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Efficacy and safety of first-line pemetrexed plus carboplatin followed by single-agent pemetrexed maintenance in elderly Chinese patients with non-squamous non-small-cell lung cancer.

ABSTRACT: Chemotherapy with pemetrexed plus carboplatin followed by pemetrexed maintenance therapy is a first-line regimen for patients with advanced non-squamous non-small-cell lung cancer. This phase II clinical study investigated the efficacy and safety of this regimen in older patients (aged ?65 years) with advanced non-squamous non-small-cell lung cancer. All patients received 4 courses of induction therapy with pemetrexed (500 mg/m2) combined with carboplatin once every 3 weeks. If patients had stable disease or achieved a complete or partial tumor response after 4 courses of pemetrexed + carboplatin therapy, maintenance treatment with pemetrexed monotherapy was administered until either disease progression or intolerable toxicity occurred. The primary endpoint was progression-free survival, while secondary endpoints were the objective response rate, overall survival, and tolerability. A total of 105 elderly patients (median age, 71 years) with advanced lung adenocarcinoma were enrolled in the trial. The ORR with induction therapy was 36.2% and the disease control rate was 70.5%. Sixty-two patients (59.0%) subsequently received pemetrexed maintenance therapy. The median progression-free survival for all patients was 8.23 months (95% CI 5.85-10.62 months) and the median overall survival was 22.6 months (95% CI 20.09-25.11 months). Grade 3 or greater toxicities included neutropenia (15.3%), thrombocytopenia (9.5%), anemia (8.6%), leukopenia (4.8%), nausea (1.0%), vomiting (1.0%), and fatigue (1.0%). No treatment-related deaths occurred. These results indicate that pemetrexed combined with carboplatin therapy maintained by single-agent pemetrexed treatment of elderly patients with advanced non-squamous non-small-cell lung cancer was effective and tolerable. ClinicalTrials.gov identifier: NCT01860508.

SUBMITTER: Zhao X

PROVIDER: S-EPMC5689692 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Efficacy and safety of first-line pemetrexed plus carboplatin followed by single-agent pemetrexed maintenance in elderly Chinese patients with non-squamous non-small-cell lung cancer.

Zhao Xinmin X Yu Hui H Zhao Jing J Wu Xianghua X Sun Si S Luo Zhiguo Z Wang Huijie H Qiao Jie J Chang Jianhua J Wang Jialei J

Oncotarget 20170923 49

Chemotherapy with pemetrexed plus carboplatin followed by pemetrexed maintenance therapy is a first-line regimen for patients with advanced non-squamous non-small-cell lung cancer. This phase II clinical study investigated the efficacy and safety of this regimen in older patients (aged ≥65 years) with advanced non-squamous non-small-cell lung cancer. All patients received 4 courses of induction therapy with pemetrexed (500 mg/m<sup>2</sup>) combined with carboplatin once every 3 weeks. If patien ...[more]

PMID: 29156802

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Project description:IntroductionPRONOUNCE 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).MethodsPatients ≥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/m, carboplatin, area under the curve = 6) followed by Pem maintenance or Pac+Cb+Bev (paclitaxel, 200 mg/m, 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.ResultsBaseline 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.ConclusionsPem+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.

Project description:ImportanceFew clinical trials have been specifically designed for elderly patients with advanced non-small cell lung cancer (NSCLC), and the anticipated increase in the number of such patients has prompted a search for new treatment options that provide a greater palliative benefit.ObjectiveTo determine whether treatment with carboplatin plus pemetrexed followed by pemetrexed maintenance is noninferior compared with docetaxel monotherapy with regard to overall survival (OS) for elderly patients with advanced nonsquamous NSCLC.Design, setting, and participantsThis open-label, multicenter, noninferiority phase 3 randomized clinical trial was conducted at 79 institutions in Japan. Cytotoxic chemotherapy-naive patients with advanced nonsquamous NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and age of 75 years or older were enrolled between August 2013 and February 2017. Data were analyzed from November 2018 to February 2019.InterventionsPatients were randomized to receive either docetaxel monotherapy (60 mg/m2) every 3 weeks or 4 cycles of carboplatin (area under the curve of 5) plus pemetrexed (500 mg/m2) administered every 3 weeks followed by maintenance therapy with the same dose of pemetrexed for 3 weeks.Main outcomes and measuresThe primary end point was OS analyzed on an intention-to-treat basis with a noninferiority margin of 1.154 for the upper limit of the 95% CI of the hazard ratio (HR) estimated with a stratified Cox regression model.ResultsOf the 433 enrolled patients, 250 (57.7%) were male, and the median (range) age was 78 (75-88) years. The median OS was 15.5 months (95% CI, 13.6-18.4) in the docetaxel group (n?=?217) and 18.7 months (95% CI, 16.0-21.9) in the carboplatin-pemetrexed group (n?=?216), with a stratified HR for OS of 0.850 (95% CI, 0.684-1.056; P for noninferiority?=?.003). Progression-free survival was also longer in the carboplatin-pemetrexed group (unstratified HR, 0.739; 95% CI, 0.609-0.896). Compared with those in the docetaxel group, those in the carboplatin-pemetrexed had lower rates of leukopenia (60 of 214 [28.0%] vs 147 of 214 [68.7%]) and neutropenia (99 of 214 [46.3%] vs 184 of 214 [86.0%]) of grade 3 or 4 and of febrile neutropenia (9 of 214 [4.2%] vs 38 of 214 [17.8%]) and higher rates of thrombocytopenia (55 of 214 [25.7%] vs 3 of 214 [1.4%]) and anemia (63 of 214 [29.4%] vs 4 of 214 [1.9%]) of grade 3 or 4. Dose reductions were less frequent with carboplatin-pemetrexed.Conclusion and relevanceCarboplatin-pemetrexed treatment followed by pemetrexed maintenance is a valid option for first-line treatment of elderly patients with advanced nonsquamous NSCLC.Trial registrationUniversity Hospital Medical Information Network Clinical Trials Registry Identifier: UMIN000011460.

Project description:ObjectiveTo evaluate the efficacy and safety of pemetrexed, carboplatin and bevacizumab (PCB) followed by maintenance therapy with pemetrexed and bevacizumab (PB) in chemotherapy-naïve patients with stage IV non-squamous non-small cell lung cancer (NSCLC) through the influence of thymidylate synthase (TS) protein and mRNA expression on several outcomes. The primary endpoints were the overall response rate (ORR), progression-free survival (PFS) and overall survival (OS).MethodsA cohort of 144 patients were administered pemetrexed (500 mg/m2), carboplatin (AUC, 5.0 mg/ml/min) and bevacizumab (7.5 mg/kg) intravenously every three weeks for up to four cycles. Maintenance PB was administered until disease progression or unacceptable toxicity.ResultsOne hundred forty-four Colombian patients with a median follow-up of 13.8 months and a median number of 6 maintenance cycles (range, 1-32) were assessed. The ORR among the patients was 66% (95% CI, 47% to 79%). The median PFS and (OS) rates were 7.9 months (95% CI, 5.9-10.0 months) and 21.4 months (95% CI, 18.3 to 24.4 months), respectively. We documented grade 3/4 hematologic toxicities, including anemia (14%), neutropenia (8%), and thrombocytopenia (16%). The identified grade 3/4 non-hematologic toxicities were proteinuria (2%), venous thrombosis (4%), fatigue (11%), infection (6%), nephrotoxicity (2%), and sensory neuropathy (4%). No grade >3 hemorrhagic events or hypertension cases were reported. OS was significantly higher in patients with the lowest TS mRNA levels [median, 29.6 months (95% CI, 26.2-32.9)] compared with those in patients with higher levels [median, 9.3 months (95% CI, 6.6-12.0); p = 0.0001]. TS expression (mRNA levels or protein expression) did not influence the treatment response.ConclusionOverall, PCB followed by maintenance pemetrexed and bevacizumab was effective and tolerable in Hispanic patients with non-squamous NSCLC. This regimen was associated with acceptable toxicity and prolonged OS, particularly in patients with low TS expression. We found a role for Ki67 and TS expression as prognostic factors.

Project description:BackgroundMany physicians consider platinum-doublet chemotherapy inappropriate for elderly patients, regardless of their medical fitness.ObjectiveThis was a retrospective subgroup analysis of data from a multicenter, randomized, phase III clinical trial evaluating pemetrexed + carboplatin versus docetaxel + carboplatin in elderly chemo-naive patients with advanced, nonsquamous non-small cell lung cancer (NSCLC).MethodsData from elderly patients (aged ≥65 years and ≥70 years) were evaluated using the same statistical methods as those used in patients aged <70 years and qualified intent-to-treat (Q-ITT) populations. The primary objective of the clinical trial was comparison of pemetrexed + carboplatin with docetaxel + carboplatin in terms of survival without grade 3 or 4 toxicity in chemo-naive NSCLC patients.ResultsThe ≥65- and ≥70-year age groups had 68 and 37 patients, respectively. Among patients aged ≥65 years, the adjusted hazard ratio (HR) for survival without grade 3-4 toxicity (HR 0.40, 95 % confidence interval [CI] 0.23-0.70) favored pemetrexed + carboplatin; this was similar to the HRs in patients aged ≥70 years (HR 0.43, 95 % CI 0.20-0.92), patients aged <70 years (HR 0.44, 95 % CI 0.32-0.62), and the Q-ITT population (HR 0.45, 95 % CI 0.34-0.61). The median values for overall survival (OS) and progression-free survival (PFS) were similar across all age-group subsets and the Q-ITT population. The HRs for OS and PFS were similar for all age-group subsets, except for the ≥70-year age group, which favored pemetrexed + carboplatin to a greater extent. The toxicity profile was similar across age groups, with the exception of diarrhea, mucosal inflammation, and grade 3-4 neutropenia and leukopenia, which were slightly more common in elderly patients in both treatment arms. Between-arm differences in the toxicity profiles for the ≥65-, ≥70- and <70-year age subgroups were similar to those in the Q-ITT population. There were no on-study deaths or unexpected toxicities.ConclusionThe benefits of pemetrexed + carboplatin were maintained, and toxicity was manageable in both elderly subgroups. The favorable risk-benefit profile of pemetrexed + carboplatin makes it an appropriate first-line treatment option for elderly patients with advanced nonsquamous NSCLC.

Project description:Maintenance therapy for non-small cell lung cancer (NSCLC) aims to extend disease control after first-line chemotherapy with active and well-tolerated agents. The utility of continuation maintenance therapy requires further research.This multicenter, randomized, phase 2 study compared continuation maintenance therapy with pemetrexed (500?mg/m2 every 21?days) and best supportive care (BSC) versus BSC alone in patients with advanced, non-squamous NSCLC who had not progressed after 4?cycles of induction chemotherapy with pemetrexed (500?mg/m2) and cisplatin (75?mg/m2). The primary endpoint was progression-free survival (PFS) from randomization, was analyzed using a Cox model, stratified for the tumor response at the end of induction therapy, at a one-sided alpha of 0.2. Secondary endpoints: response and disease control rates, overall survival (OS), one year survival rates, and treatment-emergent adverse events (TEAEs).A total of 106 patients commenced induction therapy, of whom 55 patients were randomized to maintenance pemetrexed/BSC (n?=?28) or BSC (n?=?27). Although the median PFS time for maintenance phase for both arms was 3.2?months, the one-sided p-value for the PFS HR comparison was less than the prespecified limit of 0.2 (HR?=?0.76, two-sided 95% confidence interval [CI]: 0.42 to 1.37; one-sided p-value?=?0.1815), indicating that PFS was sufficiently long in the pemetrexed/BSC arm to warrant further investigation. Similar PFS results were observed for the overall study period (induction plus maintenance) and when the PFS analysis was adjusted for sex, baseline disease stage, and the ECOG PS prior to randomization. The median OS for the maintenance phase was 12.2?months (95%CI: 5.6 to 20.6) for the pemetrexed/BSC arm and 11.8?months (95% CI: 6.3 to 25.6) for BSC arm. The one-year survival probabilities were similar for both arms for the maintenance phase and the overall study period. Both the induction and continuation maintenance therapies were generally well-tolerated, and similar proportion of patients in each arm experienced at least 1 grade 3/4 TEAE (pemetrexed/BSC, 17.9%; BSC, 18.5%).Continuation pemetrexed maintenance therapy resulted in promising PFS with an acceptable safety profile in a Middle Eastern population with advanced non-squamous NSCLC and is worthy of further investigation.NCT00606021.

Dataset Information

Efficacy and safety of first-line pemetrexed plus carboplatin followed by single-agent pemetrexed maintenance in elderly Chinese patients with non-squamous non-small-cell lung cancer.

Publications

Efficacy and safety of first-line pemetrexed plus carboplatin followed by single-agent pemetrexed maintenance in elderly Chinese patients with non-squamous non-small-cell lung cancer.

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