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Adverse events of any grade.

Adverse events of any grade and any causality.

Patient-level clinical outcome data (overall survival) and bTMB scores

GuardantOMNI assay success rates

Comparison of tTMB values

Performance of germline/somatic betabinomial classifier

ctDNA assay and bTMB algorithm methods

Purpose:Tumor mutational burden (TMB) has been shown to be predictive of survival benefit in patients with non–small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors. Measuring TMB in the blood (bTMB) using circulating cell-free tumor DNA (ctDNA) offers practical advantages compared with TMB measurement in tissue (tTMB); however, there is a need for validated assays and identification of optimal cutoffs. We describe the analytic validation of a new bTMB algorithm and its clinical utility using data from the phase III MYSTIC trial.Patients and Methods:The dataset used for the clinical validation was from MYSTIC, which evaluated first-line durvalumab (anti–PD-L1 antibody) ± tremelimumab (anticytotoxic T-lymphocyte-associated antigen-4 antibody) or chemotherapy for metastatic NSCLC. bTMB and tTMB were evaluated using the GuardantOMNI and FoundationOne CDx assays, respectively. A Cox proportional hazards model and minimal P value cross-validation approach were used to identify the optimal bTMB cutoff.Results:In MYSTIC, somatic mutations could be detected in ctDNA extracted from plasma samples in a majority of patients, allowing subsequent calculation of bTMB. The success rate for obtaining valid TMB scores was higher for bTMB (809/1,001; 81%) than for tTMB (460/735; 63%). Minimal P value cross-validation analysis confirmed the selection of bTMB ≥20 mutations per megabase (mut/Mb) as the optimal cutoff for clinical benefit with durvalumab + tremelimumab.Conclusions:Our study demonstrates the feasibility, accuracy, and reproducibility of the GuardantOMNI ctDNA platform for quantifying bTMB from plasma samples. Using the new bTMB algorithm and an optimal bTMB cutoff of ≥20 mut/Mb, high bTMB was predictive of clinical benefit with durvalumab + tremelimumab versus chemotherapy.

Analytical validation of the GuardantOMNI bTMB assay

MYSTIC study design

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 The efficacy of afatinib, an irreversible ErbB Family Blocker, was evaluated in patients who had 1 of 4 categories of solid tumors with epidermal growth factor receptor/human epidermal growth factor receptor 2 (EGFR/HER2) gene amplification or EGFR-activating mutations. METHODS Patients with previously treated but ErbB inhibitor-naive esophagogastric, biliary tract, urothelial tract, or gynecologic cancers (lung cancers were excluded) harboring EGFR/HER2 gene amplification or high polysomy were identified by fluorescence in situ hybridization (FISH). Tumors were also screened for EGFR mutations. The primary endpoint was the objective response rate; secondary endpoints included the clinical benefit rate, pharmacokinetics, and safety. RESULTS Of 385 prescreened patients, 38 had FISH-positive tumors (10 with EGFR amplification and 29 with HER2 amplification or high polysomy [1 tumor had EGFR/HER2 high polysomy]; none had EGFR-activating mutations), and 20 patients received treatment with afatinib 50 mg daily. The objective response rate was 5% (1 of 20 patients), and the best objective response included 1 complete response. Eight patients experienced stable disease. The most frequently reported adverse events were diarrhea, rash, and decreased appetite. The trial closed early because of slow recruitment. CONCLUSIONS Single-agent afatinib activity was limited, yet encouraging, in selected tumors that were screened prospectively for target activation. The implementation of a biomarker-driven approach using a low-frequency biomarker for patient selection across multiple tumor types can be challenging. Cancer 2013;119:3043—3051. © 2013 American Cancer Society.

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.

When uncomplicated neutropenia during doxorubicin (Adriamycin), bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy for the treatment of Hodgkin's lymphoma is encountered, it is unclear whether or not treatment should be modified. In the present study, we determined the incidence of neutropenia, febrile neutropenia, and the relationship of febrile neutropenia to grade III/IV neutropenia and dose modification, in a large university patient population. We reviewed the charts of patients diagnosed with Hodgkin's lymphoma between 1 January 1990 and 31 December 2002 who were treated with ABVD chemotherapy, and seen at the University of Iowa with complete diagnosis, staging, and treatment dosing records. Adequate data was available on 894 treatments in 81 patients with Hodgkin's lymphoma treated with ABVD chemotherapy. Grade III/IV neutropenia was present on the scheduled day of treatment in 187 (20.9%) treatments in 64 (79%) patients. Grade III/IV neutropenia was most common at cycle 1 day 15. Febrile neutropenia developed nine times in eight patients, and eight episodes of febrile neutropenia developed when the treatment-day absolute neutrophil count (ANC) > or =1000. Dose delay of >4 days and/or dose reduction to

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

Until recently, the monitoring of elections in a sovereign country by outside actors was extremely rare. The United Nations (UN) had significant experience in conducting plebiscites and elections in dependent territories but did not monitor an election in a formally independent country until 1989 when it reluctantly became involved in the Nicaraguan electoral process. At the regional level, the Organization of American States (OAS) occasionally sent small delegations to witness elections in member states, but these missions were too brief to permit any real observation of the processes, and failed to criticize fraud.1 Since the 1980s election-monitoring has become increasingly common in transitional elections from authoritarian to democratic rule. Non-governmental organizations (NGOs), domestic and international, were the first to become involved in election-monitoring in the 1980s followed by international and regional organizations like the UN, the OAS and the Organization for Security and Cooperation in Europe (OSCE) in the 1990s. Election-monitors played a crucial role in transitional elections held in the Philippines (1986), Chile (1989), Panama (1989), Nicaragua (1990) and Haiti (1990). In addition, elections began to form a crucial element of UN ‘peacebuilding’ strategies in countries torn apart by civil strife such as Namibia (1989), Cambodia (1993) and El Salvador (1994).

The efficacy of afatinib, an irreversible ErbB Family Blocker, was evaluated in patients who had 1 of 4 categories of solid tumors with epidermal growth factor receptor/human epidermal growth factor receptor 2 (EGFR/HER2) gene amplification or EGFR-activating mutations.Patients with previously treated but ErbB inhibitor-naive esophagogastric, biliary tract, urothelial tract, or gynecologic cancers (lung cancers were excluded) harboring EGFR/HER2 gene amplification or high polysomy were identified by fluorescence in situ hybridization (FISH). Tumors were also screened for EGFR mutations. The primary endpoint was the objective response rate; secondary endpoints included the clinical benefit rate, pharmacokinetics, and safety.Of 385 prescreened patients, 38 had FISH-positive tumors (10 with EGFR amplification and 29 with HER2 amplification or high polysomy [1 tumor had EGFR/HER2 high polysomy]; none had EGFR-activating mutations), and 20 patients received treatment with afatinib 50 mg daily. The objective response rate was 5% (1 of 20 patients), and the best objective response included 1 complete response. Eight patients experienced stable disease. The most frequently reported adverse events were diarrhea, rash, and decreased appetite. The trial closed early because of slow recruitment.Single-agent afatinib activity was limited, yet encouraging, in selected tumors that were screened prospectively for target activation. The implementation of a biomarker-driven approach using a low-frequency biomarker for patient selection across multiple tumor types can be challenging.

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: A is an irreversible ErbB family blocker. In Part A of the open-label LL5 study, pts with advanced NSCLC who had failed ≥1 line of chemotherapy and erlotinib/gefitinib received A (50 mg/day; n = 1154). In Part B, pts with >12 weeks of clinical benefit on A were eligible for randomisation and received A + P (40 mg/day, 80 mg/m2/week; n = 132) or IC (n = 60). A + P significantly improved progression-free survival (PFS) vs IC (5.6 vs 2.8 months; HR 0.6; p = 0.003); overall survival was similar (12.2 vs 12.2 month; HR 1.0; p = 0.994). Pre-specified PRO analyses are presented here. Methods: Lung cancer symptoms were assessed every 28 days until progression using the EORTC (QLQ-C30/LC13) questionnaires. Analyses of cough, dyspnea and pain were preplanned, including percentage of patients improved on therapy, time-to-deterioration (TTD) of symptoms and change in symptoms over time. Results: Baseline symptom burden was low. Median TTD in Part A was 2.8, 2.8 and 4.5 months for dyspnea, pain and cough, respectively. In Part B, compared with IC, A + P showed a trend delaying TTD for dyspnea (3.1 vs 1.8 months; HR [95% CI] 0.78 [0.55, 1.09]; p = 0.144) and pain (4.3 vs 3.5 months; HR [95% CI] 0.80 [0.56, 1.14]; p = 0.212) but not cough (5.7 vs 6.5 months; HR [95% CI] 1.13 [0.79, 1.62]; p = 0.505). Numerically, more A + P than IC patients showed improvements in dyspnea (45% vs 35%; p = 0.222) and cough (46% vs 36%; p = 0.225). Differences in mean scores over time also numerically favored A + P over IC for dyspnea (-2.9; p = 0.191) and cough (-3.8; p = 0.201). There was no significant change in the global health status (GHS)/quality of life (QoL) scale of QLQ-C30 over time with A + P (p = 0.767). Conclusions: A + P showed trends for symptom improvement and delayed TTD vs IC in heavily-pretreated NSCLC patients. GHS/QoL was maintained over time despite a doubling of median treatment time and PFS with A + P. Disclosure: D. Planchard: I have attended Advisory Boards for: AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Pfizer and Roche; K. Park: Advisory Boards for: Astellas, AstraZeneca, Boehringer Ingelheim, Clovis, Eli Lilly, Roche, Novartis, Kyowa Hakko Kirin; J. Yang: Advisory Boards for: AstraZeneca, Boehringer Ingelheim, Roche/Genentech, Merck Serono, Pfizer, Clovis Oncology, Novartis, Eli Lilly, Takeda, Innopharma, Bayer Corporate sponsored research for: Boehringer Ingelheim; J. Kim: Sponsor initiated trials for: Pfizer, Boehringer Ingelheim, Lilly and Roche; F. De Marinis: Advisory Board for: Pfizer, Boehringer Ingelheim and Roche; Y. Chen: Advisory Boards for: Roche, AstraZeneca; J. Feng: Corporate sponsored research for Boehringer Ingelheim; C. Chouaid: Advisory Boards for: Lilly, Boehringer Ingelheim, Amgen and Roche; S. Lu: Advisory Boards for: AstraZeneca and Boehringer Ingelheim; R. Wiewrodt: Advisory Boards for: Boehringer Ingelheim, Grifols, Lilly, Novartis, Roche, Talecris Corporate sponsored research for: Bayer, Boehringer Ingelheim, Lilly, Genentech, Roche; C. Zhou: Advisory Boards for: Boehringer Ingelheim, Roche and Lilly; J. Bennouna: Advisory Boards for: Boehringer Ingelheim, Roche and Novartis; J. Lungershausen: Employee of Boehringer Ingelheim; B. Wang: Employee of: Boehringer Ingelheim; V. Chand: Corporate sponsored research: Boehringer Ingelheim Employee of: Boehringer Ingelheim; M. Schuler: Advisory Board for: AstraZeneca, Boehringer Ingelheim, Novartis and Pfizer Corporate sponsored research: Boehringer Ingelheim and Novartis Patents for: University Duisburg-Essen. All other authors have declared no conflicts of interest.

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.

8063 Background: EGFR mutation+ (M+) NSCLC pts have an improved response to EGFR TKIs vs non-M+ pts. Data on EGFR FISH+ (gene amplified) and HER2 M+ pts are, however, limited. Afatinib is an irreversible ErbB Family Blocker with efficacy in Ph II/III trials in EGFR M+ NSCLC. This exploratory, open-label trial assessed afatinib in 3 genotypically and demographically defined NSCLC groups. Methods: Never/ex-smokers with stage IIIB/IV lung adenocarcinoma with EGFR M+ tumors who had failed prior EGFR TKIs, HER2 M+ tumors independent of prior therapy, or EGFR FISH+ tumors who received ≤3 prior chemotherapies were enrolled. Afatinib 50 mg qd was administered until disease progression or intolerable adverse events. Tumor assessments (RECIST 1.0) were performed every 8 wks. Pts who progressed on afatinib but experienced clinical benefit could continue treatment with afatinib 40 mg qd + paclitaxel 80 mg/m² qw on days 1, 8 and 15 every 28-day cycle. Primary endpoint: Confirmed objective response. Results: 41 pts were treated: 63% female; median age 63 yrs; 68% never smokers; 32% ex-smokers. 33 pts received afatinib monotherapy only; 8 pts received afatinib followed by afatinib/paclitaxel combination therapy. 78% (n=32) of pts were EGFR M+, 5% (n=2) were EGFR FISH+ and 17% (n=7) were HER2 M+. For afatinib monotherapy, 1 confirmed partial response (PR) was observed (EGFR FISH+), stable disease (SD) was seen in 5/7 HER2 M+, 2/2 EGFR FISH+ and 17/32 EGFR M+ pts, and overall disease control (DC) rate was 59% (n=24); mean duration of DC was 26 wks.Median PFS was 16 wks (17 wks in HER2 M+ pts). Of 8 afatinib/paclitaxel-treated pts, 1 had a confirmed PR and 2 had SD; median PFS was 7 wks. Most frequently reported drug-related AEs in afatinib monotherapy pts were diarrhea (n=39; grade ≥3 n=13), rash/acne (n=33; grade ≥3 n=4) and stomatitis (n=19; grade ≥3 n=2). In the combination arm these were diarrhea (n=4; grade ≥3 n=1) and nausea (n=3; grade ≥3 n=0). Conclusions: Efficacy of afatinib in EGFR M+ NSCLC pts has been established in previous trials. Novel activity of afatinib in HER2 M+ and EGFR FISH+ NSCLC pts has been demonstrated here, with a manageable safety profile of afatinib in the overall population. Clinical trial information: NCT00730925.

2523 Background: A is an irreversible ErbB Family Blocker that has shown additive effects when combined with P in EGFR-mutant NSCLC cell lines. This Ph I trial assessed the MTD, safety and PK of continuous and pulsed-dose A + P in pts with advanced solid tumors. Methods: In a3+3 dose-escalation design, IV P (500 mg/m2) was administered on day (d) 1 of each 21-d cycle combined with either continuous oral A qd (Schedule A; SA) on d1–21 (d2–21 in Cycle 1) or pulsed-dose oral A qd (Schedule B; SB) on d1–6 of each 21-d cycle. In SA, A starting dose was 30 mg, escalated to maximum of 50 mg. Once the MTD was reached in SA, A was administered at a starting dose of 50 mg in SB. Pts received up to 6 cycles of P with the option for A monotherapy thereafter. P and steady state A PK were analyzed by intra-individual comparison in SA only for possible drug–drug interaction. Results: 53 pts were treated (SA: n=23, median age 58 yrs; ECOG 0/1/2 [30%/65%/4%]; SB: n=30, median age 62 yrs, ECOG 0/1/2 [27%/70%/3%]). MTD of A in SA was 30 mg; 8 pts had dose-limiting toxicities (DLTs) in Cycle 1 (40 mg: 2/3 pts; 30 mg; 6/19 pts). 30-mg cohort included 19 evaluable pts; 1 pt was replaced during expansion (incomplete PK collection) and had a DLT. MTD of A in SB was 50 mg; 11 pts had DLTs in Cycle 1 (70 mg: 4/5 pts; 60 mg: 6/17 pts; 50 mg: 1/6 pts). Most frequent drug-related AEs in SA were diarrhea (91%), stomatitis (65%) and rash (61%) and in SB were diarrhea (83%), rash (83%) and fatigue (80%); most were Grade 1/2. 6 pts in SA and 8 pts in SB completed 6 treatment cycles; 1 pt in each schedule remain on treatment. Best response in SA was 1 confirmed partial response (CPR; NSCLC, prior sequential chemotherapies and erlotinib) and 6 pts with stable disease (SD). In SB, best response was 1 CPR (bladder cancer, prior sequential chemotherapies) and 10 pts with SD. No clinically relevant PK interactions between A and P were observed. Conclusions: Continuous or pulsed-dose A combined with P exhibited a manageable safety profile. No clinically relevant PK interactions were seen in SA. Continuous dose A 30 mg/d with P 500 mg/m2 (d1 of each 21d cycle) is the recommended dose for further Ph II studies. No apparent safety or dose advantage was observed in SB. Clinical trial information: NCT01169675.

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.

e13011 Background: A is an oral, irreversible, ErbB Family Blocker with single-agent activity in a variety of solid tumors. Preclinical studies have demonstrated additive antitumor effects when combining A or erlotinib with P in non-small cell lung cancer cell lines with sensitizing or resistant EGFR mutations. We hypothesized that once-daily A given with P would be safe and feasible in pts with advanced solid tumors. Methods: This Phase I trial was a standard 3+3 dose escalation design where A was administered orally at a starting dose of 30 mg/day on days 2–21 and combined with IV P (500 mg/m2) on Day 1 of a 21-day cycle. A was increased by 10 mg for each successive cohort until determination of the MTD, defined as the dose of A below which ≥2 of six pts experienced dose-limiting toxicity (DLT) in Cycle 1. MTD cohort was expanded to 18 pts and incidence and severity of AEs were graded according to CTCAE v3.0. Pts were treated to a maximum of 6 cycles with the option for A monotherapy thereafter. Results: 23 pts with advanced tumors were treated: 10 males, 13 females, ECOG 0/1/2 (30%/65%/4%), median age 58 yrs, and 57% received ≥3 prior chemotherapies. In Cycle 1, treatment-related DLTs were observed in six pts; two pts of three treated at 40 mg/day A dose and four pts of 20 treated at the MTD of 30 mg/day A dose. A and P were well tolerated, with the most frequent treatment-related AEs being diarrhea (91%; of which 86% were grade 1–2), stomatitis (65%) and rash (61%). Pts received a median of 2 cycles of treatment; five pts received >4 cycles, including one patient with serous ovarian cancer who continues on trial treatment beyond 14 months. Best response of 21 available pts included two partial responses, 14 with stable disease, and three with progressive disease. Detailed response and PK data will be further analyzed. Conclusions: In pts with relapsed or refractory advanced solid tumors, oral A at 30 mg/day combined with standard dose P (500 mg/m2) administered on Day 1 of a 21-day cycle, had an acceptable safety and tolerability profile. The study is currently evaluating an intercalated schedule of A on Days 2–6 with P based on preclinical synergy thought to arise from cell-cycle pharmacodynamic separation of A and P.

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

BACKGROUND: When neutropenia without infection is encountered while treating Hodgkin’s Lymphoma (HL) with ABVD chemotherapy clinicians may choose to delay or reduce the chemotherapy dose or maintain the dose intensity and schedule with or without neutrophil growth factor support out of concern for neutropenic complications. We sought to determine the frequency of neutropenia and febrile neutropenia (FN) during ABVD chemotherapy. METHODS: We examined the medical records of all patients seen at Univ. of Iowa diagnosed with HL between 1/1/1990 and 12/31/2002 treated with ABVD chemotherapy. We reviewed the charts with complete chemotherapy dosing records to determine the incidence of neutropenia, dose reduction, dose delay and chart record of febrile neutropenia (FN). RESULTS: 218 patients were seen at UIHC with the diagnosis of HL. 104 patients were treated with ABVD chemotherapy. Adequate dosing data was available for 82 of these patients (894 treatments). On scheduled day of treatment (Day 1 and 15 of each cycle) at least Grade III neutropenia (ANC 4 days and/or dose reduction to < 80% of original doxorubicin dose following neutropenia occurred at only 10 of 165 treatments. No episodes of FN developed in this cohort. 155 treatments at the time of neutropenia were administered without dose reduction or dose delay. Growth factor support was co-administered in 55 (36.77%) of these treatments and the remaining treatments at the time of neutropenia (73.23%, n=100) were administered without growth factor support. One episode of FN developed in each of these subsets. No FN was observed following the 56 treatments administered with an ANC < 500, including 54 managed without DM (32 with GCSF support and 22 without). 672 treatments were administered with ANC ≥ 1000 resulting in 6 episodes of FN. DM was observed in 78 of these 672 treatments with 3 subsequent episodes of FN. 57 treatments (4 with DM, 23 with GCSF, 20 without GCSF, 14 unknown GCSF) had no available ANC data and were associated with one episode of FN. FN developed a total of 9 times in 8 of 82 patients over 894 treatments. CONCLUSION: Among HL patients treated with ABVD chemotherapy we found a high frequency of neutropenia - most commonly following treatment 1. We found a very low incidence of FN that was independent of neutropenia at the time of chemotherapy administration. Dose modification for neutropenia without infection at the time of ABVD administration is not required to reduce risk of FN, and should be avoided in settings where maintaining dose intensity is considered valuable.

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.