Johannes Blatter

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

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.

Phase II Study of Pemetrexed With and Without Folic Acid and Vitamin B12 as Front-Line Therapy in Malignant Pleural Mesothelioma

PURPOSE This phase II clinical study evaluated the efficacy of pemetrexed for the treatment of malignant pleural mesothelioma (MPM). PATIENTS AND METHODS Patients with a histologically proven diagnosis of MPM, chemotherapy-naive measurable lesions, and adequate organ function received pemetrexed (500 mg/m2) intravenously over 10 minutes every 3 weeks. After a protocol change, most patients also received folic acid and vitamin B12 supplementation to improve safety. RESULTS A total of 64 patients were enrolled. Nine (14.1%) of the 64 patients had a partial response. The Kaplan-Meier estimate for median overall survival was 10.7 months. Forty-three patients received vitamin supplementation for all courses of therapy, and 21 patients did not. Seven of the nine responders were vitamin supplemented. The median overall survival was 13.0 months for supplemented patients and 8.0 months for nonsupplemented patients. Vitamin-supplemented patients completed more cycles of therapy than nonsupplemented patients (median, six v two cycles, respectively). Grade 3/4 neutropenia (23.4%) and grade 3/4 leukopenia (18.8%) were the most common laboratory toxicities. Fatigue and febrile neutropenia were the most commonly reported nonlaboratory events (grade 3, 6.3%; grade 4, 0.0% each). The incidence of these toxicities was generally lower in the supplemented patients. CONCLUSION Single-agent pemetrexed for MPM resulted in a moderate response rate (14.1%) and median overall survival of 10.7 months. Patients supplemented with folic acid and vitamin B12 tolerated treatment better (less toxicity and more cycles of treatment) and had a 5-month greater median overall survival than nonsupplemented patients. These results indicate that patients with MPM could benefit from single-agent pemetrexed treatment combined with vitamin supplementation.

Phase III Trial of Pemetrexed Plus Best Supportive Care Compared With Best Supportive Care in Previously Treated Patients With Advanced Malignant Pleural Mesothelioma

PURPOSE This multicenter, phase III study compared overall survival (OS) of second-line pemetrexed plus best supportive care (BSC) versus BSC alone in patients with advanced malignant pleural mesothelioma (MPM). Secondary end points included response rate, progression-free survival (PFS), time to tumor progression (TTP), time to treatment failure (TTF), and toxicity. PATIENTS AND METHODS Patients with relapsed MPM after first-line chemotherapy were randomly assigned to receive pemetrexed 500 mg/m(2) plus BSC (P+BSC) every 21 days or BSC alone. RESULTS The study enrolled 243 patients (123 on P+BSC arm and 120 on BSC arm). Median OS time was not significantly different between the arms (8.4 months for P+BSC and 9.7 months for BSC; P = .74). Cox regression modeling suggested a trending survival benefit for patients who responded to first-line therapy. Time-to-event measures significantly favored P+BSC (median PFS, TTP, and TTF). Partial response was achieved in 18.7% and 1.7% of patients in P+BSC and BSC arms, respectively (P < .0001), and a disease control rate (partial response plus stable disease) was achieved in 59.3% and 19.2% of patients in P+BSC and BSC arms, respectively (P < .0001). Use of postdiscontinuation chemotherapy was significantly greater among BSC patients compared with P+BSC patients (51.7% v 28.5%, respectively; P = .0002), with more BSC patients receiving pemetrexed (18.3% v 3.3%, respectively; P = .0001). Postdiscontinuation therapy was initiated earlier for BSC than P+BSC patients (median time to initiation, 4.3 v 15.7 months, respectively; log-rank P < .0001). Chemotherapy was well tolerated, with expected modest (4% to 7%) grade 3 and 4 hematologic toxicities. CONCLUSION Second-line pemetrexed elicited significant tumor response and delayed disease progression compared with BSC alone in patients with advanced MPM. Improvement in OS was not seen in this study, possibly because of the significant imbalance in postdiscontinuation chemotherapy between the arms.

Pemetrexed Plus Cisplatin or Pemetrexed Plus Carboplatin for Chemonaïve Patients with Malignant Pleural Mesothelioma: Results of the International Expanded Access Program

Introduction: Previously published results from a randomized phase III study of pemetrexed plus cisplatin in patients with malignant pleural mesothelioma (MPM) demonstrated a significant survival benefit and higher response rate compared with cisplatin. Although pemetrexed was under review by regulatory agencies, an International Expanded Access Program (EAP) provided more than 3000 mesothelioma patients with access to single-agent pemetrexed or pemetrexed in combination with cisplatin or carboplatin in 13 countries. This manuscript reports the safety and efficacy data from the nonrandomized open-label study in chemonaïve patients receiving pemetrexed plus platinum under the EAP. Methods: Patients with histologically confirmed MPM, not amenable to curative surgery, received pemetrexed 500 mg/m2 in combination with either cisplatin 75 mg/m2 or carboplatin AUC 5, once every 21 days with standard premedication. Efficacy data were recorded at the end of study participation. Results: A total of 1704 chemonaïve patients received pemetrexed plus cisplatin (n = 843) or pemetrexed plus carboplatin (n = 861) and were evaluated for safety. The efficacy evaluable population consisted of 745 patients in the pemetrexed plus cisplatin group and 752 patients in the pemetrexed plus carboplatin group for whom physician-reported tumor response was available. The pemetrexed plus cisplatin group demonstrated a response rate of 26.3% compared with 21.7% for the pemetrexed plus carboplatin group, with similar 1-year survival rates (63.1% versus 64.0%) and median time to progressive disease (7 months versus 6.9 months). The most common grade 3/4 hematologic toxicity was neutropenia in 23.9% of the pemetrexed plus cisplatin group and 36.1% of the pemetrexed plus carboplatin group. Conclusion: This large EAP confirmed the activity of pemetrexed plus cisplatin and pemetrexed plus carboplatin in chemonaïve patients with MPM, demonstrating clinically similar time to progressive disease and 1-year survival rates.

Single-agent pemetrexed for chemonaïve and pretreated patients with malignant pleural mesothelioma: Results of an international expanded access program

Introduction: Pemetrexed has established efficacy, and is the backbone for chemotherapy in patients with malignant pleural mesothelioma (MPM). An International Expanded Access Program provided >3000 mesothelioma patients with access to single-agent pemetrexed or pemetrexed plus platinum analogs (cisplatin or carboplatin) in 13 countries. In this article, we report the safety and efficacy data of MPM patients who were treated with single-agent pemetrexed (n = 812). Methods: Patients with histologically confirmed MPM, not amenable to curative surgery, received pemetrexed (500 mg/m2) once (day 1) every 21 days with standard premedication and vitamin supplementation. Investigator-determined response and survival data were recorded at the end of study participation. Myelosuppression data were also collected. Results: All 812 MPM patients (319 chemonaïve; 493 pretreated) received single-agent pemetrexed (≥1 dose) and were evaluated for safety. A total of 643 patients (247 chemonaïve, 396 pretreated) were evaluated for efficacy. Of the chemonaïve patients evaluated for efficacy (n = 247), the overall response rate was 10.5%, median time to progressive disease (TTPD) was 6.0 months, and median survival was 14.1 month. Of the pretreated patients evaluated for efficacy (n = 396), the overall response rate was 12.1%, median TTPD was 4.9 months, and the median survival was not estimable due to high censoring. Common terminology criteria grade 3/4 hematologic toxicity was mild in both groups, with neutropenia (<18%) as the main toxicity. Conclusions: In the present expanded access program, single-agent pemetrexed demonstrated promising activity in MPM in both chemonaïve and pretreated patients, with TTPD of 6.0 and 4.9 months, respectively, 1-year survival ≥54.7%, and mild hematologic toxicity.

Gemcitabine in Non-Small Cell Lung Cancer (NSCLC)

The role of chemotherapy in the treatment of non-smallcell lung cancer (NSCLC) has increased greatly in the past fewyears. While cytotoxic drugs are currently used both as singleagents and in combination for palliation in locally advanced andmetastatic disease, they have also been incorporated intomulti-modality treatment strategies of Stage I to Stage IIINSCLC. One of the main reasons for the increased acceptance ofchemotherapy is the development of new substances.Among the most promising of these new drugs is theantimetabolite gemcitabine. Several single-arm gemcitabine PhaseII studies involving more than 400 patients show validatedresponse rates in more than 20% of the patients. Thesepositive results have also been confirmed in randomized Phase IIstudies. Gemcitabines unique mechanism of action, its lack ofoverlapping toxicity with other agents, and its favorabletoxicity profile also define it as an ideal candidate forcombination therapy.The activity seen with single-agent gemcitabine therapy canbe compared with that of cisplatin-etoposide combination therapy.Gemcitabine-cisplatin combination response rates range from31% to 54%, with a median survival time between 8.4and 15.4 months and a 1-year survival rate between 30% and59%. In addition to the clinical research ofgemcitabine-cisplatin combinations, gemcitabine has also beentested in various double and triple combinations withcarboplatin, paclitaxel, docetaxel, vinorelbine, and ifosfamide.Investigations combining gemcitabine with radiation therapy areon-going. The following review will summarize results fromrepresentative Phase I/II and III studies using gemcitabine forNSCLC patients.

Gemcitabine plus etoposide in chemonaive extensive disease small-cell lung cancer: A multi-centre phase II study

BACKGROUND Both gemcitabine and etoposide are active in the treatment of small-cell lung cancer (SCLC), and are characterised by mild toxicity profiles. The combination of both drugs was found to be feasible and active in a phase I dose-finding study in solid tumours. Therefore, a phase II trial was initiated to examine the activity and toxicity of this schedule in extensive disease SCLC. PATIENTS AND METHODS Forty-two chemo-naïve extensive disease SCLC patients were enrolled to receive gemcitabine 1000 mg/m2, days 1, 8 and 15, and etoposide 80 mg/m2, days 8, 9 and 10 of a 28-day cycle. RESULTS Thirty-seven patients were evaluable for efficacy (five received less than one cycle). No complete responses were observed, but partial responses were seen in 17 patients, yielding an overall response rate of 46%. The median duration of response was 5.8 months. Disease stabilisation was obtained in another 10 patients (27%). The median survival of the 37 protocol-qualified patients was 10.5 months (95% confidence interval (CI): 7.5-12.0). The levels of WHO grade 3 and 4 toxicities were low and clinically manageable. CONCLUSION In comparison with standard platinum-based regimens, this combination of gemcitabine and etoposide resulted in a somewhat lower response rate, but a similar median survival time. Haematological toxicity was more pronounced than expected from the toxicity data of each agent individually. However, because of its mild non-haematological toxicity, and its ability to be administered in an outpatient setting, this combination provides a reasonable palliative option for patients with extensive disease SCLC.

A Randomized Phase II Trial of Pemetrexed plus Irinotecan (ALIRI) versus Leucovorin-Modulated 5-FU plus Irinotecan (FOLFIRI) in First-Line Treatment of Locally Advanced or Metastatic Colorectal Cancer

Background: This multicenter, randomized trial compared overall response rate between pemetrexed plus irinotecan (ALIRI) and leucovorin-modulated 5-fluorouracil plus irinotecan (FOLFIRI) in patients with advanced colorectal cancer. Secondary objectives included overall and progression-free survival, duration of response, toxicities, and biomarkers. Patients and Methods: ALIRI patients received pemetrexed 500 mg/m2 and irinotecan 350 mg/m2 with vitamin supplementation on day 1 of each 21-day cycle. FOLFIRI patients received irinotecan 180 mg/m2 on days 1, 15, 29; on days 1, 2, 15, 16, 29, 30, patients received leucovorin 200 mg/m2, bolus 5-fluorouracil 400 mg/m2, and 5-fluorouracil 600 mg/m2 as 22-hour infusion. Results: Of 132 patients randomly assigned, 130 patients (64 = ALIRI, 66 = FOLFIRI) received ≧1 dose of treatment. Response rates (ALIRI = 20.0%, FOLFIRI = 33.3%) were not significantly different between arms (p = 0.095). Progression-free survival was 5.7 months for ALIRI and 7.7 months for FOLFIRI (p < 0.001). Neutropenia, fatigue, diarrhea, nausea, and vomiting were the major toxicities. There were 5 drug-related deaths (ALIRI = 4, FOLFIRI = 1). Biomarker analysis failed to reveal that any of the 18 preselected genes were clearly associated with tumor response. Conclusions: Neither efficacy nor safety improved on the ALIRI arm compared to the FOLFIRI arm. Progression-free survival on FOLFIRI was significantly longer compared to ALIRI. Potential biomarkers capable of predicting response to either regimen in advanced or metastatic colorectal carcinoma need further characterization.

Correlations of mRNA expression and in vitro chemosensitivity to enzastaurin in freshly explanted human tumor cells

SummaryPurpose: Enzastaurin (LY317615) is a novel serine/threonine kinase inhibitor, targeting Protein Kinase C-beta (PKC-β), and PI3K/AKT pathways to inhibit angiogenesis and tumor cell proliferation. The aims of this study were to determine whether Enzastaurin has direct antitumor activity against freshly explanted tumor cells and to correlate mRNA expression of genes related to the proposed mechanism of action of enzastaurin with in vitro chemosensitivity. Experimental Design: Freshly biopsied tumor cells were studied using soft-agar cell cloning experiments (SACCE) to determine the in vitro chemosensitivity to enzastaurin. An aliquot of the same tumor specimens was shock-frozen and total RNA was isolated for standardized multiplex rt-PCR experiments for gene expression of PKC-β1, PKC-β2, IL-8, IL-8RA, IL-8RB, Glycogen Synthase Kinase 3 beta (GSK-3β) and TGF-β1. Correlations, threshold optimization, sensitivity, specificity, and efficiency were analyzed using the appropriate statistical methodologies. Results: Seventy-two tumor samples were collected and 63 were fully evaluable. Low levels of mRNA expression of GSK-3β and high levels of mRNA expression of IL-8 were highly significantly correlated with chemosensitivity to enzastaurin. Optimization analyses demonstrated threshold values of 4,000 copies for IL-8 and three copies for GSK-3β relative to 104 copies of β-actin. However, no correlation between mRNA expression of PKC-β1, PKC-β2, IL-8RA, IL-8RB and chemosensitivity to enzastaurin was observed. Expression of TGF-β1 mRNA was not detectable in the specimens investigated. Conclusions: mRNA expression levels of IL-8 and GSK-3β correlate with antitumor activity of enzastaurin. These results form a rational basis for clinical trials to evaluate the expression of these genes as potential predictors for treatment outcome after enzastaurin chemotherapy.