Abstract
Background
Immune checkpoint inhibitors in combination with chemotherapy have been a common first-line treatment for non-small cell lung cancer (NSCLC), but they do not work for all patients. HDAC inhibitors (HDACis) may synergize with progressive disease (PD)-1 antibodies by inducing and activating cellular immunity. In this phase II study, we assessed the efficacy and tolerability of chidamide and tislelizumab in combination with chemotherapy in NSCLC patients.
Methods
This was a single-arm, prospective study. Driver-gene negative locally advanced and metastatic NSCLC patients without prior systemic treatment were enrolled. Patients received chidamide, tislelizumab, and chemotherapy for 4-6 cycles and were then maintained by tislelizumab and chidamide. The primary endpoint was objective response rate (ORR), and secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response, overall survival (OS) and safety.
Results
Twenty patients were enrolled in the study and most of them were PD-L1 1%-49% and PD-L1 < 1%. At the data cutoff, ORR was 80% (95% CI, 56.3-94.3), and DCR was 100%. The median follow-up was 23.4 months, the median PFS was 11.0 months (95% CI, 9.1-12.9m), and the median OS was 17.5 months (95% CI, 9.2-25.8m). Eleven patients (55.0%) had ≥ Grade 3 treatment-related adverse events (TRAEs). The most common ≥ Grade 3 TRAEs were leukopenia (25.0%) and neutropenia (20.0%). No patients died from treatment-related adverse events.
Conclusions
The combination of HDACi and tislelizumab with chemotherapy showed promising antitumor effects and manageable toxicity. More studies are needed to further confirm these results.
ClinicalTrials.gov Identifier
ChiCTR2000041542
Keywords: tislelizumab, chidamide, non-small cell lung cancer (NSCLC), efficacy, safety
Disscussion
Immune checkpoint inhibitors (ICIs) combined with chemotherapy can improve the therapeutic effect of lung cancer by reducing co-inhibitory signaling in T cells. However, the components of the tumor-associated immune microenvironment are complex and not all patients can benefit from the regimen, thus more effective treatment options need to be explored.
Histone deacetylase inhibitors (HDACis) can block the activity of histone deacetylases in tumors, reverse the acetylation state, and regulate the immune response to tumors and the interactions between tumors and immune cells. Therefore, we assessed the efficacy and safety of tislelizumab and the HDACi chidamide combined with chemotherapy in the first-line treatment for driver-gene negative advanced non-small cell lung cancer (NSCLC) patients, in order to make further benefit for patients with lung cancer.
The prospective results showed that objective response rate (ORR) was 80%, and the disease control rate (DCR) was 100% in 20 patients (Figure 1), suggesting promising antitumor activity. The median time to response was 3.9 months and the median duration of response (DoR) was 8.0 months. At the time of data cutoff, the median progression-free survival (PFS) was 11.0 months, and the median overall survival (OS) was 17.5 months (Figure 2). The results indicated that adding chidamide to tislelizumab and chemotherapy exhibited great antitumor activity in the first-line treatment of driver-gene negative NSCLC.
Figure 1.
Changes in the target lesions.
Figure 2.
Kaplan‒Meier survival curve of patients (A, PFS; B, OS). OS, overall survival; PFS, progression-free survival
Treatment-related adverse events (TRAEs) occurred in 95% of the patients. The most common adverse events were anemia, alopecia, neutropenia, and leukopenia, which were more likely related to chemotherapy and the majority of TRAEs were Grade 1-2 events. Grade 3 or more TRAEs occurred in 55% of the patients. The toxicity was manageable and no treatment-related death was recorded.
In our study, we added an oral selective HDAC inhibitor chidamide to chemo-immunotherapy, and the results demonstrated promising tumor control rate and manageable toxicity. Additional study is needed to confirm the activity of this novel combination.
Lessons learned:
Histone deacetylase inhibitors and ICIs may have synergistic effects on antitumor treatment.
The combination of tislelizumab and chidamide with chemotherapy showed promising effects and manageable toxicity for first-line treatment of driver-gene negative NSCLC.
| Trial information | |
|---|---|
| Disease | Lung cancer-NSCLC |
| Stage of disease/treatment | IIIB-IV |
| Prior therapy | None |
| Type of study | Single-arm, prospective phase II study |
| Primary endpoint | Objective response rate |
| Secondary endpoints | PFS, DCR, DoR, OS, and safety |
| Investigator’s analysis | Active and should be pursued further |
Additional details of endpoints or study design
Population
Patients aged 18-75 years with treatment-naïve, histologically or cytologically confirmed locally advanced or metastatic NSCLC (stage IIIB-IV) were enrolled in the study. No EGFR/ALK mutations or fusions were detected by genetic testing. Prior neoadjuvant/adjuvant chemotherapy was required to be at least 6 months after the end of the last chemotherapy. The Eastern Cooperative Oncology Group (ECOG) score ranged from 0 to 1, and at least one measurable lesion was required (according to Response Evaluation Criteria in Solid Tumor [RECIST] v 1.1). Patients had good organ function and an expected survival time of more than 3 months.
Key exclusion criteria included pulmonary radiotherapy with doses exceeding 30 Gy within 6 months before enrollment, meningeal metastasis or symptomatic brain metastases, a history of interstitial lung disease or pneumonia requiring oral or intravenous steroids, a history of immune deficiency and a distinct history of neurological or psychiatric disorders. Informed consent was obtained from the patients who participated in the study.
Design
This was a single-center, open-label, prospective phase 2 clinical trial. During the induction phase, patients were administered 200 mg of tislelizumab and 20 mg of chidamide orally twice a week in combination with platinum-based chemotherapy (Taxol or pemetrexed combined with platinum, carboplatin area under the curve (AUC) 5; cisplatin 75 mg/m2) every 3 weeks for 4-6 cycles (at the investigator’s discretion), followed by tislelizumab plus chidamide maintenance therapy. The treatment was continued until disease progression, intolerable toxicity, withdrawal of informed consent, or death (Figure 3). Efficacy was evaluated every 6 weeks according to the RECIST 1.1, and adverse events were graded according to the CTCAE 5.0 evaluation criteria.
Figure 3.
Study profile.
Endpoint
The primary endpoint was the ORR, and the secondary endpoints were PFS, DCR, DoR, OS, and safety. The ORR was defined as the proportion of patients who achieved a complete response (CR) or partial response (PR), and the DCR referred to the proportion of patients who achieved a CR, PR, or stable disease. Progression-free survival was defined as the time from the initiation of treatment until disease progression or death from any cause, whichever occurred first. Duration of response referred to the time from the first evaluation of CR or PR to the first evaluation of progressive disease (PD) or death from any cause. Overall survival referred to the time from the initiation of treatment until death from any cause.
Statistical analyses
Descriptive statistics, including age, sex, clinical stage, smoking history, and PD-L1 expression status, were used to analyze the clinical characteristics of the patients. Considering the sample size and data distribution, the Clopper-Pearson method was used to calculate the 95% confidence intervals (CI) of the ORR. The survival curves of PFS and OS were plotted by the Kaplan‒Meier method, and the median follow-up time was calculated by the anti‒Kaplan‒Meier method
| Drug information | ||
|---|---|---|
| Arm | Arm 1 | Arm 2 |
| Generic/working name | Chidamide | Tislelizumab |
| Company name | Shenzhen Chipscreen Biosciences Co., Ltd. | Beigene (Beijing) Co., Ltd. |
| Drug type | Histone deacetylase inhibitor | Immune checkpoint inhibitor |
| Drug class | Epigenetic regulator | |
| Dose | 20 mg twice a week | 200 mg |
| Route | p.o. | p.o. |
| Schedule of administration | 20 mg twice a week, the interval between the 2 doses should not be less than 3 days | 200 mg, every 3 weeks |
Patient Characteristics
| Number of patients, male | 20 |
| Number of patients, female | 0 |
| Stage | II B-IV |
| Age: Median (range) | 63.5 (49-75) |
| Performance status: ECOG | 0: 1 1: 19 2: 0 3: 0 4: 0 |
| Cancer types or histologic subtypes | Adenocarcinoma, 10; squamous cell carcinoma, 10 |
Primary Assessment Method
| Number of patients screened | 22 |
| Number of patients enrolled | 20 |
| Number of patients evaluable for toxicity | 20 |
| Number of patients evaluated for efficacy | 20 |
| Evaluation method | RECIST 1.1 |
| Response assessment, CR | 1 (5%) |
| Response assessment, PR | 15 (75%) |
| Response assessment, SD | 4 (20%) |
| Response assessment, PD | 0 (0%) |
| Median duration assessments, PFS | 11.0 months (CI, 9.1-12.9) |
| Median duration assessments, OS | 17.5 months (CI, 9.2-25.8) |
| Response duration | 8.0 months |
Tumor-related adverse events
| TRAEs (N = 20) | Any Grade n (%) |
Grade 1-2 n (%) |
Grade 3 n(%) |
Grade 4 n (%) |
| Aaemia | 15 (75.0) | 13 (65.0) | 2(10.0) | 0(0.0) |
| Alopecia | 12 (60.0) | 12 (60.0) | 0(0.0) | 0(0.0) |
| Neutropenia | 12 (60.0) | 8 (40.0) | 3 (15.0) | 1 (5.0) |
| Leukopenia | 11 (55.0) | 6 (30.0) | 4 (20.0) | 1 (5.0) |
| Nausea | 9 (45.0) | 9 (45.0) | 0(0.0) | 0(0.0) |
| Thrombocytopenia | 9 (45.0) | 6 (30.0) | 3 (15.0) | 0(0.0) |
| Increased alanine aminotransferase (ALT) | 9 (45.0) | 8 (40.0) | 1 (5.0) | 0(0.0) |
| Increased aspartate aminotransferase (AST) | 7 (35.0) | 6 (30.0) | 1 (5.0) | 0(0.0) |
| Decreased appetite | 7 (35.0) | 7 (35.0) | 0(0.0) | 0(0.0) |
| Fatigue | 6 (30.0) | 6 (30.0) | 0(0.0) | 0(0.0) |
| Increased creatinine | 6 (30.0) | 6 (30.0) | 0(0.0) | 0(0.0) |
| Blood lipids increased | 5 (25.0) | 4 (20.0) | 1 (5.0) | 0(0.0) |
| Constipation | 5 (25.0) | 5 (25.0) | 0(0.0) | 0(0.0) |
| Diarrhea | 5 (25.0) | 3 (15.0) | 2 (10.0) | 0(0.0) |
| Pneumonia | 6 (30.0) | 3 (15.0) | 3 (15.0) | 0(0.0) |
| Hypesthesia | 3 (15.0) | 3 (15.0) | 0(0.0) | 0(0.0) |
| Adrenal insufficiency | 3 (15.0) | 2 (10.0) | 1 (5.0) | 0(0.0) |
| Hypothyroidism | 2 (10.0) | 2 (10.0) | 0(0.0) | 0(0.0) |
| Hyperglycemia | 2 (10.0) | 1 (5.0) | 1 (5.0) | 0(0.0) |
| Dermatitis | 1 (5.0) | 0(0.0) | 1 (5.0) | 0(0.0) |
| Colitis | 1 (5.0) | 0(0.0) | 1 (5.0) | 0(0.0) |
| Myositis | 1 (5.0) | 0(0.0) | 1 (5.0) | 0(0.0) |
| Neurotoxicity | 1 (5.0) | 1 (5.0) | 0(0.0) | 0(0.0) |
| Pituitary dysfunction | 1 (5.0) | 1 (5.0) | 0(0.0) | 0(0.0) |
Assessment, analysis, and discussion
| Completion | Study completed |
| Investigator’s assessment | Active and should be pursued further |
Extended discussion
Lung cancer is one of the most common malignant tumors in the world, with an incidence rate ranking second and a mortality rate ranking first according to Global Cancer Statistics in 2020.1 In recent years, with the increased understanding of the immune microenvironment, ICIs, including PD-1 and PD-L1 inhibitors, have been gradually applied in various tumors. For advanced NSCLC, ICIs in combination with chemotherapy have become a more common first-line treatment, and ICI monotherapy is also an option for patients with positive PD-L1 expression. In various large clinical trials, ICIs have demonstrated significant efficacy in both first and posterior-line treatment of advanced NSCLC.2-9 As a result, a variety of ICIs, such as pembrolizumab, nivolumab, camrelizumab, tislelizumab, sintilimab, and toripalimab, have been incorporated into clinical guidelines.
However, not all patients with NSCLC respond well to first-line therapy, and nearly 70% of patients do not benefit from ICIs for advanced NSCLC.10 Previous studies have shown that HDACis can enhance cancer cell responses to immunotherapy by increasing the expression levels of tumor-associated antigens and directing gene expression to tumor proapoptotic mechanisms.11 Histones are a group of basic proteins that are tightly bound to DNA in eukaryotic cells, and their functions are regulated by a variety of post-translational modifications. Abnormal histone acetylation can lead to abnormal gene expression, which activates oncogenes, inactivates tumor suppressor factors, inhibits programmed cell death, mediates immune escape, and ultimately leads to tumor progression. The homeostasis between histone acetylases and deacetylases controls chromatin structure and gene expression.12 HDACis can block the activity of histone deacetylases in tumors, reverse the acetylation state, and regulate the immune response to tumors and the interactions between tumors and immune cells.13 Chidamide is a selective HDACi of the benzamide oral subtype that is approved for the treatment of peripheral T-cell lymphoma and breast cancer. According to an analysis of soft tissue sarcomas, the expression of HDAC class I is associated with poor prognosis, and the inhibition of HDAC can promote apoptosis and upregulate PD-L1. Chidamide can significantly increase the expression of PD-L1, increase the infiltration of CD8 + T cells, and reduce the number of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment.
The synergistic mechanism of HDACis and ICIs may involve the following functions: (1) HDACis can upregulate MHC molecules and enhance the initiation of the immune response mediated by macrophages, monocytes, and DCs; (2) HDACis can increase the expression of T-cell chemokines and activate and induce cytotoxic T-cell and NK cell-mediated cellular immunity14; and (3) HDACis can inhibit the activity of (MDSCs.15,16 Given the synergistic effect of HDACis and ICIs, we aimed to explore whether chidamide combined with tislelizumab and chemotherapy could further enhance the therapeutic efficacy and improve clinical outcomes.
In our study, we incorporated 20 patients, the basic information was as Table 1. The ORR of patients was 80%, and the DCR was 100%, greater than that of patients treated with ICIs and chemotherapy in previous studies.5,6 One patient achieved a CR, indicating great tumor control activity. Until the deadline, 3 patients were still undergoing first-line therapy, and 4 patients were receiving posterior-line therapy after disease progression, including radiotherapy, chemotherapy, targeted therapy, and immunotherapy (Figure 4). After the addition of chidamide, PFS in our study was 11.0 months (95% CI, 9.1-12.9 m), revealing favorable efficacy. HDACis combined with PD-1/PD-L1 antibodies have also shown great efficacy in other studies. In mouse models, the combination of chidamide with anti-PD-1 antibodies significantly promoted tumor regression and improved survival.17 Chidamide and PD-L1 inhibitors can enhance tumor immunogenicity and induce an antitumor immune response in triple-negative breast cancer.18 A phase I/II clinical trial of chidamide in combination with nivolumab in solid tumors demonstrated good efficacy without additive adverse effects. Another recently developed HDACi, vorinostat, in combination with pembrolizumab, also showed good efficacy in the treatment of metastatic NSCLC. The OS in our study was 17.5 months (95% CI, 9.2-25.8 m), which was numerically relatively lower than the previous results. The relatively lower OS might be attributed to the relatively small sample size and bias in the results. One patient died of cardiovascular disease 2 months after enrollment, and the other died of a nontumor disease after 3 cycles of treatment, which greatly affected OS outcomes. Furthermore, as of the time of admission, the data were not fully available, and longer follow-up periods were required.
Table 1.
Clinical features of patients.
| Clinical factors | Number (%) |
|---|---|
| Sex | |
| Male | 20 (100) |
| Female | 0 (0) |
| Age, median(range, years | 63.5 (49-75) |
| ECOG status | |
| 0 | 1 (5.0) |
| 1 | 19 (95.0) |
| Smoking status | |
| Former or current | 18 (90.0) |
| Never | 2 (10.0) |
| Histology | |
| Adenocarcinoma | 10 (50.0) |
| Squamous cell carcinoma | 10 (50.0) |
| Stage | |
| IIIB | 1 (5.0) |
| IV | 19 (95.0) |
| Bone metastases | |
| Yes | 6(30.0) |
| No | 14(70.0) |
| PD-L1 status(TPS) | |
| < 1% | 6 (30.0) |
| 1%-49% | 7 (35.0) |
| ≥ 50% | 1 (5.0) |
| Not detected | 6 (30.0) |
Abbreviation: ECOG, Eastern Cooperative Oncology Group.
Figure 4.
Patient treatment process.
After the addition of chidamide, the variety of adverse events did not increase, and most of them were Grade 1-2. Common Grade 3 and higher adverse events, such as neutropenia and leukopenia, may be caused by chemotherapy and can be managed by symptomatic treatment and dose reduction. A serious potential immune-related adverse event was immune-associated pneumonia. Three patients developed grade 3 pneumonia and received hormone shock therapy. The other potential immune-related adverse reactions included immune-associated dermatitis, myositis, colitis, and endocrine system toxicity; most of the adverse reactions were Grade 1-2, and the patients were treated symptomatically. These findings are consistent with the results of previous studies.
In recent years, the exploration of treatments for driver-gene negative NSCLC has been continuous. However, most trials have not demonstrated significant efficacy of these treatments. In our study, we added chidamide to chemotherapy combined with ICI and observed a promising effect. The limitation of this study is that the sample size was relatively small and needs to be expanded to further evaluate the therapeutic effect and toxicity. Secondly, our data were not fully mature, which might have influenced the final results. Moreover, PD-L1 expression was not examined in every patient due to personal or economic reasons, and we were unable to further analyze the relationship between PD-L1 expression status and therapeutic efficacy.
In conclusion, the combination of tislelizumab and chidamide with chemotherapy showed promising results for first-line treatment of NSCLC. A multicenter, prospective clinical study with a larger sample size is needed to validate the efficacy of this regimen, and more basic studies should be conducted to identify the population that would benefit the most.
Acknowledgments
We would like to thank all the participants and their families, the investigators, and their teams contributed to the study.
Contributor Information
Lijie Wang, Department of Medical Oncology, Senior Department of Oncology, 5th Medical Centre of PLA General Hospital, Beijing 100071, China.
Ming Gao, Department of Medical Oncology, Senior Department of Oncology, 5th Medical Centre of PLA General Hospital, Beijing 100071, China.
Ting Wang, Medical College of Nankai University, Department of Oncology, Tianjin 300071, China.
Pengfei Cui, Department of Medical Oncology, 2nd Medical Centre of PLA General Hospital, Beijing 100036, China.
Guangying Chen, Department of Medical Oncology, Senior Department of Oncology, 1st Medical Centre of PLA General Hospital, Beijing 100036, China.
Xiao Han, Department of Medical Oncology, Senior Department of Oncology, 5th Medical Centre of PLA General Hospital, Beijing 100071, China.
Zhiqiang Ma, Department of Medical Oncology, Senior Department of Oncology, 5th Medical Centre of PLA General Hospital, Beijing 100071, China.
Wenyu Yang, Medical College of Nankai University, Department of Oncology, Tianjin 300071, China.
Fangfang Jing, Department of Medical Oncology, Senior Department of Oncology, 1st Medical Centre of PLA General Hospital, Beijing 100036, China.
Junxun Ma, Department of Medical Oncology, Senior Department of Oncology, 5th Medical Centre of PLA General Hospital, Beijing 100071, China.
Fan Zhang, Department of Medical Oncology, Senior Department of Oncology, 5th Medical Centre of PLA General Hospital, Beijing 100071, China.
Haitao Tao, Department of Medical Oncology, Senior Department of Oncology, 5th Medical Centre of PLA General Hospital, Beijing 100071, China.
Yi Hu, Department of Medical Oncology, Senior Department of Oncology, 5th Medical Centre of PLA General Hospital, Beijing 100071, China.
Funding
The trial was sponsored by Beijing Cancer Prevention&Treatment Society and Beigene (Beijing) Co., Ltd.
Conflicts of interest
None declared.
Data availability
The datasets generated and analyzed during the study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Informed consents were obtained from all patients participated in the clinical trial. The trial was approved by the Ethics Committee of Chinese PLA General Hospital (S2020-340-03). It followed the Declaration of Helsinki and any applicable regulatory requirements.
Consent for publication
All data were anonymized, and the manuscript does not contain any individually identifiable data.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated and analyzed during the study are available from the corresponding author on reasonable request.