W. Su

449PDUPDATED SAFETY AND EFFICACY FROM A PHASE I STUDY OF AZD9291 IN PATIENTS (PTS) WITH EGFR-TKI-RESISTANT NON-SMALL CELL LUNG CANCER (NSCLC)

ABSTRACT Aim: AZD9291 is a potent, selective, irreversible EGFR-TKI, effective against the EGFR-TKI-sensitising (EGFRm+) and resistance T790M mutations. Here we report updated data from the ongoing Phase I study of AZD9291 in pts with EGFRm+ NSCLC (AURA; NCT01802632). Methods: Pts with EGFRm+ NSCLC and acquired resistance to EGFR-TKIs were enrolled in a multicentre trial into dose escalation and expansion cohorts. AZD9291 was administered orally, at doses of 20–240 mg once daily. Stable brain metastases were allowed. Primary objective was safety and tolerability; anti-tumour activity was a secondary objective. Prospective mandatory central T790M testing was required in the expansion cohorts and was optional for dose escalation cohorts. Results: As of 2 April 2014, 232 pts (female 63%, median age 60, Asian/Caucasian 64%/34%, immediate prior EGFR-TKI therapy 60%) were enrolled: 31 pts in the dose escalation and 201 pts in the dose expansion cohorts, of whom 120 were T790M+ by central tumour testing. Adverse events (AEs) were mostly mild (CTCAE Grade 1/2), with diarrhoea (39%), rash (36%) and nausea (18%) the most commonly reported. 8 pts (3%) had dose reductions. Grade ≥3 AEs occurred in 24% of pts. There were 8 ILD-like reports. At the recommended Phase II dose of 80 mg QD, rash and diarrhoea occurred in 27% (Grade 3, 0%) and 20% (Grade 3, 1%) of pts, respectively. Among all evaluable pts to date, RECIST responses were observed at all dose levels. The confirmed overall response rate (ORR) in patients with centrally tested EGFR T790M+ tumours was 56% (56/100; 95% CI 46, 66%) and in patients with EGFR T790M- tumours the confirmed ORR was 17% (8/48; 95% CI 8, 30%). In 56 pts with EGFR T790M+ tumours and confirmed response: longest duration of response to date was ongoing at approx 7.5 months; 7/56 pts responded for at least >6 months and 46/56 have an ongoing response Conclusions: AZD9291 has been well tolerated at all dose levels tested. Clinical activity has been shown in pts with centrally confirmed EGFR T790M+ NSCLC, with durable responses of >6 months. Disclosure: J.C. Yang: Advisory board: Boehringer Ingelheim, Eli Lilly, Pfizer, Novartis, Roche/Genentech, AstraZeneca, Merck, Bayer, Clovis Oncology. Corporate-sponsored research: Boehringer Ingelheim; D. Planchard: Advisory boards: AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Pfizer, Roche, BMS S.S. Ramalingam: Advisory boards: AstraZeneca, Boehringer Ingelheim, Genentech; L. Horn: Research funding: Astellas. Compensated advisory boards: Bristol-Myers Squibb, Clovis, Helix Bio. Uncompensated advisory boards: PUMA, Xcovery. Steering Committee (uncompensated): Bayer. Honoraria: Boehringer Ingelheim; E. Felip: Advisory boards: Boehringer Ingelheim, Novartis, Roche, BMS, Lilly; P. Frewer, M. Cantarini and S. Ghiorghiu: Employment and stock ownership: AstraZeneca; M. Ranson: Advisory boards: AstraZeneca; P.A. Janne: Consultant or advisory role: AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Pfizer, Merrimack Pharmaceuticals, Chugai, Immunogen. Stock ownership: Gatekeeper. Other: Lab Corp. All other authors have declared no conflicts of interest.

812PDMATURE SURVIVAL (OS) DATA OF A RANDOMISED INTERNATIONAL PHASE II TRIAL (JASINT1): VINFLUNINE (VFL)-GEMCITABINE (GEM) VS. VFL-CBDCA IN CDDP-UNFIT PATIENTS (PTS) WITH ADVANCED UROTHELIAL CARCINOMA (UC)

ABSTRACT Aim: There is no standard 1st line chemotherapy (CT) for advanced or metastatic UC in pts unfit for a CDDP-based regimen. VFL, an EMA approved agent in the post-platinum setting has shown to be safe in pts with renal impairment. The study aimed to assess the benefit/risk ratio of 2 VFL-based CT regimens in UC. Methods: Pts with a creatinine clearance (CrCl) Results: 69 pts (34 arm A, 35 arm B) were enrolled over 18 months: at the median (med) follow-up of 25.9 mo 74% pts had died. Pts characteristics were similar in both groups: med age 70 yrs; PS 0 / 1 in 42% / 58%; primary sites: 52% bladder and 46% upper tract; visceral mets 49%, med CrCl 46mL/min. Med number of cycles was 5 (A) and 4 (B). More haematological G3/4 adverse events (AE) were reported in arm B: neutropenia in 68% (vs 38%) and febrile neutropenia in 14% (vs 3%) of pts. Main non-haematological G3/4 AE were fatigue (21.7%), infection (7.2%), and constipation (4.3%) without major difference between arms. DCR was 77% in both groups; ORR was 44.1% vs 28.6%, med PFS 5.9 vs 6.1 mo and med OS 14.0 vs 12.8 mo in arms A and B, respectively. Cause of death: progression in 90%, 1 drug-related AE (B), other reasons in 8%. Further anticancer drugs: 59% (A) and 51% (B); CBDCA, GEM and paclitaxel in 23%, 29% and 30%, respectively, with more taxanes in arm A (35%) and more GEM in arm B (37%). Conclusions: Both VFL doublets are feasible with a similar DCR. However, a higher ORR and OS, while showing less haematological toxicity, favour VFL-GEM which warrants further clinical study. Disclosure: M. De Santis: Advisory board: Laboratoire Pierre Fabre Corporate-sponsored research: Laboratoire Pierre Fabre Consultancy: Laboratoire Pierre Fabre; C. Lucas: Pierre Fabre employee; J. Bellmunt: Advisory board member of Laboratoires Pierre Fabre; K. Legrand and R. Fougeray: Laboratoires Pierre Fabre employee; S. Culine: Advisory board member and consultancies for Laboratoires Pierre Fabre. All other authors have declared no conflicts of interest.

1300PBUPARLISIB (BKM120) IN PATIENTS WITH PI3K PATHWAY-ACTIVATED, METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC): RESULTS FROM THE BASALT-1 STUDY

ABSTRACT Aim: In vitro, NSCLC cell lines with PIK3CA mutations have shown increased sensitivity to the oral pan-PI3K inhibitor buparlisib (BKM120). BASALT-1 is an open-label, two-stage, Phase II study to assess the safety and efficacy of buparlisib in patients (pts) with pre-treated metastatic NSCLC (squamous [sq] and non-squamous [non-sq] histology) and activated PI3K pathway (NCT01297491). Here we report results from the Stage 1 futility analysis (FA) for each histology. Methods: Pts (≥18 yrs) with previously treated, metastatic NSCLC (sq or non-sq histology) with activated PI3K pathway (defined as PIK3CA mutation and/or PTEN mutation and/or PTEN-negative staining [ Results: Thirty pts had been treated in each histologic group at the time of FA (>1200 pts screened). In the sq group, 21 pts were male (median age: 65.5 yrs); in the non-sq group, 19 pts were male (median age: 62.0 yrs). Median treatment exposure was 6.9 (sq group) and 7.2 (non-sq group) wks. Median PFS was 2.79 (95% CI: 1.38, 4.11) and 2.69 (95% CI: 1.41, 2.89) months for the sq and non-sq groups, respectively. PFS rate at 12 wks was 23.3% (95% CI: 9.9, 42.3) for the sq group and 20.0% (95% CI: 7.7, 38.6) for the non-sq group. Best overall responses (RECIST 1.1): partial response (1 pt [3.3%] in each group), stable disease (14 pts [46.7%] in each group), progressive disease (7 pts [23.3%] sq / 9 pts [30.0%] non-sq), unknown (8 pts [26.7%] sq / 6 pts [20.0%] non-sq). Most common (≥30%) AEs possibly related to study drug: hyperglycemia (36.7%), pruritus (33.3%), diarrhea (30%), and nausea (30%) for sq, and asthenia (30%) for non-sq. Conclusions: In this PI3K pathway-activated group of NSCLC pts, the futility criterion in Stage 1 was met in both histology groups. Thus, enrollment of Stage 2 was not initiated. Results of this study are in line with previous observations where single agents targeting the PI3K pathway have shown marginal activity. Studies of buparlisib in combination with docetaxel in pts with sq NSCLC are ongoing. Disclosure: J. Soria: - Research funds from Novartis (Instititution) - Compensated advisory board Novartis F. Grossi: Novartis advisory board; E. Felip: Advisory Board: BI, Novartis, Roche, BMS, Lilly; M. Thomas: AD-Board honoraria: Novartis, Roche, Lilly, BMS Speaker honoraria: BMS, Lilly; P. Roussou: - Novartis employee - Shares in Novartis; G. Atalla-Vidam: Novartis employee; P. Aimone: Novartis employee. All other authors have declared no conflicts of interest.

1228PDEPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITOR TREATMENT RESPONSE IN ADVANCED NON-SMALL CELL LUNG CANCER WITH G719X/L861Q/S768I MUTATIONS

ABSTRACT Aim: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are very effective for lung cancers with classical sensitive EGFR mutations; however, their role in tumors with uncommon mutations, such as G719X, L861Q and S768I, is still not clear. Previous studies are limited by their small sample size. Taiwan Lung Cancer Society, in conjunction with Taiwan Lung Cancer Clinical Trial Consortium, initiated a study to evaluate the clinical effectiveness of EGFR-TKI in patients with advanced non-small cell lung carcinoma (NSCLC) bearing EGFR G719X, L861Q and/or S768I mutations. Methods: Patients were eligible if they had stage IIIB or IV NSCLC bearing G719X, L861Q or S768I mutations, had been treated by gefitinib or erlotinib, and did not receive other anti-tumor therapy during EGFR-TKI treatment. Patients with tumors that had concomittant classical sensitive (exon 19 deletions and L858R mutation) or resistant (T790M and exon 20 insertions) mutations were excluded. Results: Totally 226 cases were screened from 18 institutes throughout Taiwan. One hundred and sixty-one cases were eligible and all were adenocarcinomas. Among them, 56.5% were female, 68.8% were never smokers, 95.7% were stage IV, 76.4% were PS 0-1, and 78.9% were treatment-naive. EGFR mutation status were G719X of 78 cases, L861Q of 58, S768I of 7, G719X + L861Q of 8, and G719X + S768I of 10. One hundred and twenty-seven patients were treated by gefitinib and 34 by erlotinib. Four hundred and eighty-three patients who had classical sensitive EGFR mutations and were treated by EGFR-TKI were served as the control. EGFR-TKI treatment outcomes are summarized in the Table. Patients with G719X/L861Q/S768I mutations had inferior response rate and shorter progression free survival than patients with exon 19 deletions or L858R mutations (both P ORR DCR PFS G719X/L861Q/S768I (n = 161) 40.5% 75.8% 7.7m L858R mutations (n = 253) 67.6% 95.7% 10.4m exon 19 deletions (n = 223) 64.5% 94.6% 14.1m Conclusions: Patients with advanced lung adenocarcinomas of EGFR G719X/L861Q/S768I mutations had suboptimal treatment outcome to EGFR-TKI. Prospective randomized trials are warranted to decide the most appropriate therapy for patients with these uncommon mutations. Disclosure: C. Chiu: I have received honorarium from AstraZeneca, Boehringer Ingelheim and Roche. All other authors have declared no conflicts of interest.