Safety of Tepotinib in Patients With MET Exon 14 Skipping NSCLC and Recommendations for Management

Edema; Nausea; Non-small cell lung cancerEdema; Náuseas; Cáncer de pulmón de células no pequeñasEdema; Nàusees; Càncer de pulmó de cèl·lules no petitesIntroduction The MET inhibitor tepotinib demonstrated durable clinical activity in patients with advanced MET exon 14 (METex14) skipping NSCLC. We report detailed analyses of adverse events of clinical interest (AECIs) in VISION, including edema, a class effect of MET inhibitors. Patients and Methods Incidence, management, and time to first onset/resolution were analyzed for all-cause AECIs, according to composite categories (edema, hypoalbuminemia, creatinine increase, and ALT/AST increase) or individual preferred terms (pleural effusion, nausea, diarrhea, and vomiting), for patients with METex14 skipping NSCLC in the phase II VISION trial. Results Of 255 patients analyzed (median age: 72 years), edema, the most common AECI, was reported in 69.8% (grade 3, 9.4%; grade 4, 0%). Median time to first edema onset was 7.9 weeks (range: 0.1-58.3). Edema was manageable with supportive measures, dose reduction (18.8%), and/or treatment interruption (23.1%), and rarely prompted discontinuation (4.3%). Other AECIs were also manageable and predominantly mild/moderate: hypoalbuminemia, 23.9% (grade 3, 5.5%); pleural effusion, 13.3% (grade ≥ 3, 5.1%); creatinine increase, 25.9% (grade 3, 0.4%); nausea, 26.7% (grade 3, 0.8%), diarrhea, 26.3% (grade 3, 0.4%), vomiting 12.9% (grade 3, 1.2%), and ALT/AST increase, 12.2% (grade ≥ 3, 3.1%). GI AEs typically occurred early and resolved in the first weeks. Conclusion Tepotinib was well tolerated in the largest trial of a MET inhibitor in METex14 skipping NSCLC. The most frequent AEs were largely mild/moderate and manageable with supportive measures and/or dose reduction/interruption, and caused few withdrawals in this elderly population

Tepotinib Efficacy and Safety in Patients with MET Exon 14 Skipping NSCLC: Outcomes in Patient Subgroups from the VISION Study with Relevance for Clinical Practice

Efficacy; Lung cancerEficacia; Cáncer de pulmónEficàcia; Càncer de pulmóPurpose: Primary analysis of VISION showed tepotinib had durable clinical activity in patients with MET exon 14 (METex14) skipping non–small cell lung cancer (NSCLC). We present updated outcomes for clinically relevant subgroups. Patients and Methods: This phase II, open-label, multi-cohort study of 500 mg (450 mg active moiety) tepotinib in patients with METex14 skipping NSCLC assessed efficacy and safety in predefined subgroups according to age, prior therapies (chemotherapy and immune checkpoint inhibitors), and brain metastases. An ad hoc retrospective analysis using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria assessed intracranial activity. Results: 152 patients were evaluable for efficacy (median age: 73.1). Overall, objective response rate (ORR) was 44.7% [95% confidence interval (CI): 36.7–53.0]. Patients aged <75 (n = 84) and ≥75 (n = 68) had ORRs of 48.8% (95% CI: 37.7–60.0) and 39.7% (95% CI: 28.0–52.3), respectively. Treatment-naïve (n = 69) versus previously treated (n = 83) patients showed consistent efficacy [ORR (95% CI): 44.9% (32.9–57.4) vs. 44.6% (33.7–55.9); median duration of response (95% CI): 10.8 (6.9–not estimable) vs. 11.1 (9.5–18.5) months]. Of 15 patients analyzed by RANO-BM (12 received prior radiotherapy), 13 achieved intracranial disease control; 5 of 7 patients with measurable brain metastases had partial intracranial responses. Of 255 patients evaluable for safety, 64 (25.1%) experienced grade ≥3 treatment-related adverse events (TRAE), leading to discontinuation in 27 patients (10.6%). Rates of adverse events (AE) were broadly consistent irrespective of prior therapies. Conclusions: Tepotinib showed meaningful activity across subgroups by age, prior therapies, and brain metastases, with a manageable safety profile and few treatment discontinuations.The trial was sponsored by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945)

Tepotinib Treatment in Patients With MET Exon 14-Skipping Non-Small Cell Lung Cancer: Long-term Follow-up of the VISION Phase 2 Nonrandomized Clinical Trial

Tepotinib; Non-small cell lung cancerTepotinib; Cáncer de pulmón de células no pequeñasTepotinib; Càncer de pulmó de cèl·lules no petitesImportance MET inhibitors have recently demonstrated clinical activity in patients with MET exon 14 (METex14)-skipping non–small cell lung cancer (NSCLC); however, data with longer follow-up and in larger populations are needed to further optimize therapeutic approaches. Objective To assess the long-term efficacy and safety of tepotinib, a potent and highly selective MET inhibitor, in patients with METex14-skipping NSCLC in the VISION study. Design, Setting, and Participants The VISION phase 2 nonrandomized clinical trial was a multicohort, open-label, multicenter study that enrolled patients with METex14-skipping advanced/metastatic NSCLC (cohorts A and C) from September 2016 to May 2021. Cohort C (>18 months’ follow-up) was an independent cohort, designed to confirm findings from cohort A (>35 months’ follow-up). Data cutoff was November 20, 2022. Intervention Patients received tepotinib, 500 mg (450 mg active moiety), once daily. Main Outcomes and Measures The primary end point was objective response by independent review committee (RECIST v1.1). Secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results Cohorts A and C included 313 patients (50.8% female, 33.9% Asian; median [range] age, 72 [41-94] years). The objective response rate (ORR) was 51.4% (95% CI, 45.8%-57.1%) with a median (m)DOR of 18.0 (95% CI, 12.4-46.4) months. In cohort C (n = 161), an ORR of 55.9% (95% CI, 47.9%-63.7%) with an mDOR of 20.8 (95% CI, 12.6-not estimable [NE]) months was reported across treatment lines, comparable to cohort A (n = 152). In treatment-naive patients (cohorts A and C; n = 164), ORR was 57.3% (95% CI, 49.4%-65.0%) and mDOR was 46.4 (95% CI, 13.8-NE) months. In previously treated patients (n = 149), ORR was 45.0% (95% CI, 36.8%-53.3%) and mDOR was 12.6 (95% CI, 9.5-18.5) months. Peripheral edema, the most common treatment-related adverse event, occurred in 210 patients (67.1%) (35 [11.2%] experienced grade ≥3 events). Conclusions and Relevance The findings from cohort C in this nonrandomized clinical trial supported the results from original cohort A. Overall, the long-term outcomes of VISION demonstrated robust and durable clinical activity following treatment with tepotinib, particularly in the treatment-naive setting, in the largest known clinical trial of patients with METex14-skipping NSCLC, supporting the global approvals of tepotinib and enabling clinicians to implement this therapeutic approach for such patients. Trial Registration ClinicalTrials.gov Identifier: NCT02864992The trial was sponsored by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945)

465 Bintrafusp alfa in combination with chemotherapy in patients with stage IV NSCLC: safety and pharmacokinetic results of the INTR@PID LUNG 024 study

BackgroundBintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β "trap") fused to a human IgG1 mAb blocking PD-L1. Here we report cumulative safety and pharmacokinetic (PK) results from the global, phase 1b/2 INTR@PID LUNG 024 study (NCT03840915), which evaluated bintrafusp alfa in combination with chemotherapy (CT) in patients with stage IV NSCLC.MethodsAdult patients with stage IV nonsquamous or squamous NSCLC and an ECOG PS ≤1 were included. Cohorts A, B, and C included patients with no prior systemic therapy; patients in cohort D had disease that progressed with previous anti–PD-(L)1 therapy. Cohorts received bintrafusp alfa 2400 mg every 3 weeks intravenously in combination with CT for 4 cycles (A [nonsquamous only]: cisplatin or carboplatin + pemetrexed; B: carboplatin + nab-paclitaxel or paclitaxel; C: cisplatin or carboplatin + gemcitabine; D: docetaxel) followed by bintrafusp alfa maintenance (monotherapy or in combination with pemetrexed in cohort A) for up to 31 cycles. The primary objective of this study was to evaluate the safety of bintrafusp alfa in combination with CT. Dose-limiting toxicities (DLTs) were assessed during a 3-week observation period. Serial samples were drawn to assess serum concentration and calculate PK parameters by noncompartmental analysis.ResultsAs of the May 5, 2021, data cutoff, 70 patients received bintrafusp alfa in combination with CT. Of 35 patients included in the DLT analysis, 4 experienced 1 DLT according to a safety monitoring committee (data cutoff May 5, 2021; A: n=1/8; B: n=1/8; C: n=0/8; D: n=2/11). Cumulative safety data are reported in table 1. PK data were available for 67 patients (A: n=38; B: n=9; C: n=8; D: n=12). PK profiles were similar across cohorts and between patients who did and did not experience a DLT. Observed bintrafusp alfa first-cycle exposures (Cmax, AUC, and Ctrough) were consistent with the published population PK (popPK) model.1Abstract 465 Table 1Safety results from the INTR@PID LUNG 024 studyConclusionsThe safety profile of bintrafusp alfa in combination with CT was manageable and similar to that reported for ICIs in combination with CT, with the exception of TGF-β–related skin lesions known to occur with TGF-β inhibition. No new safety signals were identified and there were no treatment-related deaths. The PK profile was consistent with the predicted monotherapy popPK model, suggesting no victim DDI potential for bintrafusp alfa with CT.AcknowledgementsThe authors thank the patients and their families, investigators, co-investigators, and the study teams at each of the participating centers, at the healthcare business of Merck KGaA, Darmstadt, Germany, and at EMD Serono, Billerica, Massachusetts, USA.Trial RegistrationNCT03840915ReferenceWilkins JJ, Vugmeyster Y, Dussault I. Population pharmacokinetic analysis of bintrafusp alfa in different cancer types. Adv Ther 2019;36:2414–2433.Ethics ApprovalThe trial was approved by each site's independent ethics committee

Tepotinib in Non–Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations

BACKGROUND: A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver MET occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population. METHODS: In this open-label, phase 2 study, we administered tepotinib (at a dose of 500 mg) once daily in patients with advanced or metastatic NSCLC with a confirmed MET exon 14 skipping mutation. The primary end point was the objective response by independent review among patients who had undergone at least 9 months of follow-up. The response was also analyzed according to whether the presence of a MET exon 14 skipping mutation was detected on liquid biopsy or tissue biopsy. RESULTS: As of January 1, 2020, a total of 152 patients had received tepotinib, and 99 patients had been followed for at least 9 months. The response rate by independent review was 46% (95% confidence interval [CI], 36 to 57), with a median duration of response of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined-biopsy group. The response rate was 48% (95% CI, 36 to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed response rate was 56% (95% CI, 45 to 66) and was similar regardless of the previous therapy received for advanced or metastatic disease. Adverse events of grade 3 or higher that were considered by investigators to be related to tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%. Adverse events led to permanent discontinuation of tepotinib in 11% of the patients. A molecular response, as measured in circulating free DNA, was observed in 67% of the patients with matched liquid-biopsy samples at baseline and during treatment. CONCLUSIONS: Among patients with advanced NSCLC with a confirmed MET exon 14 skipping mutation, the use of tepotinib was associated with a partial response in approximately half the patients. Peripheral edema was the main toxic effect of grade 3 or higher. (Funded by Merck [Darmstadt, Germany]; VISION ClinicalTrials.gov number, NCT02864992.)

Tepotinib Efficacy and Safety in Patients with MET Exon 14 Skipping NSCLC: Outcomes in Patient Subgroups from the VISION Study with Relevance for Clinical Practice

PURPOSE Primary analysis of VISION showed tepotinib had durable clinical activity in patients with MET exon 14 (METex14) skipping non-small cell lung cancer (NSCLC). We present updated outcomes for clinically relevant subgroups. PATIENTS AND METHODS This phase II, open-label, multi-cohort study of 500 mg (450 mg active moiety) tepotinib in patients with METex14 skipping NSCLC assessed efficacy and safety in predefined subgroups according to age, prior therapies (chemotherapy and immune checkpoint inhibitors), and brain metastases. An ad hoc retrospective analysis using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria assessed intracranial activity. RESULTS 152 patients were evaluable for efficacy (median age: 73.1). Overall, objective response rate (ORR) was 44.7% [95% confidence interval (CI): 36.7-53.0]. Patients aged <75 (n = 84) and ≥75 (n = 68) had ORRs of 48.8% (95% CI: 37.7-60.0) and 39.7% (95% CI: 28.0-52.3), respectively. Treatment-naïve (n = 69) versus previously treated (n = 83) patients showed consistent efficacy [ORR (95% CI): 44.9% (32.9-57.4) vs. 44.6% (33.7-55.9); median duration of response (95% CI): 10.8 (6.9-not estimable) vs. 11.1 (9.5-18.5) months]. Of 15 patients analyzed by RANO-BM (12 received prior radiotherapy), 13 achieved intracranial disease control; 5 of 7 patients with measurable brain metastases had partial intracranial responses. Of 255 patients evaluable for safety, 64 (25.1%) experienced grade ≥3 treatment-related adverse events (TRAE), leading to discontinuation in 27 patients (10.6%). Rates of adverse events (AE) were broadly consistent irrespective of prior therapies. CONCLUSIONS Tepotinib showed meaningful activity across subgroups by age, prior therapies, and brain metastases, with a manageable safety profile and few treatment discontinuations

The impact of sarcopenia on the efficacy and safety of immune checkpoint inhibitors in patients with solid tumours

Background : Evidence suggests that sarcopenia is a significant predictive factor of worst outcomes and treatment-associated toxicities in patients with metastatic solid tumours. The aim of this study was to explore the relationship between low muscle mass and clinical outcomes and immune-related severe toxicities (IrST) in patients treated with immune checkpoint inhibitors (ICIs). Methods : A retrospective cohort of 261 consecutive metastatic solid tumour patients treated with ICIs were included in our study. Low muscle mass was defined as skeletal muscle index <41 cm2/m2 for females and <43 cm2/m2 for males if body mass index (BMI) <25 kg/m2 or <53 cm2/m2 if BMI ≥ 25 kg/m2. Severe toxicities (ST), including grade III-IV toxicities and side effects leading to treatment interruption, were recorded. Results : The majority of patients (n = 179; 69%) included in this study had metastatic lung cancer. The prevalence of low muscle mass was 47%. The median progression-free survival (PFS) was 32.2 weeks for low muscle mass patients and 24.3 weeks for non-low muscle mass patients (adjusted HR, 0.80; 95% CI, 0.60–1.055; p = 0.11). For low muscle mass and non-low muscle mass lung cancer patients, median PFS was 24.0 weeks and 18.8 weeks (adjusted HR, 0.70; 95% CI, 0.50–0.98; p = 0.04) and median overall survival was 50.7 weeks and 41.1 weeks (adjusted HR, 0.77; 95% CI, 0.54–1.10, p = 0.15) respectively. Immune-related severe toxicities occurred in 3.3% and 9.4% of low muscle mass and non-low muscle mass patients respectively (adjusted OR, 0.69; 95% CI: 0.31–1.49; p = 0.35). Conclusion : No difference in outcomes and safety was observed for low muscle mass and non-low muscle mass patients treated with ICIs

Brief Report: First-line Pembrolizumab in Metastatic Non-Small Cell Lung Cancer Habouring MET Exon 14 Skipping Mutation and PD-L1 ≥50% (GFPC 01-20 Study)

International audienceNo abstract availabl

A Prospective Study to Detect Immune Checkpoint Inhibitors Associated With Myocarditis Among Patients Treated for Lung Cancer

Background: Immune checkpoint inhibitors (ICIs) are widely used in lung cancer management. However, myocarditis, which is a rare, yet potentially severe adverse-related event associated with ICIs, could be under-reported. Objectives: This study is aimed to prospectively evaluate the cumulative incidence rate of myocarditis, through systematic screening, among patients receiving ICIs for lung cancer. Methods: All patients who received the first administration of ICIs for non-small cell (NSCLC) and small cell lung cancer (SCLC), between May and November 2020, in the pulmonary department of Bordeaux University Hospital, were included. Echocardiography (ECG), troponin-I, and natriuretic peptide dosages before ICIs' first administration and before each infusion were recorded. ECG and magnetic resonance imaging (MRI) were done additionally, in case of at least three times increase in troponin levels, ECG modifications, and the onset of cardiovascular symptoms. Second, if possible, coronarography than endomyocardial biopsy was assessed. The primary outcome was defined as ICIs related to myocarditis onset, while secondary outcomes included other cardiovascular events, disease-free, and overall survival. Results: During the period of interest, 99 patients received their first infusion of ICIs for lung cancer (mean age 64 +/- 9 years; 52 men, 67% with adenocarcinoma). Three cases of myocarditis without major adverse cardiac events (MACEs) occurred (two definite and one possible), and the mean duration between the first ICIs' administration and myocarditis onset was 144 +/- 3 days. Median disease-free survival and overall survival were 169 [102; 233] days and 209 [147; 249] days, respectively. Conclusion: In our study, systematic screening of myocarditis associated with ICIs leads to a more frequent incidence and a later onset than previously reported. None of them were severe. Additional prospective evidence is needed before we could adopt routine cardiac screening in unselected patients starting ICIs; however, these data shed new light on the risk of myocarditis associated with ICIs administration

Eur J Cancer

BACKGROUND: Mutations in STK11/LKB1 gene present a negative impact on tumour immune microenvironment, especially with concomitant activating KRAS mutation. These recent data may explain a decreased response to immunotherapy treatment in STK11 mutant non-small cell lung cancer (NSCLC). OBJECTIVE: The primary objective is to evaluate, in a real-life setting, overall survival (OS) in patients with NSCLC according to the presence of STK11 mutation. The secondary objective is to assess time to treatment failure (TTF) for the first-line chemotherapy or immunotherapy. METHODS: This observational multicentric study was conducted in Nouvelle-Aquitaine (France), for 24 months. Clinical, histopathological and imagery data were collected in each centre while the next-generation sequencing analysis was performed in Bordeaux Hospital University. Patient's data were longitudinally followed from NSCLC diagnosis date to the occurrence of censoring events (therapeutic failure or death, as applicable) or until the study end date. RESULTS: median OS from the first drug administration was significantly longer for STK11(wt) patients than STK11(mut) patients (16.2 months [11 - nr] versus 4.7 months [2.5-9.4]; Log-rank test P < 0.001). The Presence of STK11 mutation was significantly associated with shortened OS (RR = 2.26 [1.35-3.79], P = 0.002). First-line TTF was significantly shorter in STK11(mut) population and the presence of the mutation was significantly associated with an increase in treatment failures (RR = 1.87 [1.21-2.89], P = 0.005). The type of treatment (chemotherapy, immunotherapy) does not influence the amplitude of reduced TTF in patients with STK11(mut). CONCLUSION: The presence of STK11 mutation is associated with poor prognosis in NSCLC