analysis, dose escalation seemed to increase response rate compared with standard dosing in patients with KRAS wild-type but not KRAS mutant tumors. CONCLUSION: Cetuximab serum concentrations increased predictably with dose. Higher dose levels were well tolerated. The possible indication for improved efficacy in the dose-escalation group warrants further investigation.

Molecular response to cetuximab and efficacy of preoperative cetuximab-based chemoradiation in rectal cancer.

PURPOSE: To characterize the molecular pathways activated or inhibited by cetuximab when combined with chemoradiotherapy (CRT) in rectal cancer and to identify molecular profiles and biomarkers that might improve patient selection for such treatments. PATIENTS AND METHODS: Forty-one patients with rectal cancer (T3-4 and/or N+) received preoperative radiotherapy (1.8 Gy, 5 days/wk, 45 Gy) in combination with capecitabine and cetuximab (400 mg/m2 as initial dose 1 week before CRT followed by 250 mg/m2 /wk for 5 weeks). Biopsies and plasma samples were taken before treatment, after cetuximab but before CRT, and at the time of surgery. Proteomics and microarrays were used to monitor the molecular response to cetuximab and to identify profiles and biomarkers to predict treatment efficacy. RESULTS: Cetuximab on its own downregulated genes involved in proliferation and invasion and upregulated inflammatory gene expression, with 16 genes being significantly influenced in microarray analysis. The decrease in proliferation was confirmed by immunohistochemistry for Ki67 (P = .01) and was accompanied by an increase in transforming growth factor-alpha in plasma samples (P < .001). Disease-free survival (DFS) was better in patients if epidermal growth factor receptor expression was upregulated in the tumor after the initial cetuximab dose (P = .02) and when fibro-inflammatory changes were present in the surgical specimen (P = .03). Microarray and proteomic profiles were predictive of DFS. CONCLUSION: Our study showed that a single dose of cetuximab has a significant impact on the expression of genes involved in tumor proliferation and inflammation. We identified potential biomarkers that might predict response to cetuximab-based CRT.