Abemaciclib in Combination with Single-Agent Options in Patients with Stage IV Non-Small Cell Lung Cancer: A Phase Ib Study.

Purpose: Abemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated preclinical activity in non-small cell lung cancer (NSCLC). A multicenter, nonrandomized, open-label phase Ib study was conducted to test safety, MTD, pharmacokinetics, and preliminary antitumor activity of abemaciclib in combination with other therapies for treatment in patients with metastatic NSCLC.Patients and Methods: An initial dose escalation phase was used to determine the MTD of twice-daily oral abemaciclib (150, 200 mg) plus pemetrexed, gemcitabine, or ramucirumab, followed by an expansion phase for each drug combination. Pemetrexed and gemcitabine were administered according to label. The abemaciclib plus ramucirumab study examined two dosing schedules.Results: The three study parts enrolled 86 patients; all received ≥1 dose of combination therapy. Across arms, the most common treatment-emergent adverse events were fatigue, diarrhea, neutropenia, decreased appetite, and nausea. The trial did not identify an abemaciclib MTD for the combination with pemetrexed or gemcitabine but did so for the combination of abemaciclib with days 1 and 8 ramucirumab (8 mg/kg). Plasma sample analysis showed that abemaciclib did not influence the pharmacokinetics of the combination agents and the combination agents did not affect abemaciclib exposure. The disease control rate was 57% for patients treated with abemaciclib-pemetrexed, 25% for abemaciclib-gemcitabine, and 54% for abemaciclib-ramucirumab. Median progression-free survival was 5.55, 1.58, and 4.83 months, respectively.Conclusions: Abemaciclib demonstrated an acceptable safety profile when dosed on a continuous twice-daily schedule in combination with pemetrexed, gemcitabine, or ramucirumab. Abemaciclib exposures remained consistent with those observed in single-agent studies. Clin Cancer Res; 24(22); 5543-51. ©2018 AACR.

Kim ES ，Kelly K ，Paz-Ares LG ，Garrido P ，Jalal S ，Mahadevan D ，Gutierrez M ，Provencio M ，Schaefer E ，Shaheen M ，Johnston EL ，Turner PK ，Kambhampati SRP ，Beckmann R ，Hossain A ，John WJ ，Goldman JW ... -  《-》

A phase 1b study of necitumumab in combination with abemaciclib in patients with stage IV non-small cell lung cancer.

Necitumumab, an anti-EGFR antibody, and abemaciclib, a CDK4/6 inhibitor, have shown activity in patients with non-small cell lung cancer (NSCLC) and have non-overlapping toxicities. A 2-part, single-arm, multicenter, phase 1b trial was conducted to test the safety and efficacy of necitumumab plus abemaciclib in patients with advanced NSCLC who had received ≤2 lines of chemotherapy, including a platinum-based one. Part A was a dose-escalation phase for abemaciclib (100, 150, 200 mg, Q12 H) in combination with necitumumab 800 mg D1D8 Q3W to determine the recommended dose for the expansion cohort, Part B. The primary endpoint was progression-free survival (PFS) rate at 3 months. Sixty-six patients entered the study: 71% male, 41% squamous histology, 15% never-smokers. In Part A (n = 15), the maximum tolerated dose of abemaciclib was 150 mg Q12H in combination with necitumumab 800 mg. In 57 patients treated at this dose level, the 3-month PFS rate was 32.3% (95% CI: 20.4-44.8); median PFS was 2.14 months (1.41-2.76). The overall response rate (ORR) was 5.3% (1.1-14.6). The median OS was 6.93 months (4.96-12.85). In the exploratory subgroup analysis of EGFR expression-negative patients (n = 10), both the 3-month PFS and ORR were 0.0%. The most common grade 3 treatment-emergent adverse events were fatigue (14%), dyspnea (9%), diarrhea (7%), vomiting (7%), and hypokalemia (7%). Abemaciclib 150 mg Q12H with necitumumab 800 mg did not produce an additive effect over single-agent activity in patients with Stage IV NSCLC. The safety profile was consistent with the individual study drugs.

Besse B ，Barlesi F ，Demedts I ，Fuentes Pradera J ，Robinet G ，Gazzah A ，Soldatenkova V ，Frimodt-Moller B ，Kim JS ，Vansteenkiste J ... -  《-》

Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non-Small Cell Lung Cancer, and Other Solid Tumors.

Patnaik A ，Rosen LS ，Tolaney SM ，Tolcher AW ，Goldman JW ，Gandhi L ，Papadopoulos KP ，Beeram M ，Rasco DW ，Hilton JF ，Nasir A ，Beckmann RP ，Schade AE ，Fulford AD ，Nguyen TS ，Martinez R ，Kulanthaivel P ，Li LQ ，Frenzel M ，Cronier DM ，Chan EM ，Flaherty KT ，Wen PY ，Shapiro GI ... -  《-》

A phase IB dose-escalation study of the safety and pharmacokinetics of pictilisib in combination with either paclitaxel and carboplatin (with or without bevacizumab) or pemetrexed and cisplatin (with or without bevacizumab) in patients with advanced non-s

The phosphatidylinositol 3-kinase (PI3K) pathway is a potential therapeutic target in non-small cell lung cancer (NSCLC). This study aimed to evaluate the pan-PI3K inhibitor pictilisib in combination with first-line treatment regimens that were the standard of care at the time of study, in patients with NSCLC. A 3 + 3 dose-escalation study was performed using a starting daily dose of 60 mg pictilisib on days 1-14 of a 21-day cycle. Depending on bevacizumab eligibility and NSCLC histology, patients also received either paclitaxel + carboplatin or pemetrexed + cisplatin, ± bevacizumab every 3 weeks. The primary objectives of the study were to assess safety and tolerability and to identify dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD) and a recommended phase II dose (RP2D), for each combination. All 66 treated patients experienced at least one adverse event (AE). Grade ≥III AEs, serious AEs and deaths occurred in 57 (86.4%), 56 (84.8%) and 9 (13.6%) patients, respectively. Three patients reported DLTs across the four arms of the study. The MTD was not reached in any arm and the RP2D of pictilisib was determined to be 330 mg (capsules) or 340 mg (tablets) on a '14 days on, 7 days off' schedule. The best confirmed response was partial response in 29 (43.9%) patients and stable disease in 20 (30.9%) patients. Combining pictilisib with various standard-of-care first-line treatment regimens is feasible from a safety perspective in patients with NSCLC, and encouraging preliminary anti-tumour activity was observed.

Soria JC ，Adjei AA ，Bahleda R ，Besse B ，Ferte C ，Planchard D ，Zhou J ，Ware J ，Morrissey K ，Shankar G ，Lin W ，Schutzman JL ，Dy GK ，Groen HJM ... -  《-》

Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial.

Necitumumab is a second-generation, recombinant, human immunoglobulin G1 EGFR antibody. In this study, we aimed to compare treatment with necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone in patients with previously untreated stage IV squamous non-small-cell lung cancer. We did this open-label, randomised phase 3 study at 184 investigative sites in 26 countries. Patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous non-small-cell lung cancer, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate organ function and who had not received previous chemotherapy for their disease were eligible for inclusion. Enrolled patients were randomly assigned centrally 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplastin chemotherapy with or without necitumumab according to a block randomisation scheme (block size of four) by a telephone-based interactive voice response system or interactive web response system. Chemotherapy was gemcitabine 1250 mg/m(2) administered intravenously over 30 min on days 1 and 8 of a 3-week cycle and cisplatin 75 mg/m(2) administered intravenously over 120 min on day 1 of a 3-week cycle. Necitumumab 800 mg, administered intravenously over a minimum of 50 min on days 1 and 8, was continued after the end of chemotherapy until disease progression or intolerable toxic side-effects occurred. Randomisation was stratified by ECOG performance status and geographical region. Neither physicians nor patients were masked to group assignment because of the expected occurrence of acne-like rash--a class effect of EGFR antibodies--that would have unmasked most patients and investigators to treatment. The primary endpoint was overall survival, analysed by intention to treat. We report the final clinical analysis. This study is registered with ClinicalTrials.gov, number NCT00981058. Between Jan 7, 2010, and Feb 22, 2012, we enrolled 1093 patients and randomly assigned them to receive necitumumab plus gemcitabine and cisplatin (n=545) or gemcitabine and cisplatin (n=548). Overall survival was significantly longer in the necitumumab plus gemcitabine and cisplatin group than in the gemcitabine and cisplatin alone group (median 11·5 months [95% CI 10·4-12·6]) vs 9·9 months [8·9-11·1]; stratified hazard ratio 0·84 [95% CI 0·74-0·96; p=0·01]). In the necitumumab plus gemcitabine and cisplatin group, the number of patients with at least one grade 3 or worse adverse event was higher (388 [72%] of 538 patients) than in the gemcitabine and cisplatin group (333 [62%] of 541), as was the incidence of serious adverse events (257 [48%] of 538 patients vs 203 [38%] of 541). More patients in the necitumumab plus gemcitabine and cisplatin group had grade 3-4 hypomagnesaemia (47 [9%] of 538 patients in the necitumumab plus gemcitabine and cisplatin group vs six [1%] of 541 in the gemcitabine and cisplatin group) and grade 3 rash (20 [4%] vs one [<1%]). Including events related to disease progression, adverse events with an outcome of death were reported for 66 (12%) of 538 patients in the necitumumab plus gemcitabine and cisplatin group and 57 (11%) of 541 patients in the gemcitabine and cisplatin group; these were deemed to be related to study drugs in 15 (3%) and ten (2%) patients, respectively. Overall, we found that the safety profile of necitumumab plus gemcitabine and cisplatin was acceptable and in line with expectations. Our findings show that the addition of necitumumab to gemcitabine and cisplatin chemotherapy improves overall survival in patients with advanced squamous non-small-cell lung cancer and represents a new first-line treatment option for this disease. Eli Lilly and Company.

Thatcher N ，Hirsch FR ，Luft AV ，Szczesna A ，Ciuleanu TE ，Dediu M ，Ramlau R ，Galiulin RK ，Bálint B ，Losonczy G ，Kazarnowicz A ，Park K ，Schumann C ，Reck M ，Depenbrock H ，Nanda S ，Kruljac-Letunic A ，Kurek R ，Paz-Ares L ，Socinski MA ，SQUIRE Investigators ... -  《-》