Final results from a Phase II study of pemetrexed and cisplatin with concurrent thoracic radiation after Pem-Cis induction in patients with unresectable locally advanced non-squamous non-small cell lung cancer (NSCLC).

OBJECTIVES: This single-arm multicenter Phase II study investigated the efficacy and safety of pemetrexed (Pem) and cisplatin (Cis) induction chemotherapy (CT) followed by full-dose Pem-Cis plus concurrent radiotherapy (RT) in patients with locally advanced non-squamous NSCLC. MATERIALS AND METHODS: Patients with unresectable Stage III non-squamous NSCLC received two 21-day cycles of Pem 500 mg/m(2) (vitamin/folic acid supplementation and dexamethasone prophylaxis per Pem-label)+Cis 75 mg/m(2) on Day 1. Eligible patients who had not progressed continued with 2 further cycles of full-dose Pem-Cis plus concurrent RT (2 Gy/fraction, 5 days/week, 66 Gy total). Primary endpoint was the 1-year progression-free survival (PFS) rate. RESULTS: Of 90 patients enrolled (all treated; median age 61 years, male/female 57%/43%, ECOG performance status 0/1 66%/34%, adenocarcinoma 90%, Stage III 36%/62%), 75 (83%) completed induction CT and started concurrent CT+RT. 64 (71%) patients received all 4 CT cycles and an RT dose ≥60 Gy. The 1-year PFS rate was 51.3% (95%CI: 42.0, 60.5). Median PFS was 10.6 months (95%CI: 8.6, 17.3), median OS was 26.2 months (95%CI: 16.7, not estimable). One patient died from enteritis (treatment-related) during Cycle 4. Four patients discontinued due to treatment-related adverse events, 1 on induction CT (renal failure), 3 on concurrent CT+RT (1 hypoacusis, 2 acute esophagitis). During induction CT, 18.9% of patients reported Grade 3/4 CTCAEs, only neutropenia (2.2%) and syncope (2.2%) were reported by >1 patient. During concurrent CT+RT, 41.3% of patients reported G3/4 CTCAEs, mainly esophagitis (12.0%), neutropenia (10.7%), and leukopenia (9.3%). CONCLUSION: In this study of Pem-Cis induction CT followed by full-dose Pem-Cis with concurrent RT, median PFS was 10.6 months and toxicity was manageable, in line with previous data on Pem-Cis plus RT.

Pemetrexed use in the adjuvant setting for completely resectable non-small-cell lung cancer.

Supported by evidence from the LACE (Lung Adjuvant Cisplatin Evaluation) metaanalysis, cisplatin-based adjuvant chemotherapy is now recommended as the standard of care for patients with surgically resected early-stage non-small-cell lung cancer (NSCLC) per American Society of Clinical Oncology and European Society for Medical Oncology clinical practice guidelines. These standard regimens, which principally include cisplatin-etoposide and cisplatin-vinorelbine, are associated with long- and short-term toxicities. Hence, cisplatin-based regimens with an improved therapeutic index and optimal safety and tolerability profile are still needed. Pemetrexed, an antifolate, is currently indicated for first-line, maintenance, and second-line therapy for advanced nonsquamous NSCLC. Pemetrexed-platinum, with or without targeted agents, has proven to be efficacious with an acceptable toxicity profile when given in the first-line metastatic setting. Therefore, it is reasonable that pemetrexed be investigated in the adjuvant setting. This review collates data from January 2000 through August 2012 on the use of pemetrexed-platinum regimens in the adjuvant setting either alone or in combination with targeted agents. To date, more than 1000 patients with early stage NSCLC have been enrolled in adjuvant therapy studies evaluating various pemetrexed-containing treatment regimens, and additional patients are being enrolled in ongoing studies. Current evidence appears to favor the combination with cisplatin over that with carboplatin. We await more robust safety and efficacy data from these ongoing adjuvant trials to define with clarity the role of pemetrexed-containing regimens in this setting.

Phase II study of pemetrexed and cisplatin plus cetuximab followed by pemetrexed and cetuximab maintenance therapy in patients with advanced nonsquamous non-small cell lung cancer.

OBJECTIVES: The aim was to determine if combined pemetrexed, cisplatin, and cetuximab was efficacious and safe as first-line treatment in advanced nonsquamous non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: In this single-arm, multicenter clinical trial, patients with Stage IIIB/IV nonsquamous NSCLC received first-line therapy consisting of pemetrexed (500 mg/m(2)) and cisplatin (75 mg/m(2)) on Day 1 (21-day cycles) plus weekly cetuximab (400 mg/m(2) loading dose, then 250 mg/m(2)) for 4-6 cycles. Non-progressing patients received maintenance therapy consisting of pemetrexed and cetuximab as above until disease progression. All patients received vitamin supplementation, dexamethasone, and antihistamine prophylaxis. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), 1-year survival rate, translational research (TR) and safety. RESULTS: Of the 113 patients receiving study drug, 109 were protocol-qualified. All patients completed ≥1 cycle of induction, and 51 (45%) and 49 (43%) patients completed ≥1 cycle of maintenance with pemetrexed and cetuximab, respectively. The ORR (n = 109) was 38.5% (80% confidence interval [CI], 32.3-45.1%), all partial responses. Median PFS was 5.8 (80% CI, 4.4-6.7) months. One-year survival rate was 45% (80% CI, 39-51%). In exploratory analyses, there was some preliminary evidence of potential prognostic relationships with efficacy outcomes for epidermal growth factor receptor and thyroid transcription factor-1 protein expression, but not for KRAS mutation or for thymidylate synthase or folate receptor-alpha protein expression. Seventy-three (64.6%) patients had study drug-related Grade 3/4 adverse events (AEs). Drug-related serious AEs were reported in 31 (27.4%) patients. There were 3 (2.7%) potentially drug-related deaths on-study or within 30 days of follow up. CONCLUSION: Pemetrexed, cisplatin, and cetuximab appeared efficacious and tolerable in advanced nonsquamous NSCLC patients. The TR outcomes are hypothesis-generating given the study's size and nonrandomized nature.