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Purpose: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of non–small cell lung cancer (NSCLC), but predictive biomarkers of their efficacy are imperfect. The primary objective is to evaluate circulating immune predictors of pembrolizumab efficacy in patients with advanced NSCLC. Experimental Design: We used high-dimensional mass cytometry (CyTOF) in baseline blood samples of patients with advanced NSCLC treated with pembrolizumab. CyTOF data were analyzed by machine-learning algorithms (Citrus, tSNE) and confirmed by manual gating followed by principal component analysis (between-group analysis). Results: We analyzed 27 patients from the seminal KEYNOTE-001 study (median follow-up of 60.6 months). We demonstrate that blood baseline frequencies of classical monocytes, natural killer (NK) cells, and ICOS+ CD4+ T cells are significantly associated with improved objective response rates, progression-free survival, and overall survival (OS). In addition, we report that a baseline immune peripheral score combining these three populations strongly predicts pembrolizumab efficacy (OS: HR = 0.25; 95% confidence interval = 0.12–0.51; P < 0.0001). Conclusions: As this immune monitoring is easy in routine practice, we anticipate our findings may improve prediction of ICI benefit in patients with advanced NSCLC.

Purpose: Targeted therapies (TT) and immune checkpoint blockers (ICB) have revolutionized the approach to non–small cell lung cancer (NSCLC) treatment in the era of precision medicine. Their impact as switch maintenance therapy based on molecular characterization is unknown. Patients and Methods: SAFIR02-Lung/IFCT 1301 was an open-label, randomized, phase II trial, involving 33 centers in France. We investigated eight TT (substudy-1) and one ICB (substudy-2), compared with standard-of-care as a maintenance strategy in patients with advanced EGFR, ALK wild-type (wt) NSCLC without progression after first-line chemotherapy, based on high-throughput genome analysis. The primary outcome was progression-free survival (PFS). Results: Among the 175 patients randomized in substudy-1, 116 received TT (selumetinib, vistusertib, capivasertib, AZD4547, AZD8931, vandetanib, olaparib, savolitinib) and 59 standard-of-care. Median PFS was 2.7 months [95% confidence interval (CI), 1.6–2.9] with TT versus 2.7 months (1.6–4.1) with standard-of-care (HR, 0.97; 95% CI, 0.7–1.36; P = 0.87). There were no significant differences in PFS within any molecular subgroup. In substudy-2, 183 patients were randomized, 121 received durvalumab and 62 standard-of-care. Median PFS was 3.0 months (2.3–4.4) with durvalumab versus 3.0 months (2.0–5.1) with standard-of-care (HR, 0.86; 95% CI, 0.62–1.20; P = 0.38). Preplanned subgroup analysis showed an enhanced benefit with durvalumab in patients with PD-L1 tumor proportion score (TPS) ≥1%, (n = 29; HR, 0.29; 95% CI, 0.11–0.75) as compared with PD-L1 Conclusions: Molecular profiling can feasibly be implemented to guide treatment choice for the maintenance strategy in EGFR/ALK wt NSCLC; in this study it did not lead to substantial treatment benefits beyond durvalumab for PD-L1 ≥ 1 patients.

Supplementary Figure 2. Forest plot with subgroup analysis for PFS in substudy 1.

Supplementary Table S1. Representativeness of Study Participants

Purpose:Targeted therapies (TT) and immune checkpoint blockers (ICB) have revolutionized the approach to non–small cell lung cancer (NSCLC) treatment in the era of precision medicine. Their impact as switch maintenance therapy based on molecular characterization is unknown.Patients and Methods:SAFIR02-Lung/IFCT 1301 was an open-label, randomized, phase II trial, involving 33 centers in France. We investigated eight TT (substudy-1) and one ICB (substudy-2), compared with standard-of-care as a maintenance strategy in patients with advanced EGFR, ALK wild-type (wt) NSCLC without progression after first-line chemotherapy, based on high-throughput genome analysis. The primary outcome was progression-free survival (PFS).Results:Among the 175 patients randomized in substudy-1, 116 received TT (selumetinib, vistusertib, capivasertib, AZD4547, AZD8931, vandetanib, olaparib, savolitinib) and 59 standard-of-care. Median PFS was 2.7 months [95% confidence interval (CI), 1.6–2.9] with TT versus 2.7 months (1.6–4.1) with standard-of-care (HR, 0.97; 95% CI, 0.7–1.36; P = 0.87). There were no significant differences in PFS within any molecular subgroup. In substudy-2, 183 patients were randomized, 121 received durvalumab and 62 standard-of-care. Median PFS was 3.0 months (2.3–4.4) with durvalumab versus 3.0 months (2.0–5.1) with standard-of-care (HR, 0.86; 95% CI, 0.62–1.20; P = 0.38). Preplanned subgroup analysis showed an enhanced benefit with durvalumab in patients with PD-L1 tumor proportion score (TPS) ≥1%, (n = 29; HR, 0.29; 95% CI, 0.11–0.75) as compared with PD-L1 n = 31; HR, 0.71; 95% CI, 0.31–1.60; Pinteraction = 0.036).Conclusions:Molecular profiling can feasibly be implemented to guide treatment choice for the maintenance strategy in EGFR/ALK wt NSCLC; in this study it did not lead to substantial treatment benefits beyond durvalumab for PD-L1 ≥ 1 patients.

Supplementary Figure legends 1-5

Supplementary Figure 1. Planned exploratory analyses by study drug for selumetinib, vistusertib and capivasertib.

Supplementary materials - substudy 1 statistical report

Supplementary Figure 4. Forest plot with subgroup analysis for PFS in substudy 2.

Supplementary Figure 5. Forest plot with subgroup analysis for OS in substudy 2.

Study protocol

Supplementary materials - substudy 2 statistical report

Supplementary Figure 3. Forest plot with subgroup analysis for OS in substudy 1.

Purpose:Immune checkpoint inhibitors (ICI) have revolutionized the treatment of non–small cell lung cancer (NSCLC), but predictive biomarkers of their efficacy are imperfect. The primary objective is to evaluate circulating immune predictors of pembrolizumab efficacy in patients with advanced NSCLC. Experimental Design:We used high-dimensional mass cytometry (CyTOF) in baseline blood samples of patients with advanced NSCLC treated with pembrolizumab. CyTOF data were analyzed by machine-learning algorithms (Citrus, tSNE) and confirmed by manual gating followed by principal component analysis (between-group analysis).Results:We analyzed 27 patients from the seminal KEYNOTE-001 study (median follow-up of 60.6 months). We demonstrate that blood baseline frequencies of classical monocytes, natural killer (NK) cells, and ICOS+ CD4+ T cells are significantly associated with improved objective response rates, progression-free survival, and overall survival (OS). In addition, we report that a baseline immune peripheral score combining these three populations strongly predicts pembrolizumab efficacy (OS: HR = 0.25; 95% confidence interval = 0.12–0.51; P < 0.0001).Conclusions:As this immune monitoring is easy in routine practice, we anticipate our findings may improve prediction of ICI benefit in patients with advanced NSCLC.

Supplementary Figure 1: Graphical Abstract Supplementary Figure 2: Overall Survival in NSCLC patients treated with pembrolizumab in KEYNOTE-001 according to EGFR mutation Supplementary Figure 3: Recursive partitioning identified classical monocytes and NK as the main immune populations whose frequency splits patients into distinct patterns of overall survival Supplementary Figure 4: Classical monocytes, NK cells and ICOS+ CD4+ T cells are associated with improved pembrolizumab efficacy in advanced NSCLC patients. Supplementary Figure 5: Gating strategy of the 3 main immune populations associated with pembrolizumab efficacy. Supplementary Figure 6: Comparison side by side of Maxstat cut-offs with cut-off from Younden index for overall survival in the 3 populations of interest. Supplementary Figure 7: Survival outcomes in NSCLC patients treated with pembrolizumab in KEYNOTE-001 according to blood baseline frequency of classical monocytes. Supplementary Figure 8: Baseline immune peripheral score is also associated with PFS in melanoma patients treated with PD-1 inhibitors.

Supplementary Figure from Comprehensive Genome Profiling in Patients With Metastatic Non–Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung Trial

Supplementary Data from Comprehensive Genome Profiling in Patients With Metastatic Non–Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung Trial

Purpose:Double inhibition of epidermal growth factor receptor (EGFR) using a tyrosine kinase inhibitor plus a monoclonal antibody may be a novel treatment strategy for non–small cell lung cancer (NSCLC). We assessed the efficacy and toxicity of afatinib + cetuximab versus afatinib alone in the first-line treatment of advanced EGFR-mutant NSCLC.Patients and Methods:In this phase II, randomized, open-label study, patients with stage III/IV EGFR-positive NSCLC were randomly assigned (1:1) to receive afatinib (group A) or afatinib + cetuximab (group A + C). Oral afatinib 40 mg was given once daily; cetuximab 250 mg/m² was administered intravenously on day 15 of cycle 1, then every 2 weeks at 500 mg/m² for 6 months. The primary endpoint was time to treatment failure (TTF) rate at 9 months. Exploratory analysis of EGFR circulating tumor DNA in plasma was performed.Results:Between June 2016 and November 2018, 59 patients were included in group A and 58 in group A + C. The study was ended early after a futility analysis was performed. The percentage of patients without treatment failure at 9 months was similar for both groups (59.3% for group A vs. 64.9% for group A + C), and median TTF was 11.1 (95% CI, 8.5–14.1) and 12.9 (9.2–14.5) months, respectively. Other endpoints, including progression-free survival and overall survival, also showed no improvement with the combination versus afatinib alone. There was a slight numerical increase in grade ≥3 adverse events in group A + C. Allele frequency of the EGFR gene mutation in circulating tumor DNA at baseline was associated with shorter PFS, regardless of the treatment received.Conclusions:These results suggest that addition of cetuximab to afatinib does not warrant further investigation in treatment-naïve advanced EGFR-mutant NSCLC.

Purpose:Targeted therapies (TT) and immune checkpoint blockers (ICB) have revolutionized the approach to non–small cell lung cancer (NSCLC) treatment in the era of precision medicine. Their impact as switch maintenance therapy based on molecular characterization is unknown.Patients and Methods:SAFIR02-Lung was an open-label, randomized, phase II trial, involving 33 centers in France. We investigated eight TT (substudy-1) and one ICB (substudy-2), compared with standard-of-care as a maintenance strategy in patients with advanced EGFR, ALK wild-type (wt) NSCLC without progression after first-line chemotherapy, based on high-throughput genome analysis. The primary outcome was progression-free survival (PFS).Results:Among the 175 patients randomized in substudy-1, 116 received TT (selumetinib, vistusertib, capivasertib, AZD4547, AZD8931, vandetanib, olaparib, savolitinib) and 59 standard-of-care. Median PFS was 2.7 months [95% confidence interval (CI), 1.6–2.9] with TT versus 2.7 months (1.6–4.1) with standard-of-care (HR, 0.97; 95% CI, 0.7–1.36; P = 0.87). There were no significant differences in PFS within any molecular subgroup. In substudy-2, 183 patients were randomized, 121 received durvalumab and 62 standard-of-care. Median PFS was 3.0 months (2.3–4.4) with durvalumab versus 3.0 months (2.0–5.1) with standard-of-care (HR, 0.86; 95% CI, 0.62–1.20; P = 0.38). Preplanned subgroup analysis showed an enhanced benefit with durvalumab in patients with PD-L1 tumor proportion score (TPS) ≥1%, (n = 29; HR, 0.29; 95% CI, 0.11–0.75) as compared with PD-L1 n = 31; HR, 0.71; 95% CI, 0.31–1.60; Pinteraction = 0.036).Conclusions:Molecular profiling can feasibly be implemented to guide treatment choice for the maintenance strategy in EGFR/ALK wt NSCLC; in this study it did not lead to substantial treatment benefits beyond durvalumab for PD-L1 ≥ 1 patients.

Supplementary Tables

Supplementary Table from Comprehensive Genome Profiling in Patients With Metastatic Non–Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung Trial

In Europe, few data regarding the characteristics of EGFR exon 20 insertion (20ins) mutations in non-small cell lung cancer (NSCLC) are available. Using a large real-world cohort, we assessed the incidence, characteristics, and outcomes of patients with non-squamous (nsq) NSCLC harboring EGFR exon 20ins. The Epidemio-Strategy and Medical Economics advanced and metastatic lung cancer data platform including advanced/metastatic nsqNSCLC patients from January 2015 was analyzed (cut-off date: June 30, 2020). Characteristics, epidermal growth factor receptor (EGFR) mutation and other mutations, treatment patterns, and clinical outcomes were assessed for patients harboring EGFR exon 20ins, common EGFR mutations, other EGFR mutations, and wild-type EGFR. Survival parameters were estimated by the Kaplan-Meier method in these four groups. Out of 9435 nsqNSCLC patients tested for EGFR, 1549 (16.4%) had a mutation, including 61 with EGFR exon 20ins (3.9% of all mutated EGFR). These 61 patients had a mean age of 63.6 years, were mostly female (68.9%) and non-smokers (55.7%), with de novo stage IV disease (73.8%) and performance status 0–1 (76.9%). Almost all patients (95.1%) with exon 20ins received systemic therapy (median, three lines). First-line systemic treatments consisted mainly of combination chemotherapy (70.7%), single-agent EGFR tyrosine kinase inhibitors (10.3%), and single-agent immunotherapy (5.2%). After a median follow-up of 25.0 (95% confidence interval [CI] 22.3–32.4) months, the median real-world overall survival was 24.3 (19.1–32.6) months in patients with exon 20ins compared to 35.4 (95% CI 32.6–37.5) in patients with common EGFR mutation (n = 1049) (p = 0.049) and 19.6 (95% CI 18.6–20.5) in patients with wild-type EGFR (n = 7866) (p = 0.2). This large national study in nsqNSCLC patients confirms that EGFR exon 20ins is a rare condition (0.6%). The prognosis associated with exon 20ins appears to be in line with that of wild-type EGFR, but worse than common EGFR mutations, highlighting the need for advancements for this rare population.

The prevalence of the musculoskeletal immune-related adverse events (irAEs) is probably underestimated, as most studies report only severe side effects. Our aim was to describe and characterize all musculoskeletal irAEs in a large cohort of patients treated with immune checkpoint inhibitors (ICI).We conducted a retrospective study among patients who received ICI from 07/27/2014 to 05/08/2020 at the medical oncology department of the Institut Paoli-Calmettes, Marseille, France. All medical files were systemically reviewed by a rheumatologist who collected clinical features, time of occurrence, treatment regimen, irAEs management, course and outcomes. We also assessed tumor response 3 months after introduction of ICI, according to severity and treatments used to manage musculoskeletal irAEs.Among 927 patients treated with ICI for a solid tumor, 118 patients (12.7%) presented a musculoskeletal irAE. Their median age was 66.5, 61% were male, and they mainly had a lung (57.6%) or urological cancer (27.1%). The most frequently involved ICI was an anti PD-1. Arthralgias and myalgias were the most frequent musculoskeletal irAEs (9.8%) and inflammatory rheumatic features were reported in 36 patients (3.9%) with elevated acute phase reactants and negative immunological markers. The median time of onset was 2 months (IC 95% 1.8; 2.7). Tumor response at 3 months did not differ according to musculoskeletal irAE severity, type of manifestation (arthralgias/myalgias versus inflammatory rheumatic features), pain patterns (mechanical versus inflammatory) or irAE treatments.Musculoskeletal irAEs in this large cohort of patients treated with ICI were frequent (12.7%), mostly mild and well tolerated.

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.

9094 Background: OSE2101 (Tedopi) is an anticancer vaccine increasing overall survival (OS) versus Standard of Care (SoC docetaxel or pemetrexed) in HLA-A2+ NSCLC patients with secondary resistance after sequential Chemo (CT)-IO (ESMO 2021 #47LBA). Here we present the QoL analysis. Methods: EGFR and ALK negative NSCLC patients who failed prior IO, ECOG PS 0-1 were randomized 2:1 to receive either OSE2101 or SoC (docetaxel or pemetrexed). Primary endpoint was OS; secondary endpoints included time to ECOG PS deterioration and QoL by EORTC QLQ-C30/LC13 questionnaires at baseline and before each treatment administration until the end of treatment (EOT). Changes in QLQ-C30/LC13 scores from baseline to EoT were assessed using mixed-effects model for repeated measures (MMRM). Overall treatment effect and associated p value were estimated using MMRM. Results: 95 out of 118 (81%) patients with secondary resistance to IO completed baseline and ≥ one follow-up questionnaire. Median OS was 11.1 mo for OSE2101 vs 7.5 mo for SoC [HR 0.59; p = 0.02]. Median time to ECOG PS deterioration was 9.0 mo for OSE2101 vs 3.3 mo for SoC [HR: 0.43; p = 0.004]. Global Health Status remained stable with OSE2101 whereas it deteriorated from the 1st cycle with SoC (p = 0.045). Most pronounced effects were observed in the physical (ability to perform activities that require physical effort; p = 0.07) and the role (ability to work and carry out daily activities; p = 0.03) functioning scores (refer table below). Patients had less mouth soreness (p = 0.01), dysphagia (p = 0.01), peripheral neuropathy (p = 0.03), alopecia (p < 0.001) and fatigue (p = 0.06) with OSE2101 than with SoC. The change from baseline of dyspnea, coughing, hemoptysis, and pain were not significantly different between the 2 groups. Conclusions: In advanced HLA-A2+ NSCLC patients with secondary resistance to IO after sequential CT-IO, OSE2101 improves OS and maintains QoL vs. SoC, especially global health status, physical and role functioning scores. Patients presented fewer symptoms typically related to adverse effects of chemotherapy as compared to SoC. Clinical trial information: NCT02654587. [Table: see text]

Background: The role and timing of whole or stereotaxic brain radiotherapy (BR) in patients with advanced non-small cell lung cancer (aNSCLC) and asymptomatic brain metastases (aBMs) are not well established. This study investigates whether deferring BR until cerebral progression was superior to upfront BR for patients with aNSCLC and aBM. Methods: This open-label, multicenter, phase III trial, randomized (1:1) aNSCLC patients with aBMs to receive upfront BR and chemotherapy: platin–pemetrexed and bevacizumab in eligible patients, followed by maintenance pemetrexed with or without bevacizumab, BR arm, or the same chemotherapy with BR only at cerebral progression, chemotherapy (ChT) arm. Primary endpoint was progression-free survival (PFS), secondary endpoints were overall survival (OS), global, extra-cerebral and cerebral objective response rate (ORR), toxicity, and quality of life [ClinicalTrials.gov identifier: NCT02162537]. Results: The trial was stopped early because of slow recruitment. Among 95 included patients, 91 were randomized in 24 centers: 45 to BR and 46 to ChT arms (age: 60 ± 8.1, men: 79%, PS 0/1: 51.7%/48.3%; adenocarcinomas: 92.2%, extra-cerebral metastases: 57.8%, without differences between arms.) Significantly more patients in the BR-arm received BR compare with those in the ChT arm (87% versus 20%; p

Double inhibition of epidermal growth factor receptor (EGFR) using a tyrosine kinase inhibitor plus a monoclonal antibody may be a novel treatment strategy for non-small cell lung cancer (NSCLC). We assessed the efficacy and toxicity of afatinib + cetuximab versus afatinib alone in the first-line treatment of advancedIn this phase II, randomized, open-label study, patients with stage III/IVBetween June 2016 and November 2018, 59 patients were included in group A and 58 in group A + C. The study was ended early after a futility analysis was performed. The percentage of patients without treatment failure at 9 months was similar for both groups (59.3% for group A vs. 64.9% for group A + C), and median TTF was 11.1 (95% CI, 8.5-14.1) and 12.9 (9.2-14.5) months, respectively. Other endpoints, including progression-free survival and overall survival, also showed no improvement with the combination versus afatinib alone. There was a slight numerical increase in grade ≥3 adverse events in group A + C. Allele frequency of theThese results suggest that addition of cetuximab to afatinib does not warrant further investigation in treatment-naïve advanced

Introduction Molecular profiling is considered a standard of care in advanced NSCLC. A comprehensive next-generation sequencing panel can discover somatic or germline BRCA1/2 mutations that are new druggable molecular alterations. However, the phenotypic and potential therapeutic relevance of BRCA1/2 mutation in NSCLC remains poorly defined. Methods From April 2014 to March 2017, 600 newly diagnosed, EGFR/ALK negative patients with advanced NSCLC were enrolled in the SAFIR02-Lung trial. Molecular profiling was done at study entry on archival tissue or frozen tissue collected from a new biopsy specimen before the third cycle of platinum-based chemotherapy. The prevalence of BRCA1/2 variants and its biological relevance were assessed. A homologous recombinant deficiency (HRD) score was based on the copy number variation data, and the germline status was determined by blood analysis. The BRCA Share database and the French CGG consortium were the references for the variant classification. Results Of 379 patients with a molecular profile discussed in a tumor molecular board, BRCA1/2 variants were identified in 20 patients (5.3%), including eight patients (2.1%) with a confirmed pathogenic BRCA mutation. Two patients (0.5%) harbored a germline BRCA2 mutation, and for six others, a somatic BRCA mutation was identified (1.6%). All were men and mainly smokers (88%). The overall response rate to chemotherapy was 13%. BRCA variants of unknown significance were detected in 12 patients (3.2%), achieving an 8.3% overall response rate with chemotherapy. One-third of tumors carrying pathogenic BRCA mutations or variants of unknown significance had biallelic inactivation and high HRD score. Overall survival of this cohort was 12.8 months. Conclusions Pathogenic BRCA1/2 mutations occur in 2.1% of patients with advanced NSCLC. The predictive role of BRCA mutation for making treatment decisions in NSCLC seems limited based on clinical response (low platinum sensitivity) and molecular features (discrepancy between biallelic inactivation and high HRD score).

Purpose: The incidence of lung cancer has dramatically increased in women. Preclinical data have suggested that combining EGFR–tyrosine kinase inhibitor (TKI) with an antiestrogen may overcome resistance to EGFR-TKI. Patients and Methods: The IFCT-1003 LADIE trial was a 2 × 2 arms parallel open-label randomized phase II trial. EGFR-TKI–naïve postmenopausal women with advanced lung cancer were treated with gefitinib (G) versus gefitinib + fulvestrant (G+F) in the EGFR-mutated group (EGFR+) or with erlotinib (E) versus erlotinib + fulvestrant (E+F) in the EGFR wild-type group (EGFR-WT). The primary objective was progression-free survival (PFS) at 3 and 9 months for EGFR-WT and EGFR+ patients. Results: Overall, 204 patients (gefitinib 104 and G+F 100) and 175 patients (erlotinib 87 and E+F 88) were enrolled in the EGFR+ and EGFR-WT cohorts. In the EGFR+ cohort, the primary endpoint was reached, with 58% of the G+F group patients being nonprogressive at 9 months. Adding fulvestrant to gefitinib was not associated with improved PFS (9.9 vs 9.4 months) or overall survival (OS; 22.1 vs 28.6 months). In the EGFR-WT cohort, the primary endpoint was also achieved (33.7% of the patients were nonprogressive at 3 months). Adding fulvestrant to erlotinib was not associated with improved outcome (PFS 1.8 vs 2.0 and OS 10.3 vs 7.3 months). No PFS difference was observed regarding estrogen receptor alpha expression. The tolerance was as expected with no treatment-related death. Conclusions: Adding fulvestrant to EGFR-TKI is feasible, but not associated with prolonged PFS regardless of EGFR status. The lack of benefits while combining fulvestrant to EGFR-TKI does not support its future development in an unselected population.

9095 Background: Targeted therapies (TT) are approved in NSCLC based on a limited number of oncogenic drivers. Numerous additional TT can be matched to other molecular alterations found in comprehensive profiles. We investigated the effect of 8 TT compared to SoC as a maintenance strategy after chemotherapy in pts with metastatic NSCLC. Methods: In SAFIR02-LUNG trial (NCT: 02117167), open-label multicentric phase II randomized trials, PS 0-1 pts with ALK/EGFR WT NSCLC after a CR/PR/SD to 4 cycles of platinum-based chemotherapy were selected. All pts underwent a fresh biopsy, followed by targeted sequencing on 70 genes and SNP-array when > 30% cancer cells were present on HES slides. In case of genomic alteration (including KRAS, ERBB2, BRAF, BRCA mutations), pts were randomized 2:1 between 8 TT and SoC. TT allocation was decided during weekly national tumor board, based on predefined guidelines. The primary endpoint was Progression-Free Survival (PFS) and the secondary endpoint was Overall Survival (OS). Results: 999 patients were enrolled and 394 had a molecular alteration eligible for the study. Among the 175 randomized pts (between July 2014 and May 2019), 116 received TT (65 selumetinib, 18 vistusertib, 9 capivasertib, 8 AZD4547, 5 AZD8931, 5 vandetanib, 4 olaparib, 1 savolitinib) and 59 SoC (54 pemetrexed, 4 gemcitabine and 1 erlotinib). Median age was 60, 40.6% were female, 4.6% never-smoker, 44% were PS 0, 88.6% had a non-squamous NSCLC and 26.9% a PR to chemotherapy. At data cut-off, 168 pts had progressed or died. With a median follow-up of 42.0 months (mo), median PFS was 2.7 mo (95% confidence interval (CI) 1.6 to 2.7) with TT vs. 2.7 mo (95%CI 1.6-4.1) with SoC (HR for disease progression or death 1.00; 95%CI = 0.73 to 1.38; p = 0.978). There was no significant PFS differences among the molecular subgroups; in the cohort with KRAS or BRAF mutation without STK11 mutations the HR for disease progression or death was 0.76; 95%CI = 0.52 to 1.13; p = 0.17. Median OS was 14.3 mo (95%CI 11.0-18.3) with TT vs. 14.1 mo (95% CI 8.0-30.9) with SoC (HR for death 1.12; 95%CI = 0.75-1.65; p = 0.581). Grade 3 or 4 treatment-related adverse events occurred in 31 pts (26.7%) on TT (G3: 30 pts (25.9%), G4: 1 pt (0.8%)) and in 13 (22%) on SoC (G3 8 pts, G4 5 pts). Conclusions: The SAFIR02-LUNG trial demonstrated the feasibility of a routine precision medicine for advanced NSCLC. However, the monotherapy TT used as maintenance therapy after platinum-based chemotherapy failed to improve PFS or OS in this advanced ALK/EGFR WT NSCLC pts population. Newly available therapeutic options (ex. for KRASG12C, RET, NTRK, ERBB2, NRG1, etc) need to be evaluated. Clinical trial information: 2013-001653-27.

9062 Background: In Europe, 10-15% of non-squamous non-small cell lung cancer (nsqNSCLC) have EGFR mutations of which 5-12% are an Exon 20 insertion (20ins). Methods: Analysis of Epidemio-Strategy and Medical Economics (ESME) Advanced and Metastatic Lung cancer (AMLC) Data Platform (NCT03848052), a multicenter real-life database using a supervised, retrospective data collection process. The database includes 13737 advanced nsqNSCLC treated from January 2015 at participating centres. The cut-off date for patient follow-up for this analysis was June 30, 2020. The aim of the study was to assess real-world patient characteristics, treatment patterns and clinical outcomes of advanced nsqNSCLC EGFR 20ins. Overall survival (OS) of EGFR cohorts (20ins, 19del/L858R without 20ins, other EGFR mutations) and EGFR wild-type/not tested cohort were assessed. Results: 1549 (11.3%) nsqNSCLC had an EGFR mutation, 61 (3.9%) of whom being an EGFR 20ins. These 61 patients (pts) are mainly female (68.9%), non-smoker (55.7%), with de novo stage IIIB/IV disease (78.6%), PS 0-1 (76.9%). Median age was 68.0 years (q1-q3: 54-74). PD-L1 status was assessed in 34 (55.7%) pts, mainly (n = 20) before first line and 22 (64.7%) had negative result. Most (63.9%) pts had EGFR 20ins positive result available before first line. Almost all pts (95.1%, n = 58) received a systemic therapy with a median number of 3 (q1-q3: 1-4) lines. In first line setting, 74% of the pts received chemotherapy (mainly chemotherapy combination), 13.7% received EGFR TKI (mainly as monotherapy) and 8.6% received immunotherapy only. Median treatment duration for pts treated with CarboPem (n = 19), CisplatinPem (n = 16) and CarboTaxol (n = 6) were 4.7 (q1-q3: 2.6-6.6), 7.4 (q1-q3: 5.0-12.8) and 3.3 (q1-q3: 2.8-3.8) months, respectively. For afatinib (n = 3), erlotinib (n = 2) and gefitinib (n = 1), median treatment durations were 1.6 (q1-q3: 0.5-2.8); 1.8 (q1-q3: 1.4-2.1) and 2.3 months, respectively. After a median follow up of 36.3 (95%CI: 34.1-39.8) months, median OS was 24.3 (95%CI: 19.1-32.6) months; 1 and 2-years OS rates were 82.5% (95%CI: 69.7-90.2) and 52.6% (95%CI: 37.3-65.9), respectively. For pts with 19del/L858R without 20ins (n = 1049) and those with other EGFR mutations (n = 439) median OS were 35.4 (95%CI: 32.6-37.5) and 41.7 (95%CI: 31.9-53.5), respectively compared to 20.7 (95%CI: 20.0-21.8] months for pts EGFR wild type/not tested (n = 12188). Conclusions: This large, national real-world analysis based on medical chart data’s confirm that EGFR 20ins is a rare disease (0.4% of advanced nsqNSCLC). Currently available EGFR TKIs appear to have low efficacy and response to chemotherapy seems identical to that of EGFR wild-type/not tested pts. Prognosis for NSCLC pts with EGFR 20ins mutations was in line with that of EGFR wild type/not tested but worse than common EGFR mutations highlighting the need for advancements for this rare population.

9561 Background: Medical treatment of lung cancer has irreversibly changed since the development of immune checkpoint inhibitors (ICI). However, immune biomarkers of efficacy are still lacking. Preliminary data in leukemia and pancreatic cancer showed that soluble immune checkpoints are associated with a reduced overall survival (OS). This led us to explore the prognostic and predictive value of soluble immune checkpoints in non-small cell lung cancer (NSCLC) patients treated with chemotherapy or ICI. Methods: We analyzed 90 advanced NSCLC patients. The pilot cohort (Rennes University Hospital, France), included 48 patients treated with platinum doublets (n = 33) or ICI (n = 15) (LOC/11-16 protocol). The confirmation cohort (Paoli-Calmettes Institute) included 42 patients treated with ICI (nivolumab or pembrolizumab) in a longitudinal prospective setting (Immunosup trial, NCT03595813). In both cohorts, enzyme-linked immunosorbent assays (ELISA) were performed in baseline plasma samples for soluble forms of PD-1, PD-L1, global BTN3, BTLA, BTN3-A1 and BTN2A1. Soluble ICI levels were linked to clinical data using Kaplan-Meier, log-rank and Cox proportional-hazards models. Cut-points were determined using maxstat package for survival, R software R 3.6.2. Results: Five soluble immune checkpoints correlated and clustered together in unsupervised analysis (PD-1, PD-L1, global BTN3, BTLA, BTN3-A1), but were not associated with ICI efficacy. In patients treated with ICI, in the pilot and confirmation cohort, a high baseline plasmatic concentration of soluble BTN2A1 was significantly associated with an improved OS (confirmation cohort with a BTN2A1 cut-point of 3.55 ng/ml: HR = 0.30, 95%CI = 0.12-0.74, p = 0.0057, median OS in BTN2A1low = 7.6 months and median OS in BTN2A1hi = 19.5 months). On the contrary, in patients treated with chemotherapy, soluble BTN2A1 concentration was not associated with overall survival. Conclusions: In advanced NSCLC patients, a high baseline plasmatic concentration of soluble BTN2A1 was correlated with improved outcomes for ICI, but not for chemotherapy, suggesting that baseline soluble BTN2A1 level is a potential predictive biomarker of ICI efficacy. Additional studies are ongoing to confirm this finding.

Background/aim Radiological evaluation after stereotactic-body-radiotherapy (SBRT) for non-small-cell lung carcinoma (NSCLC) is often difficult due to lung radiation-induced image modifications on computed tomographic (CT) scan. The aim of this study was to evaluate positron-emission tomography-computed tomography (PET-CT) using fluorodeoxyglucose after SBRT in primary lung cancer. Patients and methods Eighteen patients with histologically proven NSCLC were treated with SBRT. All had PET-CT evaluations before treatment, at 2 to 3 months and at 1 year post SBRT during the follow-up. Results Early PET-CT in 12/18 patients who did not experience local failure did not show any progression. No conclusion could be drawn in four cases because early PET-CT was disturbed by inflammatory reaction. Early PET-CT was not predictive of late outcome for two patients, as it showed a significant response followed by disease progression on late evaluation. Conclusion Early PET response appears to correlate with local control at 1 year post SBRT.

9079 Background: First-line treatment of metastatic EGFR-mutated NSCLC relies on EGFR-TKIs. However, all patients (pts) eventually develop progression. Dual inhibition of EGFR with afatinib (A), an irreversible pan-erbB TKI, and cetuximab (C), an EGFR monoclonal antibody, has shown activity in EGFR-mutated pts with acquired resistance to TKIs, regardless of the T790M status. Methods: We conducted a phase II randomized trial in advanced NSCLC pts harboring an activating EGFR mutation, who had not received prior therapy. Pts were treated with A (40 mg/d) until progression alone or with C 500 mg/m² every 2 weeks during 6 months (mos) (beginning at D15 at 250 mg/m²). Primary endpoint was time-to-treatment failure (TTF) at 9 mos for pts with del19 and L858R mutations. Secondary endpoints include safety, progression-free survival (PFS), overall survival (OS). Prospective monitoring of the T790M mutation was performed on circulating tumoral DNA (ctDNA) by digital PCR. Results: Trial was stopped early due to futility analysis after 118 pts were enrolled (59 in each arm). Baseline characteristics were balanced between the 2 arms, and especially for the types of EGFR mutation (del19, 55.9 vs 50.8%; L858R, 39 vs 40.7%; others, 5.1 vs 8.5% in AC and A arms, respectively). Treatment-related AEs of any grades were similar, although there was an excess of grade 3 AEs in the AC arm (50 vs 37.3%), but no of grade 5. The excess in grade 3-5 AEs was essentially due to cutaneous (96.6 vs 81.4%), eyes (32.8 vs 27.1%), hematological (22.4 vs 15.3%) but not to digestive toxicities (89.7 vs 98.3%). Among the 117 pts included in the efficacy analysis, 9-months TTF was 63.3% (47.5-75.6) in arm A and 65.8% (50.1-77.66) in arm AC. Median TTF was 11.1 mos (8.3-not reached [NR]) and 10.8 mos (9.2-13.7) in arms A and AC, respectively. Median PFS was 11.1 mos (8.3-NR) and 12.8 mos (9.2-13.7), respectively. Median OS was 20.8 mos (17.5-NR) and NR (17-NR), respectively. Conclusions: Efficacy of AC was similar to that of A alone. These results don’t support further evaluation of this combination in this setting. Results of ctDNA monitoring will be reported during the meeting. Clinical trial information: NCT02716311.

TPS9121 Background: New treatment strategies are needed for advanced NSCLC patients who progress on treatment with immune checkpoint inhibitors (ICI). Tedopi (OSE2101) is a neoepitope vaccine restricted to HLA-A2 positive patients (45%) targeting five tumor-associated antigens frequently expressed in lung cancer cells, ACE, HER2, MAGE2, MAGE3 and P53. Previously, in a phase II trial (Barve et al. JCO 2008), Tedopi showed a median overall survival (OS) of 17.3 months with a manageable safety profile in advanced NSCLC patients. ATALANTE-1 (NCT02654587) is a randomized, open-label, phase 3 study comparing the efficacy and safety of TEDOPI with standard of care (SoC) treatment in HLA-A2 positive patients with advanced NSCLC, as second- or third-line therapy. Methods: Patients with advanced NSCLC without EGFR-sensitizing mutations or ALK rearrangements; progressive disease to platinum-based chemotherapy (ChT) with sequential or concurrent ICI; HLA-A2 positivity (blood test); ECOG PS 0-1; with treated and asymptomatic brain metastases,, are randomized 2:1 to receive 5mg Tedopi subcutaneously Q3W for 6 cycles, then Q8W for the reminder of the year and finally Q12W, or SoC treatment with: docetaxel 75 mg/m2 Q3W or pemetrexed 500 mg/m2 Q3W (in non-squamous and pemetrexed-naïve patients). Treatment continues until progression, intolerable toxicity or consent withdrawal, in both arms. Patients are stratified by histology, best response to first line, and line rank of ICI. Tumor assessment is performed every 6 weeks (RECIST 1.1). Primary endpoint is OS. Secondary end points are PFS, ORR, DCR, and duration of response, quality of life and safety. This is a superiority study with a hazard ratio of 0.7, two-sided alpha 5% and power 80%, after 278 events are observed. An independent analysis (1year OS rate) is planned in the first 84 patients treated with Tedopi. Last trial review by the DMC in June 18 suggested that the trial continues as planned. Translational research will be performed evaluating pharmacodynamic markers of efficacy such as immunogenicity response against Tedopi vaccine neoantigens, as well as parameters in liquid and tissue biopsies. End January 19, 87 patients (51 Tedopi, 36 Soc) have been enrolled. Clinical trial information: NCT02654587.

A four-parameter score has been identified as associated with overall survival (OS) in patients with advanced cancer with an estimated survival inferior to 6 months. Here, we tested its prognostic value for OS in patients who had received more than two lines of systemic therapy. We prospectively enrolled patients with advanced cancer who were going to receive a third or more therapeutic line outside classical clinical guidelines. The four parameters (Eastern Cooperative Oncology Group performance status, number of metastatic sites, serum LDH, and serum albumin) were collected at baseline, allowing to calculate the score, which sorted the patients in three groups, A, B, and C (low, intermediate, and high score, respectively). We then searched for correlations between this grouping and clinicopathological features particularly OS. From August 2013 to March 2014, 65 patients were enrolled and corresponded after determining their score to 26 patients in group A, 30 in B, and 9 in C. The median OS of the cohort was 4.4 months, and the 6-month OS was 42%. Overall survival was different between the three groups, with respective 6-month OS equal to 80% in group A, 17% in group B, and 0% in group C and respective median OS of 9, 2.3, and 1.6 months. Such prognostic value persisted in multivariate analysis. Similar OS differences were observed in patients with PS ≤2. This simple scoring should help oncologists identify which patients, after at least two lines of systemic therapy, might benefit from best supportive care alone.

// Michael Duruisseaux 1 , Benjamin Besse 2 , Jacques Cadranel 3 , Maurice Perol 4 , Bertrand Mennecier 5 , Laurence Bigay-Game 6 , Renaud Descourt 7 , Eric Dansin 8 , Clarisse Audigier-Valette 9 , Lionel Moreau 10 , Jose Hureaux 11 , Remi Veillon 12 , Josiane Otto 13 , Anne Madroszyk-Flandin 14 , Alexis Cortot 15 , Francois Guichard 16 , Pascaline Boudou-Rouquette 17 , Alexandra Langlais 18 , Pascale Missy 19 , Franck Morin 19 , Denis Moro-Sibilot 1 1 Centre Hospitalier Universitaire Grenoble Alpes, Thoracic Oncology Unit, Chest Department, Grenoble, France 2 Medical Oncology Department, Gustave Roussy, Villejuif, France 3 Assistance Publique Hopitaux de Paris, Tenon Hospital, Chest Department, Paris, France 4 Leon-Berard Cancer Center, Lyon, France 5 Centre Hospitalier Universitaire de Strasbourg, Chest Department, Strasbourg, France 6 Larrey Hospital, Chest Department, Toulouse, France 7 Centre Hospitalier Universitaire de Brest, Brest, France 8 Oscar Lambret Cancer Center, Medical Oncology Department, Lille, France 9 Centre Hospitalier Sainte Musse, Chest Department, Toulon, France 10 Centre Hospitalier General de Colmar, Louis Pasteur Hospital, Chest Department, Colmar, France 11 Centre Hospitalier Universitaire d’Angers, Chest Department, Angers, France 12 Centre Hospitalier Universitaire de Bordeaux, Respiratory Disease Department, Pessac, France 13 Antoine Lacassagne Cancer Center, Nice, France 14 Paoli Calmettes Institute, Marseille, France 15 Centre Hospitalier Universitaire de Lille, Thoracic Oncology Unit, Lille, France 16 Medical Oncology Department, Polyclinique Bordeaux Nord Aquitaine, Bordeaux, France 17 Assistance Publique Hopitaux de Paris, Cochin-Port Royal Hospital, Medical Oncology Department, Paris, France 18 French Cooperative Thoracic Intergroup, Department of Biostatistics, Paris, France 19 French Cooperative Thoracic Intergroup, Clinical Research Unit, Paris, France Correspondence to: Denis Moro-Sibilot, email: DMoro-Sibilot@chu-grenoble.fr Keywords: lung cancer, ALK, crizotinib, ceritinib, alectinib Received: September 28, 2016 Accepted: January 10, 2017 Published: February 26, 2017 ABSTRACT Overall survival (OS) with the anaplastic lymphoma kinase (ALK) inhibitor (ALKi) crizotinib in a large population of unselected patients with ALK -positive non-small-cell lung cancer (NSCLC) is not documented. We sought to assess OS with crizotinib in unselected ALK -positive NSCLC patients and whether post-progression systemic treatments affect survival outcomes. ALK -positive NSCLC patients receiving crizotinib in French expanded access programs or as approved drug were enrolled. We collected clinical and survival data, RECIST-defined progressive disease (PD) and post-PD systemic treatment efficacy. We performed multivariable analysis of OS from crizotinib initiation and PD under crizotinib. At time of analysis, 209 (65.7%) of the 318 included patients had died. Median OS with crizotinib was 16.6 months. The line of crizotinib therapy did not impact survival outcomes. Of the 263 patients with PD, 105 received best supportive care, 74 subsequent drugs other than next-generation ALKi and 84 next-generation ALKi. Next-generation ALKi treatment correlated with better survival outcomes in multivariate analysis. These patients had a median post-PD survival of 25.0 months and median OS from metastatic disease diagnosis of 89.6 months. Unselected ALK -positive NSCLC patients achieve good survival outcomes with crizotinib therapy. Next-generation ALKi may provide survival improvement after PD under crizotinib.

9097Background: The incidence of lung cancer is increasing dramatically in women with recent findings as the preferential involvement of the EGFR pathway and the potential impact of hormonal factor...

To determine guidelines for the management of perineal small bowel fistula (PSF) after total or posterior pelvic exenteration.During 15 years, 315 curative pelvic exenterations were performed. PSF occurred in 15 patients (3.5%). We retrieved the precise modality of radiotherapy (fields and doses) and management of all patients (type of surgery, number of surgery and mortality). Delay of occurrence was divided in early (within 30 days or before hospital discharge) and delayed.All patients underwent surgery. Mortality rate was 13%. Fourteen patients (93%) had history of radiotherapy. No PSF was noted after anterior pelvic exenteration. Higher frequency of PSF was noted after total pelvic exenteration versus posterior pelvic exenteration (P = 0.04). Early PSF occurred in four patients (27%) with higher frequency of small bowel intraoperative injury. Late PSF occurred in 11 patients (73%) divided in small bowel injury in contact with pelvic staples (n = 4) and disease recurrence (n = 6, local recurrence or carcinomatosis). One patient had delayed PSF by ulceration of small bowel in contact with pelvic drain.PSF was a life-threatening complication of pelvic exenteration. Radiotherapy leads to weaken small bowel with difficulty of cicatrisation. During pelvic exenteration: (a) extreme careful dissection and interposition of great omentum could avoid small bowel injury, (b) control of pelvic vessels and closure of rectum remnant should not used staplers. Intraoperative management of PSF used successful simple repair in case of early PSF or segmentary resection indeed enlarged to right colon in case of delayed PSF. Postoperative courses had to use intravenous hyperalimentation and digestive tract discharge.

Introduction: Paclitaxel plus cisplatin is considered to be the standard first-line therapy for advanced ovarian cancer. Previous to this study, economic data on this combination resulted from randomised clinical trials (RCTs). Therefore, the objective of this study was to compare the clinical and economic outcomes associated with paclitaxel-cisplatin (PC) and cyclophosphamide-cisplatin (CC) regimens using a pragmatic perspective based on daily clinical practice in a French university hospital. Method: A retrospective cost-effectiveness analysis, from the hospital-payer perspective, was carried out as a before-after case study in fifty-nine consecutive women with verified International Federation of Gynaecology and Obstetrics (FIGO) stage II, III or IV ovarian cancer treated between 1995 and 2000. Median overall survival (OS) was used as the primary endpoint. The quality-adjusted time was assessed by the quality-adjusted time without symptoms or toxicity (Q-TWiST) method. Direct medical costs were collected for each patient. Monetary values for French prices in the year 2000 were used and converted to US dollars using an exchange rate of $US1 = 7 French francs. Several univariate sensitivity analyses were carried out varying unit costs, medical practices and administration of paclitaxel. Results: The incremental cost of the PC regimen was $US10 716 per patient. OS and quality-adjusted time were improved by 10.8 and 9.3 months with the PC regimen. The cost per life-year gained and per added QALY were $US11 907 and $US13 827, respectively. The robustness of the results was confirmed in sensitivity analyses. Conclusion: Our study suggests that PC may be a cost-effective regimen for advanced ovarian cancer in a French university hospital setting. We reported higher incremental costs and lower clinical benefits than RCT-based findings, suggesting that RCT-based findings were clearly balanced by our pragmatic approach based on clinical practices. Observational studies can provide complementary and balanced data for decision making.

Farmer's lung disease (FLD) is common in the east of France. In the absence of the primary recognized FLD agent, Saccharopolyspora rectivirgula, its etiology remains unknown. A prospective case-control study was performed to find the etiology of FLD in this area. Eleven patients were matched with 11 healthy control farmers. Twenty-two urban subjects constituted the nonexposed control group. Microorganisms from cowshed air and fodder were identified and counted. The antigens of the microorganisms most frequently isolated at the 22 farms were used for serological tests. Farms of patients with FLD contained more Absidia corymbifera than those of healthy farmers (p < 0.05 in air, p < 0.01 in fodder). Electrosyneresis, performed with A. corymbifera somatic antigen, differentiated 9 of 11 patients with FLD from control subjects (p < 0.01). Other significant results were obtained with Eurotium amstelodami (p < 0.01) and Wallemia sebi (p < 0.05). In contrast, no significant results were obtained with the other seven antigens tested, including S. rectivirgula. Absidia corymbifera and, to a lesser degree, W. sebi or E. amstelodami are likely to be the main causes of FLD in this area. Modifications in working conditions over time could explain the emergence of these new contributing etiologies.

Background Lung carcinoid tumor and low grade glioma are two uncommon malignancies. Patients and methods We report the case of 24-year-old man who presented with respiratory disease. Imaging investigations showed a right lung tumor and histological analysis confirmed a typical carcinoid tumor. As part of initial staging, brain MRI revealed an asymptomatic right frontal lesion. First, a right pulmonary lobectomy was performed without adjuvant treatment. In second time, brain tumorectomy was performed. Histological examination confirmed the diagnosis of low grade glioma (LGG). The patient remained in complete remission 2.5 years after the initial diagnosis. Results This is the first case reporting the association between LGG and lung carcinoid tumor, while no association between LGG and a systemic tumor have been published to date. Association of lung carcinoid tumor with other malignant diseases has been reported but remained uncommon. Only minimal data support a potential molecular common origin. Conclusion This exceptional association may be fortuitous. However, their concomitant diagnoses suggest a potential association between both rare diseases. A genetic susceptibility remains possible.

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract. Most of them have an activating mutation of KIT or PDGFRalpha tyrosine-kinase receptors. Imatinib is a selective tyrosine-kinase inhibitor of ABL, KIT and PDGFR, and provides a clinical benefit in about 85% of patients with advanced GIST. Unfortunately, secondary resistance following initial responses occurs in most of the cases, and molecular mechanisms are poorly understood. We sequenced KIT and PGDFRalpha exons from one patient with GIST before and after the development of imatinib resistance. We identified, in addition to a primary mutation in exon 9, a secondary mutation in KIT exon 13 (first kinase domain) in the resistant sample. We demonstrate for the first time the feasibility of sequencing such samples removed by non-surgical biopsies during imatinib therapy. Such a approach, far less invasive than surgery and combined with sequencing, will likely help in better tailoring the treatment of advanced GISTs and understanding the mechanisms of resistance and response to imatinib.