Resected EGFR-mutated non-small-cell lung cancers: incidence and outcomes in a European population (GFPC Exerpos Study).

Background: Few epidemiological data are available on surgically treated Caucasian patients with non-small-cell lung cancers (NSCLCs) harboring epidermal growth factor receptor (EGFR) mutations. The main objective of this study was to describe, in the real-world setting, these patients' incidence, clinical, and tumoral characteristics. Methods: The participating centers included all consecutive localized non-squamous NSCLC patients undergoing surgery between January 2018 and December 2019 in France. EGFR status was determined retrospectively when not available before surgery. Results: The study includes 1391 no squamous NSCLC patients from 16 centers; EGFR status was determined before surgery in 692 (49.7%) of the cases and conducted as part of the study for 699 (50.3%); 171 (12.3%) were EGFR mutated; median age: 70 (range: 36-88) years; female: 59.6%; never smokers: 75.7%; non-squamous histology 97.7%, programmed death ligand-1 expression 0%/1-49%/⩾50 in 60.5%/25.7%/13.8%, respectively. Surgery was predominantly lobectomy (81%) or segmentectomy (14.9%), with systematic lymph node dissection in 95.9%. Resection completeness was R0 for 97%. Post-surgery staging was as follows: IA: 52%, IB: 16%, IIA: 4%, IIB: 10%, IIIA: 16%, and IIIB: 0.05%; EGFR mutation exon was Del19/exon 21 (L858R)/20/18 in 37.4%/36.8%/14%, and 6.4% of cases, respectively; 31 (18%) patients received adjuvant treatment (chemotherapy: 93%, EGFR tyrosine kinase inhibitor: 0%, radiotherapy: 20%). After a median follow-up of 31 (95% confidence interval: 29.6-33.1) months, 45 (26%) patients relapsed: 11/45 (24%) locally and 34 (76%) with metastatic progression. Median disease-free survival (DFS) and overall survival were not reached and 3-year DFS was 60%. Conclusion: This real-world analysis provides the incidence and outcomes of resected EGFR-mutated NSCLCs in a European patient cohort.

Long-term effectiveness and treatment sequences in patients with extensive stage small cell lung cancer receiving atezolizumab plus chemotherapy: Results of the IFCT-1905 CLINATEZO real-world study.

BACKGROUND: Small cell lung cancer (SCLC) has a tendency towards recurrence and limited survival. Standard-of-care in 1st-line is platinum-etoposide chemotherapy plus atezolizumab or durvalumab,based on landmarkclinical trials. METHODS: IFCT-1905 CLINATEZO is a nationwide, non-interventional, retrospectivestudy of patients with extensive-SCLC receivingatezolizumab plus chemotherapy as part of French Early Access Program. Objectives were to analyse effectiveness,safetyand subsequent treatments. RESULTS: The population analyzed included 518 patients who received atezolizumabin 65 participating centers. There were 66.2% male,mean age was 65.7 years; 89.1% had a performance status (PS) 0/1 and 26.6% brain metastases. Almost all(95.9%) were smokers. Fifty-five (10.6%) received at least 1 previous treatment. Median number of atezolizumab injections was 7.0 (range [1.0-48.0]) for a median duration of 4.9 months (95% CI 4.5-5.1). Atezolizumab was continued beyond progression in 122 patients (23.6%) for a median duration of 1.9 months (95% CI: [1.4-2.3]). Best objective response was complete and partialin 19 (3.9%) and 378 (77.1%)patients. Stable diseasewas observed in 50 patients (10.2%). Median follow-up was30.8 months (95% CI: [29.9-31.5]). Median overall survival (OS), 12-, 24-month OS rates were 11.3 months (95% CI: [10.1-12.4]), 46.7% (95% CI [42.3-50.9]) and 21.2% (95% CI [17.7-24.8]). Median real-world progression-free survival, 6-, 12-month rates were 5.2 months (95% CI [5.0-5.4]), 37.5% (95% CI [33.3-41.7]) and 15.2% (95% CI [12.2-18.6]). For patients with PS 0/1, median OS was 12.2 months (95% CI [11.0-13.5]). For patients with previous treatment, median OS was 14.9 months (95% CI [10.1-21.5]). Three-hundred-and-twenty-six patients(66.4%) received subsequent treatment and27 (5.2%) were still underatezolizumabat date of last news. CONCLUSIONS: IFCT-1905 CLINATEZO shows reproductibility, in real-life,ofIMpower-133survival outcomes, possibly attributed to selection of patients fit for this regimen, adoption of pragmatic approaches,including concurrent radiotherapy and treatment beyond progression.

Impact of KRAS G12C mutation in patients with advanced non-squamous non-small cell lung cancer treated with first-line pembrolizumab monotherapy.

OBJECTIVES: Few data are available on the impact of KRAS mutation in patients with advanced non-squamous non-small cell lung cancer (aNSCLC) treated with immunotherapy. This analysis assessed the impact of KRAS mutation on the efficiency of first-line pembrolizumab immunotherapy in aNSCLC patients with PD-L1 ≥ 50 %. METHODS: This was a secondary analysis of the ESCKEYP study, a retrospective, national, multicenter study which included consecutively all metastatic NSCLC patients who initiated first-line treatment with pembrolizumab monotherapy from May 2017 (date of pembrolizumab availability in this indication in France) to November 22, 2019 (pembrolizumab-chemotherapy combination approval). Progression-free survival (PFS) and overall survival (OS) were calculated from the start of pembrolizumab treatment by the Kaplan-Meier method. Tumor response and PFS were assessed locally. RESULTS: Among the 681 non-squamous aNSCLC PD-L1 ≥ 50 % patients treated with pembrolizumab in the first line, 227 (33.0 %) had a KRAS mutation (KRAS G12C, 12.5 %; KRAS non-G12C, 20.5 %). Except among non-smokers (KRAS G12C, 0 %; KRAS non-G12C, 2.9 %; no KRAS mutation, 9.2 %), patients presented no differences in terms of sex, age, number and sites of metastatic disease at diagnosis, use of corticosteroids, use of antibiotics, and for biological factors between wild-type KRAS, KRAS G12C and non-KRAS G12C groups. Median (95 % CI) PFS in months were 7.0 (3.7-14) for KRAS G12C, 4.8 (3.4-6.7) for KRAS non-G12C and 8.5 (7.3-10.6) for wild-type KRAS genotypes (p = 0.23). Median OS were 18.4 (12.6-NR), 20.6 (11.4-NR) and 27.1 (18.7-34.2) months, respectively (p = 0.57). CONCLUSION: No difference in efficacy was observed in non-squamous aNSCLC patients treated with first-line pembrolizumab immunotherapy whether they presented a KRAS G12C, non KRAS G12C or wild-type KRAS genotype.

Adverse Events Induced by PD-1/PD-L1 Inhibitors: A Real-World Single-Centre Experience with a Management-Based Approach.

AIM: To assess the efficacy and tolerance of programmed death-1 (PD-1) and PD-ligand 1 (PD-L1) inhibitors and the impact of a standardised management-based protocol in a real-world setting. PATIENTS AND METHODS: Data from patients who had received anti-PD-(L)1 were collected from our pharmacy database. Clinical response and toxicity were assessed using RECIST criteria and CTCAE version 5.0, respectively. Overall survival (OS) and progression-free survival (PFS) were estimated with the Kaplan-Meier method. Potential prognostic factors were identified using Cox's model. RESULTS: A total of 196 patients and 201 lines of treatment were included (median age: 66 (range: 38-89) years). Types of cancer included non-small cell lung cancer (73%), transitional cell carcinoma (10%), renal cell carcinoma (6%), small cell lung cancer (5%), head and neck squamous cell carcinoma (4%) and classical Hodgkin's lymphoma (1%). Twenty-five (12%) patients had pre-existing autoimmune conditions. Our standardised management-based protocol included 129 (64%) patients. Objective response rate was 29%, median OS was 10 months (IQR: 7-15) and median PFS was 5 months (IQR: 1-22). Patients with an abnormal baseline complete blood count had a worse OS (HR=2.48 [95% CI: 1.24-4.96]; p=0.0103). Thirty-three (16%) patients experienced severe (grade 3 or 4) immune-related adverse event (irAE). There were three (1%) irAE-related deaths. AEs resolved faster when patients were assessed by an internist before anti-PD-(L)1 initiation (p=0.0205). CONCLUSION: PD-1 and PD-L1 inhibitors are effective and safe in a real-world setting. Implementation of a standardised management-based protocol with internal medicine specialists is an effective way to optimise irAE management.

Switch maintenance chemotherapy versus observation after carboplatin and weekly paclitaxel doublet chemotherapy in elderly patients with advanced non-small cell lung cancer: IFCT-1201 MODEL trial.

PURPOSE: Maintenance chemotherapy is a reasonable choice for patients with metastatic non-small cell lung carcinoma (NSCLC) not progressing after induction therapy with a platinum-based doublet. Nevertheless, there have been no studies dedicated to elderly patients. PATIENTS AND METHODS: We conducted a randomised trial in patients aged 70-89 years, with advanced NSCLC (with neither EGFR mutation nor ALK rearrangement), who had not progressed after four cycles of monthly carboplatin and weekly paclitaxel in order to compare maintenance with either pemetrexed (500 mg/m2 d1, 22) in patients with non-squamous cell carcinoma or gemcitabine (1,150 mg/m2 d1, 8, 22) in squamous cell carcinoma to simple observation. The patients were required to have a performance status (PS) 0-2, mini-mental score >23, and creatinine clearance ≥45 mL/min. The primary end-point was overall survival (OS). RESULTS: 632 patients were enrolled from May 2013 to October 2016. Of the 328 (52.3%) patients randomised after induction therapy, 166 patients were assigned to the observation arm, versus 162 to the switch maintenance arm, 119 of whom received pemetrexed and 43 gemcitabine. The median OS from randomisation was 14.1 months (95% confidence interval [CI]: 12.0-17.0) in the observation arm and 14 months (95% CI: 10.9-16.9) in the maintenance arm (p = 0.72). The median progression-free survival (PFS) from randomisation was 2.7 months (95% CI: 2.6-3.1) in the observation arm versus 5.7 months (95% CI: 4.8-7.1) in the maintenance arm (p < 0.001). CONCLUSION: Switch maintenance therapy significantly prolonged PFS but not OS and, thus, should not be proposed to elderly patients with advanced NSCLC.

Potential Antiangiogenic Treatment Eligibility of Patients with Squamous Non-Small-Cell Lung Cancer: EPISQUAMAB Study (GFPC 2015-01).

BACKGROUND: Antiangiogenic agents have improved the prognosis of non-squamous non-small-cell lung cancers (NSCLCs), even though all the patients are not eligible to receive them because of counterindications linked to the tumor's characteristics or comorbidities. Much less information is available about the eligibility of patients with squamous non-small-cell lung cancers (SQ-NSCLCs) to receive antivascular endothelial growth-factor (VEGF) treatments, even though such molecules are being developed for this histology. This study was undertaken to determine the percentage of advanced SQ-NSCLC patients who would be eligible to receive an antiVEGF agent as second-line systemic therapy. METHODS: This observational, multicenter, prospective study evaluated advanced SQ-NSCLC patients' criteria for ineligibility to receive an antiVEGF during a multidisciplinary meeting to choose their standard second-line systemic therapy. RESULTS: Among the 317 patients included, 53.6% had at least one ineligibility criterion, and ~20% had at least two, with disease extension to large vessels (39.8%), tumor cavitation (20.5%), cardiovascular disease (11%) and/or hemoptysis (7.2%) being the most frequent. Patients with an ECOG performance score of 1/2 had more cardiovascular contraindications that those with scores of 0. CONCLUSION: Almost half of the SQ-NSCLC patients included in this study would have been eligible to receive an antiVEGF agent. The development of these molecules for these indications should be encouraged.

A randomized trial comparing adjuvant chemotherapy with gemcitabine plus cisplatin with docetaxel plus cisplatin in patients with completely resected non-small-cell lung cancer with quality of life as the primary objective.

OBJECTIVES: Adjuvant chemotherapy with vinorelbine plus cisplatin (VC) improves survival in resected non-small-cell lung cancer (NSCLC), but has negative impact on quality of life (QoL). In advanced NSCLC, gemcitabine plus cisplatin (GC) and docetaxel plus cisplatin (DC) exhibit comparable efficacy, with possibly superior QoL compared to VC. This trial investigated these regimens in the adjuvant setting. METHODS: Patients with Stage IB to III NSCLC were eligible following standardized surgery. Overall, 136 patients were included, with 67 and 69 assigned to the GC and DC arms, respectively. Cisplatin (75 mg/m(2), Day [D] 1) plus gemcitabine (1250 mg/m(2), D1 and D8) or docetaxel (75 mg/m(2) D1) were administered for three cycles. Primary end-point was QoL (EORTC QLQ-C30), with the study designed to detect a 10-point difference between arms. Overall survival, safety and cost were secondary end-points. RESULTS: No between-group imbalance was observed in terms of patient characteristics. At inclusion, global health status (GHS) scores (/100) were 63.5 and 62.7 in GC and DC, respectively (P = 0.8), improving to 64.5 and 65.4 after 3 months (P = 0.8). No significant difference in functional or symptoms scores was observed between the arms except for alopecia. Grade 3/4 haematological and non-haematological toxicities were found in 33.8 and 21.7% (P = 0.11), and 33.8 and 26.1% (P = 0.33) of patients, in GC and DC, respectively. At 2 years, 92.9 and 89.8% of patients remained alive in GC and DC, respectively (P = 0.88). CONCLUSIONS: DC and GC adjuvant chemotherapies for completely resected NSCLC were well tolerated and appear free of major QoL effects, and are therefore representing candidates for comparison with the standard VC regimen.

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.

Major changes in lung cancer over the last ten years in France: the KBP-CPHG studies.

The incidence of lung cancer has dramatically increased in ten years, being now the most commonly diagnosed cancer in males and the fourth most commonly diagnosed cancer in females. Considering social and scientific evolution, the aim of the present study conducted by the French College of General Hospital Respiratory Physicians (CPHG) was to compare patient and lung cancer characteristics at a ten-year interval. Two epidemiological studies, KBP-2000-CPHG and KBP-2010-CPHG, were conducted at a ten-year interval. These prospective multicentre studies included all patients ≥ 18 years of age with primary lung cancer diagnosed between 1st January and 31st December 2000 or 2010, and managed in the respiratory departments of one of the participating general hospitals. A standardised form was completed for each patient. A steering committee checked recruitment exhaustiveness. Respectively, in 2000 and 2010, 137 and 104 centres included 5667 and 7051 patients. Compared to 2000, patients in 2010 were significantly older (65.5 ± 11.3 vs. 64.3 ± 11.5 years, p < 0.0001), more frequently women (24.3% vs. 16.0%, p < 0.0001) and never-smokers (10.9% vs. 7.2%, p < 0.0001). In 2010, adenocarcinoma was the most common tumour (45.4%, vs. 29.0% in 2000, p < 0.0001). The adenocarcinoma rate increased irrespective of sex, age, or smoking status (relative risk [RR] before and after adjustment, RR = 2.07 [1.92-2.24], p < 0.0001 and 2.06 [1.90-2.23], p < 0.0001). In ten years, lung cancer characteristics have therefore changed: more women, more never-smokers, and more adenocarcinomas. The particular high increase in adenocarcinoma rate deserves further analysis.

Phase III trial comparing carboplatin, paclitaxel, and bexarotene with carboplatin and paclitaxel in chemotherapy-naive patients with advanced or metastatic non-small-cell lung cancer: SPIRIT II.

PURPOSE: The purpose of this study was to determine whether addition of the synthetic rexinoid bexarotene (Targretin; Eisai Inc, Woodcliff Lake, NJ) to standard first-line carboplatin and paclitaxel therapy provides additional survival benefit in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IIIB disease with pleural effusion, or stage IV NSCLC and Eastern Cooperative Oncology Group performance status 0 to 1, were randomly assigned to bexarotene 400 mg/m(2)/d combined with carboplatin and paclitaxel, or assigned to carboplatin and paclitaxel alone. Bexarotene patients also received lipid-lowering agents on or before day 1. The primary efficacy end point was overall survival; secondary efficacy and supportive analyses were also conducted. RESULTS: A total of 612 patients (306 per arm) were enrolled onto the study. In the intent-to-treat population, no significant difference in survival occurred between the two arms. However, a subpopulation (approximately 40%) of bexarotene-treated patients who experienced National Cancer Institute grade 3/4 hypertriglyceridemia had significantly longer median survival than control patients (12.4 v 9.2 months; log-rank, P = .014). Bexarotene-treated patients with grade 3/4 hypertriglyceridemia who received the most benefit included those who were male, were smokers, experienced 6-month prior weight loss >or= 5%, and had stage IV disease. The incidence and severity of most adverse events were similar between arms, although hyperlipidemia, neutropenia, fatigue, leukopenia, arthralgia, and diarrhea were more frequent in the bexarotene arm. CONCLUSION: Although the addition of bexarotene to chemotherapy did not improve survival in the overall study population, occurrence of high-grade hypertriglyceridemia in bexarotene-treated patients strongly correlated with increased survival, suggesting that bexarotene may benefit a segment of first-line NSCLC patients.

Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Français de Pneumo-Cancérologie NPC 95-01 Study.

PURPOSE: We conducted a phase III study to compare the survival impact of concurrent versus sequential treatment with radiotherapy (RT) and chemotherapy (CT) in unresectable stage III non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were randomly assigned to one of the two treatment arms. In the sequential arm, patients received induction CT with cisplatin (120 mg/m2) on days 1, 29, and 57, and vinorelbine (30 mg/m2/wk) from day 1 to day 78, followed by thoracic RT at a dose of 66 Gy in 33 fractions (2 Gy per fraction and 5 fractions per week). In the concurrent arm, the same RT was started on day 1 with two concurrent cycles of cisplatin 20 mg/m2/d and etoposide 50 mg/m2/d (days 1 to 5 and days 29 to 33); patients then received consolidation therapy with cisplatin 80 mg/m2 on days 78 and 106 and vinorelbine 30 mg/m2/wk from days 78 to 127. RESULTS: Two hundred five patients were randomly assigned. Pretreatment characteristics were well balanced between the two arms. There were six toxic deaths in the sequential arm and 10 in the concurrent arm. Median survival was 14.5 months in the sequential arm and 16.3 months in the concurrent arm (log-rank test P = .24). Two-, 3-, and 4-year survival rates were better in the concurrent arm (39%, 25%, and 21%, respectively) than in the sequential arm (26%, 19%, and 14%, respectively). Esophageal toxicity was significantly more frequent in the concurrent arm than in the sequential arm (32% v 3%). CONCLUSION: Although not statistically significant, clinically important differences in the median, 2-, 3-, and 4-year survival rates were observed, with a trend in favor of concurrent chemoradiation therapy, suggesting that is the optimal strategy for patients with locally advanced NSCLC.