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F. Barlesi
Author of
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MA04 - HER2, P53, KRAS and Other Targets in Advanced NSCLC (ID 380)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
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MA04.02 - Neratinib ± Temsirolimus in HER2-Mutant Lung Cancers: An International, Randomized Phase II Study (ID 4302)
16:06 - 16:12 | Author(s): F. Barlesi
- Abstract
- Presentation
Background:
Combined inhibition of HER2 and mTOR is synergistic in models of HER2 (or ERBB2)-mutant lung cancers. PUMA-NER-4201 is an adaptive, multinational, randomized phase II study comparing the pan-HER inhibitor neratinib (Puma Biotechnology) ± the mTOR inhibitor temsirolimus in patients with advanced HER2-mutant lung cancers. In stage 1 of the study, neratinib + temsirolimus met predefined criteria for expansion into stage 2 [Besse et al. ESMO 2014].
Methods:
Patients with stage IIIB/IV locally determined HER2-mutant cancers were randomized to receive oral neratinib 240 mg once daily ± intravenous temsirolimus 8 mg once weekly (escalated to 15 mg/week after a 3-week cycle if tolerated) with loperamide prophylaxis. Primary endpoint: overall response rate (RECIST v1.1). Secondary endpoints: duration of response, progression‑free survival, overall survival, toxicity assessments (NCI-CTCAE, v4.0). ClinicalTrials.gov: NCT01827267.
Results:
Of 62 randomized patients, 60 received ≥1 dose of neratinib: neratinib alone (n=17); neratinib + temsirolimus (n=43). Baseline characteristics: male/female 32%/68%; median age 66 years; never smokers 60%; adenocarcinoma 98%. HER2 (or ERBB2) mutation type: exon 20 insertions 93.5%; missense substitutions 3.2%; unspecified 3.2%. The most common HER2 allelic variant was A775_G776insYVMA. Exploratory biomarker analysis from available tumor and plasma samples will be presented at the meeting. Efficacy and safety results are shown in the table. With loperamide prophylaxis, the incidence of grade 3 diarrhea was 12% with neratinib and 14% with neratinib + temsirolimus, which lasted for a median duration of 1.5 (interquartile range, 1.0‒2.0) days and 4.0 (interquartile range, 2.0‒16.0) days, respectively. Figure 1
Conclusion:
Neratinib (240 mg/day) + temsirolimus (8 or 15 mg/week) produced responses lasting 2 to 18+ months in 19% of patients with HER2‑mutant lung cancers. Correlative data will be presented at the meeting. Diarrhea was manageable with loperamide prophylaxis.
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P3.02a - Poster Session with Presenters Present (ID 470)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02a-034 - Vemurafenib in Patients with Non-Small Cell Lung Cancer (NSCLC) Harboring BRAF Mutation. Preliminary Results of the AcSé Trial (ID 4924)
14:30 - 14:30 | Author(s): F. Barlesi
- Abstract
Background:
BRAF is found mutated in 2-3% of stage IV NSCLC. BRAF inhibitors have been reported to have antitumor activity. A nationwide access to vemurafenib for cancer patients with tumors presenting with BRAF mutations was launched by the French National Cancer Institute (INCa) providing free access to tumor molecular diagnosis. The AcSé-Vemurafenib study is the 2[nd] exploratory multi-tumor 2-stage design phase II trial of AcSé program. We report the preliminary results of the NSCLC cohort in this nationwide program.
Methods:
BRAF mutational status was assessed on INCa molecular genetic platforms by either direct sequencing or NGS. Patients with BRAF mutation (including BRAF V600E and others less common mutations), progressing after at least one standard treatment (including a platinum-based doublet, unless pts were considered as unfit for chemotherapy) were proposed to receive vemurafenib 960 mg BID. Responses were centrally assessed using RECIST v1.1 every 8 weeks.
Results:
From Oct. 13, 2014 to June 15, 2016, 65 patients were enrolled including 55 NSCLC harboring BRAF V600E and 10 pts with other activating mutations (2 G466, 3 G469, 1 G596, 3 K601 and 1 N581). 55 patients received vemurafenib and had at least one post-baseline assessment. Median age: 67 years (range 40–84), 51% females and 100% non-squamous histology. Median number of prior chemotherapy lines: 1 (0 –5). Most frequent grade ≥3 adverse events (AEs) were skin (18% of patients) and gastrointestinal toxicities (16%). Among the 39 BRAF V600E NSCLC patients evaluable for the best overall response (BOR) with a minimum follow-up of 4 months, 15 PR, 8 SD, 10 PD, 5 deaths before assessment and 1 missing were observed. The objective response rate was 38.5% [95% CI:23.4-55.4], and the disease control rate 59% [42.1-74.4]. Median duration of response was 5.1 months [1.8-9.2]. Progression-free survival (PFS) at 4 months was 48.2% [31.8-62.8]. No response was reported among the 7 evaluable patients with other BRAF mutations with 5 PD, 1 death before assessment and 1 missing as BOR ; PFS at 4 months was 14.3% [0.7-46.5]. 18 patients were still on treatment at the cut-off date, 47 have stopped vemurafenib (25 PD, 15 AEs, 1 death, 1 doctor’s decision, 5 patient’s decisions).
Conclusion:
Vemurafenib provided response rate and DCR in BRAF V600E pretreated NSCLC but was not found efficient in NSCLC with other BRAF mutations. These results underline the interest of integrating BRAF V600E in biomarkers routine screening.
