Andrew Koustenis

PROCLAIM: Randomized Phase III Trial of Pemetrexed-Cisplatin or Etoposide-Cisplatin Plus Thoracic Radiation Therapy Followed by Consolidation Chemotherapy in Locally Advanced Nonsquamous Non–Small-Cell Lung Cancer

PURPOSE The phase III PROCLAIM study evaluated overall survival (OS) of concurrent pemetrexed-cisplatin and thoracic radiation therapy (TRT) followed by consolidation pemetrexed, versus etoposide-cisplatin and TRT followed by nonpemetrexed doublet consolidation therapy. PATIENTS AND METHODS Patients with stage IIIA/B unresectable nonsquamous non-small-cell lung cancer randomly received (1:1) pemetrexed 500 mg/m(2) and cisplatin 75 mg/m(2) intravenously every 3 weeks for three cycles plus concurrent TRT (60 to 66 Gy) followed by pemetrexed consolidation every 3 weeks for four cycles (arm A), or standard therapy with etoposide 50 mg/m(2) and cisplatin 50 mg/m(2) intravenously, every 4 weeks for two cycles plus concurrent TRT (60 to 66 Gy) followed by two cycles of consolidation platinum-based doublet chemotherapy (arm B). The primary objective was OS. The study was designed as a superiority trial with 80% power to detect an OS hazard ratio of 0.74 with a type 1 error of .05. RESULTS Enrollment was stopped early because of futility. Five hundred ninety-eight patients were randomly assigned (301 to arm A, 297 to arm B) and 555 patients (283 in arm A, 272 in arm B) were treated. Arm A was not superior to arm B in terms of OS (hazard ratio, 0.98; 95% CI, 0.79 to 1.20; median, 26.8 v 25.0 months; P = .831). Arm A had a significantly lower incidence of any drug-related grade 3 to 4 adverse events (64.0% v 76.8%; P = .001), including neutropenia (24.4% v 44.5%; P < .001), during the overall treatment period. CONCLUSION Pemetrexed-cisplatin combined with TRT followed by consolidation pemetrexed was not superior to standard chemoradiotherapy for stage III unresectable nonsquamous non-small-cell lung cancer.

MONARCH 1, A Phase II Study of Abemaciclib, a CDK4 and CDK6 Inhibitor, as a Single Agent, in Patients with Refractory HR+/HER2− Metastatic Breast Cancer

Purpose: The phase II MONARCH 1 study was designed to evaluate the single-agent activity and adverse event (AE) profile of abemaciclib, a selective inhibitor of CDK4 and CDK6, in women with refractory hormone receptor–positive (HR+), HER2− metastatic breast cancer (MBC). Experimental Design: MONARCH 1 was a phase II single-arm open-label study. Women with HR+/HER2− MBC who had progressed on or after prior endocrine therapy and had 1 or 2 chemotherapy regimens in the metastatic setting were eligible. Abemaciclib 200 mg was administered orally on a continuous schedule every 12 hours until disease progression or unacceptable toxicity. The primary objective of MONARCH 1 was investigator-assessed objective response rate (ORR). Other endpoints included clinical benefit rate, progression-free survival (PFS), and overall survival (OS). Results: Patients (n = 132) had a median of 3 (range, 1–8) lines of prior systemic therapy in the metastatic setting, 90.2% had visceral disease, and 50.8% had ≥3 metastatic sites. At the 12-month final analysis, the primary objective of confirmed objective response rate was 19.7% (95% CI, 13.3–27.5; 15% not excluded); clinical benefit rate (CR+PR+SD≥6 months) was 42.4%, median progression-free survival was 6.0 months, and median overall survival was 17.7 months. The most common treatment-emergent AEs of any grade were diarrhea, fatigue, and nausea; discontinuations due to AEs were infrequent (7.6%). Conclusions: In this poor-prognosis, heavily pretreated population with refractory HR+/HER2− metastatic breast cancer, continuous dosing of single-agent abemaciciclib was well tolerated and exhibited promising clinical activity. Clin Cancer Res; 23(17); 5218–24. ©2017 AACR.

PRONOUNCE: Randomized, Open-Label, Phase III Study of First-Line Pemetrexed + Carboplatin Followed by Maintenance Pemetrexed versus Paclitaxel + Carboplatin + Bevacizumab Followed by Maintenance Bevacizumab in Patients ith Advanced Nonsquamous Non–Small-Cell Lung Cancer

Introduction: PRONOUNCE compared the efficacy and safety of pemetrexed+carboplatin followed by pemetrexed (Pem+Cb) with paclitaxel+carboplatin+bevacizumab followed by bevacizumab (Pac+Cb+Bev) in patients with advanced nonsquamous non–small-cell lung cancer (NSCLC). Methods: Patients ≥18 years of age with stage IV nonsquamous NSCLC (American Joint Committee on Cancer v7.0), and Eastern Cooperative Oncology Group performance status 0/1 were randomized (1:1) to four cycles of induction Pem+Cb (pemetrexed, 500 mg/m2, carboplatin, area under the curve = 6) followed by Pem maintenance or Pac+Cb+Bev (paclitaxel, 200 mg/m2, carboplatin, area under the curve = 6, and bevacizumab, 15 mg/kg) followed by Bev maintenance in the absence of progressive disease or discontinuation. The primary objective was progression-free survival (PFS) without grade 4 toxicity (G4PFS). Secondary end points were PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), and safety. Resource utilization was also assessed. Results: Baseline characteristics of the patients randomized to Pem+Cb (N = 182) and Pac+Cb+Bev (N = 179) were well balanced between the arms. Median (months) G4PFS was 3.91 for Pem+Cb and 2.86 for Pac+Cb+Bev (hazard ratio = 0.85, 90% confidence interval, 0.7–1.04; p = 0.176); PFS, OS, ORR, or DCR did not differ significantly between the arms. Significantly more drug-related grade 3/4 anemia (18.7% versus 5.4%) and thrombocytopenia (24.0% versus 9.6%) were reported for Pem+Cb. Significantly more grade 3/4 neutropenia (48.8% versus 24.6%), grade 1/2 alopecia (28.3% versus 8.2%), and grade 1/2 sensory neuropathy were reported for Pac+Cb+Bev. Number of hospitalizations and overall length of stay did not differ significantly between the arms. Conclusions: Pem+Cb did not produce significantly better G4PFS compared with Pac+Cb+Bev. Pem+Cb was not superior in PFS, OS, ORR, or DCR compared with Pac+Cb+Bev. Both regimens were well tolerated, although, toxicity profiles differed.

Pemetrexed in Combination With Cisplatin Versus Cisplatin Monotherapy in Patients With Recurrent or Metastatic Head and Neck Cancer Final Results of a Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study

Recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) is associated with poor survival. Platinum‐based chemotherapy is often a first‐line treatment. Pemetrexed has shown single‐agent activity in SCCHN and in combination with cisplatin for other tumors. This trial examined the efficacy of pemetrexed‐cisplatin for SCCHN.

Randomized, open-label, phase III study of pemetrexed plus carboplatin (PemC) followed by maintenance pemetrexed versus paclitaxel/carboplatin/bevacizumab (PCB) followed by maintenance bevacizumab in patients with advanced nonsquamous (NS) non-small cell lung cancer (NSCLC).

LBA8003 Background: PemC and PCB are regimens used for first-line treatment of advanced NS-NSCLC. The primary objective was to compare progression-free survival without Grade 4 toxicity (G4PFS) between two vs three drug regimen arms. METHODS Patients ≥18 years, Stage IV NS NSCLC, AJCC (v7.0), and ECOG PS 0/1 were enrolled. Patients were randomized (1:1); received 4 cycles of induction (PemC: Pem, 500 mg/m2 and C, AUC = 6; PCB: P, 200 mg/m2, C, AUC = 6, and B, 15 mg/kg) followed by Pem (PemC Arm) or B (PCB Arm) maintenance therapy in the absence of progressive disease or discontinuation. Secondary endpoints were PFS, overall survival (OS), overall response rate (ORR), and disease control rate (DCR). The study was powered for G4PFS; assuming hazard ratio (HR) of 0.75; there was 80% power to detect superiority of PemC over PCB with a 2-sided type I error of 0.10. Efficacy data were analyzed by intent-to-treat principle using the log-rank test for time-to-event variables, and an exact test for ORR and DCR. Safety data were evaluated using CTCAE v3 for patients who received ≥1 dose of study treatment. RESULTS Patients were randomized to PemC (N = 182) or PCB (N = 179). Baseline factors were balanced between arms: median age 66/66 years; % female 42/42; % PS=0, 47/47; % stage IV M1a 29/30; for PemC vs PCB, median G4PFS (months) was 3.91/2.86 (HR = 0.85, 90% CI 0.7, 1.04, p = 0.176); PFS and OS had HR = 1.06 (95% CI 0.84, 1.35), p = 0.610, and HR = 1.07 (95% CI 0.83, 1.36), p = 0.616, respectively. The ORR (%) 23.6/ 27.4 and DCR (%) 59.9/57.0 were for PemC vs PCB, respectively. Significantly more drug-related grade 3/4 anemia (18.7% vs 5.4%), and thrombocytopenia (24.0% vs 9.6%) were seen on PemC; significantly more grade 3/4 neutropenia (48.8% vs 24.6%) and grade 1/2 alopecia (28.3 % vs 8.2%) were seen on PCB. CONCLUSIONS PemC was not superior to PCB in G4PFS; no difference in PFS or OS was observed for the two- vs three-drug regimens. There were no unexpected toxicities; the toxicity profiles demonstrated distinctions by arm, and both regimens demonstrated tolerability. CLINICAL TRIAL INFORMATION NCT00948675.

Quality of life scores as prognostic factors of overall survival in advanced head and neck cancer: Analysis of a phase III randomized trial of pemetrexed plus cisplatin versus cisplatin monotherapy

OBJECTIVES We examined the prognostic factors (clinical, demographic, and health-related quality of life [HRQoL]) of overall survival (OS) and progression-free survival (PFS) in patients with recurrent/metastatic head and neck cancer (HNC) who were treated with pemetrexed plus cisplatin versus cisplatin in a phase III, multinational, randomized trial. MATERIALS AND METHODS Five subscales of the Functional Assessment of Cancer Therapy-Head and Neck Cancer (FACT-H&N), modified to score from 0 to 100, measured HRQoL at baseline and during treatment. Univariate and multivariate Cox proportional hazards models were used on data pooled from both treatment arms to assess the effect of baseline prognostic factors on OS and PFS. RESULTS Of 795 patients randomized, 704 completed a baseline FACT-H&N and were included in the analysis. Age (<65 versus ⩾65; HR=0.74, 95% CI: 0.61-0.90), race (Caucasian versus non-Caucasian; HR=0.83, 95% CI: 0.70-0.98 per table), Eastern Cooperative Oncology Group performance status (ECOG PS; 0/1 versus 2; HR=0.44, 95% CI: 0.35-0.56), prior surgery/radiotherapy in the last 6months (no versus yes; HR=0.74, 95% CI: 0.61-0.90), and primary site of disease (oral cavity versus other; HR=1.37, 95% CI: 1.15-1.63) were significantly prognostic of OS in univariate models, as were baseline scores on four FACT-H&N subscales (physical well-being, emotional well-being, functional well-being, additional concerns-H&N; HRs=0.82-0.94; all P⩽0.002). In multivariate models, significant prognostic factors were age (HR=0.78); race (HR=0.76 per table); ECOG PS (HR=0.56); prior surgery/radiotherapy (HR=0.76); and baseline scores of the FACT-H&N subscales of physical well-being, social/family well-being, and additional concerns-H&N (HRs=0.89-0.94; all P⩽0.014 per table). CONCLUSIONS The results suggest that baseline HRQoL scores are prognostic indicators of OS in recurrent/metastatic HNC in addition to other known clinical and demographic indicators. HRQoL might be considered as a stratification factor in randomized clinical trials of recurrent/metastatic HNC.

Phase 2 Study of Pemetrexed Plus Carboplatin, or Pemetrexed Plus Cisplatin with Concurrent Radiation Therapy Followed by Pemetrexed Consolidation in Patients with Favorable-Prognosis Inoperable Stage IIIA/B Non–Small-Cell Lung Cancer

Introduction: There is no consensus chemotherapy regimen with concurrent radiotherapy (RT) for inoperable stage IIIA/B non–small-cell lung cancer. This trial evaluated pemetrexed with carboplatin (PCb) or cisplatin (PC) with concurrent RT followed by consolidation pemetrexed. Methods: In this open-label, noncomparative phase II trial, patients with inoperable stage IIIA/B non–small-cell lung cancer (initially all histologies, later restricted to nonsquamous) were randomized (1:1) to PCb or PC with concurrent RT (64–68 Gy over days 1–45). Consolidation pemetrexed monotherapy was administered every 21 days for three cycles. Primary endpoint was 2-year overall survival (OS) rate. Results: From June 2007 to November 2009, 98 patients were enrolled (PCb: 46; PC: 52). The 2-year OS rate was PCb: 45.4% (95% confidence interval [CI], 29.5–60.0%); PC: 58.4% (95% CI, 42.6–71.3%), and in nonsquamous patients was PCb: 48.0% (95% CI, 29.0–64.8%); PC: 55.8% (95% CI, 38.0–70.3%). Median time to disease progression was PCb: 8.8 months (95% CI, 6.0–12.6 months); PC: 13.1 months (95% CI, 8.3–not evaluable [NE]). Median OS (months) was PCb: 18.7 (95% CI, 12.9–NE); PC: 27.0 (95% CI, 23.2–NE). The objective response rates (ORRs) were PCb: 52.2%; PC: 46.2%. Grade 4 treatment-related toxicities (% PCb/% PC) were: anemia, 0/1.9; neutropenia, 6.5/3.8; thrombocytopenia, 4.3/1.9; and esophagitis, 0/1.9. Most patients completed scheduled chemotherapy and RT during induction and consolidation phases. No drug-related deaths were reported during chemoradiotherapy. Conclusions: Because of study design, efficacy comparisons cannot be made. However, both combinations with concurrent RT were active and well tolerated.

Abstract P6-11-12: Subgroup Analysis by prior treatment and disease burden in MONARCH 1: A phase 2 study of monotherapy abemaciclib, a CDK4 & 6 inhibitor, in patients with HR+/HER2 metastatic breast cancer (MBC) following chemotherapy

Background: The MONARCH 1 (NCT0210249) study demonstrated durable single agent activity of abemaciclib in patients (pts) with HR+/HER2- breast cancer, with an objective response rate of 19.7% and median duration of response of 8.6 months1. The MONARCH 1 study population was heavily pretreated and had a high disease burden: all pts had previously received endocrine therapy and chemotherapy, had median of 3 prior systemic therapies for metastatic disease 90.2% had visceral disease and 85.6% had ≥ 2 metastatic sites. Methods: MONARCH 1 was a phase 2 single-arm study designed to evaluate safety and efficacy of abemaciclib monotherapy in women with HR+/HER2- MBC whose disease progressed on/after endocrine therapy and chemotherapy. Abemaciclib (200 mg) was administered orally on a continuous schedule every 12 hours until disease progression. The primary objective planned to evaluate investigator-assessed objective response rate (ORR= complete response [CR] + partial response [PR]) in a sample size of approximately 128 pts) using RECIST v1.1. Subgroup analyses evaluating ORR by prior treatment and disease burden were performed. Results: A total of 132 pts were treated with abemaciclib monotherapy. Analyses of subgroups based on prior treatment and disease burden are summarized in Table 1. Conclusions: Abemaciclib monotherapy administered on a continuous schedule has consistent single agent activity across the subgroups analyzed. Citation Format: Rugo H, Nanda S, Koustenis A. Subgroup Analysis by prior treatment and disease burden in MONARCH 1: A phase 2 study of monotherapy abemaciclib, a CDK4 & 6 inhibitor, in patients with HR+/HER2 metastatic breast cancer (MBC) following chemotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-12.

Pemetrexed Continuation Maintenance Phase 3 Trials in Nonsquamous, Non–Small-Cell Lung Cancer: Focus on 2-Year Overall Survival and Continuum of Care

&NA; Although lung cancer prognosis remains poor for most patients, treatments developed in the past 2 decades have extended survival for many. For those with disease that responded to or those with stable disease after receipt of platinum‐based chemotherapy, maintenance regimens enable continued targeting of tumors beyond the induction phase, which is limited by toxicity. This overview summarizes completed phase 3 trials of pemetrexed continuation maintenance treatment in nonsquamous, non–small‐cell lung cancer with a focus on 2‐year survival, and highlights similar ongoing trials. Some studies showed survival benefits of pemetrexed maintenance treatment versus control arms, with the potential for added benefit when combined with bevacizumab. Two‐year survival rates underscore the value of maintenance therapy and suggest progress toward a clinical goal of managing non–small‐cell lung cancer as a treatable chronic disease.

Abstract CT044: MONARCH 1: Final overall survival analysis of a phase 2 study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2- breast cancer, after chemotherapy for advanced disease

Background: Abemaciclib is an oral, selective inhibitor of CDK4 and CDK6 dosed on a continuous schedule. MONARCH 1 (NCT02102490) is a phase 2 single-arm study designed to evaluate safety and efficacy of abemaciclib monotherapy in women with HR+/HER2- MBC whose disease progressed on or after endocrine therapy and chemotherapy. Final analysis of the primary endpoint, objective response rate (ORR) at 12 months (mo), showed that abemaciclib monotherapy induced objective tumor responses in patients (pts) with refractory HR+/HER2- MBC following multiple prior therapies. Treatment was well tolerated, allowing prolonged exposure to therapy. We report the final 18 mo overall survival results. Methods: Eligible pts had measurable disease, ECOG PS of 0/1, no CNS metastases, and received at least 1 but no more than 2 lines of chemotherapy in the metastatic setting. Abemaciclib (200 mg) was administered orally on a continuous schedule every 12 hours until disease progression. The primary objective was to evaluate ORR per RECIST v1.1. at 12 mo after the last pt enrolled. Secondary objectives included duration of response (DoR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR = CR + PR + SD), clinical benefit rate (CBR= CR + PR + SD ≥ 6 mo) and safety. Final OS analysis occurred 18 mo after the last pt was enrolled. Results: A total of 132 pts received abemaciclib monotherapy. The primary endpoint of ORR by investigator assessment at 12 mo was 19.7% (95% CI: 13.3, 27.5) and did not change at 18 mo. Of the 26 responding pts, 19 (73.1%) had responses ≥ 6 mo, and 6 pts still on treatment have response durations ranging from 9.5+ to 20.5+ mo. There was no change at 18 mo vs 12 mo for DCR (67.4%) or CBR (42.4%). Median PFS (6.0 mo, 95% CI: 4.2, 7.5) and median DoR (8.9 mo, 95% CI: 6.1, 14.0) were also consistent with 12 mo follow up. At the 18 mo update, 7 pts (5.3%) remained on treatment (6 PR and 1 SD). At 18 mo, the median OS was 22.3 mo (95% CI: 17.7, NR), and the survival rate was 58.7%. TEAEs ≥ Grade 3 were experienced by 93 pts (70.5%) at 18 mo, compared to 90 pts (68.2%) at 12 mo. The most common Grade 3/4 TEAEs were neutropenia (25.0%), diarrhea (19.7%), fatigue (13.6%), leukopenia (6.8%), anemia (4.5%) and nausea (4.5%). Treatment discontinuations due to AEs were infrequent (7.6 %). Conclusions: The results of the 18 month analysis are consistent with the 12 month results of MONARCH 1. Median OS was 22.3 months. The efficacy results from the MONARCH 1 study indicate that continuous administration of single-agent abemaciclib induces durable confirmed tumor responses. There were no clinically significant changes in safety. The results of the 18 month analysis support the earlier results and indicate that single-agent abemaciclib may offer a more favorable benefit-risk profile than expected from available cytotoxic chemotherapies. Citation Format: Hope S. Rugo, Sara M. Tolaney, Javier Cortes, Veronique Dieras, Debra A. Patt, Hans Wildiers, Shivani Nanda, Andrew G. Koustenis, Maura N. Dickler, Jose Baselga. MONARCH 1: Final overall survival analysis of a phase 2 study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2- breast cancer, after chemotherapy for advanced disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT044. doi:10.1158/1538-7445.AM2017-CT044