Search

Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) used in first line for the treatment of advanced EGFR-mutated non-small cell lung cancer (NSCLC).The identification of related histomolecular resistance mechanisms to first-line osimertinib is a critical step to define the optimal treatment strategy beyond progression.All consecutive patients treated in the first line with osimertinib for advanced EGFR-mutated NSCLC at 10 hospitals in the Greater Paris area between April 2015 and January 2021 were included. Histomolecular data from plasma and tissue samples taken at progression under osimertinib were collected, and all samples were analyzed using DNA next-generation sequencing. Data on objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and time to treatment discontinuation (TTD) were also collected.Overall, 104 patients were included. Most patients had adenocarcinoma (n = 102, 98%) with an exon 19 EGFR deletion (n = 54, 52%). Forty-two patients (50%) had central nervous system (CNS) metastasis at the time of osimertinib initiation. ORR was 76%, median PFS and OS were 12.6 months and 52 months, respectively, and TTD was 33 months. At the time of analysis, 44 patients (42%) had tumor progression, and among these patients, 27 (61%) contributive samples were available. The most frequent molecular alterations at progression were mesenchymal epithelial transition factor (MET) amplification (15%; n = 4) and EGFR C797S mutation (11%; n = 3). Histological transformation was found in one patient (4%). RNA next-generation sequencing was performed in eight patients and showed a CCDC6-RET fusion in one patient (12%).We confirmed the efficacy of osimertinib in patients with advanced EGFR mutation-positive NSCLC. At progression, the most frequent histomolecular alterations were MET amplification and EGFR C797S mutation.

Simple Summary EGFR exon 20 insertions are rare genetic alterations in non-small-cell lung cancers (NSCLCs) that are usually unresponsive to approved EGFR tyrosine kinase inhibitors (TKIs), but data is limited about this population. We aim to describe clinical features, survival, and response to chemotherapy and TKIs in this patient population. Abstract EGFR exon 20 insertions are rare genetic alterations in non-small-cell lung cancers (NSCLCs) that are usually unresponsive to approved EGFR tyrosine kinase inhibitors (TKIs). In this paper, we describe the clinical characteristics, efficacy of EFGR TKIs and chemotherapy, and resulting survival in this population. We retrospectively collected patients with EGFR exon 20 insertions (Exon20ins) from 11 French genetic platforms and paired them (1:2 ratio) with classic Exon 19/21 EGFR mutation patients (controls). Between 2012 and 2017, 35 Exon20ins patients were included. These patients were younger at diagnosis than the controls. All Exon20ins patients who were treated with first-line EGFR TKIs (n = 6) showed progressive disease as the best tumor response. There was no significant difference in the tumor response or the disease control rate with first-line platinum-based chemotherapy between the two groups. A trend towards shorter overall survival was observed in Exon20ins vs. controls (17 months (14—not reach(NR) 95% confidence interval(CI) vs. 29 months (17–NR 95%CI), p = 0.09), respectively. A significant heterogeneity in amino acid insertion in EGFR exon 20 was observed. EGFR exon 20 insertions are heterogeneous molecular alterations in NSCLC that are resistant to classic EGFR TKIs, which contraindicates their use as a first-line treatment.

International audience; Objectives: The understanding of histo-molecular mechanisms associated with resistance to osimertinib is a critical step to define the optimal treatment strategy in advanced EGFR-mutated Non-Small-Cell-Lung-Cancer (NSCLC).Materials and methods: We performed a multicentric retrospective analysis on a cohort of consecutive patients treated with osimertinib for an advanced EGFR-mutated NSCLC and collected histo-molecular data from plasma and tumor samples at the time of progression. Next-generation sequencing (NGS) was performed for all samples. Best Overall Response Rate (ORR), Progression Free Survival (PFS), Overall Survival (OS) and data on treatment post-progression efficacy were also collected.Results: Two-hundred and twenty-six patients were included from 9 Academic French Hospitals between April 2015-October 2018. Osimertinib was given in second-line or more in 219 patients (97%). Best ORR was 52% and best central nervous system ORR was 56%. Median PFS and OS were 9.5 months (IQR 4.0-17.2) and 24 months (IQR 12.4-NR) respectively. At the time of analysis, 150 patients (66%) had tumor progression. Among them, 73 contributive samples (56 tumor biopsies) were available. The most frequent molecular alterations were C797S mutation (n = 9 (13%)) and MET amplification (n = 8 (11%)). Histologic transformation occurred in 5 patients (9% of tumor biopsies). In T790M + NSCLC, loss of T790 M occurred in 68% of cases. Median PFS and OS with treatment beyond progression were 6.0 months (IQR 2.0-10.4) and 15.1 months (IQR 6.7-NR) respectively and longer in case of osimertinib continuation beyond progression.Conclusion: We confirmed the efficacy of osimertinib in patients with advanced EGFR mutation positive NSCLC. At progression, the most frequent molecular alterations were MET amplification and C797S mutation.

About 2-3% of non-small-cell lung cancers (NSCLCs) harbor MET exon-14-skipping (METex14) mutations. Efficacy of the MET-inhibitor crizotinib has been reported, but progression-free survival (PFS) was very short. Immune-checkpoint inhibitors (ICIs) have become a cornerstone of NSCLC treatment but appear to be less effective in non-smokers and against tumors exhibiting oncogenic addiction. We describe 6 remarkable (PFS exceeding 18 months) and durable responses to ICIs of NSCLCs harboring a METex14 mutation.Each patient's clinical and biological characteristics, and tumor responses after ICIs were examined. Complete tumor-DNA sequencing was available after starting second-line ICIs, which followed first-line chemotherapy. Tumor-cell programmed cell-death protein-1 ligand-1 (PD-L1) expression on tumor cells was evaluated using antibody clone E1L3N (Cell Signaling Technology).Among 25 patients with METex14-mutated NSCLCs, 13 of whom were ICI-treated, 6 had prolonged responses: 5 women, 1 man; 57-80 years old; 3 never-smokers, 1 ex-smoker and 2 smokers; 5 adenocarcinomas, 1 sarcomatoid carcinoma; 5 received nivolumab, 1 pembrolizumab. No EGFR, BRAF or KRAS mutations (only 1 minority KRAS mutation), or ALK or ROS translocations were detected. No concurrent MET amplification was observed. Tumor-mutation burden was low (10 mutations/Mb) in 3 tested tumors. Four partial and 2 complete responses were obtained during the first 3 months for 5 patients, while pseudoprogression was initially observed in 1. Tolerance was excellent, with only 1 grade-3 immune-related adverse event. Response was maintained for 18-49 months.ICIs could be considered to treat patients whose NSCLCs harbor a METex14 mutation. More biological marker data are needed to identify which patients are most likely to benefit from ICIs.

CERVOXY CLIN; International audience; IntroductionMET proto-oncogene (MET) exon 14 splice site (METex14) mutations were recently described in NSCLC and has been reported to correlate with efficacy of MET tyrosine kinase inhibitors. High diversity of these alterations makes them hard to detect by DNA sequencing in clinical practice. Because METex14 mutations induce increased stabilization of the MET receptor, it is anticipated that these mutations are associated with MET overexpression. We aim to determine whether NSCLC with high MET overexpression could define a subset of patients with a high rate of METex14 mutations.MethodsFrom The French Cooperative Thoracic Intergroup PREDICT.amm cohort of 843 consecutive patients with a treatment-naive advanced NSCLC who were eligible for a first-line therapy, 108 NSCLC samples with high MET overexpression defined by an immunochemistry score 3+ were tested for METex14 mutations using fragment length analysis combined with optimized targeted next-generation sequencing. MET copy number analysis was also derived from the sequencing data.ResultsMETex14 mutations were detected in two patients (2.2%) who also displayed a TP53 mutation and a PIK3CA mutation, respectively. An MET gene copy number increase was observed in seven additional patients (7.7%). Next-generation sequencing analysis revealed inactivating mutations in TP53 (52.7%) and PTEN (1.1%), and oncogenic mutations in KRAS (28.6%), EGFR (7.7%), PIK3CA (4.4%), BRAF (4.4%), NRAS (2.2%), GNAS (1.1%), and IDH1 (1.1%).ConclusionsThe rate of METex14 mutations in NSCLC with high MET overexpression was similar to that found in unselected NSCLC. Moreover, we observed a high frequency of driver alterations in other oncogenes. Consequently these findings do not support the use of MET immunohistochemistry as a surrogate marker for METex14 mutations.

9019 Background: The gut microbiome, most specifically centered on one of the most prevalent anaerobic bacterium Akkermansia muciniphila (Akk), has emerged as a potential hallmark of clinical benefit to ICI. The goal of this study was to validate the prognostic significance of Akk in advanced NSCLC patients amenable to ICI. Methods: The multicentric prospective observational study enrolled patients with advanced NSCLC amenable to single agent ICI in first and second line. Stool sample was collected at study entry. Primary end-point was investigator-assessed objective response rate (ORR). We considered that a meaningful clinical difference would correlate to a 10% ORR increase in the Akk-Pos group compared to the Akk-Neg group. At least 292 patients equally divided each in each group would be required for a power at 80% and a two-sided alpha level of 5%. Results: From Dec 2015 to Nov 2019, a total of 409 patients were screened and 311 patients enrolled across 12 academic centers in France and Canada. Median age was 64yr, 32% were female, 77% had non-squamous NSCLC and PD-L1 was ≥1% in 70% of the 213 assessable samples. Akk was detectable in 158 (51%) and absent in 153 (49%) patients. Baseline characteristics were well balanced between the two groups. When considering Akk-Pos vs Akk-Neg groups the primary endpoint ORR was 27% and 17% respectively ( p = 0.04). Rates of partial response, stable disease and progressive disease (PD) were 62%, 50% and 46% respectively in the Akk-Pos group compared to 38%, 50% and 54% in the Akk-Neg group ( p = 0.04). Moreover, 57% of patients were still alive after 12 months in the Akk-Pos group vs 43% in the Akk-Neg group ( p = 0.04). Microbiome profiling demonstrated that Akk-Pos group was associated with increase bacterial diversity and enrichment of Ruminococcus, Alistipes and Eubacterium. When considering the variations of the relative abundance of Akk within the Akk-Pos group, we obtained a large interval ranging from 0.0022% up to 64.78% with a 75th percentile at 4.42%. The relative abundance of Akk within > 0% to < 4.42% range in stools at diagnosis was associated with increased ORR, overall survival (OS) in multivariate analysis, independent of PD-L1 expression and ECOG. This sub-group was associated with more inflamed tumors with upregulation of CD3e, IfngTH1 and Vcam-1. Conversely, patients with overrepresentation of Akk > 4.42% experienced more PD and shorter OS. Antibiotic use was associated with a shift in favor of Gammaproteobacteria, enrichment of Akk ( > 4.42%) and shorter OS. Conclusions: We validated the prognostic role of Akk in patients with NSCLC. Stratification based on Akk relative abundance represents a more accurate independent predictor than the binary modality. Our study provides the rationale to develop microbiome-based approach to study gut dysbiosis in routine clinical oncology care. Clinical trial information: NCT04567446.

International audience; Introduction: Immune checkpoint inhibitors (ICIs) have revolutionised cancer care especially in lung cancer. New response patterns have been described under ICIs such as pseudo-progression or hyper-progressive disease (HPD). The definition of HPD is yet to be consensual. The aim of this study was to suggest a clinical definition of nivolumab-refractory patients and find factors associated with this entity.Methods: We performed a multi centric retrospective study including all patients who received nivolumab for the treatment of advanced non-small cell lung cancer (NSCLC) during the French authorisation for temporary use in 2015.Results: 303 patients were included in the cohort and 292 had details on the number of nivolumab injections received. 57 patients (20%) were nivolumab-refractory. These patients had worse PS at nivolumab initiation (p

We report here the first cases, to our knowledge, of pulmonary arterial hypertension induced by lorlatinib. It s the first time that a tyrosine kinase inhibitor for lung cancer is associated with pulmonary arteriel hypertension.

Introduction Solid organ transplant patients are at heightened risk of several cancers compared to the general population. Secondary to a higher number of procedures and better survival after transplantation, cancer is a rising health concern in this situation. Limited data exist for lung cancer (LC) after renal transplantation. We report here the most important series of renal transplant recipients with lung cancer. Methods Retrospective study of all cases of LC diagnosed in three French Renal Transplant Units from 2003 to 2012. A control group consisted of non-transplant patients with LC matched with the cases for age ( 65 years), gender and diagnosis date. We recruited two controls for each case. Results Thirty patients (median age 60 years; range 29–85; male/female ratio 80/20%) with LC were analysed. LC incidence was 1.89/1000 person-years over the period 2008–2012. All patients were former or active smokers (median 30 pack-years). Transplanted patients had significantly more comorbidities, mainly cardiovascular disease. The median interval of time from kidney transplantation (KT) to diagnosis of LC was 7 years (range 0.5–47 years). LC was incidentally diagnosed in 40%. Most patients (70%) had advanced LC (stage III or IV) disease. Stage of LC at diagnosis was similar in cases and controls. Surgery and chemotherapy were proposed to the same proportion of patients. In cases, mortality was cancer related in 87% and median survival time after diagnosis was 24 months. Survival was not significantly different between the 2 groups. Conclusion Despite frequent medical and radiological examinations, diagnosis of LC is usually made at an advanced stage and the overall prognosis remains poor.

The improved survival of patients since the use of highly active antiretroviral treatments has lead to the reporting of non-AIDS defining tumors, such as lung cancer.Analysis of the records of 22 HIV-infected patients with lung cancer (LC) diagnosed in three hospitals located in the Paris area (France).Twenty-one patients were smokers. The patients (86% male, 14% female) had a median age of 45 yr (range, 33-64 yr). Risk factors for HIV infection were intravenous drug use in 5 patients, homosexual transmission in 10 patients, and heterosexual transmission in 7 patients. At diagnosis of LC, seven patients had previously developed a CDC-defined AIDS manifestation, the median CD4 cell count was 364/mm3 (range 20-854/mm3) and median HIV1 RNA viral load was 3000 copies/mL. The most frequent histological subtype was squamous cell carcinoma (11 cases). A stage III-IV disease was observed in 75% of the patients. Only one patient had a small-cell lung carcinoma. Twenty-one patients received combined specific therapy, of which six patients underwent surgery for the LC. The median overall survival was 7 mo. No opportunistic infections occurred during LC therapy.LC occurs at a young age in HIV-infected smokers. LC is not associated with severe immunodeficiency. The prognosis is poor because of their initial extensive disease and a poor response to therapy. However, surgery appears to improve outcome in much the same way as in the general population.

e20543 Background: Nivolumab (NIV) is now widely used in ≥ 2ndline of advanced non-small cell lung cancer (NSCLC). The aims of this real-life study were (1) to evaluate its efficacy, (2) to identify predictive factors of worsening under NIV. Methods: This retrospective multicentric study (8 Thoracic Oncology regional centers) included all patients treated by NIV in 2015 (follow-up until 2016, June 30th). Demographics and tumor characteristics were extracted. Objective tumor response was assessed by computerized tomography (RECIST v1.1). Median NIV treatment duration and overall survival (OS) were calculated. Clinical and biological factors evaluated as predictive markers of earlyprogression (discontinuation before 1stevaluation) were: NSCLC histology, PS, smoking-history, number of previous chemotherapy received and initial albumine (alb), C-reactive protein (CRP) and lactate dehydrogenase (LDH) serum levels. For these factors, patients quickly worsened and responders were compared (Student’s t-test, Chi-2 test). Results: Our cohort included 297 patients (non-squamous NSCLC n = 181 [61%]; PS > 1 n = 66 [22%]). At first evaluation, partial response was observed in 16% (n = 47), stable disease in 18% (n = 54) and progression in 49% (n = 144). A total of 45 patients (15%) were early progressors and no evaluation could be performed. Median NIV duration of treatment was 2.8 months [0-15], OS 6.9 months [0-16] (n = 146 still alive on June 30th, 2016). Early progressor patients were PS > 1 in 42% versus (vs) 21% for responders (mean PS 1.7 vs 1.0 for responders (p < 0.001)) and an alb level of 29.9 g/L vs 33.6 (p = 0.03). Mean CRP (p = 0.06) and LDH (p = 0.08) serum levels, NSCLC histology (p = 0.64), smoking-history (p = 0.08), number of previous chemotherapy (p = 0.90) were non-significant. Conclusions: This study confirms that NIV may be effective in NSCLC, with a 16% objective response rate. However early progression observed in 15% of patients was associated with a lower initial alb level and a higher PS. Missing data for LDH and CRP levels may have influenced their non-significance. Further studies must be realized to determine the interest of these factors as predictive markers.

7511^ Background: Cisplatin-based chemotherapy and concurrent radiotherapy, the standard treatments for locally advanced unresectable NSCLC have reach a plateau. New therapeutic combinations of molecular targeted drugs are needed. IFCT-0803 phase II trial aimed to evaluate the benefit of adding cetuximab to a combination of radio and concomitant chemotherapy with cisplatin and pemetrexed in patients with stage III, non-squamous NSCLC. Methods: Based on a 2-stage Simon approach, a total of 106 patients were to accrue. An interim analysis of the first 34 patients authorized the continuation of the study. Eligible patients receive thoracic radiation (66 Gy) along with cisplatin (75 mg/m²) and pemetrexed (500 mg/m²) on D1 administered every 21 days for four cycles; weekly cetuximab (400 mg/m²) for the first week, then 250 mg/m²) is added from the first week of therapy for a total of 12 doses. The primary objective is to assess the disease control rate at the 16th week (16W-DCR), one month after the treatment ...

TPS7112 Background: MPM median OS does not exceed 13 months with pem/CDDP doublet. U.S. Intergroup phase II trial of gemcitabine/CDDP, with or without bevacizumab, gave an appealing 15.6 months median OS in the bevacizumab arm. French Intergroup aimed to test pem/CDDP with bevacizumab (PCB), in a randomized phase III trial. Methods: Eligible patients had unresectable histologically proved MPM, no prior chemo, PS 0-2, no thrombosis, nor bleeding. Primary endpoint: The primary outcome will be survival. The secondary endpoint will be Progression-Free Survival. Patients received pem 500 mg/m2, CDDP 75 mg/m2 (PC),at D1, and vitamin B12 +B9 substitution, with (arm B) or without bevacizumab (arm A), 15 mg/kg Q21D, for 6 cycles. Arm B nonprogressive patients received bevacizumab maintenance therapy until progression or toxicity. 445 patients to be recruited during a period 48 months, with at least 24 months of follow-up, and 385 events (deaths), will be needed to assure a power of 80% and detect at least a 4.3 months of median survival increase. This hypothesis leads to a Hazard Ratio (HR) of 1.33 and a 3-years survival of 14.7% in control arm and 23.6 % in experimental arm, with an absolute difference of 8.9% in survival rates. Accrual status: The first patient was included in February 2008. On January 31, 2012, 257 patients from 85 French centers had been enrolled. The end of accrual can be expected for September 2013. Ancillary studies: For molecular biomarker analyses, thoracoscopic tissue specimens (TS, ERCC1, MSH2, TUBB3, NF2, p16, RASSF1A methylation,15 microRNAs ) and blood samples (micro-RNAS, VEGF, osteopontin, SRMP) at diagnosis are centrally collected. Finally, a prospective study comparing PET-CT to standard CT with central blinded analysis, is currently on-going for evaluation of response, and accuracy of modified RECIST criteria for mesothelioma.

7521 Background: First-line EGFR-TKI in advanced BAC yielded a 2.9 to 4-month PFS in Phase II trials. We have suggested that EGFR-TKI had a reduced activity in M-BAC but that C/P and pemetrexed cou...