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Objectives In a phase Ib trial, afatinib plus cetuximab demonstrated promising clinical activity (objective response rate [ORR]: 29%; median progression-free survival [PFS]: 4.7 months) in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) with acquired resistance to erlotinib or gefitinib. Here, a separate cohort exploring afatinib plus cetuximab after progression on afatinib is reported. Materials and methods Patients with EGFR mutation-positive NSCLC who progressed on erlotinib or gefitinib received afatinib 40 mg daily until progression, followed by afatinib daily plus cetuximab 500 mg/m2 every 2 weeks until progression or intolerable adverse events (AEs). Endpoints included safety, ORR, and PFS. Results Thirty-seven patients received afatinib monotherapy. Two (5%) patients responded; median PFS was 2.7 months. Thirty-six patients transitioned to afatinib plus cetuximab. Four (11%) patients responded; median PFS was 2.9 months. Median PFS with afatinib plus cetuximab for patients who received afatinib monotherapy for ≥12 versus

Background: A is an irreversible ErbB family blocker that has shown clinical activity in pts with SCC of the head/neck and lung. This phase III trial prospectively compared A and E in pts with SCC of the lung following failure of platinum-based first-line chemotherapy. Methods: Pts with stage IIIB/IV SCC were randomized 1:1 to receive A (40 mg/day; n=335) or E (150 mg/day; n=334) until progression. The primary endpoint was PFS. Secondary endpoints were OS, ORR, DCR, patient-reported outcomes (PROs) and safety. Results: Baseline characteristics were well balanced between arms. Median PFS was significantly higher for A than E (2.4 vs 1.9 mths; HR [95% CI]: 0.82 [0.68–1.00]; p=0.04). Also, ORR (4.8 vs 3.0%; p=0.23) and DCR (45.7 vs 36.8%; p=0.02) were higher with A vs E. Overall AE profile was comparable (≥G3 AEs: 50.2 and 49.1%, serious AEs: 39.2 and 38.0% for A and E, respectively) with higher incidence of drug-related ≥G3 diarrhoea (9.7 vs 2.4%) and G3 stomatitis (3.3 vs 0%) with A and higher incidence of G3 rash/acne with E (5.5 vs 9.0%). AEs leading to treatment discontinuation were comparable (17.9 vs 13.9%). More pts had improved global health status/quality of life (36.4 vs 27.1%; p=0.03) with A than E. Changes in mean scores over time significantly favoured A vs E for cough, dyspnoea and pain. Primary OS, updated PFS, response and PRO data will be presented at the meeting. Conclusions: LL8 is the largest prospective trial comparing A vs E, an approved TKI in pts with pretreated SCC. PFS, DCR and improved global health status were significantly better for A than E. AEs were comparable and manageable.

Objectives Afatinib, an oral irreversible ErbB family blocker, has demonstrated efficacy in patients with epidermal growth factor receptor (EGFR) mutation-positive advanced lung adenocarcinoma. Other potential biomarkers predicting response to afatinib, such as human epidermal growth factor receptor-2 (HER2) mutations and EGFR gene amplification, have not been validated yet. This phase II study investigated whether afatinib conferred clinical benefit in cohorts of adenocarcinoma patients with: (1) EGFR mutation and failing on erlotinib/gefitinib; or (2) increased copy number of EGFR by fluorescence in situ hybridization (FISH); or (3) HER2 mutation. Materials and methods Patients started daily afatinib 50 mg monotherapy. Upon disease progression, patients could continue, at the investigator's discretion, afatinib (40 mg) with the addition of paclitaxel (80 mg/m2 weekly for 3 weeks/4-week cycle). Endpoints included confirmed objective response (OR), progression-free survival (PFS), disease control, and safety. Results Of 41 patients treated (cohort 1: n = 32; cohort 2: n = 2; cohort 3: n = 7), 33 received afatinib monotherapy; eight subsequently received afatinib plus paclitaxel. With afatinib monotherapy, one patient achieved a confirmed OR (partial response [PR]; cohort 2). Two further patients achieved unconfirmed PRs (one each in cohort 1 and cohort 3). Disease control was achieved by 17/32 (53%), 2/2 (100%) and 5/7 (71%) patients in cohorts 1, 2 and 3, respectively. In patients receiving combination therapy (median PFS: 6.7 weeks), one (cohort 3) had confirmed PR of 41.9 weeks. The most common afatinib-related adverse events were diarrhea (95%) and rash/acne (80%). Conclusion Afatinib demonstrated signs of clinical activity in heavily pretreated patients with activating HER2 or EGFR mutations or EGFR FISH-positive tumors.

EGFR-mutant lung cancers responsive to reversible EGFR inhibitors (gefitinib/erlotinib) develop acquired resistance, mediated by second-site EGFR T790M mutation in >50% of cases. Preclinically, afatinib (irreversible ErbB family blocker) plus cetuximab (anti-EGFR monoclonal antibody) overcomes T790M-mediated resistance. This phase Ib study combining afatinib and cetuximab enrolled heavily pretreated patients with advanced EGFR-mutant lung cancer and acquired resistance to erlotinib/gefitinib. Patients provided post–acquired-resistance tumor samples for profiling EGFR mutations. Among 126 patients, objective response rate (overall 29%) was comparable in T790M-positive and T790M-negative tumors (32% vs. 25%; P = 0.341). Median progression-free survival was 4.7 months (95% confidence interval, 4.3–6.4), and the median duration of confirmed objective response was 5.7 months (range, 1.8–24.4). Therapy-related grade 3/4 adverse events occurred in 44%/2% of patients. Afatinib–cetuximab demonstrated robust clinical activity and a manageable safety profile in EGFR-mutant lung cancers with acquired resistance to gefitinib or erlotinib, both with and without T790M mutations, warranting further investigation. Significance: This article reports the results of a trial combining afatinib and cetuximab in patients with acquired resistance and details the first clinical proof-of-concept for the preclinical hypothesis that a significant proportion of tumors in patients with acquired resistance to gefitinib/erlotinib remain dependent on EGFR signaling for survival. Cancer Discov; 4(9); 1036–45. ©2014 AACR. See related commentary by Gibbons and Byers, p. 991 This article is highlighted in the In This Issue feature, p. 973

e20510Background: Treatment (tx) options for patients (pts) with advanced SCC of the lung after progression on platinum-based chemotherapy are limited. In LL8, the irreversible ErbB family blocker, A, significantly improved OS, PFS and disease control rate vs E, a reversible EGFR TKI, in 795 pts with SCC of the lung. VeriStrat is a serum protein test that utilizes MALDI-TOF mass spectrometry to assign a ‘GOOD' (VS-G) or ‘POOR' (VS-P) classification and has demonstrated prognostic and predictive utility for EGFR targeted therapies in NSCLC.1 Here, the predictive ability of VeriStrat was tested in LL8; OS was the primary efficacy variable. Methods: Pre-tx serum samples, blinded to clinical outcome, were classified as VS-G or VS-P based on predefined reference groups. Clinical outcomes were analyzed with respect to VeriStrat status in the overall population (all pts with both clinical and VeriStrat data) and in predefined subgroups. Results: 675 pts were classified (VS-G: 412; VS-P: 263). In the VS-G group, ...

8002 Background: Treatment options for pts with advanced SCC of the lung progressing after platinum-based chemotherapy are limited. Overexpression of EGFR, ErbB receptors and the dysregulation of t...

Aim: While treatment options for SCC are limited, some pts derive modest benefit with erlotinib (E) or gefitinib (G). We previously reported interim data suggesting that A, an irreversible ErbB family blocker, had activity in pts with SCC (LL5, Part A). Subsequently, we demonstrated that continuation of ErbB blockade with A (plus P) in pts with non small cell lung cancer (NSCLC) progressing after benefit on E/G and A improved progression free survival (PFS),objective response rate (ORR) and disease control rate (DCR) vs IC (LL5, Part B). A pre-specified analysis of pts with SCC in LL5 is presented. Methods: Pts with advanced NSCLC who failed ≥1 line of chemotherapy and E/G (after ≥12 wks benefit) were treated with A (50 mg/day; n = 1154; Part A). Upon progression on A (after >12 wks benefit), pts were randomized to receive A + P (40 mg/day, 80 mg/m2/week; n = 134) or IC (n = 68; Part B). The primary endpoint was PFS in Part B (RECIST 1.1). Results: 90 pts with SCC received A in Part A (median age: 63 years; male: 71%; East Asian: 31%; never smoked: 24%). Median PFS was 3.7 months, ORR was 6%, DCR was 60.0%. Seventeen pts met eligibility criteria for Part B randomization and were treated with A + P (n = 11) or IC (n = 6). Median PFS (8.8 vs 1.9 months; p = 0.003) and OS (14.9 vs 6.6 months; p = 0.433) were observed to be longer with A + P vs IC. ORR (45.5% vs 0.0%) and DCR (72.7% vs 16.7%) were both higher with A + P than IC. In Part A, diarrhea (83.3%; grade 3, 13.3%) and rash (60.0%; grade 3, 10.0%) were the most frequently reported adverse events (AEs) in pts with SCC. In Part B, 8 (72.7%) and 2 (40.0%) SCC pts experienced grade 3 AEs with A + P and IC, respectively. The most common AEs were asthenia (27.3%) and diarrhea (18.2%). 22.2% of pts discontinued A due to AEs (Part A); 27.3% of pts discontinued A+ P due to AEs (Part B). Conclusions: In this small group of pts with SCC we observed prolonged PFS, higher OR and trend towards longer OS in patients treated with A + P vs IC following A. Such signs of activity with both A and A + P in this difficult-to-treat population are encouraging and warrant further investigation. AEs were similar to those observed in the whole trial. Disclosure: K. Park: Advisory Boards for: Astellas, AstraZeneca, Boehringer Ingelheim, Clovis, Eli Lilly, Roche, Novartis, Kyowa Hakko Kirin; J. Kim: Sponsor initiated trial from Pfizer, Boeringer Ingelheim, Lilly, Roche; M. Schuler: Advisory board: AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer Corporate sponsored research: Boehringer Ingelheim, Novartis Other substantive relationships: University Duisburg-Essen (Patents); D. Planchard: Advisory board: AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Pfizer; F. De Marinis: Advisory board: Pfizer, Boehringer, Roche; Y. Chen: Advisory board: Roche, Astra-Zeneca; C. Zhou: Advisory board: BI, Roche, Lily; J. Bennouna: Advisory board: Boehringer Ingelheim, Roche, Novartis; J. Feng: Corporate sponsored research: Boehringer Ingelheim; C. Chouaid: Advisory board: Lilly, Boeringher Ingelheim, Amgen, Roche; L. Ho: Advisory board:Boehringer Ingelheim Corporate sponsored research: Taiwan Lung Cancer Clinical Trial Consortium (TALCC); V. Chand: Corporate sponsored research: Employee of Boehringer Ingelheim Pharm. Inc. Other substantive relationships: Employee of Boehringer Ingelheim Pharm. Inc.; J. Yang: Advisory board: Astrazeneca, Boehringer Ingelheim, Roche/Genetech, Merck Serono, Pfizer, Clovis Oncology, Novartis, Eli Lilly, Takeda, Innopharma, Bayer Corporate sponsored research: Boehringer Ingelheim. All other authors have declared no conflicts of interest.

Aim: A is an irreversible ErbB family blocker that has shown promising clinical activity in pts with SCC of the head/neck and lung. Here, we report results of LL8, a phase III trial that prospectively compared A and E in pts with SCC of the lung following failure of first-line chemotherapy. Methods: Eligible pts with stage IIIB/IV SCC were randomized 1:1 to receive A (40 mg/day; 50 mg/day from Cycle 2 for pts meeting AE criteria) or E (150 mg/day) until disease progression. All pts had progressed after ≥4 cycles of platinum-based doublet chemotherapy and had not received prior EGFR TKIs. Pts were stratified based on race (eastern Asian vs other). The trial was powered for PFS and OS. The primary endpoint was PFS (RECIST 1.1) as assessed by independent radiological review (IRR). Secondary endpoints included overall survival (OS; planned at 632 events), objective response rate (ORR), disease control rate (DCR) and safety. Overall 795 pts were recruited between March 2012 and January 2014. Planned primary analysis was based on 414 PFS events by IRR in the first 669 patients randomized (A: 335, E: 334) while recruitment was ongoing. Results: Baseline characteristics were well balanced between arms: median age 65y; male 85%; eastern Asian 22%; never smoker 5%. Median PFS was significantly higher for A than E, both by IRR (2.4 vs 1.9 months; HR [95% CI]: 0.82 [0.68–1.00]; p = 0.043) and investigator review (2.7 vs 1.9 months; HR [95% CI]: 0.78 [0.65–0.93]; p = 0.005). Furthermore, ORR (4.8% vs 3.0%; p = 0.233) and DCR (45.7% vs 36.8%; p = 0.020) were higher with A vs E. Overall AE profile was comparable (pts with ≥G3 AEs: 50.2 and 49.1% for A and E) with higher incidence of drug-related ≥G3 diarrhoea (9.7 vs 2.4%) and G3 stomatitis (3.3 vs 0.0%) with A and higher incidence of G3 rash/acne with E (5.5 vs 9.0%). Conclusions: LL8 is the largest prospective trial to compare EGFR TKIs in pts with relapsed/refractory SCC. PFS and DCR were significantly better for A than E. AEs were comparable and consistent with the mechanistic profile of EGFR inhibition. Disclosure: G. Goss: Advisory board for Boehringer Ingelheim prior to initiation of study; E. Felip: Advisory Boards for: Boehringer Ingelheim, Novartis, Roche and Bristol Myers Squibb; S. Lu: Advisory Boards for: AstraZeneca and Boehringer Ingelheim; K.N. Syrigos: Advisory boards for Roche, Novartis and Leo; A. Morabito: Advisory Boards for: Lilly and Italfarmaco; A. Ardizzoni: Advisory Boards for: Boehringer Ingelheim, MSD, BMS, Lilly, GSK, Daiichi, Pierre Fabre, Pfizer; S. Gadgeel: Advisory Boards for: BI, Novartis and Genentech; J. Love: Employee of Boehringer Ingelheim; V. Chand: Employee of Boehringer Inhelheim J. Soria: Advisory Boards for: Boehringer Inhelheim. All other authors have declared no conflicts of interest.

Background Patients with advanced squamous cell carcinoma (SCC) of the lung have limited treatment options. Although treatment with the EGFR tyrosine kinase inhibitor erlotinib is indicated in the second- or third-line or maintenance setting, the benefit is limited. Afatinib is a novel, selective, orally bioavailable, ErbB family blocker, irreversibly blocking EGFR (ErbB1), HER2 (ErbB2) and HER4 (ErbB4). Based on its promising preclinical profile and clinical activity in trials of SCC of the head and neck and lung, we seek to determine if the irreversible inhibition of the ErbB family translates into clinical benefit for patients with SCC of the lung. Methods This trial will compare the efficacy of afatinib versus erlotinib as second-line treatment for patients with SCC of the lung, as measured by progression-free survival. Key patient eligibility criteria include: advanced NSCLC squamous or mixed histology, completion of at least 4 cycles of platinum-based doublet chemotherapy, eligible to receive EGFR-directed therapy as second-line therapy, ECOG PS 0–1, adequate organ function, availability of archived tumour tissue for correlative studies and no prior EGFR-directed therapy. Secondary endpoints are comparison of overall survival, objective response rate, disease control rate, tumour shrinkage, assessment of health-related quality of life and safety in both treatment groups. Eligible patients will be randomized (1:1) to receive either afatinib or erlotinib and stratified based on race (East Asian vs. other). Eight hundred patients are planned to be enrolled globally. Independent radiological assessment of the primary endpoint will be completed in a treatment-blinded manner. An independent data monitoring committee will monitor safety and efficacy of the trial. Disclosure G. Goss: Consultant or advisory relationship to Boehringer Ingelheim, compensated prior to conduct of the study. S. Lu: Consultant or advisory relationship, compensated, AstraZeneca China for Iressa. A. Ardizzoni: Other remuneration: GSK DSMC PRAME Study. V. Georgoulias: Consultant or advisory relationship, uncompensated for GSK, Novartis, Sanofi, Janssen-Cilag, Amgen. Honoraria and research funding from GSK, Novartis, Sanofi, Janssen-Cilag, Amgen. S. Gadgeel: Consultant or advisory relationship for Boehringer Ingelheim. V. Chand: Employee of Boehringer Ingelheim Pharmaceuticals, Inc. Y. Gu: Employee of Boehringer Ingelheim Pharmaceuticals, Inc. Y.S. Olivo: Employee of Boehringer Ingelheim Pharmaceuticals, Inc. J. Soria: Honoraria from Boehringer Ingelheim and Roche. All other authors have declared no conflicts of interest.

7557 Background: The benefit of sustained ErbB family blockade in NSCLC patients with acquired resistance (AR) to EGFR TKIs is unknown. We investigated afatinib, an irreversible blocker of EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptor tyrosine kinases, in patients with metastatic NSCLC, who had failed chemotherapy and E/G. Methods: This was a Phase III, randomized, open-label, multi-center trial. Patients with pathologically confirmed Stage IIIB/IV metastatic NSCLC after ≥1 line of chemotherapy who failed E/G received oral afatinib 50 mg until disease progression (Part A). After progression, patients with clinical benefit (≥12 wks) were eligible to continue afatinib 40 mg plus paclitaxel or receive investigator’s choice chemotherapy (Part B). Primary endpoint for Part A was PFS (RECIST 1.1; CT scan every 6 wks). Available tumor samples were collected for central EGFR mutation testing; local mutation data were also collected. An interim analysis of Part A, assessing afatinib monotherapy, is reported. Results: Part A enrolled April 2010 through to May 2011; 1154 patients received afatinib monotherapy. The majority had adenocarcinoma (85%), 57% were female, 43% were Asian, 54% were never smokers. Best response to prior E/G was CR (2%), PR (31%), SD (42%) and PD (20%). Median PFS for afatinib was 3.3 mths; 88 patients (8%) achieved an objective tumor response, 648 (56%) had SD. For EGFR mutation positive patients (n=49, centrally confirmed), PFS was 4.2 vs. 2.6 mths for EGFR mutation negative patients (n=35). When applying clinical enrichment criteria for AR, PFS was 4.2 mths for those with enrichment (n=597) vs. 2.8 mths for those without (n= 557; logrank test p

7558 Background: Patients with squamous NSCLC have limited treatment options. For those deriving benefit from EGFR TKIs, it is unclear whether sustained ErbB family blockade offers benefit upon progression. We evaluated afatinib, an irreversible blocker of EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptor tyrosine kinases, in patients with metastatic NSCLC who had failed chemotherapy and E/G. Here we describe a pre-specified analysis of those with squamous histology in Part A. Methods: This randomized Phase III, open-label, multi-center trial enrolled patients with pathologically confirmed metastatic NSCLC after failing ≥1 line of cytotoxic chemotherapy and E/G. In Part A, patients received oral afatinib 50 mg until disease progression. Those with clinical benefit (≥12 wks) who progressed were eligible to receive afatinib plus paclitaxel or investigator’s choice chemotherapy (Part B). Primary endpoint was PFS (RECIST 1.1). Following an amendment, an interim analysis of Part A was performed to assess afatinib monotherapy. Results: Patient enrolment into Part A was from April 2010 to May 2011. Of 1154 afatinib-treated patients, 91 (8%) had squamous histology; 18/91 and 40/91 had CR/PR and SD on prior E/G, respectively (by investigator). Median age was 63 yrs, 71% were male, 76% were current/ex-smokers. Median PFS on afatinib was 3.7 mths in the squamous histology subset. Of 91 patients, 42 had PFS ≥3 mths; 13 had PFS of ≥6 mths. In evaluable patients (n=77), 1 CR and 3 PRs were confirmed; 51 and 22 patients had best overall response of SD and PD, respectively. Of the 31 patients with PD on prior E/G with no intervening chemotherapy, 10 achieved confirmed disease control (2 PR; 8 SD) on afatinib. Most commonly reported grade 3/4 adverse events (AEs) in Part A were diarrhea (13%) and rash/acne (12%). The safety profile in the squamous histology subset was similar to that observed for the whole trial. Conclusions: Afatinib monotherapy demonstrated encouraging activity in treatment-refractory NSCLC patients with squamous histology that merits further evaluation.