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Rémi Veillon
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FP14 - Targeted Therapy - Clinically Focused (ID 252)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP14.09 - Tepotinib Safety in MET Exon 14 (METex14) Skipping NSCLC: Updated Results from the VISION Trial (ID 821)
00:00 - 00:00 | Presenting Author(s): Rémi Veillon
- Abstract
Introduction
Tepotinib, a highly selective MET inhibitor, demonstrated durable clinical activity in patients with METex14 skipping NSCLC in the Phase II VISION trial (NCT02864992). Here, we report updated safety data from this ongoing study of the largest prospective population of patients with METex14 skipping NSCLC to date.
Methods
Patients with advanced EGFR/ALK wild-type NSCLC and METex14 skipping identified by liquid or tissue biopsy received oral tepotinib 500 mg once daily until disease progression, unacceptable toxicity or withdrawal for other reasons. To manage adverse events (AEs), treatment could be interrupted for up to 21 days or the tepotinib dose could be reduced. AEs were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events v4.03.
Results
As of July 1, 2020, 255 patients had received tepotinib for a median of 5.1 months (range 0 to 43.4) and treatment was ongoing in 101 patients (39.6%). Median age was 72.0 years (range 41 to 94), 132 patients (51.8%) were female, 171 (67.1%) were white and 184 (72.2%) had Eastern Cooperative Oncology Group performance status 1. The most common treatment-related AEs (TRAEs) were peripheral edema, nausea, diarrhea, blood creatinine increased, and hypoalbuminemia, which were mostly mild or moderate (table). TRAEs led to dose reduction in 71 patients (27.8%), treatment interruption in 90 patients (35.3%) and discontinuation in 27 patients (10.6%). The most common TRAE leading to treatment modification was peripheral edema (dose reduction in 36 patients [14.1%], treatment interruption in 41 patients [16.1%], and discontinuation in 9 patients [3.5%]). Serious TRAEs were reported for 31 patients (12.2%), of which the most common were pleural effusion (9 patients [3.5%]) and peripheral edema (6 patients [2.4%]). Two patients (0.8%) had TRAEs that led to death: one patient with dyspnea, and one patient with dyspnea and acute respiratory failure. Information on TRAEs in patient subgroups and time to onset, resolution and management of key AEs will be presented.
N Any grade, n (%) Grade ≥3, n (%) TRAEs 255 220 (86.3) 64 (25.1) Peripheral edema 255 138 (54.1) 19 (7.5) Nausea 255 51 (20.0) 1 (0.4) Diarrhea 255 50 (19.6) 1 (0.4) Blood creatinine increased 255 45 (17.6) 1 (0.4) Hypoalbuminemia 255 37 (14.5) 6 (2.4) TRAE, Treatment-related adverse event.
Conclusion
In the largest prospective study of patients with NSCLC and METex14 skipping to date, tepotinib was generally well tolerated. Peripheral edema, which is a class effect of MET inhibitors, was generally mild or moderate and considered manageable with tepotinib dose reduction or treatment interruption. Proactive monitoring for edema is recommended, with potential consideration of early or prophylactic conservative management measures (e.g. support stockings, limb elevation and increased physical activity).
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MA11 - Expanding Targetable Genetic Alterations in NSCLC (ID 251)
- Event: WCLC 2020
- Type: Mini Oral
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/31/2021, 14:15 - 15:15, Scientific Program Auditorium
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MA11.05 - Tepotinib in Patients with MET exon 14 (METex14) Skipping Advanced NSCLC: Updated Efficacy Results from VISION Cohort A (ID 1361)
14:15 - 15:15 | Author(s): Rémi Veillon
- Abstract
Introduction
In the Phase II VISION study (NCT02864992), tepotinib demonstrated durable efficacy and a tolerable safety in patients with NSCLC harboring METex14 skipping. Here, we report updated efficacy outcomes from a preplanned data cut-off (July 1, 2020) in patients with at least 9 months of follow-up, including detailed subgroup analyses of treatment-naïve and previously treated patients.
Methods
Patients with advanced, EGFR/ALK wild-type, METex14 skipping NSCLC received oral tepotinib 500 mg once daily. Patients enrolled in Cohort A with ≥9 months of follow-up were assessed for efficacy. All patients with METex14 skipping NSCLC who received tepotinib in Cohort A, or confirmatory Cohort C, were assessed for safety. Primary endpoint was objective response rate (ORR) by independent review committee (IRC) using RECIST 1.1. Secondary endpoints included ORR by investigator assessment, duration of response (DOR), and safety.
Results
As of July 1, 2020, 146 patients had ≥9 months of follow-up and were assessed for efficacy; 255 patients were evaluated for safety. In the efficacy population, patients had a median age of 73.4 years (range 41 to 94), 76 were male (52.1%), 76 had a smoking history (52.1%), and 81 had received prior treatment for advanced/metastatic disease (55.5%). 72 patients had received prior platinum-based chemotherapy for metastatic disease, either alone (n=63) or in combination with immunotherapy (n=9).
The overall ORR by IRC was 45.2% (95% confidence interval [CI]: 37.0, 53.6), with a median DOR of 11.1 months (95% CI: 8.4, 18.5). ORR by investigator assessment was 54.1% (95% CI: 45.7, 62.4), with a median DOR of 12.7 months (95% CI: 9.7, 18.3).
ORR by IRC was similar in patients who were treatment-naïve (44.6%; 95% CI: 32.3, 57.5) or previously treated for advanced/metastatic disease (45.7%; 95% CI: 34.6, 57.1), and in those who received prior-platinum based chemotherapy for metastatic disease (50.0%; 95% CI: 38.0, 62.0). ORR was also comparable in patients who received immunotherapy, regardless of the treatment regimen used (figure).
Grade ≥3 treatment-related adverse events (TRAEs) were reported in 25.1% of patients; 27 (10.6%) discontinued due to TRAEs. Peripheral edema was mostly low grade and rarely led to discontinuation (3.5%). The safety profile was similar across subgroups.
Conclusion
In VISION, the largest study in patients with NSCLC harboring METex14 skipping, treatment with tepotinib showed durable clinical activity that was consistent across clinically relevant subgroups. Tepotinib demonstrated a safety profile consisting of mostly mild-to-moderate AEs with few treatment discontinuations.
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P84 - Targeted Therapy - Clinically Focused - ALK (ID 261)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P84.06 - Alectinib in ALK-Rearranged NSCLC Patients Following Crizotinib. Final Results and Biological Outcomes - Phase II ATALK Study (ID 3361)
00:00 - 00:00 | Author(s): Rémi Veillon
- Abstract
Introduction
Patients (pts) with advanced Anaplastic Lymphoma Kinase (ALK+) Non-Small Cell Lung Cancer (NSCLC) treated with crizotinib as first ALK inhibitor often develop acquired resistance during the 1st year of treatment. The ATALK study aimed at evaluating the efficacy and safety of alectinib, a 2nd generation ALK inhibitor, in selected pts with ALK-rearranged NSCLC, having progressed on prior treatment with crizotinib, without any supposed resistance mechanism to alectinib.
Methods
ATALK is an open-label, multicenter, single-arm, phase II study. Pts with ALK+ advanced or metastatic NSCLC progressing after crizotinib, whatever the line of treatment, received alectinib 600 mg twice daily until progressive disease (PD). Pts harbouring a mechanism suspected to confer resistance to alectinib (including selected ALK mutations, loss of ALK rearrangement, histological transformation) on a liquid or solid biopsy performed at inclusion were excluded. Pts were followed-up for 12 months.
The primary endpoint was the objective response rate (ORR) per investigator assessed from the Best Overall Response (BOR) using RECIST 1.1 within the 12 months following the first intake of alectinib.
Major secondary objectives were Progression-Free Survival (PFS), Overall Survival (OS), Disease Control Rate (DCR) and safety.
Results
Sixty four (64) pts were screened and 4 were excluded due to suspected resistance mechanisms to alectinib. A total of 44 pts were included (ITT/Safety population) and 39 pts had measurable disease at baseline (mITT population).
In the ITT population, 21 contributive fresh tumor tissue biopsies were obtained, all showed ALK rearrangement and absence of resistance mechanism to alectinib. Recruited pts were mostly men (57%), with a median age of 57 and an ECOG PS of 0-1 (89%)). Central nervous system (CNS) metastases were identified in 61% pts, of whom 16% had already been treated mainly with radiotherapy. All pts had ≥ 1 prior NSCLC therapy and 52% had received a 2nd therapy line; 11% had undergone ≥1 prior lung cancer surgery and 27 % ≥1 prior cancer radiotherapy.
In the mITT population, ORR was 51% (CI95%:34.8-67.6) and only 2 pts experienced a PD. The disease control rate was 94.9% (CI95%:82.7-99.4). In 11 pts with measurable CNS metastases at baseline, the CNS-ORR was 91% (CI95%:58.7-99.8).
In the ITT population, the median PFS was 14.4 months (9.2-NR). The OS rate at 12 months was 87.1% (71.6-94.4), median OS was not reached.
Efficacy outcomes regarding single nucleotide variants, ALK variants and ALK amplification are ongoing and will be presented later.
Grade ≥ 3 adverse events occurred in 34.1% pts, mainly respiratory disorders (13.6%) and cardiac disorders (6.8%). Death was reported in 11.4% pts, none was related to the treatment (pneumonia, stroke, general health deterioration, suffocation and ventricular dysfunction).
Conclusion
Alectinib efficacy and safety profile in this study align with known alectinib results in post-crizotinib setting. Identification of mechanisms of resistance emerging from exposure to previous ALK inhibitor was feasible and helped selecting subsequent treatment options.
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P85 - Targeted Therapy - Clinically Focused - MET (ID 262)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P85.01 - Activity of Tepotinib in Brain Metastases (BM): Preclinical and Clinical Data in MET Exon 14 (METex14) Skipping NSCLC (ID 1785)
00:00 - 00:00 | Author(s): Rémi Veillon
- Abstract
Introduction
Approximately 20% of METex14 skipping NSCLC cases involve brain lesions at diagnosis. Tepotinib is an oral, once-daily, highly selective MET inhibitor that has shown clinical activity in MET-driven tumors. We investigated the activity of tepotinib in preclinical models and patients with baseline BM in the Phase II VISION study.
Methods
Brain penetration was assessed in Wistar rats (n=3) at tepotinib dose 3.66 mg/kg/h intravenously by determining unbound brain (fu br) and plasma (fu pl) concentrations using liquid chromatography with tandem mass spectrometry.
Preclinical efficacy was assessed in two patient-derived xenografts (PDX) obtained from BM harboring high MET amplification (MET copy number gain: 11 for LU5349 and 24 for LU5406). NOD-SCID mice with PDX orthotopically implanted into the brain (n=10/group) were treated with tepotinib 125 mg/kg or vehicle control orally once daily. Intracranial tumor growth was monitored by gadolinium-based MRI.
Patients enrolled in VISION Cohort A with METex14 skipping NSCLC and asymptomatic BM (prior brain-specific therapy allowed) received tepotinib 500 mg once daily. Endpoints included systemic response per RECIST v1.1, duration of response (DOR), and progression-free survival (PFS) by independent review committee (IRC).
Results
The fraction of unbound tepotinib in rat brain tissue (fu br = 0.4%) was low compared with plasma (fu pl = 4%), indicating high binding in the brain. Upon treatment with tepotinib, both PDX tumors from MET-driven NSCLC BM regressed significantly in orthotopic brain models (mean tumor volume reduction of 63% for LU5406 and 84% for LU5349).
VISION Cohort A enrolled 22 patients with baseline BM (identified by IRC or investigator assessment), whose demographic characteristics were similar to the overall population (N=152).
As of July 1, 2020, 21 patients with baseline BM had ≥9 months’ follow-up and were included in efficacy analyses. Confirmed systemic best overall response was partial response in 11 patients for an ORR (95% confidence interval [CI]) of 52.4% (29.8, 74.3), which was comparable to that in overall population (table). Median DOR (95% CI) was 9.5 months (5.5, not estimable), and median PFS (95% CI) was 9.5 months (5.7, 11.2). Case studies illustrating response of brain lesions in VISION patients will also be presented.
Patients with baseline brain metastases (n=21) Overall (N=146)
Systemic objective response rate, % (95% CI)
52.4 (29.8, 74.3)
45.2 (37.0, 53.6)
Disease control rate, % (95% CI)
76.2 (52.8, 91.8)
69.9 (61.7, 77.2)
Best overall response, n (%) Complete response 0 0 Partial response 11 (52.4) 66 (45.2) Stable disease 5 (23.8) 36 (24.7)
Conclusion
Tepotinib administration resulted in regression of orthotopic BM in preclinical models. Patients in the VISION study with baseline BM had a comparable systemic response to that in the overall population. Tepotinib activity against BM will be further assessed by follow-up brain scans in the confirmatory VISION Cohort C.
