Open Access

Long-term Progression-free Survival With Pemetrexed Plus Bevacizumab in NSCLC Patients


1Division of Respiratory Medicine, Ibaraki Seinan Medical Center Hospital, Sakai, Japan

2Division of Respiratory Medicine, Ryugasaki Saiseikai Hospital, Ryugasaki, Japan

3Division of Respiratory Medicine, Faculty of Clinical Medicine, University of Tsukuba, Tsukuba, Japan

4Division of Respiratory Medicine, Mito Medical Center, University of Tsukuba, Mito, Japan

Cancer Diagnosis & Prognosis May-June; 3(3): 377-382 DOI: 10.21873/cdp.10227
Received 16 February 2023 | Revised 29 May 2023 | Accepted 01 March 2023
Corresponding author
Hiroaki Satoh, MD, Ph.D., Division of Respiratory Medicine, Mito Medical Center, University of Tsukuba, 3100015, Mito, Ibaraki, Japan. Tel: +81 292312371, Fax: +81 292215137, email:


Background/Aim: Pemetrexed (PEM) and bevacizumab (BEV) are commonly used in combination as second or subsequent line regimens and maintenance therapy after platinum + PEM + BEV therapy for advanced non-small cell lung cancer (NSCLC). Median progression-free survival (PFS) for PEM + BEV has been reported to be less than six months in both clinical trials and clinical practice, but in clinical practice, we found that some patients demonstrate long-term PFS. Furthermore, there is a paucity of clinical practice data on whether long-term administration of PEM + BEV causes renal dysfunction. This study aimed to clarify these aspects in clinical practice. Patients and Methods: A retrospective review of patients with advanced NSCLC treated with PEM + BEV between September 2011 and June 2022 at four hospitals was conducted. Long-term PFS in PEM + BEV therapy was defined as ≥12 months. Results: During the study period, 109 patients received PEM + BEV treatment. Of them, 42 (38.5%) achieved long-term PFS ≥12 months. No significant differences in patient characteristics were found between patients with PFS ≥12 months and <12 months, except for ‘relapse after resection’. Univariate and multivariate analysis showed that the favorable factor for PFS was ‘relapse after resection’. With regard to influence on renal function of PEM + BEV therapy, no significant difference was found before and after PEM+BEV therapy between these two groups. Conclusion: NSCLC patients commonly achieved long-term PFS with PEM + BEV therapy with no observed effects on renal function.
Keywords: non-small cell lung cancer, long-term progression-free survival, pemetrexed, bevacizumab

Pemetrexed (PEM) is an antimetabolite antineoplastic agent that exerts its antitumor effect by inhibiting DNA synthesis via simultaneously inhibiting multiple folate-metabolizing enzymes. Bevacizumab (BEV) is an antivascular endothelial growth factor receptor-2 (anti-VEGFR2) monoclonal antibody (1,2). BEV suppresses tumor growth by preventing VEGF from binding to VEGFR2 and activating downstream angiogenic signals (1,2). During the past two decades, platinum + PEM + BEV has been a first-line chemotherapy regimen for patients with advanced non-squamous non-small cell lung cancer (NSCLC), due to its effective antitumor effects and mild toxicity. Currently, PEM + BEV combination therapy is widely used for advanced NSCLC as second-line and subsequent therapy or as maintenance therapy after platinum + PEM + BEV therapy (3-9). This combination regimen is widely recognized as a treatment regimen that has a low incidence of difficult-to-manage myelosuppression, peripheral neuropathy, and febrile neutropenia (3-9). Despite these favorable evaluations, the median progression-free survival (PFS) from primary treatment including platinum, or from the start of PEM+BEV in clinical practice was 5.7 to 7.5 months (3-7) and 6.0-7.36 months (8,9), respectively.

Although NSCLC patients with long-term PFS on PEM+BEV therapy have been rarely reported (10), there are patients undergoing long-term PEM+BEV therapy in real-world clinical practice. In our two decades of practice, we have regularly observed patients with a long-term PFS with this treatment regimen. Therefore, we performed a retrospective study with the aim of clarifying: 1) the percentage of patients with long-term PFS, and 2) the characteristics of patients who have long-term PFS. Favorable factors associated with long-term PFS with PEM + BEV therapy were investigated in this study. Since there has been some concern about the deterioration of renal function due to long-term administration of these drugs (11,12), we also investigated renal function of patients who received long-term administration of these drugs.

Patients and Methods

Patients. The medical records of all patients diagnosed with NSCLC and treated with PEM+BEV for any treatment line between September 2011 and June 2022 at four tertiary hospitals in Japan (Mito Medical Center, University of Tsukuba-Mito Kyodo General Hospital, Ryugasaki Saiseikai Hospital, and Seinan Medical Center Hospital) were investigated. Using the World Health Organization classification, NSCLC was diagnosed pathologically. Prior to the initiation of any anticancer therapy, clinical staging was determined with tumor node metastasis staging (TNM Classification, eighth edition) (13) using computed tomography/magnetic resonance imaging of the head, ultrasonography/computed tomography of the abdomen, and bone scans. Patient information such as age, sex, Eastern Cooperative Oncology Group score for performance status, histopathology, disease stage, programmed death-ligand 1 expression, objective tumor response, and survival were extracted from medical records. Driver mutations including epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements were surveyed. Tumor response was categorized as complete response, partial response, stable disease, or progressive disease according to the Response Evaluation Criteria in Solid Tumors (version 1.1) (14). Adverse events were classified using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0) (15).

Definition of long-term PFS for PEM+BEV. Most of the reported ‘long-term PFS’ relate to PFS for first-line chemotherapy (16). There are few reports on PFS in second- or later-line treatment of NSCLC (17-20). PEM+BEV are usually delivered as second- or later-line chemotherapy. As such, this may be the reason we did not find any reports with a search for ‘long-term PFS’ and this regimen. ‘Long-term PFS’ was then defined using clinical trial PFS and actual clinical practice, where the median PFS with this regimen was less than 6 months (3-9). Based on these results (3-9) and this study, ‘long-term PFS’ was defined as a PFS of ≥12 months.

Renal function. Renal impairment was assessed by examining changes in blood urea nitrogen (BUN) and creatinine before and after PEM+BEV treatment and comparing a group of patients with PFS of 12 months or more with a group of patients with PFS of less than 12 months. We also investigated the percentage of patients with (+) and (++) proteinuria at the end of PEM+BEV treatment.

Statistical analysis. The chi-square test was used to test proportions. Values with unknown population variance were compared using the nonparametric Mann–Whitney test. Commonly used in cancer therapy, PFS is defined as the time from initiation of anticancer therapy to progression. PFS of PEM+BEV was calculated according to this definition. Kaplan–Meier curves were used to display PFS. In univariate analysis, the log-rank test was used to compare PFS. Cox’s proportional hazards model was used for multivariate analysis. Multivariate analysis was performed using only variables with p-values less than 0.2 in univariate analysis. All statistical analyses were performed using SPSS version 23 (IBM Corporation, Armonk, NY, USA). A p-value less than 0.05 was considered statistically significant.

Ethics. The present study complied with the ethical guidelines for clinical research issued by the Ministry of Health, Labor, and Welfare of Japan. Written informed consent to participate in a non-interventional retrospective study was obtained from each patient. The Ethical Committee of Mito Medical Center-University of Tsukuba approved this study (no. 20-57).


Patient characteristics. A total of 109 patients with NSCLC diagnosed during the study period received PEM+BEV. Of these, 71 were driver gene-negative and 38 were positive (EGFR mutation, 29 patients; ALK rearranged mutation, 9 patients). The median PFS for these 109 patients was 8.0 months (range=1.0-78.0 months). Figure 1 shows the specific treatment sequences for these 109 patients. Forty-two patients (38.5%) had PFS ≥12 months. Table I shows the characteristics of patients when grouped by their PFS (<12 months and ≥12 months). There were no significant differences in age, sex, or histology in these patient groups. Fourteen of the 38 patients positive for a driver gene mutation (36.8%) and 24 of the 71 patients negative for a driver gene mutation (33.8%) had a PFS ≥12 months. There was no significant difference between the driver gene positive and negative groups. Twenty-two of the 42 patients (52.4%) with a PFS ≥12 months received platinum + PEM + BEV prior to PEM+BEV treatment, and 37 of the 67 patients (55.2%) had a PFS <12 months on the same treatment. There was no significant difference between these two groups (p=0.8444). The proportion of patients receiving PEM+BEV as first or second line therapy tended to differ between the two groups (p=0.0677), and there was a significant difference in ‘relapse after resection’ between them (p=0.0479).

Favorable factors for long-term PFS. With the aim of identifying favorable factors associated with long-term PFS, univariate and multivariate analysis of clinical characteristics of all 109 patients were performed. Results are shown in Table II. In univariate analysis, only ‘relapse after resection’ was a significant favorable factor for PFS. In multivariate analysis, only ‘relapse after resection’ was a significant favorable factor for PFS.

Renal function in PEM+BEV therapy. Table III shows a comparison of renal function before and after PEM+BEV in patients with PFS <12 months and ≥12 months. Between the two patient groups, there was no statistical difference in changes in BUN or creatinine levels, or percentage of patients with proteinuria at the end of PEM+BEV treatment. There was no patient who had a toxicity criterion of grade 3 (upper limit of normal <3.0, proteinuria >4+).


In the present study, we revealed that 39% of NSCLC patients on PEM+BEV therapy had a PFS ≥12 months. Relapse after resection was associated with long-term PFS. In uni- and multivariate analyses of all patients treated with PEM+BEV, ‘relapse after resection’ was a favorable factor in the 109 patients. Between patients with PFS <12 months and ≥12 months, there were no statistical differences in changes in BUN or creatinine levels, or the percentage of patients with proteinuria at the end of PEM+BEV treatment.

PEM+BEV therapy has been evaluated as one of the standard treatments for second- or later-line regimens, and maintenance therapy after platinum + PEM + BEV therapy for advanced NSCLC (3-9). The median PFS with PEM+BEV has been reported to be around 5-7 months in both clinical trials and clinical practice (3-9). Although there have been very few reports of patients with long-term responses to PEM+BEV (10), we occasionally encountered patients with long-term response in routine clinical practice. Therefore, this study determined the frequency and characteristics of these patients.

With no established definition of long-term PFS in second- and later-line chemotherapy, in this study we defined ‘long-term response’ as having a PFS of 12 months or longer. Under this definition we revealed that there was a considerable number of patients with long-term PFS receiving PEM + BEV therapy. Although we were not able to identify a distinct signature of patients with long-term PFS, we were able to show that patients with ‘relapse after resection’ are likely to have long-term PFS. Moreover, a certain number of patients that received PEM + BEV therapy were able to demonstrate long-term PFS of 12 months or more. To our best knowledge, no reports have examined the proportion of patients achieving long-term PFS with PEM + BEV therapy and the associated favorable factors in a substantial number of patients. We can only speculate on our observed association of long-term PFS with ‘relapse after resection’. It may indicate a relationship with smaller tumor burden and less spread of lesions. All postoperative patients were monitored regularly with particular attention to ‘relapse after resection’ (21-23). Thus, we speculate that patients with ‘relapse after resection’ were more likely to have a relapse with relatively low tumor burden and a low number of distant metastases.

This study also focused on renal impairment as a side effect of PEM + BEV therapy by comparing patients with a PFS of more than 12 months to those with a PFS of less than 12 months. None of the patients with a PSF ≥12 months or <12 months had grade 3 (upper limit of normal <3.0, proteinuria >4+) toxicity criteria. However, it is possible that renal dysfunction was a consequence, and comparisons between PFS of ≥12 months and <12 months were not sufficient.

In addition to this, our study had some limitations. Data from patients were obtained across four institutions, but this was a retrospective study with a relatively small number of patients with varying background characteristics. It should be noted that our results are preliminary and do not provide final, statistically valid conclusions. EGFR mutation and ALK rearrangements were examined as driver genes in all patients, however, tests for additional driver genes were performed in a subset of patients as they became newly available during the study period. As a result, most of the driver gene-positive patients carried an EGFR mutation or ALK rearrangement. In this study, driver mutations were not a significant factor in favor of PFS. However, it might have been better to analyze driver gene-positive patients separately.

The real practice of patients with advanced NSCLC has increased treatment options, including immune checkpoint inhibitors. As a result, longer survival is being achieved. Even in second- or later-line therapies, longer PFS than that observed with current therapies will be provided. In the near future, ‘long-term PFS’ will be defined even after second-line treatment, and treatment ‘quality evaluation’ must be required even for the second- or later-line therapy, including PEM+BEV. It is expected that more investigations will be conducted into the long-term response to PEM+BEV therapy. In this sense, our report provides valuable data for later comparison.

Conflicts of Interest

The Authors have no conflicts of interest to declare in relation to this study.

Authors’ Contributions

SH, KM, TS, SO, HSaku, and HS designed the study. SH, KM, TS, SO, HSaku, TA and HS collected the data. SH, SO and HS analyzed the data. SH, SO, HS and NH prepared the manuscript. AN, HS and NH supervised the study. All Authors approved the final version for submission.


1 Janning M & Loges S Anti-angiogenics: Their value in lung cancer therapy. Oncol Res Treat. 41(4) 172 - 180 2018. PMID: 29631257. DOI: 10.1159/000488119
2 Alshangiti A Chandhoke G & Ellis PM Antiangiogenic therapies in non-small-cell lung cancer. Curr Oncol. 25(Suppl 1) S45 - S58 2018. PMID: 29910647. DOI: 10.3747/co.25.3747
3 Seto T Azuma K Yamanaka T Sugawara S Yoshioka H Wakuda K Atagi S Iwamoto Y Hayashi H Okamoto I Saka H Mitsuoka S Fujimoto D Nishino K Horiike A Daga H Sone T Yamamoto N Nakagawa K & Nakanishi Y Randomized phase III study of continuation maintenance bevacizumab with or without pemetrexed in advanced nonsquamous non-small-cell lung cancer: COMPASS (WJOG5610L). J Clin Oncol. 38(8) 793 - 803 2020. PMID: 31880966. DOI: 10.1200/JCO.19.01494
4 Ramalingam SS Dahlberg SE Belani CP Saltzman JN Pennell NA Nambudiri GS McCann JC Winegarden JD Kassem MA Mohamed MK Rothman JM Lyss AP Horn L Stinchcombe TE & Schiller JH Pemetrexed, bevacizumab, or the combination as maintenance therapy for advanced nonsquamous non-small-cell lung cancer: ECOG-ACRIN 5508. J Clin Oncol. 37(26) 2360 - 2367 2019. PMID: 31361535. DOI: 10.1200/JCO.19.01006
5 Barlesi F Scherpereel A Rittmeyer A Pazzola A Ferrer Tur N Kim JH Ahn MJ Aerts JG Gorbunova V Vikström A Wong EK Perez-Moreno P Mitchell L & Groen HJ Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol. 31(24) 3004 - 3011 2013. PMID: 23835708. DOI: 10.1200/JCO.2012.42.3749
6 Okamoto I Aoe K Kato T Hosomi Y Yokoyama A Imamura F Kiura K Hirashima T Nishio M Nogami N Okamoto H Saka H Yamamoto N Yoshizuka N Sekiguchi R Kiyosawa K Nakagawa K & Tamura T Pemetrexed and carboplatin followed by pemetrexed maintenance therapy in chemo-naïve patients with advanced nonsquamous non-small-cell lung cancer. Invest New Drugs. 31(5) 1275 - 1282 2013. PMID: 23475281. DOI: 10.1007/s10637-013-9941-z
7 Patel JD Socinski MA Garon EB Reynolds CH Spigel DR Olsen MR Hermann RC Jotte RM Beck T Richards DA Guba SC Liu J Frimodt-Moller B John WJ Obasaju CK Pennella EJ Bonomi P & Govindan R PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 31(34) 4349 - 4357 2013. PMID: 24145346. DOI: 10.1200/JCO.2012.47.9626
8 Winfree KB Torres AZ Zhu YE Muehlenbein C Aggarwal H Woods S & Abernethy A Treatment patterns, duration and outcomes of pemetrexed maintenance therapy in patients with advanced NSCLC in a real-world setting. Curr Med Res Opin. 35(5) 817 - 827 2019. PMID: 30421624. DOI: 10.1080/03007995.2018.1547273
9 Walker MS Wong W Ravelo A Miller PJE & Schwartzberg LS Effectiveness outcomes and health related quality of life impact of disease progression in patients with advanced nonsquamous NSCLC treated in real-world community oncology settings: results from a prospective medical record registry study. Health Qual Life Outcomes. 15(1) 160 2017. PMID: 28806963. DOI: 10.1186/s12955-017-0735-4
10 Natsume M Honda T Haruyama T Ishihara M Fukasawa Y Sakamoto T Tanzawa S Usui R Ota S Ichikawa Y Watanabe K & Seki N A case of lung adenocarcinoma with marked improvement of pulmonary lymphangitic carcinomatosis by adding bevacizumab to cisplatin and pemetrexed. Case Rep Oncol. 10(3) 1065 - 1069 2017. PMID: 29515397. DOI: 10.1159/000484662
11 Sassier M Dugué AE Clarisse B Lesueur P Avrillon V Bizieux-Thaminy A Auliac JB Kaluzinski L Tillon J Robinet G Le Caer H Monnet I Madroszyk A Boza G Falchero L Fournel P Egenod T Toffart AC Leiber N Do P & Gervais R Renal insufficiency is the leading cause of double maintenance (bevacizumab and pemetrexed) discontinuation for toxicity to advanced non-small cell lung cancer in real world setting. Lung Cancer. 89(2) 161 - 166 2015. PMID: 26037036. DOI: 10.1016/j.lungcan.2015.05.005
12 Nakamura H Satoh H Kaburagi T Nishimura Y Shinohara Y Inagaki M Endo T Saito T Hayashihara K Hizawa N Kurishima K Nawa T Kagohashi K Kishi K Ishikawa H Ichimura H Hashimoto T Sato Y Sakai M Kamiyama K Matsumura T Unoura K & Furukawa K Bevacizumab-containing chemotherapy for non-small cell lung cancer patients: a population-based observational study by the Ibaraki thoracic integrative (POSITIVE) research group. Med Oncol. 29(5) 3202 - 3206 2012. PMID: 23117478. DOI: 10.1007/s12032-012-0318-5
13 Goldstraw P Chansky K Crowley J Rami-Porta R Asamura H Eberhardt WE Nicholson AG Groome P Mitchell A Bolejack V International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee, Advisory Boards, and Participating Institutions & International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee Advisory Boards and Participating Institutions The IASLC lung cancer staging project: Proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer. J Thorac Oncol. 11(1) 39 - 51 2016. PMID: 26762738. DOI: 10.1016/j.jtho.2015.09.009
14 Eisenhauer EA Therasse P Bogaerts J Schwartz LH Sargent D Ford R Dancey J Arbuck S Gwyther S Mooney M Rubinstein L Shankar L Dodd L Kaplan R Lacombe D & Verweij J New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 45(2) 228 - 247 2009. PMID: 19097774. DOI: 10.1016/j.ejca.2008.10.026
15 National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0).. Available at:
16 Dempke WC Targeted therapy for NSCLC – a double-edged sword. Anticancer Res. 35(5) 2503 - 2512 2015. PMID: 25964523.
17 Gridelli C Chella A Valmadre G Allegrini G Brighenti M Bidoli P Rossi A Maione P Migliorino MR Ricciardi S & DE Marinis F Second-line erlotinib or intermittent erlotinib plus docetaxel in male ex-smokers with squamous NSCLC: The TALISMAN randomized trial. Anticancer Res. 36(12) 6535 - 6540 2016. PMID: 27919979. DOI: 10.21873/anticanres.11255
18 Gong W Sun P Mu Z Liu J Yu C & Liu A Efficacy and safety of nab-paclitaxel as second-line chemotherapy for locally advanced and metastatic non-small cell lung cancer. Anticancer Res. 37(8) 4687 - 4691 2017. PMID: 28739772. DOI: 10.21873/anticanres.11873
19 Wills B Cardona AF Rojas L Ruiz-Patiño A Arrieta O Reguart N Carranza H Vargas C Otero J Corrales L Martín C Cuello M Pino LE Rolfo C Rosell R Zatarain-Barrón ZL & Latin-American Consortium for the Investigation of Lung Cancer (CLICaP) Survival outcomes according to TIMP1 and EGFR expression in heavily treated patients with advanced non-small cell lung cancer who received biweekly irinotecan plus bevacizumab. Anticancer Res. 37(11) 6429 - 6436 2017. PMID: 29061829. DOI: 10.21873/anticanres.12097
20 Igawa S Yokoba M Takakura A Hosotani S Nakahara Y Sato T Mitsufuji H Sasaki J & Naoki K Real-world evaluation of second line chemotherapy for patients with advanced non-small cell lung cancer harboring preexisting interstitial lung disease. Invest New Drugs. 40(1) 182 - 189 2022. PMID: 34415485. DOI: 10.1007/s10637-021-01162-x
21 Yuan Q Wang W Zhang Q Wang Y Chi C & Xu C Clinical features and prognostic factor of thoracic postoperative oligo-recurrence of non-small-cell lung cancer. Cancer Manag Res. 12 1397 - 1403 2020. PMID: 32158271. DOI: 10.2147/CMAR.S230579
22 Li WC Wang Z Gao J Zhou H Li J & Zhu XX Clinical outcomes and prognostic factors of salvage stereotactic body radiotherapy for post-surgical thoracic oligo-recurrence/metastasis of non-small-cell lung cancer. Cancer Manag Res. 13 1887 - 1896 2021. PMID: 33654433. DOI: 10.2147/CMAR.S287993
23 Nakamura R Yoneyama S Tobita R Kurihara S Hatori T Numata T Ota K Yanai H Endo T Inadome Y Satoh H & Inage Y Effect of postoperative muscle loss after resection of non-small cell lung cancer on surgical outcomes. Anticancer Res. 42(6) 3159 - 3168 2022. PMID: 35641288. DOI: 10.21873/anticanres.15805