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Induction Therapy:

Patients receive paclitaxel IV over 3 hours, carboplatin IV over 15-30 minutes, and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Maintenance Therapy:

Patients achieving complete response, partial response or stable disease following induction therapy are randomized to 1 of 3 treatment arms. Patients in arm A receive bevacizumab IV over 30-90 minutes on day 1 of every cycle until progression or unacceptable toxicity.

Induction Therapy:

Patients receive paclitaxel IV over 3 hours, carboplatin IV over 15-30 minutes, and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Maintenance Therapy:

Patients achieving complete response, partial response or stable disease following induction therapy are randomized to 1 of 3 treatment arms. Patients in arm B receive pemetrexed IV over 10 minutes on day 1 of every cycle until progression or unacceptable toxicity.

Induction Therapy:

Patients receive paclitaxel IV over 3 hours, carboplatin IV over 15-30 minutes, and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Maintenance Therapy:

Patients achieving complete response, partial response or stable disease following induction therapy are randomized to 1 of 3 treatment arms. Patients in arm C receive bevacizumab as in arm A and pemetrexed as in arm B.

Pemetrexed Disodium Heptahydrate

Suresh Ramalingam, MD

RATIONALE: Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of non-small cell lung cancer by blocking blood flow to the tumor. Pemetrexed disodium may stop the growth of tumor cells by blocking some enzymes needed for cell growth. It is not yet known whether giving bevacizumab or pemetrexed disodium alone or in combination is more effective in treating non-squamous non-small cell lung cancer.

PURPOSE: This randomized phase III trial is studying bevacizumab and pemetrexed disodium alone or in combination after induction therapy to see how well they work in treating patients with advanced non-squamous non-small cell lung cancer.

OBJECTIVES:

Primary

* To compare the overall survival (OS) of patients with advanced non-squamous non-small cell lung cancer (NSCLC) treated with maintenance therapy with bevacizumab vs pemetrexed disodium vs bevacizumab and pemetrexed disodium following induction therapy.

Secondary

* To determine the response rate in patients treated with these regimens.
* To evaluate the progression-free survival (PFS) of patients treated with these regimens.
* To define the toxicity of these regimens in these patients.
* To determine the frequency of polymorphisms in VEGF 3578 AA, 1154 AA, ABCB1 G2677TT/AA, and ERCC-118 TT in patients treated with induction therapy comprising paclitaxel, carboplatin and bevacizumab and determine the association between genotypes and response rate.
* To determine the association between bevacizumab and pemetrexed disodium population pharmacokinetics and patient-specific covariate with bevacizumab or pemetrexed disodium toxicity.
* To determine the frequency of TSER\*3 polymorphisms in NSCLC and the association between TSER polymorphisms and benefit from pemetrexed disodium.
* To evaluate TS and ERCC1 expression by RT-PCR and MTAP mutations in existing tumor specimens as a predictor of pemetrexed disodium response.
* To evaluate polymorphisms within CYPs 2C8, 3A4, 3A5 and/or the UGT1A1 collectively or monogenically as markers for variation in efficacious and/or toxic response of individuals to treatment with taxanes.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to gender (male vs female), stage of disease (IIIB-T4Nx \[with nodule in ipsilateral lung lobe and not candidate for combined chemotherapy and radiation\] and IV M1a vs IV M1b vs recurrent), best response to first-time therapy (complete response/partial response vs stable disease), and smoking status (never vs smoker).

* Induction therapy (Arm I): Patients receive paclitaxel IV over 3 hours, carboplatin IV over 15-30 minutes, and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
* Maintenance Therapy: Patients achieving complete response, partial response or stable disease following induction therapy are randomized to 1 of 3 treatment arms. Treatment begins within 6 weeks of the last day of induction chemotherapy administration.

  * Arm A: Patients receive bevacizumab IV over 30-90 minutes on day 1.
  * Arm B: Patients receive pemetrexed disodium IV over 10 minutes on day 1.
  * Arm C: Patients receive bevacizumab as in arm A and pemetrexed as in arm B. In all arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Some patients undergo blood sample collection at baseline and periodically during study for correlative studies.

After completion of study therapy, patients are followed up every 3 months for 2 years and then every 6 months for 2-5 years.

Bevacizumab or Pemetrexed Disodium Alone or In Combination After Induction Therapy in Treating Patients With Advanced Non-Squamous Non-Small Cell Lung Cancer

Randomized Phase III Study of Maintenance Therapy With Bevacizumab, Pemetrexed, or a Combination of Bevacizumab and Pemetrexed Following Carboplatin, Paclitaxel and Bevacizumab for Advanced Non-Squamous NSCLC

Individual participant data may be made available upon request as per the ECOG-ACRIN Data Sharing Policy.

To determine the frequency of polymorphisms in VEGF 3578 AA, 1154 AA, ABCB1 G2677TT/AA and ERCC-118 TT in patients with NSCLC receiving paclitaxel, carboplatin and bevacizumab therapy and determine the association between genotypes and response rate.

Overall survival is defined as the time from randomization to death or date last known alive.

The primary analysis is among patients who were randomized to the maintenance therapy. Patients who received induction therapy only and did not participate in the randomization part of the study were not included in this analysis.

Progression-free survival is defined as the time from randomization to progression or death, whichever occurs first. Progression is evaluated based on RECIST criteria and defined as appearance of one or more new lesions, unequivocal progression of existing non-target lesions, or at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on current step. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

The primary analysis is among patients who were randomized to the maintenance therapy. Patients who received induction therapy only and did not participate in the randomization part of the study were not included in this analysis.

Response is evaluated based on RECIST criteria v1.1 and defined as either complete response or partial response. Complete response is defined as disappearance of all lesions. Partial response is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the current step's baseline sum diameters.

The primary analysis is among patients who were randomized to the maintenance therapy. Patients who received induction therapy only and did not participate in the randomization part of the study were not included in this analysis.

National Cancer Institute (NCI)

ECOG-ACRIN Cancer Research Group

Only patients who started protocol therapy are included in the analysis of adverse events. All registered patients are included in the analysis of all-cause mortality.

Induction Therapy:

Patients receive paclitaxel IV over 3 hours, carboplatin IV over 15-30 minutes, and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Arm I (Induction Therapy - Carboplatin, Paclitaxel & Bevacizumab)

Maintenance Therapy:

Patients achieving complete response, partial response or stable disease following induction therapy are randomized to 1 of 3 treatment arms. Patients in arm A receive bevacizumab IV over 30-90 minutes on day 1 of every cycle until progression or unacceptable toxicity.

Arm A (Maintenance Therapy - Bevacizumab)

Maintenance Therapy:

Patients achieving complete response, partial response or stable disease following induction therapy are randomized to 1 of 3 treatment arms. Patients in arm B receive pemetrexed IV over 10 minutes on day 1 of every cycle until progression or unacceptable toxicity.

Arm B (Maintenance Therapy - Pemetrexed)

Maintenance Therapy:

Patients achieving complete response, partial response or stable disease following induction therapy are randomized to 1 of 3 treatment arms. Patients in arm C receive bevacizumab IV over 30-90 minutes and pemetrexed IV over 10 minutes on day 1 of every cycle until progression or unacceptable toxicity.

Arm C (Maintenance Therapy - Bevacizumab + Pemetrexed)

Induction Therapy But Not Randomized

Arm A (Induction Then Maintenance With Bevacizumab)

Arm B (Induction Then Maintenance With Pemetrexed)

Induction Therapy:

Patients receive paclitaxel IV over 3 hours, carboplatin IV over 15-30 minutes, and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Maintenance Therapy:

Patients achieving complete response, partial response or stable disease following induction therapy are randomized to 1 of 3 treatment arms. Patients in arm C receive bevacizumab IV over 30-90 minutes and pemetrexed IV over 10 minutes on day 1 of every cycle until progression or unacceptable toxicity.

Arm C (Inductio Then Maintenance With Bevacizumab & Pemetrexed)

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Study Statistician

Arm B (Induction Then Maintenance With Pemetrexed

Arm C (Induction Then Maintenance With Bevacizumab and Pemetrexed)

Overall Survival

Progression-free Survival

Response Rate

The Association Between Genotypes and Response Rate

The Association Between Bevacizumab and Pemetrexed Population Pharmacokinetics and Patient Specific Covariates With Bevacizumab or Pemetrexed Toxicity

The Frequency of TSER*3 Polymorphisms in NSCLC and the Association Between TSER Polymorphisms and Benefit From Pemetrexed

The Association Between TS and ERCC1 Expression and Pemetrexed Response

The Associations Between Polymorphisms Within CYPs 2C8, 3A4, 3A5 and/or the UGT1A1 Collectively or Monogenically and Efficacy and/or Toxicities

Induction Therapy But Not Randomized to Maintenance Therapy

Step 1: Induction Therapy

Step 2: Maintenance Therapy

Spots Global Cancer Trial Database for pemetrexed disodium heptahydrate