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There is no dedicated study on second-line treatment for elderly patients with advanced nonsmall cell lung cancer (NSCLC). We report the results on second-line erlotinib therapy from our previously published phase III study comparing single-agent therapy with platinum-based doublet (carboplatin plus paclitaxel) therapy in 451elderly patients. Erlotinib was given to patients exhibiting disease progression or experiencing excessive toxicity during first-line therapy, until further progression or unacceptable toxicity. In total, 292 (64.7%) patients received erlotinib as second-line therapy. Initial performance status 0–1, stage IV NSCLC and an Activities of Daily Living score of 6 were independent factors for receiving erlotinib. Median (95% CI) overall survival was 4 (3.2–6.7) versus 6.8 (5.0–8.3) months in the single-agent and doublet arms, respectively (p=0.089). Performance status 0–1, never having smoked, adenocarcinoma and weight loss ≤5% were favourable independent prognostic factors of survival, whereas the randomisation arm had no significant impact. Among the 292 patients who received erlotinib, 60 (20.5%) experienced grade 3–4 toxic effects, the most frequent being rash. Erlotinib as second-line therapy is feasible, leading to efficacy results similar to those obtained in a previous randomised study that was not dedicated to elderly patients, with acceptable toxicity. Erlotinib is a feasible second-line therapy in elderly patients with advanced nonsmall cell carcinoma

Evaluation of: Jalal SI, Riggs HD, Melnyk A et al. Updated survival and outcomes for older adults with inoperable stage III non-small-cell lung cancer treated with cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel: analysis of a Phase III trial from the Hoosier Oncology Group (HOG) and US Oncology. Ann. Oncol. doi:10.1093/annonc/mdr565 (2011) (Epub ahead of print). The paper by Jalal et al. reports updated survival of a Phase III trial of concurrent chemoradiation with or without consolidation docetaxel for locally advanced non-small-cell lung cancer, and efficacy and tolerability data in patients ≥70 years. Of the 243 enrolled patients, 166 were randomized and 64 were aged ≥70 years (26%). There was no benefit of consolidation docetaxel. Median and 3-year survival was 17.1 months and 21.8% in patients ≥70 years, and 22.8 months and 34% in patients

International audience; BACKGROUND: To compare 3 treatment strategies in chemotherapy naive patients with advanced NSCLC and a PS 2-3. PATIENTS AND METHODS: Patients were assigned to gefitinib 250mg daily (n=43) or to gemcitabine (1250mg/m(2) d 1, 8 q 21d) (n=42) or docetaxel (75mg/m(2) d 1 q 21d) (n=42). Treatments were taken until progression or toxicity. The primary endpoint was progression-free survival. Secondary end points were response and overall survival. RESULTS: Disease control rates were 20.9%, 33.4% and 38.1%, respectively. Median PFS was 1.9 months in the gefitinib arm, 2.0 months in the gemcitabine arm and 2.0 months in the docetaxel arm (HR gemcitabine versus gefitinib: 0.74, 95%CI: [0.48; 1.16], HR docetaxel versus gefitinib: 0.67, 95%CI: [0.43; 1.05]). Median survival times were 2.2, 2.4 and 3.5 months, respectively (HR gemcitabine versus gefitinib: 0.76, 95%CI: [0.48; 1.20], HR docetaxel versus gefitinib: 0.69, 95%CI: [0.44; 1.09]). There were more grade 3-4 adverse events in the docetaxel arm when compared with either the gefitinib arm or the gemcitabine arm. CONCLUSION: In unselected NSCLC patients with PS 2-3, gefitinib, gemcitabine and docetaxel achieved similar results. Docetaxel was associated with higher rates of adverse events.

Purpose Intergroupe Francophone de Cancerologie Thoracique-0401 phase II trial aimed to evaluate the efficacy and safety of gefitinib as a first-line treatment for patients with adenocarcinoma with bronchioloalveolar carcinoma subtype (ADC-BAC). Methods Chemotherapy-naive patients ( n = 88) with advanced ADC-BAC were treated with 250 mg/d of gefitinib. The primary objective was assessment of disease control rate (DCR [objective response + stable disease]) at 3 months using World Health Organization criteria. A disease control rate of 25% or greater would be of interest in this patient population. Progression-free survival (PFS), overall survival (OS), and toxicity were the secondary criteria. Clinical and disease characteristics that conferred a favorable prognosis under gefitinib were also analyzed. Results Disease control was achieved in 25 patients (29.4%); 11 patients (12.9%) had partial response and 14 (16.4%) had stable disease. Median PFS was 2.9 months (95% confidence interval [CI], 2.3–3.2) and median OS was 13.2 months (95% CI, 10.2–17.3). Never smokers, patients with low respiratory symptoms score, occurrence of cutaneous rash, and nonmucinous ADC-BAC subtype were associated with increased probability of disease control. Nonmucinous ADC-BAC was associated with increased PFS and OS at 3 years. Patients with nonmucinous BAC had longer OS and PFS compared with patients with other ADC-BAC variants; median PFS for nonmucinous BAC was 11.3 months (95% CI, 3.2–14.7), whereas it was 2.6 months (95% CI, 2.1–3) for mucinous BAC. As expected, toxicity was low, with dermatological problems, diarrhea, and nausea being the most common adverse events. Conclusion Results from the Intergroupe Francophone de Cancerologie Thoracique-0401 trial demonstrate that gefitinib combines efficacy with low toxicity and is, therefore, suitable as a first-line treatment of advanced ADC-BAC, particularly in patients with nonmucinous BAC subtype.

International audience; BACKGROUND: There is scarce data available about epidermal growth factor receptor (EGFR) mutations other than common exon 19 deletions and exon 21 (L858R) mutations. PATIENTS AND METHODS: EGFR exon 18 and/or exon 20 mutations were collected from 10 117 non-small-cell lung cancer (NSCLC) samples analysed at 15 French National Cancer Institute (INCa)-platforms of the ERMETIC-IFCT network. RESULTS: Between 2008 and 2011, 1047 (10%) samples were EGFR-mutated, 102 (10%) with rare mutations: 41 (4%) in exon 18, 49 (5%) in exon 20, and 12 (1%) with other EGFR mutations. Exon 20 mutations were related to never-smoker status, when compared with exon 18 mutations (P \textless 0.001). Median overall survival (OS) of metastatic disease was 21 months [95% confidence interval (CI) 12-24], worse in smokers than in non-smoker patients with exon 20 mutations (12 versus 21 months; hazard ratio [HR] for death 0.27, 95% CI 0.08-0.87, P = 0.03). Under EGFR-tyrosine kinase inhibitors (TKIs), median OS was 14 months (95% CI 6-21); disease control rate was better for complex mutations (6 of 7, 86%) than for single mutations (16 of 40, 40%) (P = 0.03). CONCLUSIONS: Rare EGFR-mutated NSCLCs are heterogeneous, with resistance of distal exon 20 insertions and better sensitivity of exon 18 or complex mutations to EGFR-TKIs, probably requiring individual assessment.

International audience; HYPOTHESIS:: This study explored whether chemotherapy after first-line gefitinib was effective in patients with advanced lepidic predominant adenocarcinoma (LPA), formerly advanced bronchioloalveolar carcinoma, who were enrolled in the Intergroupe Francophone de Cancérologie Thoracique (IFCT)-0401 trial. METHODS:: Overall, 88 patients presenting advanced LPA were enrolled in the IFCT-0401 trial, receiving gefitinib as first-line therapy. No predefined second-line treatment was mandatory in the case of progression or limiting toxicity under gefitinib. However, the carboplatin plus paclitaxel regimen was recommended for patients with a performance status (PS) 0 or 1 and gemcitabine monotherapy for those with a PS 2. For these patients, data concerning treatment efficacy was collected from the IFCT-0401 trial database. RESULTS:: In total, 47 patients (53%) received second-line treatment after the failure of gefitinib, with 43 having PS 0 or 1. Regarding treatment, 43 were treated with chemotherapy, with 38 receiving a platinum-doublet regimen (taxane-based, n = 29; gemcitabine-based, n = 9) and five receiving monotherapy (gemcitabine, n = 3; pemetrexed, n = 2). The overall response rate (ORR) to chemotherapy was 21% (95% confidence interval [CI]: 10-36), disease control rate 56% (95% CI: 40-71), and median progression-free survival (PFS) 3.0 months (95% CI: 2.4-4.9). For patients receiving a platinum doublet (n = 38), ORR was 21% (95% CI: 10-37), with disease control rate being 55% (95% CI: 38-71), and median PFS 2.9 months (95% CI: 2.4-4.4). For patients receiving taxane-based regimen (n = 29) and gemcitabine-based regimen (n = 12), ORR was 28% and 0%, respectively, with a median PFS of 3.3 and 2.0 months, respectively, (p = 0.0243). The two patients receiving pemetrexed experienced a prolonged response. Multivariate Cox model analysis revealed that only the use of taxane-based chemotherapy or pemetrexed was related to PFS. CONCLUSION:: Platinum-doublet chemotherapy showed some effectiveness in treating advanced LPA patients after first-line gefitinib. Our findings also suggest that taxane-based chemotherapy and pemetrexed should be investigated further in future clinical trials.

Cisplatin is a pivotal drug in combined chemotherapy for non-small cell and small-cell lung cancers (NSCLC or SCLC), but its renal toxicity limits its use. Current guidelines recommend 24 h hydration: thus hospitalization is required. The aim of this retrospective study was to confirm the safety of short hydration before giving an intermediate-to-high dose of cisplatin in an outpatient clinic.Patients eligible had NSCLC or SCLC and were being treated with a chemotherapy regimen that included cisplatin ≥ 75 mg/m(2). They were given the same short hydration protocol for 1 day. Nephrotoxicity was defined as ≥ grade 1 according to NCIC common toxicity criteria. Predictive factors for nephrotoxicity were analyzed.Three hundred and fifty-seven consecutive patients (median age 58 years, range: 25-81) were reviewed. Twenty-one patients (6%) had ≥ grade 1 nephrotoxicity and all except one had grade 1 toxicity according to NCIC criteria for common toxicity (SC1,5 N). Predictive factors independently associated with nephrotoxicity included associated co-morbid conditions (hypertension, diabetes, heart disease) (OR = 4.97 CI 95% [1.8-13.7] P = 0.002), initial serum creatinine ≥ 100 μmol/L (OR = 8.3 CI 95% [2.55-27.4] P = 0.0005), and dose cycle of cisplatin ≥ 100 mg/m(2) (OR = 10.8 CI 95% [3.6-32.5] P0.0001).Rapid outpatient administration of a single dose of cisplatin at ≥ 75 mg/m(2) is feasible without a high risk of nephrotoxicity.

International audience; OBJECTIVE: To evaluate the impact of highly active antiretroviral therapy (HAART) on survival in HIV infected patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: All consecutive HIV infected patients with NSCLC diagnosed between 06/1996 and 03/2007 at two University hospitals in Paris (France) were prospectively followed until death. The association between survival and clinical and biological factors was analyzed by univariate and multivariate models. Survival analysis was performed by Kaplan-Meier estimates and the Cox proportional hazards regression model. RESULTS: During the study period, NSCLC was diagnosed in 49 consecutive HIV infected patients (median age 46 years); 84% had advanced disease. Median survival was 8.1 months (range 5-10 months). In multivariate analysis, baseline parameters with significant positive impact on survival included performance status (PS) < or =1 (HR=0.2, 95%CI [0.09, 0.46], p=0.0001), stage I-II disease (HR=0.15, 95%CI [0.04, 0.53], p=0.003), and use of HAART (HR=0.4, 95%CI [0.2, 0.9], p=0.027). CONCLUSION: HAART is a good prognostic factor for survival in HIV infected patients with NSCLC. Stage of disease and PS are two other valid survival prognostic factors.

There is no optimal established therapy for treating advanced or recurrent adenocarcinoma with bronchioloalveolar carcinoma features (ADC-BAC), and it remains unclear whether chemotherapy achieves therapeutic results comparable to those seen in the more common non-small lung carcinoma subtypes. In order to improve the decisions made during the treatment of advanced ADC-BAC, we attempted to better characterize the mucinous and non-mucinous ADC-BAC subtypes. Fifty pathological samples were obtained from 62 patients included in a multicenter prospective phase II trial (IFCT0401) conducted to evaluate gefitinib as a first-line therapy for non-resectable ADC-BAC. These samples were centrally reviewed and re-classified as non-mucinous (n=25) or mucinous (n=25) subtypes. We demonstrated that demographic data, clinical characteristics and stage at presentation (extrathoracic versus lung metastasis, as well as TNM staging) did not distinguish between the two subtypes. In contrast, three biological markers (PAS staining, TTF-1 expression and EGFR genomic gain combined with mutation analysis) enabled us to independently segregate all but 2 of the 50 patients into the mucinous and non-mucinous ADC-BAC subtypes. Finally, only mucinous tumors appeared to be resistant to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Additional prospective studies are required to better approach therapeutic strategy in mucinous tumors, which are a distinct entity from non-mucinous tumors.

8081 Background: To evaluate the benefit of adding cisplatin or carboplatin (P) to docetaxel (D) chemotherapy (CT) in patients with the first metastatic relapse after perioperative chemotherapy and surgery. Methods: Patients (Pts) with histologically or cytologically confirmed inoperable non-small cell-lung cancer not eligible for curative radiotherapy (local or metastatic relapse), disease progression after perioperative chemotherapy and surgery and PS 0-1. Pts were randomized to D 75 mg/m² combined with cisplatin 75 mg/m² or carboplatin AUC5 every 3 weeks (Arm A) or alone (Arm B). The primary endpoint was progression-free survival (PFS). Results: Due to low accrual the trial was interrupted after inclusion of 88 patients. From November 2007 to August 2012, 68 males and 20 females, median age (range) 61 (41-75), ECOG PS 0/1/ 49%/50%, squamous histology 39%, Arm A and Arm B 44 patients each, were enrolled. Interval from last cycle of perioperative CT ou last cycle of adjuvant CT was ≥ 12 months in 69% of pts. 79.5% of patients received DP full treatment. A non-statistically significant increase in PFS favoring combined CT was observed with a HR of 0.73 (95% CI: 0.46-1.15; p = 0.18), median PFS 8 months vs 5.6. Objective response rate was increased in the P-containing arm; p -4). However, overall survival was not improved by the addition of P to D; the HR for death was 0.90 (95% CI: 0.55-1.48; p = 0.68) median OS 15.9 months vs 12.4 months. Overall grade 3/4 toxicity was observed in 36 pts (DP) vs 30 (D) : neutropenia (32 pts vs 26), febrile neutropenia (8 vs 3), non-hematological toxicities (18 vs 6). Conclusions: PFS and OS weresurprisingly longer than expected in this cohort of NSCLC patients with metastasis, and comparable with that observed in historical cohorts of NSCLC treated in first-line. DP resulted in a non significant 27% reduction of hazard of progression as compared to D alone. A reduced statistical power related to a slow and insufficient accrual may explain this lack of significance. Considering survival data and toxicity profile, we suggest that these patients behave like first-line patients and may probably be treated accordingly with a platinum-based doublet. Clinical trial information: NCT00535275.

7515 Background: IFCT-0002 trial compared two perioperative CT regimens, CDDP-Gemcitabine vs.CBDCA-Paclitaxel in 528 stage I-II NSCLC patients. Paraffin-embedded post-chemo specimens were collected in the 490 non-complete responder patients for tissue expression studies of DNA-repair proteins. Methods: Surgical specimens were processed for immunohistochemistry as previously published. Variables were studied as continuous variables. Cut-off values were validated by bootstrap. Multivariate backward Cox regressions were used to adjust for patients’ characteristics associated with the corresponding outcome at p

7505 Background: Surgical resection followed by adjuvant platinum-based CT is the standard of care in stages II and III of NSCLC. ERCC1 is considered as a molecular determinant of benefit to platin-based CT and is an independent good prognostic marker in resected NSCLC. EGFR mutations predict for erlotinib efficacy. We included ERCC1 IHC status and EGFR mutational status in a prospective randomized multicentric phase II/III customized adjuvant CT trial. Methods: Completely resected patients (pts) with non-squamous tumors, mediastinal lymph node dissection and pathological stage IIA, IIB or IIIA (N2 excluded) (6th TNM edition) were randomized either to a control arm (A) or a customized arm (B). Surgical blocks were centralized for biomarkers analyses. The control arm encompassed 4 cycles of standard dose cisplatin-pemetrexed (CP). In the experimental arm, EGFR mutated pts received erlotinib 150 mg for one year. ERCC1 negative pts received four cycles of CP. ERCC1 positive pts were closely monitored. The Fleming’s single stage phase II primary endpoint was feasibility (ie % of patients able to start therapy within 2 months of surgery and for which the biomarker’s status was readily available) (H0 64%, H180%, α 5% and β 95%). Results: 150 pts were randomized between May 2009 and July 2012, 74 in arm A and 76 in arm B. Most pts were male (61%), ≤ 60 years (51%), and smokers (91%). Pathological stage was IIA in 69 pt, IIB in 48 pt and IIIA in 32 pt. ERCC1 was positive in 38 pts (19 in each arm), EGFR mutation was identified in 10 pts (3 in arm A, 7 in arm B). In arm A, all pts received CP. In arm B, 7 pts received erlotinib, 53 pts received CP and 16 were followed-up. The median exposure time to erlotinib was 276 days (10-365). Out of 127 pts allocated to CP, 82% received the expected 4 cycles with a very good tolerability profile (no febrile neutropenia). The success rate was 80% (120 out of 150 pts). Conclusions: This adjuvant trial met its primary end point for its phase II component, demonstrating the feasibility of a national biology-driven trial in the adjuvant setting. Nevertheless the phase III was canceled due to the unexpected unreliability of the ERCC1 IHC read-out. Clinical trial information: NCT00775385.

Background The IFCT-0501 randomised, phase 3 trial showed a significant survival benefit for the experimental arm using carboplatin-weekly paclitaxel doublet chemotherapy (Arm B) over vinorelbine or gemcitabine monotherapy (Arm A), in elderly patients with advanced NSCLC (Quoix et al, Lancet 2011; 378:1079-88). In case of progression or toxicity, second-line (2nd) treatment with erlotinib was administered in both arms. Here we report the results of this 2nd-line therapy. Methods Patients aged 70 to 89 years, with locally advanced or metastatic NSCLC, received erlotinib 150 mg daily as 2nd-line treatment until disease progression or excessive toxicity. Results Among 443 patients who completed first-line chemotherapy, 292 received 2nd-line erlotinib, at the same proportion in both arms (A: 64%, B: 67%, p = 0.46). Median duration of erlotinib treatment was not different according to first-line treatment arm, 2.01 and 2.24 months for arm A and arm B, respectively. Ability to receive 2nd-line treatment was significantly associated with performance status (0-1 vs. 2-3), weight loss (≤5% vs. >5%), MMS (≤23 vs. >23) and ADL ( 80), sex or histology (squamous vs. non squamous). Response evaluated after 2 months of erlotinib was: CR: 1 (0,35%), PR : 25 (8,77%) and SD : 63 (22,1%). From the Day 1 of erlotinib administration, median overall survival was 4 and 6.8 months in arm A and B, respectively, with a 1-yr survival rate of 26.4% and 33.7%, respectively (p = 0.08). Progression-Free Survival was 2.2 and 2.6 months, respectively (p = 0.36). Grade 3/4/5 toxicity was 19.9/1/0%. Conclusions In elderly patients with advanced NSCLC, administration of 2nd-line erlotinib is feasible, well tolerated, with a response rate comparable to that observed in previous trials, and maintained the survival advantage obtained with first-line carboplatin-weekly paclitaxel (NCT002598415). Disclosure E. Quoix: Travel grants for meetings : lilly roche Advisory board : Lilly,Roche Grants for the study given to IFCT: BMS, pierre Fabre, Roche. V. Westeel: stock ownership: No membership on an advisory board or board of directors: roche, Lilly corporate-sponsored research: Roche other substantive relationships: Roche, Lilly, AstraZeneca, Boehringer Ingelheim. B. Milleron: stock ownership: No membership on an advisory board or board of directors: Yes Lilly, Roche corporate-sponsored research: No other substantive relationships: travel grants from Lilly and Roche. All other authors have declared no conflicts of interest.

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

7007 Background: No survival differences was observed between any arms in the 528 early stage NSCLC randomized patients of the IFCT-0002 phase III trial comparing two chemotherapy timing, all pre- ...

2 Background: Incidence of advanced NSCLC in the elderly is increasing. Specific trials for elderly are seldom and those patients are not optimally treated. Current recommendations are monotherapies with gemcitabine or vinorelbine. Methods: French multicentric randomized phase III study in pts aged 70 to 89, PS 0-2 with advanced NSCLC not irradiable, comparing a 3-weekly single agent therapy (gemcitabine 1,150 mg/m2 or vinorelbine 30 mg/m2, d1, d8: arm A) with carboplatin AUC 6 every 4 weeks + paclitaxel 90 mg/m2 (d1,8,15) doublet (arm B). Five cycles of single agent and 4 cycles of the doublet were to be given. Second-line in case of toxicity or progressive disease was fixed with erlotinib 150 mg/d. The main endpoint was overall survival. Results: 451 pts were included from 04/2005 to 12/2009 by 60 centers. Males were 73.8%, median age was 77.2 years (range 70-89). PS was 0-1 in 73.6%. The 2 arms were well-balanced for pts characteristics. At time of second planned intermediate analysis (after two-third of expected deaths, i.e. 224), 451 pts were randomized, out of the 522 initially planned. The steering committee advice was to stop the inclusions. Overall survival of the 313 pts analysed at this time was significantly longer in arm B (median: 10.4 months, 95%CI: [8.2; 15.0] vs. 6.2 months, 95%CI: [5.3; 7.5] for arm A, (HR = 0.60, 95%CI : [0.46; 0.78], p = 0.0001). Median PFS was 6.3 months, 95%CI: [5.5; 6.9] in arm B vs. 3.2 months, 95%CI: [0.44; 0.70] (HR = 0.55, 95%CI: [0.44; 0.70], p < 0.0001). Grade 3-4 haematological toxicities were significantly more frequent in arm B (17.9% vs. 54.1%). No significant difference was observed in early deaths (arm A: 23.7%, arm B: 16.6%). Survival, response and toxicity data for the whole series of 451 pts will be updated at time of the meeting. Conclusions: Paclitaxel and carboplatin doublet provides a significantly longer survival in elderly pts with advanced NSCLC than current standard single agent therapy, with acceptable toxicity, making it a new treatment paradigm for PS 0-2 pts ≥ 70 years. [Table: see text]

8071 Background: A prospective multicentric trial evaluated gefitinib as 1st-line in non-resectable ADC-BAC. Tissue samples were collected to identify biomarkers associated with disease control, PF...