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Efficacy and safety of combined immunotherapy and antiangiogenic therapy for advanced non-small cell lung cancer: a real-world observation study
BMC Pulmonary Medicine volume 23, Article number: 175 (2023)
Abstract
Purpose
This study was performed to investigate the efficacy and safety of combined immunotherapy and antiangiogenic therapy for advanced non-small cell lung cancer (NSCLC) in the real world.
Methods
Data on clinicopathological features, efficacy and adverse events (AEs) were collected retrospectively in advanced NSCLC patients who received immunotherapy combined with antiangiogenic therapy.
Results
A total of 85 advanced NSCLC patients were enrolled. The patients had a median progression-free survival (PFS) of 7.9 months and a median overall survival (OS) of 18.60 months. The objective response rate and disease control rate were 32.9% and 83.5%, respectively. Subgroup analysis revealed that NSCLC patients with stage IV (p = 0.042), brain metastasis (p = 0.016) and bone metastasis (p = 0.016) had shorter PFS. NSCLC patients with brain metastasis (p = 0.025), liver metastasis (p = 0.012), bone metastasis (p = 0.014) and EGFR mutations (p = 0.033) had shorter OS. Multivariate analysis revealed that brain metastasis (HR = 1.798, 95% CI: 1.038, 3.112, p = 0.036) and bone metastasis (HR = 1.824, 95% CI: 1.077, 3.090, p = 0.025) were independent predictive factors of PFS, and bone metastasis (HR = 2.00, 95% CI: 1.124, 3.558, p = 0.018) was an independent predictive factor of OS. In addition, patients receiving immunotherapy combined with antiangiogenic therapy in second-line therapy had longer OS than those receiving immunotherapy in third- or later-line therapy (p = 0.039). Patients with EGFR mutations who received combination therapy had worse OS than those with KRAS mutations (p = 0.026). Furthermore, PD-L1 expression was associated with treatment responses in advanced NSCLC (χ2 = 22.123, p = 0.000). AEs of different grades occurred in 92.9% (79/85) of NSCLC patients, most of which were mild grade 1/2 AEs. No grade 5 fatal AEs occurred.
Conclusion
Immunotherapy combined with antiangiogenic therapy was an option for advanced NSCLC patients with good safety and tolerability. Brain metastases and bone metastases were potentially independent negative predictors of PFS. Bone metastases were a potential independent negative predictor of OS. PD-L1 expression was a potential predictor of response for immunotherapy combined with antiangiogenic therapy.
Introduction
Lung cancer is still the most common malignant tumour with morbidity and mortality in China and seriously threatens the life and health of Chinese people [1]. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancers. In recent years, with the continuous progress of molecular biology technology, NSCLC has been increasingly identified as a highly heterogeneous disease. Targeted therapy and immunotherapy for different molecular types have greatly improved the prognosis of patients [2]. Especially for advanced NSCLC patients without targetable driver oncogenes, immune checkpoint inhibitors (ICIs) provide new therapeutic options with longer progression-free survival (PFS) and overall survival (OS) [3]. However, the overall effective rate of ICI monotherapy in NSCLC is only 20% [4]. How to obtain the dominant population of immunotherapy and improve the efficacy of immunotherapy is a hot topic in clinical research.
Antiangiogenic drugs, including monoclonal antibodies targeting vascular endothelial growth factor (VEGF) or VEGF receptors (VEGFRs), such as bevacizumab [5, 6], and small-molecule tyrosine kinase inhibitors (TKIs) targeting multiple angiogenic pathways, such as anlotinib [7, 8] and apatinib [9, 10], have shown antitumour effects in NSCLC.
A preclinical study revealed that tumour angiogenesis is closely related to the immune microenvironment [11]. Tumour vascular normalization and immune reprogramming form a reinforcing loop that reconditions the tumour immune microenvironment to induce durable antitumour immunity [12]. Antiangiogenic therapy can normalize the blood vessels in this part of the tumour, weaken the suppression of immune factors, and thus promote the development of immunotherapy, which is beneficial for the application of immunotherapy. Additionally, ICIs can normalize the tumour vascular system by activating effector T cells and increasing the infiltrating and killing functions of effector T cells [12].
At present, a large number of clinical studies have explored the efficacy of the model of ICIs combined with antiangiogenic therapy in a variety of tumours and have observed good results [11, 13]. Impower150 is the first successful Phase III clinical study of the efficacy of immunotherapy combined with antiangiogenic therapy in NSCLC [14]. The results show that the addition of immunization to antiangiogenic therapy can significantly improve patients' OS (19.5 vs. 14.7 months; hazard rate [HR] 0.80; 95% confidence interval [CI] 0.67–0.95) [15]. Based on this, antiangiogenic therapy combined with immunotherapy (programmed death ligand 1 [PD-L1] inhibitor) and chemotherapy has been approved by the FDA as first-line treatment for advanced NSCLC patients. The phase III ORIENT-31 study also proved the clinical efficacy of chemotherapy combined with immunotherapy (programmed death-1[PD-1] inhibitor) and antiangiogenic therapy [16].
However, a higher number of drug combinations is associated with a greater economic burden and a relatively higher incidence of adverse events (AEs) despite improving treatment efficacy [15, 16]. Especially for elderly patients with poor general status, aggressive chemotherapy is often intolerable [17]. In 2022, ESMO published the results of the Phase III IPSOS study of first-line atezolizumab vs. single-agent chemotherapy in patients with NSCLC who were not eligible for platinum-containing chemotherapy, showing that compared with chemotherapy, first-line ICI had an OS benefit (HR = 0.78; 95% CI: 0.6, 0.97; p = 0.028) with stable health-related quality of life and good tolerance [18]. Chemotherapy-free models are increasingly popular. At present, a number of clinical studies on chemotherapy-free models have been carried out in NSCLC patients, showing promising clinical significance [19]. Therefore, we retrospectively analysed 85 patients with advanced NSCLC who received ICIs combined with antiangiogenic drugs and evaluated the efficacy and safety of this chemotherapy-free combination regimen in the real world to provide more options and a basis for the treatment of advanced NSCLC patients.
Methods
Patients
Patients were enrolled according to the following inclusion criteria: (1) patients were pathologically diagnosed with advanced or metastatic NSCLC in the First Affiliated Hospital of Zhengzhou University; (2) ICIs combined with antiangiogenic therapy were used during the treatment and regardless of the treatment lines from March 1, 2019, to September 30, 2021; (3) there were measurable lesions according to Response Evaluation Criteria of Solid Tumours (RECIST) 1.1 version [20]; and (4) all patients agreed to participate in the study and signed informed consent.
Patients were excluded for the following reasons: (1) patients with other malignant tumours that were not cured in five years; (2) chemotherapy was combined with ICIs and antiangiogenic therapy.
Treatment
The ICIs included pembrolizumab, camrelizumab, sintilimab, tislelizumab and toripalimab. Patients were treated with pembrolizumab, camrelizumab, sintilimab or tislelizumab at a dose of 200Â mg every three weeks. Toripalimab was administered at a dose of 240Â mg every 3Â weeks. The antiangiogenic drugs included bevacizumab, anlotinib, and apatinib. Bevacizumab was administered at a dose of 15Â mg/kg every three weeks. Anlotinib was administered at a dose of 12Â mg/10Â mg/8Â mg depending on the tolerance of patients for two weeks and stopped for one week. Apatinib was administered at a dose of 250Â mg daily.
Efficacy and safety
The assessment of treatment efficacy was based on RECIST version 1.1 [20]. The tumour responses of target lesions were divided into complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Objective Response Rate (ORR) = CR + PR/total number of enrolled cases; Disease Control Rate (DCR) = CR + PR + SD/total enrolled cases. PFS was defined as the time from the start of combination therapy to PD or death from any cause. OS was defined as the period from the start of combination therapy until death from any cause or the last follow-up. The deadline for follow-up was August 31, 2022. AEs were evaluated and recorded according to the Common Terminology Criteria Adverse Events (CTCAE) V5.0.
Statistical analysis
Survival curves and median PFS and OS were generated using the Kaplan‒Meier survival method. Risk factors for subgroups were calculated using the Cox proportional hazards regression model.
Multivariate analyses were based on the Cox proportional hazards regression model. Clinical treatment responses were analysed using χ2 tests. All statistical analyses were performed using SPSS 26.0 statistical software, and p < 0.05 was considered statistically significant.
Results
Patient characteristics
A total of 85 NSCLC patients who received a combination of ICIs and antiangiogenic drugs were enrolled in the study (Table 1). The median age was 62 (ranging from 33 to 90). The male-to-female ratio was 3.5:1 (66 cases and 19 cases, respectively). PD-L1 expression was evaluated in all patients by immunohistochemistry with the 22C3 assay. All of the 48 lung adenocarcinoma patients underwent genetic testing: 7 patients (14.6%) harboured epidermal growth factor receptor (EGFR) exon 21 L858R mutations, 4 patients (8.3%) harboured EGFR exon 19 deletion mutation, 2 patient (4.2%) harboured primary EGFR exon 20 T790 mutation, 3 patients (6.3%) harboured EGFR nonclassical mutations (exon 21 L861Q and exon 18 deletion mutation, exon 20 insertion mutation), 2 patients (4.2%) harboured anaplastic lymphoma kinase (ALK) fusion, 2 patients (4.2%) harboured ROS proto-oncogene 1 (ROS1) fusion, 2 patient (4.2%) harboured v-raf murine sarcoma viral oncogene homologue B (BRAF) V600E mutation, 13 patients (27.1%) harboured kirsten rat sarcoma viral oncogene homologue (KRAS) mutation and another 2 patients (4.2%) harboured epidermal growth factor receptor 2 (HER-2) exon 20 insertion mutation. Among the 37 squamous cell carcinoma NSCLC patients, 19 patients underwent genetic testing and 1 patient (2.7%) harboured EGFR exon 19 deletion mutation and 1 (2.7%) patient harboured KRAS-L19F mutation.
Treatment strategies
In total, 5 patients (5.88%) received combination therapy with PD-1 inhibitors and antiangiogenic agents as first-line treatment, 35 patients (41.18%) received the combination regimen as second-line treatment, and 45 patients (52.94%) received the combination regimen as third-line or later treatment. The most frequently used ICIs and angiogenetic drugs were camrelizumab (71.76%) and anlotinib (68.23), respectively (Table 2).
PFS and OS
By the time of data cut-off, the median follow-up was 17.4 months. The median PFS (mPFS) of 85 NSCLC patients was 7.9 months (95% CI: 5.568, 10.232), and the median OS (mOS) was 18.60 months (95% CI: 13.24, 23.96) (Figs. 1A and 2A). Subgroup analysis showed that NSCLC patients with stage IV (p = 0.042), brain metastasis (p = 0.037) and bone metastasis (p = 0.016) who received combination therapy with PD-1 inhibitors and antiangiogenic drugs had shorter PFS (Table 3 and Fig. 2B-D).
Patients with brain metastasis (p = 0.025), liver metastasis (p = 0.012), bone metastasis (p = 0.014) and EGFR mutations (p = 0.033) who received combination therapy with PD-1 inhibitors and antiangiogenic drugs had shorter OS (Table 4 and Fig. 2B-E). Furthermore, by introducing uni-variants with p < 0.05, multivariate Cox regression showed that brain metastasis (HR = 1.798, 95% CI: 1.038, 3.112, p = 0.036) and bone metastasis (HR = 1.824, 95% CI: 1.077, 3.090, p = 0.025) were independent predictive factors of PFS, and bone metastasis (HR = 2.00, 95% CI: 1.124, 3.558, p = 0.018) was an independent predictive factor of OS. Additionally, we found that patients receiving immunotherapy combined with antiangiogenic therapy in second-line therapy had longer OS than those in third- or later-line therapy (p = 0.039) (Table 4). Patients with EGFR mutations who received combination therapy had worse OS than those with KRAS mutations (p = 0.026) (Table 4).
Treatment responses
Of the 85 NSCLC patients with ICIs combined antiangiogenic therapy, 28 achieved PR, 43 achieved SD, and 14 achieved PR. The ORR was 32.9%, and the DCR was 83.5% (Table 5). PD-LI expression was associated with treatment responses in advanced NSCLC patients (p = 0.000), both in adenocarcinoma (p = 0.007) and squamous cell carcinoma (p = 0.049). Notably, 1 patient obtained SD and 1 patient obtained PD for each pair of patients with ALK fusion, with BRAF V600E mutation, and with HER-2 exon 20 insertion mutation.
Safety
AEs of different grades occurred in 92.9% (79/85) of the 85 advanced NSCLC patients, most of whom had mild grade 1/2 AEs, and no grade 5 fatal AEs occurred. The most common adverse reactions were fatigue (32.9%), proliferation of capillaries (31.8%), hypotension (29.4%), proteinuria (27.1%), abnormal thyroid function (25.9%), and hand-foot syndrome (23.5%) (Table 6). Grade 3/4 AEs were observed in 32.9% (28/85) of patients, and the most common was hypotension (4.7%), which could be controlled with aggressive medication.
Discussion
How to improve the efficacy of immunotherapy is a hot topic in clinical research. Preclinical studies have confirmed that ICIs combined with antiangiogenic therapy achieve a 1 + 1 > 2 antitumour effect. An increasing number of clinical studies have begun to explore the application prospects of the chemotherapy-free mode in advanced NSCLC [19].
Domestic and international clinical studies revealed that the mPFS of immunotherapy combined with antiangiogenic therapy in the subsequent treatment of advanced NSCLC was approximately 6Â months, and the ORR and DCR were approximately 30% and 80%, respectively [21,22,23,24]. Indirectly compared with the previous literature data, the effect of combination therapy is superior to ICI monotherapy, and the mPFS of ICI monotherapy in subsequent therapy in advanced NSCLC was less than 4Â months, and the response rate was only approximately 20% [25,26,27].
In our present study, we retrospectively analysed the efficacy and safety of 85 NSCLC patients who received ICIs combined with antiangiogenic therapy. A total of 94.1% (80/85) of NSCLC patients received second-line and subsequent treatment, the mPFS was 7.5Â months, and the ORR and DCR were 31.25% and 82.5%, respectively. The research data of our centre were basically consistent with the real data reported in the past and were slightly better. A 2-centre, retrospective study in the real world revealed that 57 previously treated advanced NSCLC patients who received any PD-1 antibody combined with antiangiogenic drugs exhibited a PFS of 4.2Â months and a DCR of 63.2% [28].
A retrospective analysis of 67 advanced NSCLC patients who had previously received PD-1 antibody in combination with anlotinib showed that 19 patients had PR (28.4%), 39 had SD (58.2%) and 9 had PD (13.4%). The mPFS was 6.9Â months, and the OS was 14.5Â months. The study also found that the benefit of anti-PD-1 plus anlotinib was also observed in patients with EGFR mutation positivity, liver metastases, and brain metastases [29]. In our present study, NSCLC patients with brain metastasis and bone metastasis had shorter PFS and OS, and patients with liver metastasis and EGFR mutations had shorter OS. Although previous studies have found that patients with EGFR mutations do not respond well to immunotherapy [25, 27, 30, 31], in this study, the combination of ICIs and antiangiogenic therapy also achieved a PFS of 4.4Â months and an OS of 12.7Â months. Among the 17 patients with EGFR mutations, 2 achieved PR, and 10 achieved SD, with a DCR of 70.6%. This study suggested that immunotherapy combined with antiangiogenic therapy can be an option for patients with EGFR mutations after drug resistance, as shown by Impower 150 [15] and ORIENT-31 [16]. KRAS mutations have been linked to better immunotherapy responses in lung cancer [32,33,34]. Our study showed that patients with KRAS mutations had longer PFS (9.4Â months) and OS (24.4Â months).
In addition, it was found that patients with high PD-L1 expression were more likely to obtain PR in the combination regimen, a result consistent with the previous conclusion that PD-L1 expression predicts the efficacy of immunotherapy [27, 35]. However, both the PD-L1 high expression group and the positive group had longer PFS and OS. There was no significant difference. Therefore, whether PD-L1 expression status can be used as a predictor of the efficacy of combination treatment modes needs to be further confirmed by large-sample, prospective clinical studies.
Advanced NSCLC patients who received ICIs combined with antiangiogenic therapy at or above 3 lines achieved a PFS of 5.5Â months and an OS of 14.7Â months. These data could be compared with the results of a retrospective study of 30 samples from Xu et al., in which the mPFS was 5.0Â months and the mOS was 14.3Â months. Similarly, it was also found that patients with higher PD-L1 expression had longer PFS, but the difference was not statistically significant [36].
Another scholar performed a cohort study of the efficacy and safety of ICIs plus anlotinib versus ICIs alone as the treatment of advanced NSCLC in the real world. The results revealed that the mPFS of patients in the ICI plus anlotinib group was also much longer than that of patients in the ICI monotherapy group (6.37 vs. 3.90 months; P < 0.001). Combining ICIs with anlotinib could improve the outcomes of patients with bone metastasis [37]. The above results of this real-world study suggest that ICIs combined with antiangiogenic therapy are a good option for advanced NSCLC patients who have failed first-line therapy.
Surprisingly, the efficacy of immunotherapy combined with antiangiogenic therapy as the first-line treatment for NSCLC patients has also been explored. In the 2019 World Lung Cancer Congress, a study from Professor Han et al. revealed the efficacy of sintilimab combined with anlotinib as the first-line treatment for stage IV NSCLC patients with negative driver genes. A total of 16/22 patients achieved PR, and the ORR was 72.7% (95% CI: 49.8–89.3); DCR was up to 100% (95% C: 84.6–100); mPFS was 15 months (95% CI: 8.3-NR); mOS data were not mature [38]. Based on the current data, sintilimab combined with anlotinib had a great advantage in the first-line treatment of advanced NSCLC.
In our present study, there were 5 NSCLC patients who received ICIs combined with antiangiogenic therapy as the first-line treatment. The mPFS was 8.0Â months, and the mOS was not mature, slightly worse than those shown in the study of Han et al. The reason may be that the general status of the included population was relatively poor, and ICIs combined with antiangiogenic therapy were treated as a compromise protocol. In addition, the number of cases included was so small that the strength of the data was limited.
Currently, a phase III clinical study (NCT04964479) in which TQB-2450 (a humanized monoclonal antibody against PD-L1) is combined with anlotinib versus pembrolizumab as a first-line treatment for advanced NSCLC patients with PD-L1 ≥ 1% is ongoing. It is expected that this study will provide good evidence for anlotinib combined with immunotherapy in the first-line treatment of advanced NSCLC. In summary, immunotherapy combined with antiangiogenic therapy has shown good antitumour effects in the first and posterior lines. However, it is difficult to determine which line is better. An indirect comparison with previous literature indicated that first-line single-agent immunotherapy was superior to second-line immunotherapy [27, 35, 39]. The KEYNOTE-001 study revealed that immunotherapy had a longer mOS in untreated patients than in treated patients (22.3 vs. 10.5 months) [40]. In addition, the PFS2 analysis of the KEYNOTE-024 [39] study also showed that the earlier immunotherapy was used, the better the efficacy. However, whether combined immunotherapy must also be performed as early as possible remains to be further explored.
Conclusion
Immunotherapy combined with antiangiogenic therapy has been increasingly recognized in advanced NSCLC and has been favoured by many clinicians because of its relatively mild adverse effects. In the present study, we retrospectively analysed the efficacy and safety of immunotherapy combined with antiangiogenic therapy in advanced NSCLC in the real world. Regardless of the number of treatment lines, chemotherapy-free combination therapy was an option for advanced NSCLC patients with good safety and tolerability. In particular, patients without brain metastases, bone metastases, liver metastases, and EGFR mutations had longer OS. Immunotherapy combined with antiangiogenic therapy could also be a good choice for patients with KRAS mutations. In addition, NSCLC patients with high PD-L1 expression were more likely to respond to combination therapy and had longer PFS and OS.
Since this study was a retrospective study based on a small sample, sampling differences may affect the results. In addition, ICIs and antiangiogenic drugs were not qualified in this study, and there could be differences in efficacy between different drugs. Finally, this study did not exclude patients who had used ICIs or antiangiogenic drugs alone in the past, and whether cross-line use has an effect on the efficacy of immunotherapy combined with antiangiogenic therapy remains to be further explored.
In the future, more exploration is needed into how to screen the advantaged population. Additionally, more phase III clinical studies are needed to verify the feasibility of clinical application and provide survival benefits to more patients.
Availability of data and materials
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
References
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209–49. https://doi.org/10.3322/caac.21660.
Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553(7689):446–54. https://doi.org/10.1038/nature25183.
Grant MJ, Herbst RS, Goldberg SB. Selecting the optimal immunotherapy regimen in driver-negative metastatic NSCLC. Nat Rev Clin Oncol. 2021;18(10):625–44. https://doi.org/10.1038/s41571-021-00520-1.
Zeng H, Chen W, Zheng R, Zhang S, Ji JS, Zou X, Xia C, Sun K, Yang Z, Li H, et al. Changing cancer survival in China during 2003–15: a pooled analysis of 17 population-based cancer registries. Lancet Glob Health. 2018;6(5):e555–67. https://doi.org/10.1016/S2214-109X(18)30127-X.
Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355(24):2542–50. https://doi.org/10.1056/NEJMoa061884.
Zhou C, Wu YL, Chen G, Liu X, Zhu Y, Lu S, Feng J, He J, Han B, Wang J, et al. BEYOND: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase III Study of First-Line Carboplatin/Paclitaxel Plus Bevacizumab or Placebo in Chinese Patients With Advanced or Recurrent Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2015;33(19):2197–204. https://doi.org/10.1200/JCO.2014.59.4424.
Han B, Li K, Zhao Y, Li B, Cheng Y, Zhou J, Lu Y, Shi Y, Wang Z, Jiang L, et al. Anlotinib as a third-line therapy in patients with refractory advanced non-small-cell lung cancer: a multicentre, randomised phase II trial (ALTER0302). Br J Cancer. 2018;118(5):654–61. https://doi.org/10.1038/bjc.2017.478.
Han B, Li K, Wang Q, Zhang L, Shi J, Wang Z, Cheng Y, He J, Shi Y, Zhao Y, et al. Effect of Anlotinib as a Third-Line or Further Treatment on Overall Survival of Patients With Advanced Non-Small Cell Lung Cancer: The ALTER 0303 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2018;4(11):1569–75. https://doi.org/10.1001/jamaoncol.2018.3039.
Liang J, Gu W, Jin J, Zhang H, Chen Z, Tang Y, Zhang S, Yang S, Deng Y, Feng W. Efficacy and safety of apatinib as third- or further-line therapy for patients with advanced NSCLC: a retrospective study. Ther Adv Med Oncol. 2020;12:1758835920968472. https://doi.org/10.1177/1758835920968472.
Zhang L, Shi M, Huang C, Liu X, Xiong JP, Chen G, Liu W, Liu W, Zhang Y, Li K: A phase II, multicenter, placebo-controlled trial of apatinib in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) after two previous treatment regimens. J Clin Oncol. 2012;30(15_suppl):7548. https://doi.org/10.1200/jco.2012.30.15_suppl.7548.
Rahma OE, Hodi FS. The Intersection between Tumor Angiogenesis and Immune Suppression. Clin Cancer Res. 2019;25(18):5449–57. https://doi.org/10.1158/1078-0432.CCR-18-1543.
Huang Y, Kim BYS, Chan CK, Hahn SM, Weissman IL, Jiang W. Improving immune-vascular crosstalk for cancer immunotherapy. Nat Rev Immunol. 2018;18(3):195–203. https://doi.org/10.1038/nri.2017.145.
Yap TA, Parkes EE, Peng W, Moyers JT, Curran MA, Tawbi HA. Development of Immunotherapy Combination Strategies in Cancer. Cancer Discov. 2021;11(6):1368–97. https://doi.org/10.1158/2159-8290.CD-20-1209.
Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodriguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288–301. https://doi.org/10.1056/NEJMoa1716948.
Socinski MA, Nishio M, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodriguez-Abreu D, Moro-Sibilot D, Thomas CA, et al. IMpower150 Final Overall Survival Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in First-Line Metastatic Nonsquamous NSCLC. J Thorac Oncol. 2021;16(11):1909–24. https://doi.org/10.1016/j.jtho.2021.07.009.
Lu S, Wu L, Jian H, Chen Y, Wang Q, Fang J, Wang Z, Hu Y, Sun M, Han L et al. Sintilimab plus bevacizumab biosimilar IBI305 and chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): first interim results from a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2022;23(9):1167-79. https://doi.org/10.1016/S1470-2045(22)00382-5.
Gridelli C. Does chemotherapy have a role as palliative therapy for unfit or elderly patients with non-small-cell lung cancer? Lung Cancer. 2002;38(Suppl 2):S45-50. https://doi.org/10.1016/s0169-5002(02)00357-4.
Lee SM, Schulz C, Prabhash K, Han B, Szczesna A, Cortinovis D, Rittmeyer A, Vincente D, Califano R, Le AT, et al. IPSOS: Results from a Phase 3 study of first-line (1L)atezolizumab (atezo) vs single-agent chemotherapy (chemo) in patients(pts) with NSCLC not eligible for a platinum-containing regimen. ESMO Open. 2022. LBA11.
Ren S, Xiong X, You H, Shen J, Zhou P. The Combination of Immune Checkpoint Blockade and Angiogenesis Inhibitors in the Treatment of Advanced Non-Small Cell Lung Cancer. Front Immunol. 2021;12:689132. https://doi.org/10.3389/fimmu.2021.689132.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47. https://doi.org/10.1016/j.ejca.2008.10.026.
Gao G, Zhao J, Ren S, Wang Y, Chen G, Chen J, Gu K, Guo R, Pan Y, Wang Q, et al. Efficacy and safety of camrelizumab plus apatinib as second-line treatment for advanced squamous non-small cell lung cancer. Ann Transl Med. 2022;10(8):441. https://doi.org/10.21037/atm-21-4792.
Taylor MH, Lee CH, Makker V, Rasco D, Dutcus CE, Wu J, Stepan DE, Shumaker RC, Motzer RJ. Phase IB/II Trial of Lenvatinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma, Endometrial Cancer, and Other Selected Advanced Solid Tumors. J Clin Oncol. 2020;38(11):1154–63. https://doi.org/10.1200/JCO.19.01598.
Han B, Zhang W, Shi C, Chu T, Yang Z. P15.07 Safety and Efficacy Profile of TQB-2450 Alone/with Anlotinib in Previously-Treated Advanced NSCLC: A Phase IB Single-Arm Trial. JTO. 2021;16(3):S346.
Lv W, Pei X, Zhao W, Cong Y, Wei Y, Li T, Zhang H, Lin Z, Saito Y, Kim JJ, et al. Safety and efficacy of nivolumab plus recombinant human endostatin in previously treated advanced non-small-cell lung cancer. Transl Lung Cancer Res. 2022;11(2):201–12. https://doi.org/10.21037/tlcr-22-49.
Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373(17):1627–39. https://doi.org/10.1056/NEJMoa1507643.
Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372(21):2018–28. https://doi.org/10.1056/NEJMoa1501824.
Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540–50. https://doi.org/10.1016/S0140-6736(15)01281-7.
Yao J, Wang Z, Sheng J, Wang H, You L, Zhu X, Pan H, Han W. Efficacy and safety of combined immunotherapy and antiangiogenic therapy for advanced non-small cell lung cancer: A two-center retrospective study. Int Immunopharmacol. 2020;89(Pt A):107033. https://doi.org/10.1016/j.intimp.2020.107033.
Wang P, Fang X, Yin T, Tian H, Yu J, Teng F. Efficacy and Safety of Anti-PD-1 Plus Anlotinib in Patients With Advanced Non-Small-Cell Lung Cancer After Previous Systemic Treatment Failure-A Retrospective Study. Front Oncol. 2021;11:628124. https://doi.org/10.3389/fonc.2021.628124.
Gainor JF, Shaw AT, Sequist LV, Fu X, Azzoli CG, Piotrowska Z, Huynh TG, Zhao L, Fulton L, Schultz KR, et al. EGFR Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non-Small Cell Lung Cancer: A Retrospective Analysis. Clin Cancer Res. 2016;22(18):4585–93. https://doi.org/10.1158/1078-0432.CCR-15-3101.
Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389(10066):255–65. https://doi.org/10.1016/S0140-6736(16)32517-X.
Liu C, Zheng S, Jin R, Wang X, Wang F, Zang R, Xu H, Lu Z, Huang J, Lei Y, et al. The superior efficacy of anti-PD-1/PD-L1 immunotherapy in KRAS-mutant non-small cell lung cancer that correlates with an inflammatory phenotype and increased immunogenicity. Cancer Lett. 2020;470:95–105. https://doi.org/10.1016/j.canlet.2019.10.027.
Huang Q, Zhang H, Hai J, Socinski MA, Lim E, Chen H, Stebbing J. Impact of PD-L1 expression, driver mutations and clinical characteristics on survival after anti-PD-1/PD-L1 immunotherapy versus chemotherapy in non-small-cell lung cancer: A meta-analysis of randomized trials. Oncoimmunology. 2018;7(12):e1396403. https://doi.org/10.1080/2162402X.2017.1396403.
Lee CK, Man J, Lord S, Cooper W, Links M, Gebski V, Herbst RS, Gralla RJ, Mok T, Yang JC. Clinical and Molecular Characteristics Associated With Survival Among Patients Treated With Checkpoint Inhibitors for Advanced Non-Small Cell Lung Carcinoma: A Systematic Review and Meta-analysis. JAMA Oncol. 2018;4(2):210–6. https://doi.org/10.1001/jamaoncol.2017.4427.
Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019;393(10183):1819–30. https://doi.org/10.1016/S0140-6736(18)32409-7.
Xu Z, Li T, Hu X, Hao X, Xing P, Li J. Efficacy and safety profile of combining programmed cell death-1 (PD-1) inhibitors and antiangiogenic targeting agents as subsequent therapy for advanced or metastatic non-small cell lung cancer (NSCLC). Thorac Cancer. 2021;12(17):2360–8. https://doi.org/10.1111/1759-7714.14078.
Shi Y, Ji M, Jiang Y, Yin R, Wang Z, Li H, Wang S, He K, Ma Y, Wang Z, et al. A cohort study of the efficacy and safety of immune checkpoint inhibitors plus anlotinib versus immune checkpoint inhibitors alone as the treatment of advanced non-small cell lung cancer in the real world. Transl Lung Cancer Res. 2022;11(6):1051–68. https://doi.org/10.21037/tlcr-22-350.
Chu T, Zhong R, Zhong H, Zhang B, Zhang W, Shi C, Qian J, Zhang Y, Chang Q, Zhang X, et al. Phase 1b Study of Sintilimab Plus Anlotinib as First-line Therapy in Patients With Advanced NSCLC. J Thorac Oncol. 2021;16(4):643–52. https://doi.org/10.1016/j.jtho.2020.11.026.
Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, Peled N, Tafreshi A, Cuffe S, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375(19):1823–33. https://doi.org/10.1056/NEJMoa1606774.
Leighl NB, Hellmann MD, Hui R, Carcereny E, Felip E, Ahn MJ, Eder JP, Balmanoukian AS, Aggarwal C, Horn L, et al. Pembrolizumab in patients with advanced non-small-cell lung cancer (KEYNOTE-001): 3-year results from an open-label, phase 1 study. Lancet Respir Med. 2019;7(4):347–57. https://doi.org/10.1016/S2213-2600(18)30500-9.
Acknowledgements
The present study was financially supported by the Natural Science Foundation of Henan Province (grant number: 212300410251) and the Henan Medical Science and Technology Foundation (grant number: 2018020022).
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This work was supported by the Natural Science Foundation of Henan Province (grant number: 212300410251) and the Henan Medical Science and Technology Foundation (grant number: 2018020022).
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All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Xingya Li and Ke Ma proposed and designed the study. Material preparation, data collection and analysis were performed by Ke Ma and Qianqian Guo. The first draft of the manuscript was written by Ke Ma. Xingya Li and Qianqian commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University. Informed consent was obtained from all individual participants included in the study.
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Ma, K., Guo, Q. & Li, X. Efficacy and safety of combined immunotherapy and antiangiogenic therapy for advanced non-small cell lung cancer: a real-world observation study. BMC Pulm Med 23, 175 (2023). https://doi.org/10.1186/s12890-023-02470-z
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DOI: https://doi.org/10.1186/s12890-023-02470-z
Keywords
- Immunotherapy
- Antiangiogenic therapy
- Chemotherapy-free
- Non-small cell lung cancer