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. 2016 May 18;11(5):e0154293.
doi: 10.1371/journal.pone.0154293. eCollection 2016.

Pemetrexed/Carboplatin/Bevacizumab followed by Maintenance Pemetrexed/Bevacizumab in Hispanic Patients with Non-Squamous Non-Small Cell Lung Cancer: Outcomes according to Thymidylate Synthase Expression

Andrés Felipe Cardona  1   2 , Leonardo Rojas  2   3 , Beatriz Wills  1   2 , Oscar Arrieta  4 , Hernán Carranza  1   2 , Carlos Vargas  1   2 , Jorge Otero  1   2 , Mauricio Cuello  5 , Luis Corrales  6 , Claudio Martín  7 , Carlos Ortiz  1 , Sandra Franco  1 , Rafael Rosell  8 ; CLICaP
Affiliations

Pemetrexed/Carboplatin/Bevacizumab followed by Maintenance Pemetrexed/Bevacizumab in Hispanic Patients with Non-Squamous Non-Small Cell Lung Cancer: Outcomes according to Thymidylate Synthase Expression

Andrés Felipe Cardona et al. PLoS One. .

Abstract

Objective: To evaluate the efficacy and safety of pemetrexed, carboplatin and bevacizumab (PCB) followed by maintenance therapy with pemetrexed and bevacizumab (PB) in chemotherapy-naïve patients with stage IV non-squamous non-small cell lung cancer (NSCLC) through the influence of thymidylate synthase (TS) protein and mRNA expression on several outcomes. The primary endpoints were the overall response rate (ORR), progression-free survival (PFS) and overall survival (OS).

Methods: A cohort of 144 patients were administered pemetrexed (500 mg/m2), carboplatin (AUC, 5.0 mg/ml/min) and bevacizumab (7.5 mg/kg) intravenously every three weeks for up to four cycles. Maintenance PB was administered until disease progression or unacceptable toxicity.

Results: One hundred forty-four Colombian patients with a median follow-up of 13.8 months and a median number of 6 maintenance cycles (range, 1-32) were assessed. The ORR among the patients was 66% (95% CI, 47% to 79%). The median PFS and (OS) rates were 7.9 months (95% CI, 5.9-10.0 months) and 21.4 months (95% CI, 18.3 to 24.4 months), respectively. We documented grade 3/4 hematologic toxicities, including anemia (14%), neutropenia (8%), and thrombocytopenia (16%). The identified grade 3/4 non-hematologic toxicities were proteinuria (2%), venous thrombosis (4%), fatigue (11%), infection (6%), nephrotoxicity (2%), and sensory neuropathy (4%). No grade >3 hemorrhagic events or hypertension cases were reported. OS was significantly higher in patients with the lowest TS mRNA levels [median, 29.6 months (95% CI, 26.2-32.9)] compared with those in patients with higher levels [median, 9.3 months (95% CI, 6.6-12.0); p = 0.0001]. TS expression (mRNA levels or protein expression) did not influence the treatment response.

Conclusion: Overall, PCB followed by maintenance pemetrexed and bevacizumab was effective and tolerable in Hispanic patients with non-squamous NSCLC. This regimen was associated with acceptable toxicity and prolonged OS, particularly in patients with low TS expression. We found a role for Ki67 and TS expression as prognostic factors.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Kaplan Meier Curves for Overall Survival and Progression Free Survival.
Fig 2
Fig 2. Overall survival according to Ki67.
Fig 3
Fig 3. Kaplan-Meier Curves for Overall Survival and Progression Free Survival according to TS mRNA levels.
Fig 4
Fig 4. Kaplan Meier Curves according to TS protein expression.
Fig 5
Fig 5. Overall survival according to TS protein expresson level (stratified).
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