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


Transl Lung Cancer Res. 2021;10(7):3059-3070. 

In This Article

Abstract and Introduction


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.

Trial Registration: University hospital Medical Information Network Clinical Trial Registry (ID: UMIN000013354).


Lung cancer is a leading cause of cancer deaths worldwide, and the survival rates are low even in developed countries.[1] Non-small cell lung cancer (NSCLC) accounts for approximately 75–80% of lung cancer cases, and the majority of patients are at an advanced stage (IIIB/IV) when they are diagnosed.[2,3] In general, adenocarcinoma is the most common type of non-squamous (ns) NSCLC.[4]

Bevacizumab is a humanized monoclonal antibody that targets vascular endothelial growth factor. Bevacizumab combined with platinum-doublet chemotherapy improves progression-free survival (PFS) and overall survival (OS) of patients with advanced nsNSCLC.[5–8] Both carboplatin + paclitaxel + bevacizumab (CarPacBev) and carboplatin + pemetrexed + bevacizumab (CarPemBev) regimens are widely used in clinical practice.[9] In a phase 3 study (PointBreak study), PFS was significantly improved with CarPemBev when compared with CarPacBev, but OS (the primary study endpoint) did not improve with the CarPemBev regimen compared with the CarPacBev regimen.[10] Thus, CarPac is the most effective evidence-based regimen combined with Bev in advanced nsNSCLC.

However, cisplatin with pemetrexed (CisPem) is the most effective platinum-based chemotherapy for patients with advanced nsNSCLC and has shown better tolerability compared with other platinum-based regimens.[11–14] Therefore, CisPem would appear to be a promising regimen for combination with Bev. In fact, in a single-arm phase 2 study investigating the efficacy and safety of CisPemBev followed by PemBev in Japanese patients, PFS and OS were 12.0 and 31.0 months, respectively.[15] The phase 3 AVAPERL clinical trial showed that CisPemBev induction therapy followed by PemBev maintenance therapy significantly prolonged PFS compared with Bev alone maintenance therapy.[16] However, no study has been conducted to directly compare the efficacy and safety of CisPemBev and CarPacBev for advanced nsNSCLC.

Recently, anti-programmed cell death protein-1 (PD-1) or anti-programmed death-ligand 1 (PD-L1) plus platinum-based chemotherapy became a standard treatment for patients with advanced NSCLC.[17,18] In the phase 3 KEYNOTE-189 trial, the addition of pembrolizumab (an anti-PD-1 antibody) to CisPem or CarPem was shown to improve OS in patients with advanced NSCLC.[17] Similarly, in the phase 3 IMpower150 study, the combination of atezolizumab (a humanized monoclonal antibody targeting PD-L1) and CarPacBev significantly improved OS in patients with advanced NSCLC.[18] However, no study has evaluated the efficacy and safety of the combination of atezolizumab and CisPemBev.

This study aimed to select the most effective platinum-based regimen combined with bevacizumab with the intention of studying the combination of this platinum-based regimen with atezolizumab in the future. Thus, we compared the efficacy and safety of CisPemBev vs. CarPacBev in previously untreated advanced or recurrent nsNSCLC patients. We present the following article in accordance with the CONSORT reporting checklist (available at