PARAMOUNT: Final Overall Survival Results of the Phase III Study of Maintenance Pemetrexed Versus Placebo Immediately After Induction Treatment With Pemetrexed Plus Cisplatin for Advanced Nonsquamous Non–Small-Cell Lung Cancer

2013 ◽  
Vol 31 (23) ◽  
pp. 2895-2902 ◽  
Author(s):  
Luis G. Paz-Ares ◽  
Filippo de Marinis ◽  
Mircea Dediu ◽  
Michael Thomas ◽  
Jean-Louis Pujol ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Maintenance Therapy ◽  
Small Cell Lung Cancer ◽  
Disease Progression ◽  
Performance Status ◽  
Small Cell ◽  
Phase Iii ◽  
Small Cell Lung ◽  
Continuation Maintenance

Purpose In the phase III PARAMOUNT trial, pemetrexed continuation maintenance therapy reduced the risk of disease progression versus placebo (hazard ratio [HR], 0.62; 95% CI, 0.49 to 0.79; P < .001). Here we report final overall survival (OS) and updated safety data. Patients and Methods In all, 939 patients with advanced nonsquamous non–small-cell lung cancer (NSCLC) received four cycles of pemetrexed-cisplatin induction therapy; then, 539 patients with no disease progression and Eastern Cooperative Oncology Group performance status 0 or 1 were randomly assigned (2:1) to maintenance pemetrexed (500 mg/m2 on day 1 of 21-day cycles; n = 359) or placebo (n = 180). Log-rank test compared OS between arms as measured from random assignment (α = .0498). Results The mean number of maintenance cycles was 7.9 (range, one to 44) for pemetrexed and 5.0 (range, one to 38) for placebo. After 397 deaths (pemetrexed, 71%; placebo, 78%) and a median follow-up of 24.3 months for alive patients (95% CI, 23.2 to 25.1 months), pemetrexed therapy resulted in a statistically significant 22% reduction in the risk of death (HR, 0.78; 95% CI, 0.64 to 0.96; P = .0195; median OS: pemetrexed, 13.9 months; placebo, 11.0 months). Survival on pemetrexed was consistently improved for all patient subgroups, including induction response: complete/partial responders (n = 234) OS HR, 0.81; 95% CI, 0.59 to 1.11 and stable disease (n = 285) OS HR, 0.76; 95% CI, 0.57 to 1.01). Postdiscontinuation therapy use was similar: pemetrexed, 64%; placebo, 72%. No new safety findings emerged. Drug-related grade 3 to 4 anemia, fatigue, and neutropenia were significantly higher in pemetrexed-treated patients. Conclusion Pemetrexed continuation maintenance therapy is well-tolerated and offers superior OS compared with placebo, further demonstrating that it is an efficacious treatment strategy for patients with advanced nonsquamous NSCLC and good performance status who did not progress during pemetrexed-cisplatin induction therapy.

scholarly journals Maintenance Chemotherapy for Advanced Non–Small-Cell Lung Cancer: New Life for an Old Idea

2013 ◽  
Vol 31 (8) ◽  
pp. 1009-1020 ◽  
Author(s):  
David E. Gerber ◽  
Joan H. Schiller
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Maintenance Therapy ◽  
Small Cell Lung Cancer ◽  
Small Cell ◽  
Maintenance Chemotherapy ◽  
Small Cell Lung ◽  
First Line ◽  
Continuation Maintenance ◽  
Line Chemotherapy

Although well established for the treatment of certain hematologic malignancies, maintenance therapy has only recently become a treatment paradigm for advanced non–small-cell lung cancer. Maintenance therapy, which is designed to prolong a clinically favorable state after completion of a predefined number of induction chemotherapy cycles, has two principal paradigms. Continuation maintenance therapy entails the ongoing administration of a component of the initial chemotherapy regimen, generally the nonplatinum cytotoxic drug or a molecular targeted agent. With switch maintenance (also known as sequential therapy), a new and potentially non–cross-resistant agent is introduced immediately on completion of first-line chemotherapy. Potential rationales for maintenance therapy include increased exposure to effective therapies, decreasing chemotherapy resistance, optimizing efficacy of chemotherapeutic agents, antiangiogenic effects, and altering antitumor immunity. To date, switch maintenance therapy strategies with pemetrexed and erlotinib have demonstrated improved overall survival, resulting in US Food and Drug Administration approval for this indication. Recently, continuation maintenance with pemetrexed was found to prolong overall survival as well. Factors predicting benefit from maintenance chemotherapy include the degree of response to first-line therapy, performance status, the likelihood of receiving further therapy at the time of progression, and tumor histology and molecular characteristics. Several aspects of maintenance therapy have raised considerable debate in the thoracic oncology community, including clinical trial end points, the prevalence of second-line chemotherapy administration, the role of treatment-free intervals, quality of life, economic considerations, and whether progression-free survival is a worthy therapeutic goal in this disease setting.

Randomized, Phase III Study of Gemcitabine or Erlotinib Maintenance Therapy Versus Observation, With Predefined Second-Line Treatment, After Cisplatin-Gemcitabine Induction Chemotherapy in Advanced Non–Small-Cell Lung Cancer

2012 ◽  
Vol 30 (28) ◽  
pp. 3516-3524 ◽  
Author(s):  
Maurice Pérol ◽  
Christos Chouaid ◽  
David Pérol ◽  
Fabrice Barlési ◽  
Radj Gervais ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Disease Progression ◽  
Induction Chemotherapy ◽  
Small Cell ◽  
Phase Iii ◽  
Second Line ◽  
Small Cell Lung ◽  
Phase Iii Study ◽  
Continuation Maintenance

Purpose This phase III study investigated whether continuation maintenance with gemcitabine or switch maintenance with erlotinib improves clinical outcome compared with observation in patients with advanced non–small-cell lung cancer (NSCLC) whose disease was controlled after cisplatin-gemcitabine induction chemotherapy. Patients and Methods Four hundred sixty-four patients with stage IIIB/IV NSCLC without tumor progression after four cycles of cisplatin-gemcitabine were randomly assigned to observation or to gemcitabine (1,250 mg/m2 days 1 and 8 of a 3-week cycle) or daily erlotinib (150 mg/day) study arms. On disease progression, patients in all three arms received pemetrexed (500 mg/m2 once every 21 days) as predefined second-line therapy. The primary end point was progression-free survival (PFS). Results PFS was significantly prolonged by gemcitabine (median, 3.8 v 1.9 months; hazard ratio [HR], 0.56; 95% CI, 0.44 to 0.72; log-rank P < .001) and erlotinib (median, 2.9 v 1.9 months; HR, 0.69; 95% CI, 0.54 to 0.88; log-rank P = .003) versus observation; this benefit was consistent across all clinical subgroups. Both maintenance strategies resulted in a nonsignificant improvement in overall survival (OS); patients who received second-line pemetrexed or with a performance status of 0 appeared to derive greater benefit. Exploratory analysis showed that magnitude of response to induction chemotherapy may affect the OS benefit as a result of gemcitabine maintenance. Maintenance gemcitabine and erlotinib were well tolerated with no unexpected adverse events. Conclusion Gemcitabine continuation maintenance or erlotinib switch maintenance significantly reduces disease progression in patients with advanced NSCLC treated with cisplatin-gemcitabine as first-line chemotherapy. Response to induction chemotherapy may affect OS only for continuation maintenance.

scholarly journals Randomized Phase III Study of Continuation Maintenance Bevacizumab With or Without Pemetrexed in Advanced Nonsquamous Non–Small-Cell Lung Cancer: COMPASS (WJOG5610L)

2020 ◽  
Vol 38 (8) ◽  
pp. 793-803
Author(s):  
Takashi Seto ◽  
Koichi Azuma ◽  
Takeharu Yamanaka ◽  
Shunichi Sugawara ◽  
Hiroshige Yoshioka ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Maintenance Therapy ◽  
Small Cell Lung Cancer ◽  
Disease Progression ◽  
Induction Therapy ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Wild Type ◽  
Small Cell Lung ◽  
Continuation Maintenance

PURPOSE Patients with non–small-cell lung cancer (NSCLC) have been shown to benefit from maintenance therapy. COMPASS evaluated the efficacy and safety of bevacizumab with or without pemetrexed as continuation maintenance therapy after carboplatin, pemetrexed, and bevacizumab induction therapy. PATIENTS AND METHODS Patients with untreated advanced nonsquamous NSCLC without confirmed EGFR 19 deletion or L858R mutation received first-line therapy with carboplatin area under the curve 6, pemetrexed 500 mg/m2, and bevacizumab 15 mg/kg once every 3 weeks for 4 cycles. Patients without disease progression during the induction therapy were randomly assigned 1:1 for maintenance therapy with pemetrexed 500 mg/m2 plus bevacizumab 15 mg/kg or bevacizumab 15 mg/kg once every 3 weeks until disease progression or unacceptable toxicity. The primary end point was overall survival (OS) after random assignment. RESULTS Between September 2010 and September 2015, 907 patients received induction therapy. Of those, 599 were randomly assigned: 298 received pemetrexed plus bevacizumab, and 301 received bevacizumab. The median OS was 23.3 v 19.6 months (hazard ratio [HR], 0.87; 95% CI, 0.73 to 1.05; 1-sided stratified log-rank P = .069). In the wild-type EGFR subset, the OS HR was 0.82 (95% CI, 0.68 to 0.99; 1-sided unstratified log-rank P = .020). The median progression-free survival (PFS) was 5.7 v 4.0 months (HR, 0.67; 95% CI, 0.57 to 0.79; 2-sided log-rank P < .001). The safety data were consistent with previous reports of treatment regimens. CONCLUSION In terms of the primary end point of OS, no statistically significant benefit was observed; however, PFS in the total patient population and OS in patients with wild-type EGFR was prolonged with the addition of pemetrexed to bevacizumab maintenance therapy.

Phase III Study of Matrix Metalloproteinase Inhibitor Prinomastat in Non–Small-Cell Lung Cancer

2005 ◽  
Vol 23 (4) ◽  
pp. 842-849 ◽  
Author(s):  
Donald Bissett ◽  
Ken J. O’Byrne ◽  
J. von Pawel ◽  
Ulrich Gatzemeier ◽  
Allan Price ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Extracellular Proteins ◽  
Phase Iii ◽  
Survival Times ◽  
Small Cell Lung ◽  
Study Results

Purpose Matrix metalloproteinases (MMPs) degrade extracellular proteins and facilitate tumor growth, invasion, metastasis, and angiogenesis. This trial was undertaken to determine the effect of prinomastat, an inhibitor of selected MMPs, on the survival of patients with advanced non–small-cell lung cancer (NSCLC), when given in combination with gemcitabine-cisplatin chemotherapy. Patients and Methods Chemotherapy-naive patients were randomly assigned to receive prinomastat 15 mg or placebo twice daily orally continuously, in combination with gemcitabine 1,250 mg/m2 days 1 and 8 plus cisplatin 75 mg/m2 day 1, every 21 days for up to six cycles. The planned sample size was 420 patients. Results Study results at an interim analysis and lack of efficacy in another phase III trial prompted early closure of this study. There were 362 patients randomized (181 on prinomastat and 181 on placebo). One hundred thirty-four patients had stage IIIB disease with T4 primary tumor, 193 had stage IV disease, and 34 had recurrent disease (one enrolled patient was ineligible with stage IIIA disease). Overall response rates for the two treatment arms were similar (27% for prinomastat v 26% for placebo; P = .81). There was no difference in overall survival or time to progression; for prinomastat versus placebo patients, the median overall survival times were 11.5 versus 10.8 months (P = .82), 1-year survival rates were 43% v 38% (P = .45), and progression-free survival times were 6.1 v 5.5 months (P = .11), respectively. The toxicities of prinomastat were arthralgia, stiffness, and joint swelling. Treatment interruption was required in 38% of prinomastat patients and 12% of placebo patients. Conclusion Prinomastat does not improve the outcome of chemotherapy in advanced NSCLC.

Randomized Phase III Study of Gemcitabine-Cisplatin Versus Etoposide-Cisplatin in the Treatment of Locally Advanced or Metastatic Non–Small-Cell Lung Cancer

1999 ◽  
Vol 17 (1) ◽  
pp. 12-12 ◽  
Author(s):  
Felipe Cardenal ◽  
M. Paz López-Cabrerizo ◽  
Antonio Antón ◽  
Vicente Alberola ◽  
Bartomeu Massuti ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Disease Progression ◽  
Cell Lung Cancer ◽  
Advanced Nsclc ◽  
Response Rate ◽  
Small Cell ◽  
Phase Iii ◽  
Small Cell Lung ◽  
Grade 3

PURPOSE: We conducted a randomized trial to compare gemcitabine-cisplatin with etoposide-cisplatin in the treatment of patients with advanced non–small-cell lung cancer (NSCLC). The primary end point of the comparison was response rate. PATIENTS AND METHODS: A total of 135 chemotherapy-naive patients with advanced NSCLC were randomized to receive either gemcitabine 1,250 mg/m2 intravenously (IV) days 1 and 8 or etoposide 100 mg/m2 IV days 1 to 3 along with cisplatin 100 mg/m2 IV day 1. Both treatments were administered in 21-day cycles. One hundred thirty-three patients were included in the intent-to-treat analysis of response. RESULTS: The response rate (externally validated) for patients given gemcitabine-cisplatin was superior to that for patients given etoposide-cisplatin (40.6% v 21.9%; P = .02). This superior response rate was associated with a significant delay in time to disease progression (6.9 months v 4.3 months; P = .01) without an impairment in quality of life (QOL). There was no statistically significant difference in survival time between both arms (8.7 months for gemcitabine-cisplatin v 7.2 months for etoposide-cisplatin; P = .18). The overall toxicity profile for both combinations of drugs was similar. Nausea and vomiting were reported more frequently in the gemcitabine arm than in the etoposide arm. However, the difference was not significant. Gemcitabine-cisplatin produced less grade 3 alopecia (13% v 51%) and less grade 4 neutropenia (28% v 56% ) but more grade 3 and 4 thrombocytopenia (56% v 13%) than did etoposide-cisplatin. However, there were no thrombocytopenia-related complications in the gemcitabine arm. CONCLUSION: Compared with etoposide-cisplatin, gemcitabine-cisplatin provides a significantly higher response rate and a delay in disease progression without impairing QOL in patients with advanced NSCLC.

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