Objectives: Platinum-based chemotherapy for advanced non small-cell lung cancer (NSCLC) has modest benefit overall, but has the potential to amplify immune responses. In cohorts A-C of the multicohort phase 1/2 study KEYNOTE-021 (Clinicaltrials.gov, NCT02039674), we evaluated combinations of platinum-doublet chemotherapy with the anti programmed death 1 monocloncal antibody pembrolizumab. Materials and methods: Patients with previously untreated, advanced NSCLC without EGFR/ALK aberrations were randomized to pembrolizumab 2 or 10 mg/kg Q3W plus carboplatin area under the serum concentration time curve (AUC) 6 mg/mL/min plus paclitaxel 200 mg/m(2) (cohort A, any histology), carboplatin AUC 6 mg/mL/min plus paclitaxel 200 mg/m(2) plus bevacizumab 15 mg/kg (cohort B, non-squamous), or carboplatin AUC 5 mg/mL/min plus pemetrexed 500 mg/m(2) (cohort C, non-squamous) for 4 cycles followed by maintenance pembrolizumab (cohort A), pembrolizumab plus bevacizumab (cohort B), or pembrolizumab plus pemetrexed (cohort C). Response was assessed by blinded independent central review. Results: Overall, 74 patients were randomized; median follow-up was 21.4, 16.4, and 17.4 months in cohorts A, B, and C, respectively. No dose-limiting toxicities occurred in any cohort at either pembrolizumab dose. Most frequent treatment-related adverse events (AEs) were alopecia, fatigue, and nausea. Treatment-related grade 3/4 AEs occurred in 40%, 42%, and 46% of patients in cohorts A, B, and C, respectively; AEs with possible immune etiology occurred in 24%, 50%, and 38% of patients, respectively. Objective response rates were 48%, 56%, and 75% in cohorts A, B, and C, respectively. Conclusion: Pembrolizumab in combination with carboplatin-paclitaxel and with pemetrexed-carboplatin yielded encouraging antitumor activity and toxicity consistent with known toxicities of platinum-based chemotherapy or pembrolizumab monotherapy.

9016 Background: The anti–PD-1 antibody pembro exhibits robust antitumor activity in patients (pts) with advanced NSCLC. In cohorts A-C of KEYNOTE-021 (NCT02039674), we evaluated the efficacy and safety of pembro + various chemotherapy combinations in advanced NSCLC. Methods: Chemotherapy-naive, advanced, EGFR/ALK (-) NSCLC pts, PS 0 or 1, were randomly assigned to pembro 2 or 10 mg/kg Q3W plus either carboplatin AUC 6 + paclitaxel 200 mg/m2 (A, any histology), carboplatin AUC 6 + paclitaxel 200 mg/m2 + bevacizumab (BEV) 15 mg/kg (B, nonsquamous), or carboplatin AUC 5 + pemetrexed (PEM) 500 mg/m2(C, nonsquamous) for 4 cycles followed by maintenance pembro (A), pembro + BEV (B), or pembro + PEM (C). Response was assessed every 6 wk by central imaging vendor. Results: As of Dec 16, 2015, 74 pts (25 in A, 25 in B, and 24 in C) had been treated; median follow-up duration was 12 mo (A = 13; B = 9; C = 16). 1 DLT occurred in cycle 1 (gr 3 rash, C). Gr 3-4 treatment-related AEs occurred in 36%, 46%, and 42% of pts, in cohorts A, B, and C, respectively, most commonly AST elevation (n = 3 in C), anemia (n = 2 each in A and C), neutropenia (n = 2 each in A and B), and febrile neutropenia (n = 2 each in A and B). 1 treatment-related death occurred (B, pericardial effusion). Efficacy is shown by cohort and by PD-L1 status and pembro dose with cohorts combined. At data cutoff, 24 pts remained on treatment. Conclusions: Pembro in combination with standard chemotherapy regimens is feasible and yields substantial clinical efficacy regardless of pembro dose or PD-L1 status in treatment-naive advanced NSCLC. Longitudinal follow-up is ongoing. A randomized phase 3 study evaluating pemetrexed/platinum +/- pembro is currently recruiting. Clinical trial information: NCT02039674. N ORR (confirmed) Survival, median (95% CI), mo n (%) 95% CI PFS OS Total 74 42 (57) 45-68 10 (6-NR) NR (17-NR) Cohort A 25 13 (52) 31-72 10 (4-NR) NR (11-NR) Cohort B 25 12 (48) 28-69 NR (4.1-NR) NR (NR-NR) Cohort C 24 17 (71) 49-87 10 (6-15) NR (14-NR) PD-L1 25 15 (60) 39-79 15 (6-15) 17 (15-NR) TPS ≥50% TPS ≥1%-49% 26 14 (54) 33-73 14 (6-NR) NR (14-NR) TPS <1% 22 12 (55) 32-76 6 (4-NR) 11 (7-NR) Pembro dose 2 mg/kg 37 23 (62) 45-78 NR (6-NR) NR (15-NR) 10 mg/kg 37 19 (51) 34-68 7 (4-10) NR (10-NR) NR = not reached; TPS = tumor proportion score.

Aim The aim of this trial was to evaluate the efficacy and tolerability of ubrogepant (MK-1602), a calcitonin gene-related peptide receptor antagonist (CGRP-RA), for the acute treatment of migraine.Methods This double-blind, placebo-controlled study randomized 834 participants to treat one migraine attack with ubrogepant 1mg, 10mg, 25mg, 50mg, 100mg, or placebo in a 1:1 ratio. The co-primary endpoints were pain freedom and headache response at two hours. The first primary hypothesis tested the dose-response trend for two-hour pain freedom using a logistic regression model. Subsequent hypotheses tested the effects of each dose on the co-primary endpoints, using a closed sequential testing procedure to control for multiplicity.Results A total of 527 participants received ubrogepant and 113 received placebo. A positive response trend in the proportion of participants achieving two-hour pain freedom was demonstrated (p<0.001). Ubrogepant 100mg was significantly superior to placebo for two-hour pain freedom (25.5% vs 8.9%) but not for two-hour headache response. Per the prespecified multiplicity strategy, this nonsignificant result precluded further formal hypothesis testing, although the 50mg and 25mg doses demonstrated nominal significance over placebo for two-hour pain freedom (unadjusted p<0.05). Overall, adverse events were similar between ubrogepant and placebo.Conclusion This trial supports ubrogepant's efficacy and provides further evidence that CGRP-RAs are viable options for the acute treatment of migraine.

8031 Background: As monotherapy, the anti–PD-1 antibody pembro has shown robust antitumor activity in advanced NSCLC patients (pts). KEYNOTE-021 evaluated the safety, tolerability, and clinical activity of pembro + PDC for treatment-naive advanced NSCLC. Methods: Pts with stage IIIB/IV NSCLC and no prior systemic therapy were randomized 1:1 to pembro 2 or 10 mg/kg Q3W plus carboplatin AUC 6 + paclitaxel 200 mg/m2 (cohort A; any histology) or carboplatin AUC 5 + pemetrexed 500 mg/m2 (cohort C; nonsquamous without EGFR sensitizing mutation or ALK translocation only). Pts received pembro + PDC for 4 cycles followed by pembro maintenance in A and pembro + pemetrexed in C. The dose-limiting toxicity (DLT) observation window was the first 3 wk after initial dosing. Key eligibility criteria included ECOG PS 0-1, measurable disease, and adequate tumor sample for PD-L1 assessment. Response was assessed every 6 wk until confirmed progression (RECIST v1.1, investigator review). Results: As of Dec 2014, 44 pts (20 in cohort A and 24 in cohort C) were treated. One DLT was reported (hospitalization for gr 3 rash, C [pembro 10 mg/kg]). Gr 3-4 treatment-related AE rate was 27% (15% in A, 38% in C); AEs were reversible transaminase elevation (n = 3 in C), anemia (n = 1 in A, 2 in C), rash (n = 1 in A, 1 in C), and colitis (n = 2 in C); no gr 3-4 febrile neutropenia was observed. One patient in C discontinued due to treatment-related gr 3 rash. No treatment-related deaths have occurred. Preliminary ORR (confirmed and unconfirmed) is 30% in A and 58% in C (Table). At the time of analysis, 16 pts in A and 21 pts in C remained on treatment. Conclusions: These data suggest that pembro + PDC has a reasonable safety profile and provides antitumor activity as front-line therapy for stage IIIB/IV NSCLC. Based on the promising ORR observed for pembro + carboplatin and pemetrexed, this combination is being evaluated in a larger cohort. Clinical trial information: NCT02039674. A (carboplatin/paclitaxel) C (carboplatin/pemetrexed) Pembro 10 n = 10 Pembro 2 n = 10 Pembro 10 n = 12 Pembro 2 n = 12 ORR (all PR) 3 (30%) 3 (30%) 8 (67%) 6 (50%) SD 3 (30%) 5 (50%) 4 (33%) 5 (42%) DCR (PR + SD) 6 (60%) 8 (80%) 12 (100%) 11 (92%) PD 3 (30%) 1 (10%) 0 0 No assessment 1 (10%) 1 (10%) 0 1 (8%)

8011 Background: Pembro is a potent anti–PD-1 monoclonal antibody. IPI, an anti–CTLA-4 antibody, has shown activity in advanced NSCLC. In melanoma, combined anti–PD-1 and anti–CTLA-4 treatment has shown robust efficacy and manageable toxicity. We report interim results from a phase 1 study evaluating pembro + IPI in patients (pts) with recurrent NSCLC. Methods: Pts with stage IIIB/IV NSCLC that recurred after ≤ 2 prior regimens received pembro + IPI every 3 wk for 4 cycles followed by maintenance pembro. Based on emerging data from the nivolumab + IPI advanced NSCLC study, doses were reduced from 10 mg/kg to 2 mg/kg for pembro and from 3 mg/kg to 1 mg/kg for IPI). Primary end point was safety and incidence of dose-limiting toxicities (DLTs) in the first 3 wk of dosing. Response was assessed every 6 wk per RECIST 1.1 by investigator review. Results: As of Dec 2014,17 pts were enrolled: 3 at pembro 10 mg/kg + IPI 3 mg/kg, 3 at pembro 10 mg/kg + IPI 1 mg/kg, and 11 at pembro 2 mg/kg + IPI 1 mg/kg. No DLTs or dose modifications were reported for the 15 pts treated at the time of analysis. 10 pts experienced drug-related AEs (DRAEs); none led to discontinuation or death. There were 2 gr 3 DRAEs, both rash. Gr 2 DRAEs were diarrhea and vomiting (n = 2 each) and chills, cough, decreased appetite, decreased weight, dehydration, depression, dysphonia, fatigue, myalgia, pruritus, and pyrexia (n = 1 each). Responses were seen in all dose groups among the 11 pts on treatment for ≥ 6 wk at the time of analysis, including 1 CR (9%) and 5 PRs (45%) (Table); all pts achieved disease control. 12 pts remain on treatment (range, 6 + to 26 + wk); 3 pts discontinued for PD. Conclusions: Preliminary data from KEYNOTE-021 cohort D demonstrate an acceptable toxicity profile and robust antitumor activity for pembro + IPI in pts with recurrent NSCLC.The use of lower pembro and IPI doses did not appear to negatively impact efficacy. Clinical trial information: NCT02039674. Pembro 10 + IPI 3 n = 3 Pembro 10 + IPI 1 n = 3 Pembro 2 + IPI 1 n = 5 Total n = 11 CRa 1 (33%) 0 0 1 (9%) PRa 0 2 (67%) 3 (60%) 5 (45%) SD ≥6 wk 2 (67%) 1 (33%) 2 (40%) 5 (45%) ORR (CR+PR)a 1 (33%) 2 (67%) 3 (60%) 6 (55%) Disease control rate (CR+PR+SD ≥6 wk)a 3 (100%) 3 (100%) 5 (100%) 11 (100%) aRECIST v1.1 confirmed + unconfirmed.

Objective: To evaluate the efficacy and tolerability of rizatriptan versus placebo in pediatric migraineurs. Background Acute migraine treatment options for children are limited because it has been difficult to demonstrate efficacy over placebo in trials. Design/Methods: Children, ages 6-17yrs, who had not, historically, achieved satisfactory response to treatment with NSAIDs/acetaminophen, were enrolled in a novel design utilizing a single-blind run-in phase, followed by randomization into a double-blind, placebo-controlled phase with weight-based rizatriptan dosing (5-mg for Results: 702 patients 12-17yrs of age treated, with 570 evaluable for efficacy. Rizatriptan demonstrated a significantly higher response rate compared to placebo for pain-freedom at 2hrs in 12-17yr-olds: 87/284 (30.6%) versus 63/286 (22.0%), odds ratio=1.55 [95% CI: 1.06, 2.26], p-value=0.025. The incidences of adverse events within 14-days postdose in 12-17yr-olds were similar between rizatriptan and placebo: 81/337 (24.0%) versus 83/365 (22.7%). 977 patients 6-17yrs of age treated during the study, with 770 evaluable for efficacy; the pattern of findings was similar to 12-17yr-olds. Conclusions: Rizatriptan was statistically significantly more effective than placebo in eliminating pain and generally well-tolerated in pediatric migraineurs. Supported by: Merck & Co., Inc. Disclosure: Dr. Ho has received personal compensation for activities with Merck & Co., Inc. as an employee.Dr. Ho holds stock and/or stock options in Merck & Co., Inc. Dr. Pearlman has received personal compensation for activities with GSK, Merck, Allergan, and Nautilus Pharmaceuticals as a consultant.Dr. Pearlman has received research support from GSK, Merck, and AstraZenenca. Dr. Lewis has received personal compensation for activities with Merck, Astra Zeneca, and GlaxoSmithKline.Dr. Lewis has received research support from Abbott, Astra Zeneca, Almirall, GlaxoSmithKline, Merck, and Ortho-McNeil. Dr. Hamalainen has received personal compensation for activities with Merck. Ms. Connor has received personal compensation for activities with Merck & Co., Inc. Ms. Connor holds stock and/or stock options in Merck & Co., Inc. Dr. Michelson has nothing to disclose. Dr. Zhang has received personal compensation for activities with Merck & Co., Inc. Dr. Harper-Mozley has received personal compensation for activities with Merck as an employee.Dr. Harper-Mozley holds stock and/or stock options in Merck. Ms. Strickler has received personal compensation for activities with Merck & Co., Inc., as an employee. Ms. Strickler holds stock and/or stock options in Merck & Co., Inc. Mr. Bachman has received personal compensation for activities with Merck & Co., Inc. as an employee. Mr. Bachman holds stock and/or stock options in Merck & Co., Inc. Dr. Mahoney has received personal compensation for activities with Merck & Co, Inc. as an employee. Dr. Mahoney holds stock and/or stock options in Merck & Co, Inc. Dr. Lines has received personal compensation for activities with Merck as an employee.Dr. Lines holds stock and/or stock options in Merck. Dr. Hewitt has received personal compensation for activities with Merck & Co., Inc. as an employee.

ObjectiveTo evaluate the safety/tolerability of rizatriptan in the long‐term acute treatment of migraine in pediatric patients.BackgroundAcute migraine treatment options for children are limited. A recent single‐attack trial demonstrated that rizatriptan is effective in eliminating migraine headache pain in this population. We evaluated the long‐term safety and efficacy of rizatriptan when used for intermittent acute treatment.MethodsOpen‐label study in pediatric migraineurs ages 12‐17 years. Patients weighing <40 kg received rizatriptan (orally disintegrating tablet) 5 mg, and those weighing ≥40 kg received 10 mg. Patients could treat up to 8 mild/moderate/severe migraine attacks per month for up to 12 months. One dose of study medication was allowed in a 24‐hour period.ResultsA total of 674 patients were enrolled, and 606 patients were treated with study medication (N = 583 for 10 mg, N = 23 for 5 mg). The mean duration in the study was 292 days, and the mean number of doses of study medication taken was 20. Over the course of the study within 14 days post‐any‐dose, 66.0% (400) of the 606 treated patients had any adverse event, 2.3% (14) discontinued due to an adverse event, 2.6% (16) had a serious adverse event, and 23.4% (142) had a triptan‐related adverse event. Of the 16 patients with serious adverse events within 14 days post‐any‐dose, the adverse events in 3 were considered drug‐related; all 3 patient's adverse events were classified as serious only because they were associated with an overdose (use of >1 dose of study medication in a 24‐hour period). The mean percentage of patient's attacks with pain freedom at 2‐hours post‐dose was 46.3%; this was relatively consistent over time (Months 1‐3 = 43.7%, Months 4‐6 = 51.9%, Months 7‐9 = 49.9%, Months 10‐12 = 49.5%).ConclusionRizatriptan was generally safe and well tolerated in the long‐term acute treatment of migraine in pediatric patients aged 12‐17 years and demonstrated a consistent treatment effect over time.

Background Treatment options for children and adolescents with migraine are limited. This study evaluated rizatriptan for the acute treatment of migraine in children and adolescents. Methods Randomized, double-blind, placebo-controlled, parallel-group trial in migraineurs 6–17 years old with unsatisfactory response to nonsteroidal anti-inflammatory drugs or acetaminophen/paracetamol. The trial included a double-blind run-in with weight-based rizatriptan dosing (5 mg for <40 kg, 10 mg for ≥40 kg). In the Stage 1 run-in, patients were randomized in a ratio of 20:1 placebo:rizatriptan and were instructed to treat within 30 minutes of a moderate/severe migraine. Patients with mild/no pain after 15 minutes of treatment (responders) took no further study medication, whereas patients with moderate/severe pain (non-responders) proceeded to take study medication in Stage 2. Non-responders who received placebo in Stage 1 were randomized 1:1 to rizatriptan:placebo, whereas non-responders who received rizatriptan in Stage 1 were allocated to placebo in Stage 2. The primary efficacy endpoint was pain freedom at 2 hours after Stage 2 dose in 12–17-year-olds. Results A higher proportion of 12–17-year-olds on rizatriptan had pain freedom at 2 hours compared with those on placebo: 87/284 (30.6%) versus 63/286 (22.0%), odds ratio = 1.55 [95% CI: 1.06 to 2.26], p = 0.025. Adverse events within 14 days of dose in 12–17-year-olds were similar for rizatriptan and placebo. The pattern of findings was similar in 6–17-year-olds. Conclusion Rizatriptan demonstrated a statistically significant improvement over placebo in eliminating pain and was generally well tolerated in migraineurs aged 12–17 and 6–17 years. Trial Registration ClinicalTrials.gov NCT01001234

Objective: To evaluate the safety/tolerability of rizatriptan in the long-term acute treatment of migraine in pediatric patients. Background Acute migraine treatment options for children are limited. A recent single-attack trial demonstrated that rizatriptan was statistically significantly more effective than placebo in eliminating pain in this population. We evaluated the long-term safety and efficacy of rizatriptan for intermittent acute migraine treatment. Design/Methods: Open-label study in pediatric migraineurs ages 12-17yrs. Patients weighing 1 dose of study medication in a 24-hour period was considered an overdose, and any AE associated with an overdose was automatically classified as serious. Results: 606 patients treated with study-medication (N=583, for 10-mg, N=23 for 5-mg). The mean duration in the study was 292 days and the mean number of study-medication doses taken was 20. Over the course of the study within 14 days post-any-dose, 400/606 (66.0%) patients had any AE, 14/606 (2.3%) discontinued due to an AE, 16/606 (2.6%) had a serious AE, and 142/606 (23.4%) had a triptan-related AE. Of the 16 patients with serious AEs, the AEs in 3 were considered drug-related; all 3 patient9s AEs were classified as serious because they were associated with an overdose. The mean percentage of patient9s attacks with pain freedom at 2-hours postdose was 46.3%; this was relatively consistent over time (Months 1-3=43.7%, Months 4-6=51.9%, Months 7-9=49.9%, Months 10-12=49.5%). Conclusions: Rizatriptan was generally safe and well-tolerated in the long-term acute treatment of migraine in pediatric patients age 12-17 years, and demonstrated a consistent treatment effect over time. Supported by: Merck & Co., Inc. Disclosure: Dr. Hewitt has received personal compensation for activities with Merck & Co., Inc. as an employee. Dr. Pearlman has received personal compensation for activities with GSK, Merck, Allergan, and Nautilus Pharmaceuticals as a consultant.Dr. Pearlman has received research support from GSK, Merck, and AstraZenenca. Dr. Lewis has received personal compensation for activities with Merck, Astra Zeneca, and GlaxoSmithKline.Dr. Lewis has received research support from Abbott, Astra Zeneca, Almirall, GlaxoSmithKline, Merck, and Ortho-McNeil. Dr. Hamalainen has received personal compensation for activities with Merck. Ms. Connor has received personal compensation for activities with Merck & Co., Inc. Ms. Connor holds stock and/or stock options in Merck & Co., Inc. Dr. Michelson has nothing to disclose. Dr. Ceesay has received personal compensation for activities with Merck & Co., Inc. Dr. Ceesay holds stock and/or stock options in Merck & Co., Inc. Mr. Bachman has received personal compensation for activities with Merck & Co., Inc. as an employee. Mr. Bachman holds stock and/or stock options in Merck & Co., Inc. Dr. Harper-Mozley has received personal compensation for activities with Merck as an employee.Dr. Harper-Mozley holds stock and/or stock options in Merck. Dr. Dupre has received personal compensation for activities with Merck as an employee.Dr. Dupre holds stock and/or stock options in Merck. Ms. Strickler has received personal compensation for activities with Merck & Co., Inc., as an employee. Ms. Strickler holds stock and/or stock options in Merck & Co., Inc. Dr. Mahoney has received personal compensation for activities with Merck & Co, Inc. as an employee. Dr. Mahoney holds stock and/or stock options in Merck & Co, Inc. Dr. Lines has received personal compensation for activities with Merck as an employee.Dr. Lines holds stock and/or stock options in Merck. Dr. Ho has received personal compensation for activities with Merck & Co., Inc. as an employee.Dr. Ho holds stock and/or stock options in Merck & Co., Inc.

Background: This study evaluated the CGRP receptor antagonist MK-3207 for acute treatment of migraine.Methods: Multicenter, double-blind, randomized, placebo-controlled, parallel-group, two-stage adaptive study with two interim efficacy analyses to facilitate optimal dose selection. Migraine patients were initially randomized to MK-3207 2.5, 5, 10, 20, 50 and 100 mg or placebo to treat a moderate/severe migraine. One or more doses were to be discontinued based on the first interim analysis and a lower or higher dose could be added based on the second interim analysis. The primary endpoint was two-hour pain freedom.Results: A total of 547 patients took study medication. After the first interim analysis, the two lowest MK-3207 doses (2.5, 5 mg) were identified as showing insufficient efficacy. Per the pre-specified adaptive design decision rule, only the 2.5-mg group was discontinued and the five highest doses (5, 10, 20, 50, 100 mg) were continued into the second stage. After the second interim efficacy analysis, a 200 mg dose was added due to insufficient efficacy at the top three (20, 50, 100 mg) doses. A positive dose-response trend was demonstrated when data were combined across all MK-3207 doses for two-hour pain freedom (p <. 001). The pairwise difference versus placebo for two-hour pain freedom was significant for 200 mg (p <. 001) and nominally significant for 100 mg and 10 mg (p <. 05). The incidence of adverse events appeared comparable between active treatment groups and placebo, and did not appear to increase with increasing dose.Conclusions: MK-3207 was effective and generally well tolerated in the acute treatment of migraine.