Histomolecular Resistance Mechanisms to First-Line Osimertinib in EGFR-Mutated Advanced Non-Small Cell Lung Cancer: A Multicentric Retrospective French Study.

BACKGROUND: 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). OBJECTIVE: The identification of related histomolecular resistance mechanisms to first-line osimertinib is a critical step to define the optimal treatment strategy beyond progression. PATIENTS AND METHODS: 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. RESULTS: 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%). CONCLUSIONS: 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.

Gene expression profile of high PD-L1 non-small cell lung cancers refractory to pembrolizumab.

BACKGROUND: Despite high expression of PD-L1, around half of advanced non-small cell lung cancer (NSCLC) will not experience tumor response with pembrolizumab. There is an need for a better understanding of the resistance mechanisms in this setting. METHODS: This bi-centric retrospective study included all consecutive patients with PDL1 ≥ 50% advanced NSCLC treated with pembrolizumab in first-line treatment between 2016 and 2020. We compared the clinical characteristics of patients with early progression (refractory) vs others. We performed a comprehensive gene expression profile screening by RNAseq capture on tumor samples. RESULTS: We included 46 patients. Twenty-two patients were refractory to pembrolizumab, mainly women, with poor performance status and lower albumin concentration. RNAseq analysis was performed on 19 samples. Hierarchical clustering allowed the identification of 3 clusters with various proportion of refractory tumors: intermediate (C1: 57%), high (C2: 71%) and low proportion (C3: 40%). Comparative analysis between C2 and C3 allowed the identification of overexpressed (n = 137) and underexpressed (n = 40) genes. Among the genes of interest, C2 exhibits higher activation of pathways associated with stemness phenotype (Hedgehog, Notch and Hippo pathways) and pathways associated with loss of PTEN and JAK2. In C2, genes associated with PD-1, toll-like receptor-9 (TLR-9), major histocompatibility complex (MHC) and interferon-γ pathways were underexpressed. CONCLUSION: This study gives an overview of activated and downregulated pathways in high PD-L1 NSCLC refractory to pembrolizumab. These tumors showed activation of pathways associated with cancer stem cells, loss of PTEN and JAK2, and inhibition of both priming and effector phases of the immune response.

Resistance mechanisms to osimertinib in EGFR-mutated advanced non-small-cell lung cancer: A multicentric retrospective French study.

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.

Evidence of slight improvement in five-year survival in non-small-cell lung cancer over the last 10 years: Results of the French KBP-CPHG real-world studies.

BACKGROUND: Although improved during the last decades, the prognosis of lung cancer is poor. In 2000, the French College of general hospital respiratory physicians, conducted KBP-2000-CPHG, a prospective multicenter epidemiological study including all volunteer adult patients diagnosed for primary lung cancer; with the five-year survival as primary endpoint. The primary objective of KBP-2010-CPHG was to compare overall five-year survival data with KBP-2000-CPHG ones. MATERIAL AND METHODS: All consecutive patients≥18 years of age with primary lung cancer diagnosed between 1st January and 31st December 2010 were included. The KBP-2010-CPHG protocol was approved by the advisory committee on research information processing in the health field (CCTIRS) on November 19, 2009. RESULTS: Respectively, 5667 and 7051 patients were included in KBP-2000-CPHG and KBP-2010-CPHG. Five-year survival was improved: 12.7% [11.9%-13.5%] in 2010 versus 10.0% [9.2%-10.9%] in 2000 (P<0.001). Non-small-cell lung cancer showed improvement (13.8% [13.0%-14.8%] in 2010 versus 11.4% [10.5%-12.4%] in 2000; P<0.001); but not small-cell lung cancer (5.7% [4.4%-7.4%] in 2010 versus 3.3% [2.3%-4.7%] in 2000; P=0.56). The KBP-2010-CPHG study showed an overall 6% reduction in risk of death (HR=0.94 [0.89-0.98]; P=0.004). CONCLUSIONS: Survival of patients with lung cancer improved over a 10-year period. This improvement was slight and limited to non-small-cell lung cancer, possibly partly because of 2010 advances in diagnosis and targeted therapy.

Haematological immune-related adverse events induced by anti-PD-1 or anti-PD-L1 immunotherapy: a descriptive observational study.

BACKGROUND: Anti-programmed cell death 1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) antibodies are novel immunotherapies for cancer that can induce immune-related adverse events (irAEs). These adverse events can involve all organs, including the haemopoietic system. Thus far, haematological irAEs (haem-irAEs) have not been extensively characterised. This study aims to provide a comprehensive report of the haem-irAEs induced by anti-PD-1 or anti-PD-L1. METHODS: In this descriptive observational study, we included consecutive patients aged at least 18 years with grade 2 or worse haem-irAEs induced by anti-PD-1 or anti-PD-L1 immunotherapy registered in three French pharmacovigilance databases: the Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC; a prospective registry of patients treated with anti-PD-1 or anti-PD-L1 at a single centre), the ImmunoTOX committee of Gustave Roussy (a national referral database of suspected irAEs in patients treated with immunotherapy), and the registry of the Centre de Référence des Cytopénies Auto-Immunes de l'Adulte (CeReCAI; a national database of autoimmune cytopenias). Cases were reviewed by a central committee; adverse events had to be classed as certainly or probably related to anti-PD-1 or anti-PD-L1 therapy, and their severity was assessed according to the Common Terminology Criteria for Adverse Events (version 4.03). The primary endpoint was clinical description of haem-irAEs, as reported in all databases, and their frequency, as reported in the prospective REISAMIC registry. FINDINGS: We screened 948 patients registered in the three databases from June 27, 2014, to June 29, 2018 (745 from REISAMIC, 190 from the ImmunoTOX committee, and 13 from CeReCAI). 35 patients (21 men and 14 women) with haem-irAEs related to anti-PD-1 or anti-PD-L1 were included in the study. Of 745 patients in the REISAMIC registry treated with anti-PD-1 or anti-PD-L1, four had haem-irAEs, giving a frequency of 0·5%. Median age in the 35 patients was 65 years (IQR 51-75), and the most common tumour types were melanoma (15 [43%] patients), non-small-cell lung cancer (12 [34%] patients), and lymphoma (four [11%] patients). 20 (57%) patients received nivolumab, 14 (40%) received pembrolizumab, and one (3%) received atezolizumab. Among the 35 patients, neutropenia, autoimmune haemolytic anaemia, and immune thrombocytopenia were the most common types of haem-irAE (each in nine patients [26%]), followed by pancytopenia or aplastic anaemia (five patients [14%]), bicytopenia (one patients with thrombocytopenia plus anaemia and one patient with neutropenia plus anaemia [6%]), and pure red cell aplasia (one patient [3%]). The maximum grade of severity was grade 2 in three (9%) patients, grade 3 in five (14%) patients, and grade 4 in 25 (71%) patients; two (6%) patients died from febrile neutropenia during haem-irAE related to anti-PD-1. Haem-irAEs resolved in 21 (60%) of the 35 patients. INTERPRETATION: Haem-irAEs induced by PD-1 or PD-L1 inhibitors are rare but potentially life-threatening events. The most common clinical presentations are neutropenia, autoimmune haemolytic anaemia, immune thrombocytopenia, and aplastic anaemia. Investigations into earlier detection and better management are warranted. FUNDING: Gustave Roussy and Gustave Roussy Immunotherapy Program.

Prognostic role of a comprehensive geriatric assessment on the management of elderly patients with advanced non-small cell lung cancer (NSCLC): a pooled analysis of two prospective phase II trials by the GFPC Group.

BACKGROUND: The prognostic role of a comprehensive geriatric assessment (CGA) on the management of elderly patients with advanced-stage non-small cell lung cancer (NSCLC) remains to be established. The objective of this analysis was to determine the prognostic role of each CGA domain on overall survival (OS) among elderly patients with advanced-stage NSCLC. METHODS: We pooled individual data from two prospective, randomized phases II trials in patients over 65 years old with advanced-stage NSCLC, who were considered fit (0405 trial) or no-fit (0505 trial) based on a CGA. Both trials compared first-line chemotherapy followed by second-line erlotinib with the reverse strategy in terms of progression-free survival (PFS) and OS. Factors prognostic of OS were sought by using the Kaplan-Meier method and the log rank test for univariate analysis, and a Cox model for multivariate analysis. RESULTS: Analysis performed on 194 patients (mean age: 77 years, male gender: 70%, never- or ex-smokers: 56%) showed, in univariate analysis that performance status (PS), smoking status, Charlson, simplified Charlson, nutritional scores, and a mobility score were prognostics of OS. In multivariate analysis, PS [HR: 1.4 (1.02-1.9), P=0.04] and the Charlson score [HR: 1.46 (1.07-1.99), P=0.02] were independently prognostic of OS, while the nutritional score [HR: 0.69 (0.46-1.04), P=0.07] and the mobility score [HR: 0.25 (0.06-1.01), P=0.06] were close to significance. CONCLUSIONS: PS and comorbidities appear to be the main predictors of OS in elderly advanced NSCLC patients selected on the basis of CGA.

Use of a Comprehensive Geriatric Assessment for the Management of Elderly Patients With Advanced Non-Small-Cell Lung Cancer: The Phase III Randomized ESOGIA-GFPC-GECP 08-02 Study.

PURPOSE: Comprehensive geriatric assessment (CGA) is recommended to assess the vulnerability of elderly patients, but its integration in cancer treatment decision making has never been prospectively evaluated. Here, in elderly patients with advanced non-small-cell lung cancer (NSCLC), we compared a standard strategy of chemotherapy allocation on the basis of performance status (PS) and age with an experimental strategy on the basis of CGA. PATIENTS AND METHODS: In a multicenter, open-label, phase III trial, elderly patients ≥ 70 years old with a PS of 0 to 2 and stage IV NSCLC were randomly assigned between chemotherapy allocation on the basis of PS and age (standard arm: carboplatin-based doublet if PS ≤ 1 and age ≤ 75 years; docetaxel if PS = 2 or age > 75 years) and treatment allocation on the basis of CGA (CGA arm: carboplatin-based doublet for fit patients, docetaxel for vulnerable patients, and best supportive care for frail patients). The primary end point was treatment failure free survival (TFFS). Secondary end points were overall survival (OS), progression-free survival, tolerability, and quality of life. RESULTS: Four hundred ninety-four patients were randomly assigned (standard arm, n = 251; CGA arm, n = 243). Median age was 77 years. In the standard and CGA arms, 35.1% and 45.7% of patients received a carboplatin-based doublet, 64.9% and 31.3% received docetaxel, and 0% and 23.0% received best supportive care, respectively. In the standard and CGA arms, median TFFS times were 3.2 and 3.1 months, respectively (hazard ratio, 0.91; 95% CI, 0.76 to 1.1), and median OS times were 6.4 and 6.1 months, respectively (hazard ratio, 0.92; 95% CI, 0.79 to 1.1). Patients in the CGA arm, compared with standard arm patients, experienced significantly less all grade toxicity (85.6% v 93.4%, respectively P = .015) and fewer treatment failures as a result of toxicity (4.8% v 11.8%, respectively; P = .007). CONCLUSION: In elderly patients with advanced NSCLC, treatment allocation on the basis of CGA failed to improve the TFFS or OS but slightly reduced treatment toxicity.

Feasibility and clinical impact of re-biopsy in advanced non small-cell lung cancer: a prospective multicenter study in a real-world setting (GFPC study 12-01).

OBJECTIVES: When advanced non-small-cell lung cancer (NSCLC) progresses during first-line treatment, re-biopsy may be indicated to detect a possible new biological profile (comparison to initial status, emergence of resistance biomarkers, or assessment of new biomarkers). The aim of this pragmatic prospective multicenter study was to assess the feasibility and clinical utility of re-biopsy in advanced NSCLC in a real-world setting. METHODS: The main inclusion criteria were advanced NSCLC with an indication for repeat biopsy identified by the patient's clinician. The primary outcome was the percentage of successful procedures. Secondary outcomes were the type of procedure, new biological status, tolerability of the procedure, and clinical utility (treatment modification). RESULTS: From May 2012 to May 2013, 18 centers enrolled 100 patients (males: 44%; median age: 64.8 years; PS 0/1: 88%; adenocarcinoma: 89%; EGFR mutated: 50%; no initial biological profile: 16.4%). Re-biopsy was not possible in 19.5% of cases and provided no or too few tumor cells in 25.6% of cases. Repeat biopsy was useful for guiding treatment in 30.4% (25/82) of cases. Complications were infrequent (2 cases of moderate bleeding and 1 case of pneumothorax). CONCLUSION: Re-biopsy of advanced NSCLC is feasible in the real-world setting, with acceptable adverse events. Guidelines are needed on the indications of re-biopsy, the choice of procedure, the sampling site, and laboratory analysis.

A phase II study of cisplatin with intravenous and oral vinorelbine as induction chemotherapy followed by concomitant chemoradiotherapy with oral vinorelbine and cisplatin for locally advanced non-small cell lung cancer.

BACKGROUND: Concomitant platinum-based chemotherapy and radiotherapy (CT-RT) is the recommended treatment for unresectable locally advanced stage III non-small cell lung cancer (NSCLC). We conducted a phase II study to evaluate the efficacy and safety of fractionated oral vinorelbine with cisplatin as induction CT followed by CT-RT. METHODS: Patients with stage III NSCLC received 2 induction cycles of intravenous vinorelbine 25 mg/m2 and cisplatin 80 mg/m2 on day 1 and oral vinorelbine 60 mg/m2 on day 8. Responding patients received 2 more cycles of cisplatin 80 mg/m2 on day 1 and oral vinorelbine 20 mg on days 1, 3 and 5 concomitantly with radiotherapy 2 Gy daily, 5 days/week for a total of 66 Gy. RESULTS: Seventy patients, median age 61 years, were enrolled. Overall response rate (ORR) was 50.0%; Disease Control Rate was 81.42%. Median PFS was 14.58 months [95% CI, 10.97-18.75]. Median OS was 17.08 months [95% CI, 13.57-29.57]. One-year and 2-year survival rates were 68.6% [95% CI, 57.7-79.4] and 37%. One patient had a grade 3 pulmonary radiation injury and 26.5% had graded 1/2 esophagitis. CONCLUSION: In non-operable IIIA-IIIB NSCLC, the combination oral vinorelbine (fractionated fixed dose) plus cisplatin, during concomitant CT-RT, could offer a well-tolerated option, with comparable activity to I.V. vinorelbine-based chemoradiotherapy regimens. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01839032.

Cost analysis of erlotinib versus chemotherapy for first-line treatment of non-small-cell lung cancer in frail elderly patients participating in a prospective phase 2 study (GFPC 0505).

BACKGROUND: A large proportion of elderly patients (>70 years) with newly diagnosed NSCLC are shown to be frail by a comprehensive geriatric assessment. This population is more vulnerable to adverse effects of chemotherapy and might thus benefit more from targeted therapy. The objective of this study was to assess the cost-effectiveness of erlotinib followed by chemotherapy after progression, compared with the reverse strategy, in frail elderly patients with advanced NSCLC participating in a prospective randomized phase II trial (GFPC 0505). MATERIALS AND METHODS: Outcomes (progression-free survival and overall survival) and costs (limited to direct medical costs, from the third-party payer perspective) were collected prospectively until second progression. Costs after progression and health utilities (based on disease states and grade 3-4 toxicities) were derived from the literature. RESULTS: Median overall survival, QALYs, and total costs for the erlotinib-first strategy were 3.9 months, 0.33, and €15,233, respectively, compared with 4.4 months, 0.35, and €15,363 for the chemotherapy-first strategy. There was no significant difference between the 2 strategies in term of cost-effectiveness (respectively €47,381 and €44,350 per QALY). CONCLUSION: No difference in cost-effectiveness was found between an erlotinib-first strategy and a chemotherapy-first strategy in frail elderly patients with NSCLC.

Cost effectivenes of erlotinib versus chemotherapy for first-line treatment of non small cell lung cancer (NSCLC) in fit elderly patients participating in a prospective phase 2 study (GFPC 0504).

BACKGROUND: The median age of newly diagnosed patients with non-small cell lung cancer (NSCLC) is 67 years, and one-third of patients are older than 75 years. Elderly patients are more vulnerable to the adverse effects of chemotherapy, and targeted therapy might thus be a relevant alternative. The objective of this study was to assess the cost-effectiveness of erlotinib followed by chemotherapy after progression, compared to the reverse strategy, in fit elderly patients with advanced NSCLC participating in a prospective randomized phase 2 trial (GFPC0504). METHODS: Outcomes (PFS and overall survival) and costs (limited to direct medical costs, from the third-party payer perspective) were prospectively collected until second progression. Costs after progression and health utilities (based on disease states and grade 3-4 toxicities) were derived from the literature. RESULTS: Median overall survival, QALY and total costs for the erlotinib-first strategy were respectively 7.1 months, 0.51 and 27 734 €, compared to 9.4 months, 0.52 and 31 688 € for the chemotherapy-first strategy. The Monte Carlo simulation demonstrates that the two strategies do not differ statistically. CONCLUSION: In terms of cost effectiveness, in fit elderly patients with NSCLC, erlotinib followed by chemotherapy compares well with the reverse strategy.

Cost-effectiveness of second-line chemotherapy for non-small cell lung cancer: an economic, randomized, prospective, multicenter phase III trial comparing docetaxel and pemetrexed: the GFPC 05-06 study.

BACKGROUND: There are few data on the cost-effectiveness of second-line chemotherapies for non-small cell lung cancer (NSCLC). The objective of this phase III, randomized, multicenter, prospective study was to compare the cost-effectiveness of docetaxel and pemetrexed, two widely used drugs. METHODS: We compared, from a payer's perspective, the directs costs and effectiveness of docetaxel (75 mg/m, arm A) and pemetrexed (500 mg/m, arm B) administered every 3 weeks to NSCLC patients who had progressed after first-line platinum-based chemotherapy. Monthly health utilities (based on disease states: responding, stable or progressive, and grade 3/4 toxicities) were derived from the literature. Costs were prospectively assessed. RESULTS: One hundred fifty patients were enrolled between February 2006 and June 2008. The patients in the docetaxel and pemetrexed arms had similar clinical characteristics and treatment efficacy (respective objective response rates 10.7% and 12%; median progression-free survival times 2.8 and 2.5 months; median survival times 8.0 and 6.4 months, respectively). Grade 3/4 toxicities were significantly less frequent with pemetrexed (52.0% versus 33.3%, p = 0.02). Docetaxel was associated with lower treatment-period costs (€9709 ± €6272 versus €13,436 ± €6508, p < 0.001). Docetaxel had a more favorable cost-utility ratio than pemetrexed. When compared with best supportive care, the cost-utility was €32,652/quality-adjusted life year for docetaxel and €40,980/quality-adjusted life year for pemetrexed. CONCLUSION: Second-line treatment for NSCLC is more cost-effective with docetaxel than with pemetrexed. Both strategies have acceptable cost-effectiveness ratios compared with commonly used and reimbursed regimens for advanced NSCLC.