Phase III Trial of Cisplatin Plus Gemcitabine With Either Placebo or Bevacizumab As First-Line Therapy for Nonsquamous Non–Small-Cell Lung Cancer: AVAiL

Reck, Martin; Pawel, Joachim von; Zatloukal, Petr; Ramlau, Rodryg; Gorbounova, Vera; Hirsh, Vera; Leighl, Natasha B.; Mezger, J.; Archer, Venice; Moore, N.; Manegold, Christian

doi:10.1200/jco.2007.14.5466

Cited by 1,353 publications

(1,050 citation statements)

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“…Some notable differences between the PARAMOUNT and JMDB populations were the NSCLC stage percentages (stage IIIB NSCLC: 9% versus 21%, respectively), "Other or indeterminate histology" (approximately 6% versus 17%, respectively), and smoking status "Unknown" (1% versus 35%, respectively). In general, the distribution of patient and disease characteristics represented in these three groups is similar to that seen in other recent phase III studies [7], [12], [13] and [14]. Percentages not totaling 100% are due to rounding or missing data.…”

Section: Resultssupporting

confidence: 80%

Efficacy and safety of maintenance pemetrexed in patients with advanced nonsquamous non-small cell lung cancer following pemetrexed plus cisplatin induction treatment: A cross-trial comparison of two phase III trials

et al. 2014

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Highlights•Compared advanced NSCLC phase III trials: pemetrexed-cisplatin with or without pem maintenance.•4 cycles pem-cis followed by pem maintenance improves survival over 6 cycles pem-cis.•Longer exposure to pem-cis or maintenance pem increases some toxicities, but overall incidence low. Abstract ObjectivesTwo phase III trials of advanced NSCLC patients were compared to examine relative efficacy and safety of differing treatment regimens. The JMDB trial investigated first-line pemetrexed-cisplatin (pemetrexed 500 mg/m 2 plus cisplatin 75 mg/m 2 every 21 days; maximum: 6 cycles). The PARAMOUNT phase III trial compared maintenance pemetrexed versus placebo after patients with nonsquamous NSCLC completed 4 cycles of first-line pemetrexed-cisplatin without disease progression. MethodsOverall survival (OS) and progression-free survival (PFS), analyzed by Kaplan-Meier and Cox methods, and toxicity rates were compared between the PARAMOUNT arms and a selected homogeneous population from JMDB: 346 patients with disease and prior treatment characteristics matching the PARAMOUNT population. ResultsOutcomes for the PARAMOUNT placebo arm were similar to the JMDB homogeneous group (median PFS: 5.6 versus 6.2 months, p = 0.117, HR = 1.16; median OS: 14.0 versus 14.2 months, p = 0.979, HR = 1.00). The PARAMOUNT maintenance pemetrexed group had statistically superior efficacy compared with the JMDB homogeneous group (median PFS: 7.5 versus 6.2 months, p < 0.00001, HR = 0.66; median OS: 16.9 versus 14.2 months, p = 0.003, HR = 0.75). Patients who received pemetrexed maintenance (median 4 cycles, range 1-44) following 4 cycles of pemetrexed-cisplatin exhibited a higher incidence of drug-related serious adverse events compared with JMDB patients (median 6 cycles of pemetrexed-cisplatin) (10.6% versus 2.9%); grade 3/4 fatigue and renal toxicity were also higher in the pemetrexed arm of PARAMOUNT. ConclusionsThe across-trial comparison of a relevant JMDB study population with the two arms of the PARAMOUNT study supported the efficacy of the pemetrexed continuation maintenance strategy and suggested the results are not influenced by limiting the pemetrexed-cisplatin induction treatment to four cycles. Although longer exposure to pemetrexed-cisplatin or maintenance pemetrexed increased some toxicities, the overall incidence remained low, underscoring the relative safety of these treatment regimens.

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Section: Resultssupporting

confidence: 80%

Efficacy and safety of maintenance pemetrexed in patients with advanced nonsquamous non-small cell lung cancer following pemetrexed plus cisplatin induction treatment: A cross-trial comparison of two phase III trials

et al. 2014

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“…Mild or moderate fatigue and gastrointestinal adverse effects were the most frequent nonhematologic toxicities, consistent with findings from previous studies with combined S-1 and carboplatin. 12 Hypertension and proteinuria have been associated with bevacizumab administration 6,8 and also were observed in the current study. Two patients experienced grade 3 proteinuria in the maintenance period; however, both cases were fully reversible without dose reduction or cessation of treatment.…”

Section: Discussionsupporting

confidence: 80%

“…Two patients experienced grade 3 proteinuria in the maintenance period; however, both cases were fully reversible without dose reduction or cessation of treatment. Because clinically significant (grade 3) hemoptysis was observed in 0.9% to 1.9% of patients who received bevacizumab in the ECOG E4599 and AVAiL trials, 6,8 the lack of fatal bleeding events and treatment-related deaths in the current study also is noteworthy. Patients with brain metastases have been excluded from most clinical trials of bevacizumab for fear of intracranial hemorrhage.…”

Section: Discussionmentioning

confidence: 75%

“…Patients with brain metastases have been excluded from most clinical trials of bevacizumab for fear of intracranial hemorrhage. 6,8 However, recent data suggest that the risk of developing intracranial hemorrhage is independent of bevacizumab therapy in patients with NSCLC who have brain metastases. 18 Conversely, another study suggested that intracranial hemorrhage is more likely to become clinically symptomatic in larger (>2 cm) brain metastases.…”

Section: Discussionmentioning

confidence: 99%

“…7 In a confirmatory phase 3 study (the Avastin in Lung [AVAiL] trial), the addition of bevacizumab to cisplatin and gemcitabine resulted in a significant improvements in the ORR and PFS. 8,9 These observations provide a rationale for combining bevacizumab with platinum-doublet chemotherapy in individuals with advanced nonsquamous NSCLC. …”

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confidence: 98%

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Phase 2 study of S‐1 and carboplatin plus bevacizumab followed by maintenance S‐1 and bevacizumab for chemotherapy‐naive patients with advanced nonsquamous non–small cell lung cancer

Urata

Okamoto

Takeda

et al. 2013

Cancer

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BACKGROUND:A previous phase 3 trial demonstrated noninferiority in terms of overall survival for combined S-1 (an oral fluoropyrimidine) and carboplatin compared with combined paclitaxel and carboplatin as first-line treatment for advanced non-small cell lung cancer (NSCLC). In the current study, the authors evaluated the efficacy and safety of combined S-1, carboplatin, and bevacizumab followed by maintenance with S-1 and bevacizumab in chemotherapy-naive patients with advanced nonsquamous NSCLC. METHODS: Patients received carboplatin (area under the concentration-time curve, 5 mg mL 21 per minute) and bevacizumab (15 mg/kg) on day 1 plus oral S-1 (80 mg/m 2 per day) on days 1 through 14 every 21 days for up to 6 cycles. For patients without disease progression, S-1 and bevacizumab were continued until disease progression or unacceptable toxicity developed. RESULTS: Forty-eight patients were enrolled in the phase 2 study; of these, 35 patients (72.9%) completed at least 4 cycles. Most toxicities of grade 3 were hematologic, and no increase in relative incidence associated with maintenance with S-1 and bevacizumab was observed. The objective response rate was 54.2% (95% confidence interval, 39.2%-68.6%), and the median progression-free survival was 6.8 months (95% confidence interval, 4.3-8.2 months). CONCLUSIONS: The regimen of combined S-1, carboplatin, and bevacizumab followed by maintenance with S-1 and bevacizumab was active and feasible as first-line treatment for advanced nonsquamous NSCLC. Cancer 2013;119:2275-81. INTRODUCTIONLung cancer is the leading cause of death related to cancer worldwide, with non-small cell lung cancer (NSCLC) accounting for 85% of lung cancer cases. 1 For individuals with advanced or metastatic NSCLC, platinum-based chemotherapy is the mainstay of first-line treatment 2,3 on the basis of the moderate improvement in survival and quality of life it affords compared with best supportive care alone. 4 A phase 3 study, the Eastern Cooperative Oncology Group (ECOG) E4599 trial, demonstrated that bevacizumab, a humanized monoclonal antibody specific for vascular endothelial growth factor, 5 given with paclitaxel and carboplatin resulted in significant improvements in the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) compared with paclitaxel and carboplatin alone in individuals with advanced nonsquamous NSCLC. 6 A Japanese phase 2 study also indicated that bevacizumab in combination with paclitaxel and carboplatin improved the ORR and PFS compared with paclitaxel and carboplatin alone. 7 In a confirmatory phase 3 study (the Avastin in Lung [AVAiL] trial), the addition of bevacizumab to cisplatin and gemcitabine resulted in a significant improvements in the ORR and PFS. 8,9 These observations provide a rationale for combining bevacizumab with platinum-doublet chemotherapy in individuals with advanced nonsquamous NSCLC.

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Treatment-Related Mortality With Bevacizumab in Cancer Patients

Ranpura¹,

Hapani²,

Wu³

2011

JAMA

393

224

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Phase III Trial of Cisplatin Plus Gemcitabine With Either Placebo or Bevacizumab As First-Line Therapy for Nonsquamous Non–Small-Cell Lung Cancer: AVAiL

Abstract: Combining bevacizumab (7.5 or 15 mg/kg) with CG significantly improved PFS and objective response rate. Bevacizumab plus platinum-based chemotherapy offers clinical benefit for bevacizumab-eligible patients with advanced NSCLC.

Cited by 1,353 publications

References 17 publications

Efficacy and safety of maintenance pemetrexed in patients with advanced nonsquamous non-small cell lung cancer following pemetrexed plus cisplatin induction treatment: A cross-trial comparison of two phase III trials

Efficacy and safety of maintenance pemetrexed in patients with advanced nonsquamous non-small cell lung cancer following pemetrexed plus cisplatin induction treatment: A cross-trial comparison of two phase III trials

Phase 2 study of S‐1 and carboplatin plus bevacizumab followed by maintenance S‐1 and bevacizumab for chemotherapy‐naive patients with advanced nonsquamous non–small cell lung cancer

Treatment-Related Mortality With Bevacizumab in Cancer Patients

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