Non-small cell lung cancer (NSCLC) is a common cause of cancer mortality worldwide (1). A majority of patients with NSCLC have a metastatic disease at diagnosis, for which no curative therapy exists. Although treatments for driver mutations have yielded impressive improvements in many regions, most patients relapse despite using breakthrough tyrosine kinase inhibitors such as osimertinib (2). Actually, a majority of the patients do not have sensitive driver mutations associated with approved targeted drugs, and platinum-based chemotherapies plus immune checkpoint inhibitors (ICIs) are the standard first-line treatment for NSCLC patients with good performance status in recent years (3-5). Although some patients have long-term survival after using platinum-based chemotherapy combined with ICIs, most patients experience disease progression after administration.
Some clinically approved second-line therapies for NSCLC patients include docetaxel (DOC), pemetrexed, and vinorelbine (6-8). Particularly, DOC plus ramucirumab (RAM) significantly increased the progression-free survival (PFS), overall survival (OS), and complete overall response rate (ORR) when directly compared to DOC monotherapy in the REVEL trial (9). Therefore, DOC plus RAM has been recommended as an optimal therapy for previously treated patients in many countries.
Although a few reports have been published concerning the retrospective analysis of DOC plus RAM as a therapeutic regimen, such as evaluating the effect of age and previous ICIs usage, analyses of the effect of clinical factors, such as Eastern Cooperative Oncology Group (ECOG) performance status (PS) on survival are still limited (10-13).
Currently, two anti-vascular endothelial growth factor (VEGF) antibodies have been clinically used for NSCLC patients: bevacizumab (BEV) and RAM. BEV is a humanized monoclonal antibody (mAb) that targets all isoforms of VEGF-A, which prevents the activation of the membrane receptors such as vascular endothelial growth factor receptor (VEGFR) 1 and VEGFR2. RAM is a fully human antagonistic mAb which targets VEGFR2. By binding to VEGFR1 and VEGFR2, VEGF-A induces inflammatory responses and disrupts cell-to-cell connections to increase vascular permeability (14). BEV has been effective in patients with malignant pleural effusion (MPE) by blocking the binding of VEGF-A to its receptors (15-17). Liver metastases also benefit from BEV because of the overexpression of VEGF-A in liver lesions (4,18-21). However, the clinical efficacy of RAM for these metastatic sites is still unknown.
Therefore, we performed a multicenter retrospective observational cohort study for previously treated patients with NSCLC who were administered DOC plus RAM to identify the clinical factors which affect its efficacy and to elucidate the relationship between metastatic sites and efficacy.
We present the following article in accordance with the STROBE reporting checklist (available at http://dx.doi.org/10.21037/tlcr-20-1263).
This study was a multicenter, observational, retrospective study. Participants consisted of previously treated NSCLC patients who received DOC plus RAM between June 2016 and March 2020 in four medical facilities in Japan, including the Osaka International Cancer Institute, the Osaka Habikino Medical Center, the Osaka General Medical Center, and the National Hospital Organization Kinki-Chuo Chest Medical Center. This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and the World Health Organization’s Guidelines for Good Clinical Practice, and the protocol was reviewed and approved by the Institutional Review Board at the Osaka International Cancer Institute (IRB No.20098), the Osaka Habikino Medical Center (IRB No.1046), the Osaka General Medical Center (IRB No.2020-060), and the National Hospital Organization Kinki-Chuo Chest Medical Center (IRB No. 2020-034). The patient’s informed consent was waived for the retrospective nature of study, and we used an opt-out method so that patients and families could refuse to participate in the study.
We collected data on age, sex, smoking status, ECOG-PS, histology, EGFR mutation, and metastatic site (MPE, lung, liver, or brain) from electronic medical records and pharmacy databases. Data on age, ECOG-PS, and metastatic site were evaluated just before the start of DOC plus RAM. Clinical responses were defined according to the Response Evaluation Criteria in Solid Tumors, version 1.1 (22).
The ORR included all patients with complete response (CR) and partial response (PR). The disease control rate (DCR) included the patients with stable disease (SD) or PR. We defined the anti-tumor effect of MPE as follows: PR was defined as the status with an obvious decrease of MPE without thoracentesis and SD was defined as the status without an unequivocal increase of MPE at the evaluation after more than 6 weeks from initiation of DOC plus RAM compared to baseline. The PFS was determined from the date of commencing DOC plus RAM therapy to the date of disease progression or death from any cause. The OS was determined from the date of commencement of the relevant therapy to the date of death. Patients were followed until June 30, 2020.
The survival outcomes were analyzed using the Kaplan-Meier method. The differences between patient groups according to each factor were compared using the log-rank test. P values <0.05 were regarded as statistically significant. Cox regression analysis was used to calculate the hazard ratio (HR) of each factor with 95% confidence interval (CI). To identify prognostic factors (such as age, sex, smoking status, ECOG-PS, and metastatic site), univariate and multivariate analyses were conducted. χ2 test was used for categorical variables. Statistical analyses were performed using SPSS version 26.0 (IBM, Armonk, NY).
A total of 237 previously treated patients with NSCLC were included in this study. Patient characteristics are summarized in Table 1. The median age was 66.0 years (range, 33–82 years), and a few elderly (≥75 years) patients (12.7%) were included. A majority of the patients were men (63.3%), had adenocarcinoma (75.9%), had a history of smoking (75.5%), and had an ECOG-PS of 0–1 (79.7%). Sixty-six patients (29.5%) had sensitive EGFR mutations. Approximately 60% of patients received DOC plus RAM on the early line such as 2nd or 3rd line. In addition, 40% of patients received immunotherapy as the front-line treatment (Table S1). RAM was not used with any regimens except for DOC. Of the investigated metastatic sites, lung metastasis (100 cases) was the most detected site, followed by MPE (71 cases), brain metastasis (60 cases), and liver metastasis (38 cases).
Treatment efficacy in all patients
In all patients, the ORR, DCR, and progressive disease rate were 25.2%, 63.9%, and 36.1%, respectively. At the time of analysis, the PFS was based on 195 events (82.3% maturity), whereas the OS was based on 148 events (62.4% maturity). The median follow-up time in censored patients was 12.5 months (range, 3.1–42.6 months). The median PFS was 4.5 (95% CI, 3.36–5.62) months (Figure 1A) and the median OS was 13.4 (95% CI, 11.7–15.1) months (Figure 1B).
The log-rank test revealed no differences in the median PFS of patient treated with DOC plus RAM in terms of age (<75 vs. ≥75) (Figure 2A), sex (male vs. female) (Figure 2B), and smoking status (non-smoker vs. smoker) (Figure 2C). Conversely, the median PFS in ECOG-PS groups (0–1 vs. 2–4) were significantly different [5.46 (95% CI: 4.42–6.51) vs. 2.79 (95% CI: 2.18–3.39) months; P<0.001] (Figure 2D).
Treatment efficacy by metastatic site
The ORR and DCR are listed by metastatic site in Figure 3. The ORR of DOC plus RAM for MPE was relatively low, and DOC plus RAM seemed to be unable to decrease pleural effusion. However, about 50% of patients were able to prevent an increase in pleural effusion. The ORR and DCR for lung and liver metastasis were higher than those in all patients, showing 30.3% and 77.5%, and 48.6% and 71.4%, respectively. The ORR and DCR for brain metastasis were almost the same as those of all patients. Of 60 patients with brain metastases, 52 patients (86.7%) received palliative treatment in addition to DOC plus RAM. Among these, five patients underwent surgery and 48 received radiation therapy, with one patient receiving both therapies.
The log-rank test revealed no differences in the median PFS of patients who received DOC plus RAM concerning MPE (positive vs. negative) (Figure 4A), lung metastasis (positive vs. negative) (Figure 4B) and liver metastasis (positive vs. negative) (Figure 4C). The median PFS of patients with brain metastasis (positive vs. negative) was significantly different [3.14 (95% CI: 2.38–3.90) vs. 5.14 (95% CI: 4.25–6.03) months; P=0.002] (Figure 4D).
Association between patient characteristics and progression free survival
The results of the Cox proportional hazards model for predicting the PFS in patients treated with DOC plus RAM are shown in Table 2. In the univariate analysis, ECOG-PS (0–1 vs. 2–4, HR: 1.76, 95% CI: 1.24–2.50, P=0.002) and brain metastasis (negative vs. positive, HR: 1.63, 95% CI: 1.19–2.25, P=0.003) were significantly associated with poorer PFS. Similarly, in the multivariate analysis, ECOG-PS (0–1 vs. 2–4, HR: 1.66, 95% CI: 1.14–2.40, P=0.008) and brain metastasis (negative vs. positive, HR: 1.71, 95% CI: 1.23–2.37, P=0.001) were identified as independent factors significantly associated with poorer PFS.
In the univariate and multivariate analyses for predicting the OS, ECOG-PS (0–1 vs. 2–4, HR: 2.02, 95% CI: 1.37–2.97, P=0.001) and MPE (negative vs. positive, HR: 1.63, 95% CI: 1.15–2.31, P=0.007) were significant poor prognostic factors, whereas brain metastasis was not consistently identified as a poor prognostic factor of OS (Table S2).
Our study provides the most comprehensive set of data regarding the efficacy of DOC plus RAM in previously treated patients with NSCLC in a clinical setting. To the best of our knowledge, this is the first study that elucidates the relationship between metastatic site and therapeutic efficacy. Our findings demonstrate that poor ECOG-PS (≥2) and brain metastasis were independent factors significantly associated with a shorter PFS in patients who received DOC plus RAM. Furthermore, no differences in the PFS between patients with and without MPE and lung metastasis were found. There are several possible explanations as to why these differences in the PFS were observed in our study.
Although there are no reports on the efficacy of DOC plus RAM for patients with poor ECOG-PS, there are various reports about the efficacy and safety of DOC alone in ECOG-PS 2 patients. These studies have made its use controversial because of the significant increase in febrile neutropenia (23-25). Although the 2018 National Comprehensive Cancer Network Guidelines recommend DOC plus RAM treatment in previously treated patients with ECOG-PS 0–2 with NSCLC, ECOG-PS 2 patients were not included in the REVEL trial and there is no evidence that demonstrates the efficacy and safety in ECOG-PS 2 patients (26). We first showed that poor ECOG-PS was a significant and independent factor associated with a shorter PFS and OS. Although the number of treatment cycles was not collected, there was no significant difference in the discontinuation rate due to adverse events between good and poor PS patients. Nevertheless, the shorter survival of poor PS patients may result from the tumor burden at the start of DOC plus RAM. Therefore, further investigations on poor PS populations are needed.
The most common sites of metastatic disease in patients with NSCLC have been reported to be the bone, lungs, liver, brain, and adrenal glands (27,28). The MPE, occurring in approximately 15.0% of patients with NSCLC, also affects patient management and quality of life and is a prognostic factor for poor survival (29,30). NSCLC patients with MPE or liver metastasis have a poorer prognosis than patients without MPE or liver metastasis (14,30,31). Brain metastasis is also considered a poor prognostic factor in NSCLC patients; therefore, patients with brain metastasis have often been an excluded from clinical trials (32). BEV has been reported to be effective for metastatic sites, such as the MPE, lung, liver, and brain by binding to serum VEGF-A and inhibiting the binding of VEGF-A and VEGFR (14-18,20,33,34). Although RAM also inhibits VEGF-A/VEGFR signaling using a method similar to BEV (i.e., by binding to VEGFR2), the relationship between these metastatic sites and RAM efficacy is unknown.
Our study revealed that brain metastasis was a factor associated with poor PFS. This is similar to previously reported data that patients with brain metastasis have a poorer prognosis than those without brain metastasis (34). Subsequently, the blocking of VEGFR2 alone may be a weak preventive strategy against angiogenesis in the brain. According to existing research, in tissues with high vascular density, such as the brain, tumors grow not only by angiogenesis, but also by vessel co-option, which is a non-angiogenic process through which tumor cells utilize pre-existing tissue blood vessels. However, the same study also shows that blocking VEGF-A resulted in the undetectability of tumors (35). These observations may contribute to the difference of efficacy between BEV and RAM in treating brain metastasis in mouse models. Although the reason brain metastasis was not a poor prognostic factor of OS remains unclear, the number of prior treatments and the treatment regimen before and after administration may be involved.
Although there were no differences in the PFS and OS between patients with and without lung and liver metastasis in our study, the ORR and DCR for lung and liver metastasis were higher than those for all patients. There are several reasons as follows: VEGFR2 is constitutively phosphorylated, especially in the liver, lungs, and kidneys in vivo, and highly expressed in surgically resected lung specimen of NSCLC (36,37). It has been reported that VEGFR2 antibody inhibited the growth of lung metastasis of renal cell carcinoma by 26% (38). VEGFR2 is also up-regulated in patients with hepatocellular carcinoma and induces angiogenesis with consecutive endothelial growth in the hepatic sinusoids (39). Clinically, RAM was approved for patients with hepatocellular carcinoma who were previously treated with sorafenib on the basis of the REACH-2 trial results in 2019 (40). Although further studies are required to determine whether DOC plus RAM improves the PFS and OS in patients with lung or liver metastasis, according to our data on anti-tumor effects, the therapy may be effective for patients with rapid progression of lung or liver metastasis. Recently, some studies have showed the efficacy of combination therapies of DOC and anti-angiogenic agents after ICIs. Brueckl et al. demonstrated the high response rate and long-term survival of DOC plus RAM followed immediately after ICIs (41). Grohé et al. also revealed the combination therapy of DOC plus nintedanib, triple angiokinase inhibitor after ICIs showed the clinical benefit in the prospective study (42). Our study included 40% of patients who received immunotherapy as the previous therapy, which may have affected the ORR and DCR for lung and liver metastasis.
MPE was associated with the low response and significantly shortened the OS. Generally, VEGF-A/VEGFR2 signaling increases vascular permeability and promotes pleural effusion retention. VEGF-A/VEGFR1 signaling may also contribute to tumor-associated angiogenesis (43). Unlike BEV, RAM does not block the VEGF-A/VEGFR1 pathway. As a result, MPE may hardly have been decreased, which may have affected poor OS. However, about 50% of patients were able to prevent an increase in pleural effusion, and therefore MPE was likely not a significant poor prognostic factor of PFS. Furthermore, regarding the clinical efficacy of MPE, results of prospective studies such as the PLEURAM study are expected in the future (44).
This study has several limitations. First, biases are inevitable due to the retrospective study design, including selection bias. However, confounding effects were adjusted for using multivariate models. Second, data on first-line and further lines of treatments before DOC plus RAM were not analyzed. Therefore, the OS may not have been evaluated accurately. Third, the efficacy of DOC plus RAM on metastatic sites was not directly compared to that of DOC monotherapy in this study. Therefore, it is difficult to elucidate the efficacy of RAM alone for each metastatic site. Further comparative studies are needed to validate our findings.
In conclusion, a poor ECOG-PS and brain metastasis were independently associated with poor PFS in patients with NSCLC treated with DOC plus RAM in a clinical setting. Careful monitoring is required for patients with these factors. Although DOC plus RAM did not prolong the PFS of patients with lung metastasis, and liver metastasis, the ORR and DCR for lung and liver metastasis were higher than those of all patients. DOC plus RAM could be an optimal therapy for patients with previously treated NSCLC who have lung and liver metastasis. Further studies are warranted to confirm the results of our study.
We thank all the patients who participated in this study.
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at http://dx.doi.org/10.21037/tlcr-20-1263
Data Sharing Statement: Available at http://dx.doi.org/10.21037/tlcr-20-1263
Peer Review File: Available at http://dx.doi.org/10.21037/tlcr-20-1263
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-20-1263). AT reports personal fees from Chugai Pharmaceutical, grants and personal fees from AstraZeneka, personal fees from Boehringer Ingelheim, grants and personal fees from Ono Pharmaceutical, grants and personal fees from Bristol-Myers Squibb, personal fees from MSD, personal fees from Taiho, personal fees from Pfizer, personal fees from Eli Lilly, personal fees from Kissei, outside the submitted work. S.A reports grants and personal fees from AstraZeneca, grants and non-financial support from F. Hoffmann-La Roche, grants and personal fees from Ono, grants and personal fees from Taiho, grants and personal fees from Boehringer Ingelheim, grants and personal fees from Pfizer, grants and personal fees from Bristol-Myers Squibb, personal fees from Hisamitsu, grants and personal fees from MSD, grants and personal fees from Eli Lilly, grants and personal fees from Chugai, personal fees from Kyowa Hakko Kirin, grants and personal fees from Merck, outside the submitted work. MT reports grants and personal fees from Boehringer Ingelheim, grants and personal fees from Ono Pharmaceutical, grants and personal fees from Bristol-Myers Squibb, personal fees from Chugai Pharmaceutical, personal fees from AstraZeneca, personal fees from Taiho Pharmaceutical, personal fees from Eli Lilly, personal fees from Asahi Kasei Pharmaceutical, personal fees from MSD, outside the submitted work. HS reports personal fees from Chugai Pharmaceutical, personal fees from MSD, personal fees from AstraZeneca, outside the submitted work. TH reports grants and personal fees from Ono Pharmaceutical Co. Ltd, grants and personal fees from Lilly Japan Co. Ltd, grants and personal fees from AstraZeneca Co. Ltd, grants and personal fees from Taiho Pharmaceutical Co. Ltd, grants and personal fees from Chugai Pharmaceutical Co. Ltd., grants from Merck Serono Co. Ltd., grants from Boehringer Ingelheim, grants and personal fees from MSD Oncology Co. Ltd, outside the submitted work. The other authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was performed in accordance with the Declaration of Helsinki (as revised in 2013). This study was reviewed and approved by the Institutional Review Board at the Osaka International Cancer Institute (IRB No.20098), the Osaka Habikino Medical Center (IRB No.1046), the Osaka General Medical Center (IRB No.2020-060), and the National Hospital Organization Kinki-Chuo Chest Medical Center (IRB No.2020-034). Consent to participate was waived by the ethics board.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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