Bevacizumab plus platinum-based chemotherapy in advanced non-squamous non-small-cell lung cancer: A randomized, open-label phase 2 study (CLEAR)

Hibiki Udagawa, Eri Sugiyama, Toshiyuki Harada, Shinji Atagi, Ryo Koyama, Satoshi Watanabe, Yukiko Nakamura, Daijiro Harada, Osamu Hataji, Fumihiro Tanaka, Hiroshi Kida, Miyako Satouchi, Ken Maeno, Akira Inoue, Kiyotaka Yoh, Yuki Yamane, Yoshiko Urata, Hiroshige Yoshioka, Takeharu Yamanaka, Koichi Goto

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Background: Atezolizumab combined with bevacizumab plus platinum-based chemotherapy is a standard treatment for advanced non-squamous non-small-cell lung cancer (nsNSCLC). We aimed to determine the most effective platinum-based combination, such that future studies with atezolizumab can be conducted to further improve patient outcomes. Methods: This phase 2 study enrolled treatment-naïve patients with advanced or recurrent nsNSCLC who were randomly assigned to either cisplatin (75 mg/m2) + pemetrexed (500 mg/m2) + bevacizumab (15 mg/kg) (CisPemBev) followed by maintenance PemBev (N=132) or carboplatin (area under the concentration–time curve of 6 mg/mL/min) + paclitaxel (200 mg/m2) + bevacizumab (15 mg/kg) (CarPacBev) followed by maintenance Bev (N=67). The primary endpoint was progression-free survival (PFS, by central review). Secondary endpoints included overall survival (OS) and overall response rate (ORR). Adverse events (AEs) were evaluated for safety. This study was designed with the point estimate of the hazard ratio (HR) for PFS calculated based on an expected HR <0.830 with a probability ≥80%. Results: The HR for PFS (CisPemBev/CarPacBev) was 0.825 [95% confidence interval (CI), 0.600–1.134, median PFS, 7.6 vs. 7.0 months]. Because the observed point estimate of the HR for PFS was <0.830, the primary endpoint was met, and CisPem doublet therapy was deemed to be more effective than CarPac in terms of PFS. Median OS was 23.4 months for CisPemBev and 21.6 months for CarPacBev (HR 0.845; 95% CI, 0.583–1.242). The ORR was 57% for CisPemBev and 55% for CarPacBev. Both CisPemBev and CarPacBev were well tolerated; grade ≥3 AEs were reported in 67% and 82% of patients, respectively. Conclusions: CisPem combined with Bev was more effective in improving PFS compared with CarPacBev in patients with advanced nsNSCLC. CisPemBev was also well tolerated by this patient population. A study to evaluate the efficacy of atezolizumab plus CisPemBev is warranted.

Original languageEnglish
JournalTranslational Lung Cancer Research
Issue number7
Publication statusPublished - 2021 Jul


  • Bevacizumab
  • Carcinoma
  • Chemotherapy
  • Non-small cell lung
  • Phase II
  • Survival

ASJC Scopus subject areas

  • Oncology


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