Background: In 2013, the French National Cancer Institute initiated the AcSé program to provide patients with secure access to targeted therapies outside of their marketed approvals. Efficacy and safety was then assessed using a two-stage Simon phase II trial design. When the study design was designed, crizotinib was approved only as monotherapy for adults with anaplastic lymphoma kinase plus non-small-cell lung cancers (NSCLC).Patients and methods: Advanced NSCLC patients with c-MET 6 copies, c-MET-mutated, or ROS-1-translocated tumours were enrolled in one of the three cohorts. Patients were treated with crizotinib 250 mg twice daily. Efficacy was assessed using the objective response rate (ORR) after two cycles of crizotinib as primary outcome. Secondary outcomes included disease control rate at four cycles, best ORR, progression-free survival, overall survival, and drug tolerance.Results: From August 2013 to March 2018, 5606 patients had their tumour tested for crizotinib targeted molecular alterations: 252 patients had c-MET 6 copies, 74 c-MET-mutation, and 78 ROS-1-translocated tumour. Finally, 25 patients in the c-MET 6 copies cohort, 28 in the c-MET-mutation cohort, and 37 in the ROS-1-translocation cohort were treated in the phase II trial. The ORR was 16% in the c-MET 6 copies cohort, 10.7% in the mutated, and 47.2% in the ROS-1 cohort. The best ORR during treatment was 32% in the c-MET-6 copies cohort, 36% in the c-MET-mutated, and 69.4% in the ROS-1-translocation cohort. Safety data were consistent with that previously reported.Conclusions: Crizotinib activity in patients with ROS1-translocated tumours was confirmed. In the c-MET-mutation and c-MET 6 copies cohorts, despite insufficient ORR after two cycles of crizotinib, there are signs of late response not sufficient to justify the development of crizotinib in this indication. The continued targeting of c-MET with innovative therapies appears justified.
Purpose: The limited knowledge on the molecular profile of patients with BRAF-mutant non-small cell lung cancer (NSCLC) who progress under BRAF-targeted therapies (BRAF-TT) has hampered the development of subsequent therapeutic strategies for these patients. Here, we evaluated the clinical utility of circulating tumor DNA (ctDNA)-targeted sequencing to identify canonical BRAF mutations and genomic alterations potentially related to resistance to BRAF-TT, in a large cohort of patients with BRAFmutant NSCLC.Experimental Design: This was a prospective study of 78 patients with advanced BRAF-mutant NSCLC, enrolled in 27 centers across France. Blood samples (n ¼ 208) were collected from BRAF-TT-naïve patients (n ¼ 47), patients nonprogressive under treatment (n ¼ 115), or patients at disease progression (PD) to BRAF-TT (24/46 on BRAF monotherapy and 22/46 on BRAF/ MEK combination therapy). ctDNA sequencing was performed using InVisionFirst-Lung. In silico structural modeling was used to predict the potential functional effect of the alterations found in ctDNA.Results: BRAF V600E ctDNA was detected in 74% of BRAF-TTnaïve patients, where alterations in genes related with the MAPK and PI3K pathways, signal transducers, and protein kinases were identified in 29% of the samples. ctDNA positivity at the first radiographic evaluation under treatment, as well as BRAF-mutant ctDNA positivity at PD were associated with poor survival. Potential drivers of resistance to either BRAF-TT monotherapy or BRAF/MEK combination were identified in 46% of patients and these included activating mutations in effectors of the MAPK and PI3K pathways, as well as alterations in U2AF1, IDH1, and CTNNB1.Conclusions: ctDNA sequencing is clinically relevant for the detection of BRAF-activating mutations and the identification of alterations potentially related to resistance to BRAF-TT in BRAFmutant NSCLC.
Missense mutations in the polymerase epsilon (POLE) gene have been reported to generate proofreading defects resulting in an ultramutated genome and sensitize tumors to checkpoint blockade immunotherapy. However, many POLE mutated tumors do not respond to such treatment. To better understand the link between POLE mutation variants and response to immunotherapy, we. prospectively assessed the efficacy of nivolumab in a multicenter clinical trial in patients bearing advanced mismatch repair proficient POLE-mutated solid tumors. We found that only tumors harboring selective POLE pathogenic mutations in the DNA binding or catalytic site of the exonuclease domain presented high mutational burden with specific single base substitution signature, high T-cell infiltrates, and high response rate to anti-PD1 monotherapy. This study illustrates how specific DNA repair defects can sensitize to immunotherapy, POLE proofreading deficiency representing a novel tumor agnostic biomarker for response to PD-1 checkpoint blockade therapy.
Background Ameloblastomas are uncommon locally aggressive tumors of odontogenic epithelium that rarely metastasize. Currently, there is no standard of care for the metastatic forms. Several studies have shown that ameloblastomas frequently have a BRAF mutation. Case presentation We report a case of a 33-year-old Caucasian woman with ameloblastoma diagnosed 30 years ago who developed lung metastasis 19 years ago. Systemic oral treatment with vemurafenib, a BRAF inhibitor, was initiated 28 months ago within the AcSé French basket clinical trial of vemurafenib. Conclusions The patient has shown a durable clinical, functional, and radiographic partial response with vemurafenib. These observations suggest the possibility of introducing neoadjuvant and/or adjuvant targeted therapy in locally advanced ameloblastoma to improve outcome. BRAF inhibition has proved to be an efficient strategy in patients with a BRAF-mutated ameloblastoma.
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