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Summary Background Both innate and adaptive immune responses are important components of anticancer immunity. The CD47–SIRPα interaction could represent an important pathway used by tumour cells to evade immune surveillance. We aimed to evaluate the safety, pharmacokinetics, pharmacodynamics, and anticancer activity of evorpacept (also known as ALX148), a high-affinity CD47-blocking protein with an inactive IgG Fc region in patients with solid tumours. Methods We did a first-in-human, open-label, multicentre, phase 1 dose-escalation and dose-expansion study at nine hospitals and one clinic in the USA and Korea. Eligible patients for the dose-escalation and safety lead-in phases were aged 18 years or older with histological or cytological diagnosis of advanced or metastatic solid tumours with no available standard therapy, measurable or unmeasurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1, and an Eastern Cooperative Oncology Group performance status score of 0 or 1. In the dose-escalation phase, which used a 3 + 3 design, patients received intravenous evorpacept at either 0·3, 1, 3, or 10 mg/kg once per week in 21-day cycles, or 30 mg/kg once every other week in 28-day cycles. In the safety lead-in phase, patients were given the maximum tolerable dose of evorpacept from the dose-escalation phase plus either intravenous pembrolizumab (200 mg administered once every 3 weeks) or intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg once every 3 weeks). In the dose-expansion phase, additional patients aged 18 years or older with second-line or later-line advanced malignancies were enrolled into three parallel cohorts: those with head and neck squamous cell carcinoma (HNSCC) and those with non-small-cell lung cancer (NSCLC) were given the maximum tolerated dose of evorpacept plus intravenous pembrolizumab (200 mg administered once every 3 weeks), and patients with HER2-positive gastric or gastroesophageal junction cancer were given the maximum tolerated dose of evorpacept plus intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg once every 3 weeks) until disease progression, voluntary withdrawal from the study, or unacceptable toxicity. The primary endpoint was the maximum tolerated dose of evorpacept administered as a single agent and in combination with pembrolizumab or trastuzumab, measured by the occurrence of dose-limiting toxicities during the first cycle, and was assessed in all patients who had received at least one dose of evorpacept. Secondary outcomes included the safety, tolerability, and antitumour activity of evorpacept, alone or in combination with pembrolizumab or trastuzumab. The primary outcome, safety, and tolerability were assessed in all patients who had received at least one dose of evorpacept, and antitumour activity was assessed in those who recieved at least one dose of study treatment and underwent at least one post-baseline tumor assessment. This trial is registered with ClinicalTrials.gov , NCT03013218 . Findings Between March 6, 2017, and Feb 21, 2019, 110 patients received single-agent evorpacept (n=28), evorpacept plus pembrolizumab (n=52), or evorpacept plus trastuzumab (n=30), and were included in the safety analysis. Median follow-up was 29·1 months (95% CI not calculable [NC]–NC) in the single-agent cohort, 27·0 months (25·1–28·8) in the evorpacept plus pembrolizumab cohort, and 32·7 months (27·0–32·7) in the evorpacept plus trastuzumab cohort. Two (7%) dose-limiting toxicities in the first cycle were reported in patients who received single-agent evorpacept; neutropenia with an associated infection in one patient with gastroesophageal junction cancer who received 3 mg/kg once per week, and thrombocytopenia with associated bleeding in one patient with pancreatic cancer who received 30 mg/kg once every other week. No maximum tolerated dose was reached; the maximum administered doses were 10 mg/kg once per week or 30 mg/kg once every other week. The 10 mg/kg once per week dose was used in the expansion cohorts in combination with pembrolizumab or trastuzumab. The most common grade 3 or worse treatment-related adverse events were thrombocytopenia with single-agent evorpacept (two [7%] patients) and evorpacept plus pembrolizumab (two [4%]), and thrombocytopenia (two [7%]) and neutropenia (two [7%]) with evorpacept plus trastuzumab. In patients who received single-agent evorpacept, four treatment-related serious adverse events were reported. Five serious treatment-related adverse events related to evorpacept plus pembrolizumab were reported, and one serious adverse event related to evorpacept plus trastuzumab was reported. In response-evaluable patients in the dose-escalation phase (n=15) receiving single-agent evorpacept once per week, four (27%) had a best overall response of stable disease (two received 0·3 mg/kg, one received 3 mg/kg, and one received 10 mg/kg); in the 11 patients who received single-agent evorpacept at the highest dose of 30 mg/kg once every other week, two (18%) had stable disease. In the dose-expansion cohort, overall responses were recorded in four (20·0%; 95% CI 5·7–43·7) of 20 patients with HNSCC who received evorpacept plus pembrolizumab, in one (5·0%; 0·1–24·9) of 20 patients with NSCLC who received evorpacept plus pembrolizumab, and in four (21·1%; 6·1–45·6) of 19 patients with gastric or gastroesophageal junction cancer who received evorpacept plus trastuzumab. Interpretation The safety findings support the use of evorpacept in combination with pembrolizumab or trastuzumab for patients with advanced solid tumours. Preliminary antitumour activity results support future investigation of evorpacept combined with pembrolizumab or trastuzumab in patients with HNSCC, gastric or gastroesophageal junction cancer, and NSCLC. Funding ALX Oncology.

Summary Background Phase 3 clinical data has shown higher proportions of patients with objective response, longer response duration, and longer overall survival with nivolumab versus docetaxel in patients with previously treated advanced non-small-cell lung cancer (NSCLC). We aimed to evaluate the long-term benefit of nivolumab and the effect of response and disease control on subsequent survival. Methods We pooled data from four clinical studies of nivolumab in patients with previously treated NSCLC (CheckMate 017, 057, 063, and 003) to evaluate survival outcomes. Trials of nivolumab in the second-line or later setting with at least 4 years follow-up were included. Comparisons of nivolumab versus docetaxel included all randomised patients from the phase 3 CheckMate 017 and 057 studies. We did landmark analyses by response status at 6 months to determine post-landmark survival outcomes. We excluded patients who did not have a radiographic tumour assessment at 6 months. Safety analyses included all patients who received at least one dose of nivolumab. Findings Across all four studies, 4-year overall survival with nivolumab was 14% (95% CI 11–17) for all patients (n=664), 19% (15–24) for those with at least 1% PD-L1 expression, and 11% (7–16) for those with less than 1% PD-L1 expression. In CheckMate 017 and 057, 4-year overall survival was 14% (95% CI 11–18) in patients treated with nivolumab, compared with 5% (3–7) in patients treated with docetaxel. Survival subsequent to response at 6 months on nivolumab or docetaxel was longer than after progressive disease at 6 months, with hazard ratios for overall survival of 0·18 (95% 0·12–0·27) for nivolumab and 0·43 (0·29–0·65) for docetaxel; for stable disease versus progressive disease, hazard ratios were 0·52 (0·37–0·71) for nivolumab and 0·80 (0·61–1·04) for docetaxel. Long-term data did not show any new safety signals. Interpretation Patients with advanced NSCLC treated with nivolumab achieved a greater duration of response compared with patients treated with docetaxel, which was associated with a long-term survival advantage. Funding Bristol-Myers Squibb.

Introduction The FIR phase II study (NCT01846416) evaluated the efficacy and safety of anti–programmed death-ligand 1 (PD-L1) atezolizumab in advanced NSCLC selected by tumor cell (TC) or tumor-infiltrating immune cell (IC) PD-L1 expression. Methods Patients with PD-L1 TC2/3 (PD-L1 staining on ≥5% of TC) or IC2/3 tumors (PD-L1 staining on ≥5% of IC; determined by SP142 PD-L1 immunohistochemistry assay) with paired fresh and archival histology samples were recruited into cohort 1 (chemotherapy-naive/>6 months between adjuvant chemotherapy and recurrence), cohort 2 (≥ second-line without brain metastases), or cohort 3 (≥ second-line with treated brain metastases). Patients received 1200 mg atezolizumab on day 1 (21-day cycles). Primary endpoint was investigator-assessed modified Response Evaluation Criteria in Solid Tumors, objective response rate (Response Evaluation Criteria in Solid Tumors v1.1). Secondary endpoints were overall survival, progression-free survival, duration of response, and safety. Results Patients (N = 138) were enrolled (137 evaluable for response: cohort 1, n = 31; cohort 2, n = 93; and cohort 3, n = 13). Investigator-assessed objective response rate was 32%, 21%, and 23% for cohorts 1, 2, and 3, respectively. Treatment-related adverse events were reported in 81%, 67%, and 69% of patients, respectively, including grade 3–4 treatment-related adverse events in 16%, 19%, and 15%, respectively. Moreover, 88.6% (86 of 97) paired baseline tumor samples had Conclusions Atezolizumab monotherapy showed clinical activity in patients with NSCLC, including those with brain metastases; safety was consistent with previous trials. Atezolizumab has completed phase III monotherapy studies in second-line. Front-line trials are ongoing, confirming these favorable results.

Background Long-term data with immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC) are limited. Two phase III trials demonstrated improved overall survival (OS) and a favorable safety profile with the anti-programmed death-1 antibody nivolumab versus docetaxel in patients with previously treated advanced squamous (CheckMate 017) and nonsquamous (CheckMate 057) NSCLC. We report results from ≥3 years’ follow-up, including subgroup analyses of patients with liver metastases, who historically have poorer prognosis among patients with NSCLC. Patients and methods Patients were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks) until progression or discontinuation. The primary end point of each study was OS. Patients with baseline liver metastases were pooled across studies by treatment for subgroup analyses. Results After 40.3 months’ minimum follow-up in CheckMate 017 and 057, nivolumab continued to show an OS benefit versus docetaxel: estimated 3-year OS rates were 17% [95% confidence interval (CI), 14% to 21%] versus 8% (95% CI, 6% to 11%) in the pooled population with squamous or nonsquamous NSCLC. Nivolumab was generally well tolerated, with no new safety concerns identified. Of 854 randomized patients across both studies, 193 had baseline liver metastases. Nivolumab resulted in improved OS compared with docetaxel in patients with liver metastases (hazard ratio, 0.68; 95% CI, 0.50–0.91), consistent with findings from the overall pooled study population (hazard ratio, 0.70; 95% CI, 0.61–0.81). Rates of treatment-related hepatic adverse events (primarily grade 1–2 liver enzyme elevations) were slightly higher in nivolumab-treated patients with liver metastases (10%) than in the overall pooled population (6%). Conclusions After 3 years’ minimum follow-up, nivolumab continued to demonstrate an OS benefit versus docetaxel in patients with advanced NSCLC. Similarly, nivolumab demonstrated an OS benefit versus docetaxel in patients with liver metastases, and remained well tolerated. Clinical trial registration CheckMate 017: NCT01642004; CheckMate 057: NCT01673867.

The discovery of anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) in 2007 led to the development and subsequent approval of the ALK inhibitor crizotinib in 2011. However, despite its clinical efficacy, resistance to crizotinib invariably develops. There is now a next generation of ALK inhibitors, including two that have been approved-ceritinib and alectinib-and others that are in development-brigatinib, lorlatinib and X-396. Ceritinib and the other next-generation ALK inhibitors are more potent than crizotinib and can overcome tumor cell resistance mechanisms. Ceritinib gained US Food and Drug Administration approval in 2014 following accelerated review for the treatment of patients with ALK-positive (ALK+) metastatic NSCLC who have progressed on or are intolerant to crizotinib. In pre-clinical studies, it demonstrated more potent inhibition of ALK than crizotinib in enzymatic assays, more durable responses in xenograft models and the ability to potently overcome crizotinib resistance mutations in vitro (including the gatekeeper mutation). There is also evidence for ceritinib penetration across the blood-brain barrier. In clinical trials, ceritinib has demonstrated durable responses and progression-free survival in ALK-inhibitor-pre-treated and -naïve NSCLC patients, including high overall and intracranial response rates in those with central nervous system metastases. Selective gastrointestinal toxicity of ceritinib, such as diarrhea, nausea and vomiting is generally manageable with prophylactic medication and prompt dose reduction or interruption. Future progress in treating ALK+ NSCLC will focus on determining the optimal sequencing of therapies and strategies to overcome acquired resistance, an ongoing challenge in treating ALK-mutation-driven tumors.

Introduction Historiquement, la survie des patients atteints de CBNPC avance etait mediocre, avec des taux a 5 ans Methodes Les patients (n = 854 ; CM 017/057 regroupes) atteints d’un CBNPC avance, avec un ECOG PS ≤ 1 et dont la maladie avait progresse pendant ou apres une premiere ligne de chimiotherapie ont ete randomises 1 :1 pour recevoir nivolumab 3 mg/kg toutes les 2 semaines ou docetaxel 75 mg/m2 toutes les 3 semaines jusqu’a progression ou toxicite inacceptable. La SG etait le critere principal d’evaluation pour les deux etudes. Resultats A 5 ans de suivi, 50 patients dans le bras nivolumab et 9 patients dans le bras docetaxel etaient en vie. Les caracteristiques initiales des survivants a 5 ans dans les deux bras etaient similaires a celles de la population globale et a celles des patients ayant survecu Conclusion Les CM 017 et CM 057 sont les premiers essais de phase III a rapporter les resultats a 5 ans d’un anti-PD1 dans le CBNPC avance prealablement traite et font etat d’une augmentation de plus de 4 fois des taux de SG a 5 ans avec nivolumab (13 %) par rapport au docetaxel (3 %). Le traitement par nivolumab reste bien tolere, sans nouveau signal de toxicite.

Background LM are seen in approximately 5% of ALK+ NSCLC patients (pts), and are associated with poor prognosis with standard treatment. Ceritinib is highly active in ALK+ NSCLC pts with previously reported intracranial/central nervous system activity. We report the efficacy and safety of ceritinib in ALK+ NSCLC pts with LM enrolled in the ASCEND-7 study (NCT02336451). Methods Pts with documented ALK + (FISH) NSCLC, CSF invasiveness with radiologically or cytologically confirmed LM, and ≥1 extracranial measurable lesion using RECIST v1.1 were eligible. The study objectives included evaluation of antitumor activity based on overall response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Data cut-off was Feb 6, 2019. Results Of the 18 LM pts enrolled, 14 pts (77.8%) also had brain metastases and 8 pts (44.4%) had measurable brain metastases at baseline. Majority of the pts (n = 16, 88.9%) had received prior crizotinib and 7 pts (38.9%) had received prior brain radiotherapy. Median duration of exposure to ceritinib was 18.1 weeks (range: 1.7–125.9). Whole body ORR by investigator assessment was 16.7% (95% CI: 3.6, 41.4) with median duration of response of 5.5 months (95% CI: 3.7, 9.9) and a clinically significant median PFS of 5.2 months (95% CI: 1.6, 7.2). Median duration of follow-up for PFS was 3.84 months (range: 0.5–13). Additional efficacy endpoints are included in the below Table. Adverse events (AEs, all grades, regardless of study drug relationship) were reported in all 18 pts. Grade 3/4 AEs occurring in ≥ 10% of pts were increased alanine aminotransferase (22.2%), hyperglycemia (16.7%), increased gammaglutamyltransferase (11.1%), pneumonia (11.1%), and increased lipase (11.1%). Table: Efficacy results Table: 390O . Endpoint per investigator assessment Arm 5 (ALK+ NSCLC pts with LM) N = 18 Whole body Response (RECIST v1.1) ORR, % (95% CI) 16.7 (3.6, 41.4) DCR, % (95% CI) 66.7 (41.0, 86.7) Median DOR, (months) [95% CI] 5.5 (3.7, 9.9) Median PFS, (months) [95% CI] 5.2 (1.6, 7.2) Intracranial response * (modified RECIST v1.1) M = 8 ORR, % (95% CI) 12.5 (0.3, 52.7) DCR, % (95% CI) 62.5 (24.5, 91.5) Extracranial response (RECIST v1.1) ORR, % (95% CI) 22.2 (6.4, 47.6) DCR, % (95% CI) 72.2 (46.5, 90.3) Median OS, months (95% CI) 7.2 (1.6, 16.9) * In patients with measurable brain metastases M, number of patients with measurable brain metastases at baseline DCR, disease control rate; DOR, duration of response; NE, not estimable; ORR, overall response rate; OS, overall survival; PFS, progression free survival; RECIST, Response Evaluation Criteria in Solid Tumors. Conclusions Ceritinib demonstrated a clinically meaningful efficacy and a safety profile similar to earlier reported results in this largest reported set of ALK+ NSCLC pts with LM. Clinical trial identification NCT02336451. Editorial acknowledgement Aarti Kamaraj, Novartis Healthcare Pvt Ltd (Hyderabad, India). Legal entity responsible for the study Novartis Pharmaceuticals. Funding Novartis Pharmaceuticals. Disclosure F. Barlesi: Honoraria (self): AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer–Ingelheim, Eli Lilly Oncology; Honoraria (self): F. Hoffmann–La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer and Takeda; Research grant / Funding (institution): Abbvie, ACEA, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer–Ingelheim, Eisai, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Genentech, Ipsen, Ignyta, Innate Pharma, Loxo, Novartis, Medimmune, Merck, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis; Non-remunerated activity/ies, Principal investigator: AstraZeneca, BMS, Merck, Pierre Fabre and F. Hoffmann-La Roche, Ltd, sponsored trials (or ISR); Research grant / Funding (institution): Takeda. D. Kim: Research grant / Funding (institution): Alpha Biopharma, AstraZeneca/Medimmune, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, ONO Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, and Yuhan. E.M. Bertino: Advisory / Consultancy: Takeda; Speaker Bureau / Expert testimony: Pfizer. M.J. van den Bent: Honoraria (self): Celgene, Agios, Boehringer, BMS, Abbvie; Research grant / Funding (institution): Abbvie. H. Wakelee: Honoraria (self): Novartis, AZ; Advisory / Consultancy, Compensated: AstraZeneca, Xcovery, Janssen; Advisory / Consultancy, Not compensated: Merck, Takeda, Genentech/Roche; Research grant / Funding (institution): ACEA Biosciences, Arrys Therapeutics, AstraZeneca/Medimmune, Bayer (under Suki and not me), BMS, Celgene, Clovis Oncology, Exelixis, Genentech/Roche, Gilead, Lilly, Merck, Novartis, Pfizer, Pharmacyclics, Xcovery; Travel / Accommodation / Expenses: AstraZeneca; Officer / Board of Directors: International Association for the Study of Lung Cancer (IASLC). P.Y. Wen: Advisory / Consultancy: Agios, AstraZeneca, Beigene, Eli Lily, Genentech/Roche, Karyopharm, Kazia, MediciNova, Merck, Novartis, Oncoceutics, Sanofi-Aventis, VBI Vaccines, Tocagen; Speaker Bureau / Expert testimony: Merck, Prime Oncology; Research grant / Funding (institution): Agios, AstraZeneca, Beigene, Eli Lily, Genentech/Roche, Karyopharm, Kazia, MediciNova, Merck, Novartis, Oncoceutics, Sanofi-Aventis, VBI Vaccines. P. Garrido Lopez: Advisory / Consultancy: Roche, MSD, BMS, Boerhinger Ingelheim, Pfizer, Abbvie, Guardant Health, Novartis, Lilly, AstraZeneca, Jansen, Sysmex, Blueprint Medicines, Takeda; Speaker Bureau / Expert testimony: Roche, MSD, BMS, Pfizer, Novartis, Boerhinger Ingelheim, Rovi; Research grant / Funding (institution), Financial support for clinical trials: Roche, MSD, BMS, Takeda, Lilly, Pfizer, Novartis, Pharmamar, Celgene, Sanofi, GSK, Theradex Oncology, BluePrint Medicines; Research grant / Funding (institution), Financial support for contracted research: Guardant Health, Sysmex. M. Majem: Advisory / Consultancy: Roche, MSD, AstraZeneca, Boehringer, Tesaro, Takeda, Pierre Fabre; Speaker Bureau / Expert testimony: Roche, BMS, MSD, AstraZeneca, Boehringer, Hellsin, Pierre Fabre, Amgen; Research grant / Funding (self): BMS; Travel / Accommodation / Expenses: BMS, MSD, AstraZeneca, Lilly. M. McKeage: Advisory / Consultancy: Novartis, Pfizer; Research grant / Funding (institution): Novartis, Pfizer, Roche. C. Yu: Honoraria (self): Roche, AstraZeneca, Ono pharma, Boehringer-Ingelheim; Advisory / Consultancy: Roche, AstraZeneca, Ono pharma, Boehringer-Ingelheim. F.K. Hurtado: Shareholder / Stockholder / Stock options: Novartis Pharmaceuticals Corp.; Full / Part-time employment: Novartis Pharmaceuticals Corp. P. Cazorla Arratia: Shareholder / Stockholder / Stock options: Novartis Pharmaceuticals Corporation; Full / Part-time employment: Novartis Pharmaceuticals Corporation. Y. Song: Shareholder / Stockholder / Stock options, Restricted Stock Unit: Novartis Pharmaceutical Corporation; Full / Part-time employment: Novartis Pharmaceutical Corporation. F. Branle: Shareholder / Stockholder / Stock options: Novartis AG; Full / Part-time employment: Novartis AG. M. Shi: Shareholder / Stockholder / Stock options: Novartis; Full / Part-time employment: Novartis Pharmaceuticals Corporation. L.Q. Chow: Advisory / Consultancy: Bristol-Myers Squibb, Merck, Genentech, AstraZeneca/Medimmune, Pfizer, Seattle Genetics, Novartis, Dynavax Inc., Alkermes, Amgen, Sanofi-Genzyme, Takeda; Research grant / Funding (institution): Bristol-Myers Squibb, Merck, Genentech, AstraZeneca/Medimmune, Pfizer, Seattle Genetics, Novartis, Dynavax Inc. and Alkermes,Incyte, VentiRx and Lily/Imclone. All other authors have declared no conflicts of interest.

Introduction First-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment of advanced non–small-cell lung cancer with EGFR -activating mutations improves outcomes compared with chemotherapy, but resistance develops in most patients. Compensatory signaling through type 1 insulin-like growth factor 1 receptor (IGF-1R) may contribute to resistance; dual blockade of IGF-1R and EGFR may improve outcomes. Patients and Methods We performed a randomized, double-blind, placebo-controlled phase II study of linsitinib, a dual IGF-1R and insulin receptor tyrosine kinase inhibitor, plus erlotinib versus placebo plus erlotinib in chemotherapy-naive patients with EGFR -mutation positive, advanced non–small-cell lung cancer. Patients received linsitinib 150 mg twice daily or placebo plus erlotinib 150 mg once daily on continuous 21-day cycles. The primary end point was progression-free survival. Results After randomization of 88 patients (44 each arm), the trial was unblinded early owing to inferiority in the linsitinib arm. The median progression-free survival for the linsitinib versus the placebo group was 8.4 months versus 12.4 months (hazard ratio, 1.37; P = .29). Overall response rate (47.7% vs. 75.0%; P = .02) and disease control rate (77.3% vs. 95.5%; P = .03) were also inferior. Whereas most adverse events were ≤ grade 2, linsitinib plus erlotinib was associated with increased adverse events that led to decreased erlotinib exposure (median days, 228 vs. 305). No drug-drug interaction was suggested by pharmacokinetic and pharmacodynamic results. Conclusion Adding linsitinib to erlotinib resulted in inferior outcomes compared with erlotinib alone. Further understanding of the signaling pathways and a biomarker that can predict efficacy is needed prior to further clinical development of IGF-1R inhibitors in lung cancer.

an AESI reported in 2% of pts in the N single-agent treatment to progression phase were rash (Any Gr: 25.5%; Gr 3: 4.0%, hypomagnesemia (Any Gr: 16.0%; Gr 3: 2.5%), conjunctivitis (Any Gr: 4.7%; Gr 3: 0.7%), venous thromboembolic events (Any Gr: 2.5%; Gr 3 1.8%), and arterial thromboembolic events (Any Gr: 2.2%; Gr 3: 1.8%). Conclusions: OS and PFS were statistically significantly improved when N was added to GC. Pts who continued on N single-agent to progression had substantially better outcomes than the general population, and long-term use of N did not result in any unexpected increases in AESIs. Author Disclosure: M.A. Socinski: None. N. Thatcher: F. Honoraria; Eli Lilly and others. H. Speakers Bureau; Eli Lilly and others. K. Advisory Board; Eli Lilly and others. A.V. Luft: None. A. Szczesna: None. T. Ciuleanu: None. W. Szafra nski: None. R. Ramlau: None. B. Balint: None. A. Kazarnowicz: None. O. Molinier: G. Consultant; Eli Lilly. K. Advisory Board; Roche. H. Depenbrock: A. Employee; Eli Lilly. M. Stock; Eli Lilly. S. Nanda: A. Employee; Eli Lilly. M. Stock; Eli Lilly. C. Obasaju: A. Employee; Eli Lilly. M. Stock; Eli Lilly. N. Stock Options; Eli Lilly. L. Paz-Ares: F. Honoraria; Eli Lilly.

Other; Novartis, Roche, Boehringer-Ingelheim. M. Thomas: F. Honoraria; Lilly, Bristol Meyers Squibb, Roche. G. Consultant; Lilly, Bristol Meyers Squibb, Roche, Novartis. M. Schuler: E. Research Grant; Boehringer Ingelheim, Novartis. F. Honoraria; Boehringer Ingelheim, Celgene, GlaxoSmithKline, Lilly, Novartis, Pfizer. G. Consultant; AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer. G. Liu: G. Consultant; Astra Zeneca, Pfizer, Novartis. A. Santoro: None. M. Geraldes: A. Employee; Novartis Pharmaceuticals. M. Stock; Novartis Pharmaceuticals. A.L. Boral: A. Employee; Novartis Pharmaceuticals. A. Yovine: A. Employee; Novartis Pharma AG. A.T. Shaw: G. Consultant; Ignyta. K. Advisory Board; Novartis, Pfizer, Ariad, Chugai, Genentech.

First-Line Monotherapy With Nivolumab (Anti-PD-1; BMS-936558, ONO-4538) in Advanced Non-Small Cell Lung Cancer (NSCLC): Safety, Efficacy, and Correlation of Outcomes With PD-L1 Status Metastatic Non-Small Cell Lung Cancer N.A. Rizvi, F.A. Shepherd, S.J. Antonia, J.R. Brahmer, L.Q. Chow, J. Goldman, R. Juergens, H. Borghaei, N.E. Ready, D.E. Gerber, Y. Shen, C. Harbison, A.C. Chen, and S. Gettinger; Memorial Sloan Kettering Cancer Center, New York, NY, Princess Margaret Cancer Centre, Toronto, ON, Canada, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, University of Washington, Seattle, WA, University of California, Los Angeles, Los Angeles, CA, Juravinski Cancer Centre at McMaster University, Hamilton, QC, Canada, Fox Chase Cancer Center, Philadelphia, PA, Duke University Medical Center, Durham, NC, UT Southwestern Medical Center, Dallas, TX, BristolMyers Squibb, Princeton, NJ, Yale Cancer Center, New Haven, CT

an AESI reported in 2% of pts in the N single-agent treatment to progression phase were rash (Any Gr: 25.5%; Gr 3: 4.0%, hypomagnesemia (Any Gr: 16.0%; Gr 3: 2.5%), conjunctivitis (Any Gr: 4.7%; Gr 3: 0.7%), venous thromboembolic events (Any Gr: 2.5%; Gr 3 1.8%), and arterial thromboembolic events (Any Gr: 2.2%; Gr 3: 1.8%). Conclusions: OS and PFS were statistically significantly improved when N was added to GC. Pts who continued on N single-agent to progression had substantially better outcomes than the general population, and long-term use of N did not result in any unexpected increases in AESIs. Author Disclosure: M.A. Socinski: None. N. Thatcher: F. Honoraria; Eli Lilly and others. H. Speakers Bureau; Eli Lilly and others. K. Advisory Board; Eli Lilly and others. A.V. Luft: None. A. Szczesna: None. T. Ciuleanu: None. W. Szafra nski: None. R. Ramlau: None. B. Balint: None. A. Kazarnowicz: None. O. Molinier: G. Consultant; Eli Lilly. K. Advisory Board; Roche. H. Depenbrock: A. Employee; Eli Lilly. M. Stock; Eli Lilly. S. Nanda: A. Employee; Eli Lilly. M. Stock; Eli Lilly. C. Obasaju: A. Employee; Eli Lilly. M. Stock; Eli Lilly. N. Stock Options; Eli Lilly. L. Paz-Ares: F. Honoraria; Eli Lilly.

Aim: Background: The highly selective, anti-PD-1 humanized monoclonal antibody pembro has shown antitumor activity in several solid tumors, including HNC. We present updated safety, tolerability, and antitumor activity of pembro for recurrent/metastatic HNC (Clinicaltrials.gov: NCT01848834). Methods: During screening, PD-L1 expression in archival or newly obtained tumor samples was assessed using a prototype immunohistochemistry assay; PD-L1 expression in stroma or ≥1% of tumor cells was required for study entry. Pembro 10 mg/kg was given every 2 wk until complete response, progression, unacceptable toxicity, physician decision, or consent withdrawal. Adverse events (AEs) were recorded throughout the study. Response was assessed every 8 wk. Primary end point was overall response rate (ORR) per RECIST v1.1. Results: Out of 104 HNC pts screened, 81 (78%) were PD-L1-positive, 61 enrolled, and 60 received ≥1 pembro dose: 23 HPV+, 37 HPV-. After a median follow-up of 10.2 mo, 15 pts (25%) remain on pembro. ORR (confirmed + unconfirmed) per RECIST v1.1 by investigator review was 20%, and response duration ranged from 8+ to 41+ weeks (median not reached). 9 of 11 responders had a smaller target lesion burden (ie, sum below the median) at baseline. ORR was similar in HPV+ and HPV- pts, whereas PFS and OS were longer in HPV+ pts (Table). PD-L1 expression was positively correlated with ORR (P = 0.018) and PFS (P = 0.024). ORR was 50% in the 12 pts with high PD-L1 expression. Drug-related AEs of any grade occurred in 58% of pts (grade ≥3 in 17%). The most common drug-related AEs were fatigue (18%), pruritus (10%), and nausea (8%). There were no drug-related deaths. Conclusions: Pembro is safe and tolerable and shows antitumor activity in both HPV+ and HPV- advanced HNC. These findings support further development of pembro in advanced HNC. Overall N = 61* HPV+ n = 23* HPV– n = 38* ORR, n (%) 11 (20) 4 (20) 7 (19) Median PFS (95% CI), wk 9.3 (8.0-20.1) 17.2 (8.0-41.7) 8.1 (7.9-15.6) Median OS (95% CI), mo 12.6 (8.2-12.6) NR (9.6-NR) 9.5 (3.9-12.6) *ORR and PFS were evaluated in the 56 pts (20 HPV+, 36 HPV-) who received ≥1 pembro dose and had measurable disease per RECIST v1.1 by investigator review. Disclosure: L.Q. Chow: Advisory Board Member for Bristol Myers Squibb, Novartis, Celgene; Research funding from Bristol Myers Squibb, Novartis, AstraZeneca/Medimmune, Genentech/Roche, VentiRx, Pfizer, Lily/Imclone; B. Burtness: Advisory board membership for VentiRx and Novartis; Research funding from Merck, Genentech, Boehringer Ingelheim, and Pfizer; E.J. Gonzalez, J.K. Lunceford, C. Gause and J.D. Cheng: Employee of and stock ownership in Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc.; J. Pulini, J. Johnson, M. Dolled-Filhart, K. Emancipator and K. Pathiraja: Employee of Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc.; T. Seiwert: Advisory board membership for Novartis and Onyx/Bayer; Research funding from Boehringer Ingelheim and Genentech; Honoraria from Merck. All other authors have declared no conflicts of interest.

Aim: We report interim data from a phase 1 study of nivolumab (N), a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody, combined with PT-DC or ERL in advanced chemotherapy-naive NSCLC patients (pts). Methods: Pts (n = 56) were assigned by histology to receive N 10 mg/kg IV Q3W + concurrent IV gemcitabine 1250 mg/m2 + cisplatin 75 mg/m2 (squamous [sq]) or pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 (non-sq), or N 5 or 10 mg/kg IV Q3W + IV paclitaxel 200 mg/m2 + carboplatin AUC6 (sq + non-sq). N + PT-DC was given for 4 cycles, with continued N to progression/unacceptable toxicity. EGFR mutant (EGFR MT) NSCLC pts (n = 21) received N 3 mg/kg IV Q2W + ERL 150 mg PO daily until progression/unacceptable toxicity. Objective response rate (ORR) was assessed by RECIST 1.1. Results: Across N + PT-DC arms (median follow-up [mF/U] 75 wks), grade 3–4 related AEs occurred in 45% of pts (25–73% across arms); 4 pts (7%) had grade 3–4 pneumonitis; 0–33% discontinued due to related AEs, any-grade pneumonitis (7%) most common. ORR with N + PT-DC was 33–47%; PD as best overall response (BOR) was infrequent (7%). Progression-free survival (PFS) rate at wk 24 was 38–71%; 1-yr OS rate was 50–87%. With N + ERL (mF/U 72 wks), grade 3–4 related AEs occurred in 5 pts; no pneumonitis was observed. Related AEs led to discontinuation in 4 pts (grade 3 AST ↑, grade 3 diarrhea, grade 2 nephritis, grade 2 flushing). ORR was 19% (median duration of response [DOR] not reached; range 60.1, 72.3+ wks); 24-wk PFS rate was 51%. Three of 20 pts (15%) with acquired ERL resistance achieved PR (DOR 60.1, 64.6 + , 70+ wks; 2 ongoing); 9/20 pts had BOR of SD, with 3/9 not progressed (time to progression/death 9.9+–53 wks); 1 pt had an ongoing unconventional response. One pt was EGFR TKI naive and achieved PR (DOR 72.3+ wks; ongoing). Conclusions: N + PT-DC demonstrated acceptable antitumor activity and safety reflecting additive nivolumab and PT-DC toxicities in pts with advanced NSCLC. N + ERL may provide durable clinical benefit and an acceptable safety profile in TKI-refractory, EGFR MT pts. These data support further evaluation of nivolumab combination regimens in pts with advanced NSCLC. Disclosure: S. Gettinger: Consultant advisor BMS; Honoraria for BMS advisory board; N. Rizvi: Consultant Advisor-BMS; Honoraria-BMS, Medimmune, Genentech/Roche; L.Q. Chow: BMS Stock; Research Funding-Bristol-Myers Squibb funding goes to University of Washington; H. Borghaei: Consultant advisor-Genentech, BMS; Research Funding- Pfizer, Arisaph, Millenium; Honoraria-Genentech; J.R. Brahmer: Consultant advisor BMS; Stock BMS; Research Funding BMS; R. Juergens: Research funding BMS; F.A. Shepherd: Consultant advisor (compensated), honoraria-BMS; J. Goldman: Research funding-BMS, Genentech; Y. Shen: BMS Employee; BMS Stock; C. Harbison: BMS-employee, stock; A. Chen: BMS-employee, stock; S.J. Antonia: Consultant advisor, honoraria, research funding for BMS MedImmune provides funding for clinical trials. All other authors have declared no conflicts of interest.

Aim: ALK+ tumors are sensitive to ALK tyrosine kinase inhibitors such as crizotinib (CRZ) but resistance invariably develops. Ceritinib (LDK378), a novel ALK inhibitor (ALKi), is more potent than CRZ in vitro and is effective in CRZ-resistant disease. Updated data from ASCEND-1 (NCT01283516) are presented, focused on pts receiving ceritinib at the recommended 750 mg/day dose and with longer follow-up. Methods: Investigator assessment of efficacy is presented for pts with ALK+ NSCLC receiving ≥1 dose of ceritinib at 750 mg/day prior to 31 Oct 2013. Results with additional follow-up will be presented. Results: 246 pts with ALK+ NSCLC had 7 months median duration of follow up. Of these, 230 (93%) had received prior antineoplastic therapy, 166 (67%) with ≥2 prior regimens.163 (66%) had received prior ALKi, all of whom had received CRZ; of these, 91% had progressive disease during prior ALKi therapy and 78% had received ALKi as last prior therapy. Efficacy is shown below. Endpoint All NSCLC n = 246 ALKi-pretreated n = 163 ALKi-naive n = 83 ORR, n (%) [95% CI] 144 (58.5) [52.1, 64.8] 89 (54.6) [46.6, 62.4] 55 (66.3) [55.1, 76.3] DOR, median (months) [95% CI] 9.7 [7.0, 11.4] 7.4 [5.4, 10.1] NEa [9.6, NE] Time to first response, median (weeks) [min, max] 6.1 wks [3.0, 24.1] 6.1 wks [4.6, 24.1] 6.1 wks [3.0, 24.1] PFS, median (months) [95% CI] 8.2 [6.7, 10.1] 6.9 [5.4, 8.4] NEb [8.3, NE] aDOR rate at 12 mos 65.2% [95% CI: 46.4, 78.8] bPFS rate at 12 mos 61.3% [95% CI: 47.7, 72.3] NE = Not estimable. Discontinuation of treatment due to adverse event (AE) occurred in 24 (10%) pts with NSCLC; 17 (10%) ALKi-pretreated pts and 7 (8%) ALKi-naive pts. Among all 255 pts receiving ceritinib 750 mg/day, 99 (39%) and 51 (20%) required 1 and >1 ceritinib dose reduction, respectively. The most common AEs of any grade (>50%) were diarrhea (86%), nausea (80%), vomiting (60%), abdominal pain (54%), fatigue (52%). Most common lab abnormalities of any grade (>50%) were decreased hemoglobin (84%), increased ALT (80%), increased AST (75%), increased creatinine (58%). Most common Grade 3/4 lab abnormalities (>10%) were increased ALT (27%), increased AST (13%), increased glucose (13%). One treatment-related death (interstitial lung disease) was reported. Conclusions: Ceritinib 750 mg/day shows potent anti-tumor activity in ALK+ NSCLC pts regardless of prior ALKi treatment status. Discontinuation due to toxicity was uncommon. Disclosure: E. Felip: Advisory board: BI, Novartis, Roche, BMS, Lilly; D. Kim: Consultation for Novartis, Pfizer, Lilly; Honorarium from Pfizer, Lilly; R. Mehra: Spouse is an employee of GSK, consulting to Bristol-Myers Squibb and Novartis; L.Q. Chow: Employee: University of Washington; Research grant and research support, consultant, travel expenses and advisory board: Novartis; D.R. Camidge: Advisory boards/consultancy/honoraria for Servier, Eli Lilly, Genentech/Roche, Astex, Ariad, ImmunoGen, Clarient, Excelixis, indiPharm, Astellas, Boehringer Ingelheim, Chugai, Clovis, Array Biopharma, AstraZeneca, Aveo, Novartis, Synta, Pfizer; J.F. Vansteenkiste: Speaker for Novartis; S. Sharma: Research grant, Consultant: Novartis. Stock: Salarius Pharma, Beta Cat Pharma, ConverGene. Leadership: Board member, TheraTarget and Member, VLB Therapeutics IDMC; B. Solomon: Honoraria/Ad board: Novartis, Pfizer, Clovis, Clovis oncology, AZ, Roche; J. Wolf: Employee of University Hospital of Cologne. Ad boards, speakers bureau and research funding: AZ, Novartis, Roche, Pfizer, BI, BMS, Clovis. Research support: Novartis, Roche, BI; M. Thomas: Honoraria: Lilly, BMS, Roche. Consultant: Lilly, BMS, Roche, Novartis ; M. Schuler: Consultant: AZ, BI, Novartis, Pfizer. Research grants to institution: BI, Novartis. Honoraries for CME lectures: BI, Celgine, GSK, Lilly, Novartis, Pfizer; G. Lui: Consultant: AZ, Pfizer, Novartis; M. Geraldes: Margarida Geraldes is an employee of Novartis and is a stock owner; A.L. Boral: Antony L Boral is an employee of Novartis; A. Yovine: Alejandro Yovine is an employee of Novartis and is a stock owner; A.T. Shaw: Advisory board: Novartis, Pfizer, Ariad, Chugai, Genentech. All other authors have declared no conflicts of interest.