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 necitumumab and pembrolizumab combination therapy in patients with Stage IV non-small cell lung cancer.

Efficacy and safety of necitumumab when combined with pembrolizumab was assessed in patients with Stage IV non-small cell lung cancer (NSCLC) of squamous and nonsquamous histology, who had progressed after treatment with a platinum-based doublet. This single-arm, multicenter, phase Ib study had a dose-finding phase, in which escalating doses of necitumumab (600 mg and 800 mg IV) were administered on Day 1 and 8 every 3 weeks (Q3W) in combination with pembrolizumab (200 mg IV) on Day 1 Q3W, and expansion cohorts. Patients were treated until progressive disease (PD), toxicity requiring cessation, protocol noncompliance, or withdrawal of consent. Efficacy was evaluated by overall response rate (ORR). In 64 treated patients (32 patients [50 %] were programmed death-ligand 1 [PD-L1] negative), confirmed ORR was 23.4 % (95 % confidence interval [CI] 13.8 %-35.7 %). Two patients (3.1 %) had complete response (CR), 13 patients (20.3 %) had partial response (PR), 26 patients (40.6 %) had stable disease, 17 patients (26.6 %) had PD, and 6 patients (9.4 %) were not evaluable. Regardless of histology or PD-L1 status, median PFS (mPFS) was 4.1 months (95 % CI 2.4-6.9 months) and OS at 6 months was 74.7 % (61.5%-83.9%). Confirmed disease control rate was 64.1 % (95 % CI 51.5-75.7). Patients with programmed death-ligand 1 (PD-L1) ≥1% had numerically improved ORR and median progression-free survival when compared with patients with PD-L1 negative cancer. No dose-limiting toxicities were recorded and the combination of necitumumab 800 mg with pembrolizumab 200 mg was considered tolerable. Results suggest modest benefits of second-line necitumumab and pembrolizumab combination therapy in patients with Stage IV NSCLC. Safety profiles were consistent with class effects typical of epidermal growth factor receptor inhibitors and immunotherapies with no additive toxicities.

Besse B ，Garrido P ，Cortot AB ，Johnson M ，Murakami H ，Gazzah A ，Gil M ，Bennouna J ... -  《-》

An Open-Label, Randomized, Controlled Phase II Study of Paclitaxel-Carboplatin Chemotherapy With Necitumumab Versus Paclitaxel-Carboplatin Alone in First-Line Treatment of Patients With Stage IV Squamous Non-Small-Cell Lung Cancer.

The combination of necitumumab with gemcitabine-cisplatin significantly improved overall survival (OS) in patients with stage IV squamous non-small-cell lung cancer (NSCLC), in the phase III SQUamous NSCLC treatment with the Inhibitor of EGF REceptor (SQUIRE) trial. Paclitaxel-carboplatin was selected as an alternative standard of care in the current phase II study. Patients were randomized (stratified according to Eastern Cooperative Oncology Group performance status and sex) 2:1 to ≤ six 3-week cycles (Q3W) of paclitaxel and carboplatin with or without necitumumab. Chemotherapy was paclitaxel 200 mg/m2 on day 1 Q3W and carboplatin area under the curve 6 on day 1 Q3W. Necitumumab 800 mg, on days 1 and 8, was continued until disease progression or intolerable toxicity occurred. The primary end point was objective response rate (ORR) on the basis of Response Evaluation Criteria In Solid Tumors version 1.1. One hundred sixty-seven patients were randomized to the necitumumab-containing arm (n = 110) or the chemotherapy-only arm (n = 57). The combination of necitumumab with chemotherapy resulted in an ORR of 48.9% versus 40.0%. Median progression-free survival and OS were 5.4 versus 5.6 months (hazard ratio [HR], 1.0) and 13.2 versus 11.2 months (HR, 0.83; P = .379) in each treatment arm, respectively. Disease control rate was 87.2% versus 84.0%. Grade ≥ 3 adverse events typically associated with epidermal growth factor receptor (EGFR) monoclonal antibodies showing a > 2% increase were hypomagnesemia (5.7% vs. 0) and rash (2.8% vs. 0). Any Grade thromboembolic events occurred in < 4% of patients in either arm. The results of our study support previously reported results that the combination of necitumumab with chemotherapy improves survival in patients with advanced squamous NSCLC and shows a safety profile consistent with that of EGFR monoclonal antibodies.

Spigel DR ，Luft A ，Depenbrock H ，Ramlau R ，Khalil M ，Kim JH ，Mayo C ，Chao GY ，Obasaju C ，Natale R ... -  《-》

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 ... -  《-》

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 ... -  《-》