The Differential Efficacy of Pemetrexed According to NSCLC Histology: A Review of Two Phase III Studies

Abstract Background. Recent studies of pemetrexed have identified a predictive role for non-small cell lung cancer (NSCLC) histology. We further reviewed the differential efficacy of pemetrexed according to histology in two large, phase III NSCLC trials. Methods. One study tested pemetrexed versus docetaxel in previously treated patients (n = 571) and the other tested cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemotherapy-naive patients (n = 1,725) with advanced NSCLC. Cox proportional hazard models were used to test for covariate-adjusted treatment-by-histology interactions (THIs) for overall survival (OS) and progression-free survival (PFS). For each histologic subgroup, the Kaplan–Meier method was used to estimate unadjusted within-arm medians, and Cox models were used to estimate covariate-adjusted between-arm hazard ratios (HRs). Results. In both studies, treatment arms were well balanced for histology. THIs were statistically significant (p < .005) for both OS and PFS. Nonsquamous patients treated with pemetrexed-based therapy experienced longer survival than the comparators (HR, 0.78 and 0.84, respectively), whereas squamous patients had shorter survival (HR, 1.56 and 1.23, respectively). Whereas the efficacy of pemetrexed regimens differed according to histology, it did not differ for docetaxel or for cisplatin plus gemcitabine. Pemetrexed was well tolerated across histologic groups. Conclusions. The consistency of these results across studies confirms the predictive effect of histology for pemetrexed and the survival advantage for pemetrexed in patients with nonsquamous histology. These analyses suggest pemetrexed should not be recommended for the treatment of squamous cell carcinoma, but, because of efficacy and safety advantages, pemetrexed may be preferable to other agents for treatment of patients with nonsquamous NSCLC

Mitomycin C and Vinorelbine for second-line chemotherapy in NSCLC – a phase II trial

Single-agent therapy with Docetaxel or Pemetrexed is the current therapy of choice for second-line treatment in advanced non-small-cell lung cancer (NSCLC). The role of older agents was underattended over the last years. This study presents the combination of Mitomycin C and Vinorelbine in pretreated patients. Forty-two patients (stage IIIB and IV, pretreated with platinum-based chemotherapy) received 8 mg m−2 Mitomycin C on day 1 and 25 mg m−2 Vinorelbine on days 1 and 8 of a 28-day cycle. End points were objective tumour response, survival, and toxicity. Additionally, quality of life (QoL) was assessed. Five patients (11.9 %) achieved partial responses and 13 patients (31.9%) stable disease. Progression-free survival was 16 weeks. The median overall survival was 8.5 month. Eleven patients (26.2 %) suffered from grade 3 or 4 neutropenia and four patients (9.52%) from grade 3 or 4 anaemia. Evaluation of QoL showed that some items ameliorated during therapy. The therapeutic concept including Mitomycin C and Vinorelbine offers an efficacious and well-tolerated regimen, with relatively low toxicity. Objective response and survival data correlate with other second-line studies using different medication. As costs of Mitomycin C and Vinorelbine are lower compared with current drugs of choice, this regimen is likely to be cost-saving

A randomised phase II trial of docetaxel vs docetaxel and irinotecan in patients with stage IIIb–IV non-small-cell lung cancer who failed first-line treatment

Response rate and toxicity of second-line therapy with docetaxel (75 mg m−2) or docetaxel, irinotecan, and lenogastrim (60 mg m−2, 200 mg m−2, and 150 μg m−2 day−1, respectively) were compared in 108 patients with stage IIIb–IV non-small-cell lung cancer. Addition of irinotecan to docetaxel does not improve response rate, and increases gastrointestinal toxicity

Treatment of non-small-cell lung cancer: a perspective on the recent advances and the experience with gefitinib

Worldwide, non-small-cell lung cancer (NSCLC) is a leading cause of cancer-related mortality and, until screening detects early disease, treatment for the majority of patients will consist of radiation therapy, chemotherapy or combinations thereof. Modern mono and doublet chemotherapy regimens have translated into modest increases in life expectancy and improved quality of life, but at the expense of systemic and pulmonary adverse events (AEs). There is a great unmet need to provide effective therapy for advanced NSCLC that does not have the toxicity burden of conventional chemotherapy and radiotherapy. Novel drugs that inhibit a range of growth factor receptors, such as the epidermal growth factor receptor tyrosine kinase inhibitors gefitinib (‘Iressa’) and erlotinib (‘Tarceva’) or the monoclonal antibody cetuximab (‘Erbitux’), have recently been evaluated. Having demonstrated antitumour activity and rapid symptom improvement in pretreated patients with advanced NSCLC, gefitinib was approved in the USA, Japan and other countries. Gefitinib is well tolerated with a low incidence of grade 3/4 AEs. Interstitial lung disease has been reported in a small number of patients receiving gefitinib, although this may be attributed to other treatments and conditions. Nevertheless, although the use of novel treatments requires vigilance for unexpected AEs such as pulmonary toxicity, in this area of high unmet clinical need, the benefits outweigh the risks in patients for whom no other proven effective treatment exists

Phase I study of IMGN901, a CD56-targeting antibody-drug conjugate, in patients with CD56-positive solid tumors.

Background IMGN901 is a CD56-targeting antibody-drug conjugate designed for tumor-selective delivery of the cytotoxic maytansinoid DM1. This phase 1 study investigated the safety, tolerability, pharmacokinetics, and preliminary activity of IMGN901 in patients with CD56-expressing solid tumors. Methods Patients were enrolled in cohorts of escalating IMGN901 doses, administered intravenously, on 3 consecutive days every 21 days. A dose-expansion phase accrued patients with small cell lung cancer (SCLC), Merkel cell carcinoma (MCC), or ovarian cancer. Results Fifty-two patients were treated at doses escalating from 4 to 94 mg/m(2)/day. The maximum tolerated dose (MTD) was determined to be 75 mg/m(2). Dose-limiting toxicities included fatigue, neuropathy, headache or meningitis-like symptoms, chest pain, dyspnea, and myalgias. In the dose-expansion phase (n = 45), seven patients received 75 mg/m(2) and 38 received 60 mg/m(2) for up to 21 cycles. The recommended phase 2 dose (RP2D) was established at 60 mg/m(2) during dose expansion. Overall, treatment-emergent adverse events (TEAEs) were experienced by 96.9 % of all patients, the majority of which were Grade 1 or 2. The most commonly reported Grade 3 or 4 TEAEs were hyponatremia and dyspnea (each 8.2 %). Responses included 1 complete response (CR), 1 clinical CR, and 1 unconfirmed partial response (PR) in MCC; and 1 unconfirmed PR in SCLC. Stable disease was seen for 25 % of all evaluable patients who received doses ≥60 mg/m(2). Conclusions The RP2D for IMGN901 of 60 mg/m(2) administered for 3 consecutive days every 3 weeks was associated with an acceptable tolerability profile. Objective responses were observed in patients with advanced CD56+ cancers

Phase II Trial of Cediranib in Combination With Cisplatin and Pemetrexed in Chemotherapy-Naïve Patients With Unresectable Malignant Pleural Mesothelioma (SWOG S0905).

PurposeAntiangiogenic agents combined with chemotherapy have efficacy in the treatment of unresectable malignant pleural mesothelioma (MPM). Cediranib (AstraZeneca, Cheshire, United Kingdom), a vascular endothelial growth factor receptor and platelet-derived growth factor receptor inhibitor, demonstrated therapeutic potential in a prior phase I trial. We evaluated a phase II trial for efficacy.Patients and methodsSWOG S0905 (ClinicalTrials.gov identifier: NCT01064648) randomly assigned cediranib or placebo with platinum-pemetrexed for six cycles followed by maintenance cediranib or placebo in unresectable chemotherapy-naïve patients with MPM of any histologic subtype. Primary end point was Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 progression-free survival (PFS). Secondary end points included overall survival, PFS by modified RECIST v1.1, response (modified RECIST and RECIST v1.1), disease control, and safety/toxicity. The trial was designed to detect a difference in RECIST v1.1 PFS at the one-sided 0.1 level using a stratified log-rank test.ResultsNinety-two eligible patients were enrolled (75% epithelioid and 25% biphasic or sarcomatoid). The cediranib arm had more grade 3 and 4 diarrhea, dehydration, hypertension, and weight loss. Cediranib improved PFS by RECIST v1.1 (hazard ratio, 0.71; 80% CI, 0.54 to 0.95; P = .062; 7.2 months v 5.6 months) and increased modified RECIST v1.1 response (50% v 20%; P = .006). By modified RECIST v1.1, cediranib numerically increased PFS (hazard ratio, 0.77; 80% CI, 0.59 to 1.02; P = .12; median, 6.9 months v 5.6 months). No significant difference in overall survival was observed.ConclusionThe addition of cediranib to platinum-pemetrexed improved PFS by RECIST v1.1 and response rate by modified RECIST in patients with unresectable MPM. Whereas adding antiangiogenics to chemotherapy has been a successful strategy for some patients, the cediranib toxicity profile and small incremental survival benefit precludes additional development in MPM

Dopaminergic Polymorphisms Associated with Time-on-Task Declines and Fatigue in the Psychomotor Vigilance Test

Prolonged demands on the attention system can cause a decay in performance over time known as the time-on-task effect. The inter-subject differences in the rate of this decline are large, and recent efforts have been made to understand the biological bases of these individual differences. In this study, we investigate the genetic correlates of the time-on-task effect, as well as its accompanying changes in subjective fatigue and mood. N = 332 subjects performed a 20-minute test of sustained attention (the Psychomotor Vigilance Test) and rated their subjective states before and after the test. We observed substantial time-on-task effects on average, and large inter-individual differences in the rate of these declines. The 10-repeat allele of the variable number of tandem repeats marker (VNTR) in the dopamine transporter gene and the Met allele of the catechol-o-methyl transferase (COMT) Val158Met polymorphism were associated with greater vulnerability to time-on-task. Separately, the exon III DRD4 48 bp VNTR of the dopamine receptor gene DRD4 was associated with subjective decreases in energy. No polymorphisms were associated with task-induced changes in mood. We posit that the dopamine transporter and COMT genes exert their effects by increasing dopaminergic tone, which may induce long-term changes in the prefrontal cortex, an important mediator of sustained attention. Thus, these alleles may affect performance particularly when sustained dopamine release is necessary

A randomised phase II trial of preoperative chemotherapy of cisplatin–docetaxel or docetaxel alone for clinical stage IB/II non-small-cell lung cancer: results of a Japan Clinical Oncology Group trial (JCOG 0204)

Preoperative chemotherapy is a promising strategy in patients with early-stage resectable non-small-cell lung cancer (NSCLC); optimal chemotherapy remains unclear. Clinical (c-) stage IB/II NSCLC patients were randomised to receive either two cycles of docetaxel (D)–cisplatin (P) combination chemotherapy (D 60 mg m−2 and P 80 mg m−2 on day 1) every 3–4 weeks or three cycles of D monotherapy (70 mg m−2) every 3weeks. Thoracotomy was performed 4–5 weeks (DP) or 3–4 weeks (D) after chemotherapy. The primary end point was 1-year disease-free survival (DFS). From October 2002 to November 2003, 80 patients were randomised. Chemotherapy toxicities were mainly haematologic and well tolerated. There were two early postoperative deaths with DP (one intraoperative bleeding and one empyema). Pathologic complete response was observed in two DP patients. Docetaxel–cisplatin was superior to D in terms of response rate (45 vs 15%) and complete resection rate (95 vs 87%). Both DFS and overall survival were better in DP. Disease-free survival at 1, 2 and 4 years were 78, 65 and 57% with DP, and were 62, 44 and 36% with D, respectively. Preoperative DP was associated with encouraging resection rate and DFS data, and phase III trials for c-stage IB/II NSCLC are warranted

Chemotherapy with cisplatin and vinorelbine for elderly patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC)

BACKGROUND: Although modest improvements in the survival of patients with non-small cell lung cancer (NSCLC) can be achieved with cisplatin-based chemotherapy (CT), its value is disputed in the geriatric setting. In this study, we evaluate the feasibility of vinorelbine/cisplatin CT for elderly NSCLC patients. METHODS: In this pilot phase I/II trial, all patients received CT with vinorelbine 25 mg/m(2), on day 1 and 8, and cisplatin on day 1, in 28 days-cycles. After stratification for age (up to 75 years), younger patients were sequentially allocated to moderate cisplatin doses (80 mg/m(2 )or 90 mg/m(2)), and older patients were allocated to lower cisplatin doses (60 mg/m(2 )or 70 mg/m(2)). We recruited patients aged over 70 years with newly diagnosed NSCLC, clinical stage III or IV, Karnofsky performance status ≥ 70%, normal serum creatinine, peripheral neuropathy ≤ grade 1, and no prior cancer therapy. RESULTS: Analysis was by intention to treat. Main toxicities (grade 3–4) was as follows: neutropenia, 20%; anemia, 11%; and thrombocytopenia, 2%; alopecia, 55%; fatigue, 11%; and peripheral neurotoxicity, 2%. No grade 3–4 emesis or renal toxicity occurred. Global median time to progression (TTP) and overall survival (OS) were 27.0 (95% CI: 10.1 to 43.7) weeks and 30.1 (95% CI: 24.4 to 35.8) weeks; 1- and 2-year survival rates were 36.3% and 13.2%, respectively. Overall response rate was 50.0% (95% CI: 35.4% to 64.5%), with 1 complete response; no difference on response rate was noticed according to cisplatin dose. Median overall survival was 30.1 weeks, with 1- and 2-year survival rates of 36.3% and 13.2%, respectively. CONCLUSION: Age does not preclude assessment on the role of cisplatin-vinorelbine CT for elderly NSCLC patients with good performance status and adequate bodily functions