Clinical observation of the efficacy of PD‐1/PD‐L1 inhibitors in the treatment of patients with advanced solid tumors

Abstract Introduction Programmed death 1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) inhibitors are proved to be promising and are applied for the treatment of a variety of solid tumors. This retrospective study evaluated the efficacy of PD‐1/PD‐L1 inhibitors in patients with advanced solid tumors and explore the effect of clinical characteristics on it. Materials and Methods From October 2017 to April 2020, a total of 90 patients from Capital Medical University Affiliated Beijing Friendship Hospital were enrolled. Results At a median follow‐up of 10.55 months, objective response was observed in 23 patients and the objective response rate was 25.6%. The median progression‐free survival (PFS) was 5.5 months (95% confidence interval [CI], 3.69–7.37). The 6m‐PFS was 45.8% and 12m‐PFS was 25.1%. The median overall survival (OS) was 16.9 months (95% CI, not reached [NR]‐NR). The 12m‐OS was 58.1% and 18m‐OS was 48.1%. Conclusion The efficacy of PD‐1/PD‐L1 inhibitors in the treatment of advanced solid tumors was comparable to previous studies. ECOG performance status, smoking status, liver metastasis, neutrophil‐to‐lymphocyte ratio were independently correlated with PFS while liver metastasis and lactate dehydrogenase level were independently correlated with OS.


| Patients
We conducted an observational retrospective analysis of patients with advanced solid tumors who received treatment with PD-1/PD-L1 inhibitor in Capital Medical University Affiliated Beijing Friendship Hospital between October 1, 2017 and April 1, 2020. Eligible criterial were as follows: (1) age ≥18 years; (2) histologically diagnosed malignant solid tumor; (3) blood routine, liver and kidney function is generally normal; (4) unresectable or multiple metastases; (5) at least one measurable or evaluable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 9 ; (6) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 or less.
Patients were excluded if they had an autoimmune disease or were receiving any form of systemic immunotherapy or immunosuppressive therapy such as PD-1/PD-L1 inhibitors, interleukin, interferon, thymosin, or anti-rejection drugs after organ transplantation.
This study was approved by the Ethics Committee for Clinical Investigation of Capital Medical University Affiliated Beijing Friendship Hospital and conducted according to the Declaration of Helsinki. All patients had signed informed consent for data collection and study purposes.

| Treatment regimes
All the patients received PD-1/PD-L1 inhibitors monotherapy or combined with other treatment regimens every 3 weeks administered in accordance with guidelines until disease progression, unacceptable toxicity, or other termination criteria (pregnancy, patients' personal reasons, or intercurrent illness) were met. Other treatment regimens included chemotherapy and targeted therapy. Patients were evaluated every two or three cycles (6-9 weeks).

| Data collection and efficacy assessment
The data collected included demographic data (gender, age, ECOG PS, history of smoking, family history of cancer), laboratory test of peripheral blood (lactate dehydrogenase [LDH], neutrophil-to-lymphocyte ratio [NLR] and platelet-to-lymphocyte ratio [PLR]), and treatment regime of PD-1/PD-L1 inhibitors (line, specific drug, and whether combined with others). The baseline characteristics of patients were derived from the medical records of patients at the beginning of immunotherapy. All data were identified before be released to the main investigator.
According to RECIST v1.1, the antitumor efficacy was evaluated by computed tomography (CT) or magnetic resonance imaging (MRI) every 2-3 treatment cycles, resulting in complete response (CR), partial response (PR), stable disease (SD), or progressed disease (PD). The objective was to describe the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Additionally, further analysis was conducted to explore the effect of clinical characteristics on the PFS and OS. PFS is defined as the time from the start of immunotherapy to disease progression/death or the date of their last disease assessment, whichever occurs first. OS was defined as the time from the beginning of PD-1/ PD-L1 inhibitor treatment to death or to the final followup time. Those who did not progress were reviewed on the date of their last disease assessment. DOR refers to the time from the first recorded response to tumor progression or death or the last evaluation for patients with target response.

| Statistical analysis
The Kaplan-Meier approach was used to estimate PFS, OS, and DOR and 95% confidence interval (CI). Patients who lost follow-up were reviewed on the date of last follow-up time. PFS of subgroups were compared with the log-rank test to determine the relationship between patients' clinical characteristics (age, gender, smoking status, ECOG PS, systemic metastasis, etc.) and recurrence outcomes. Cox regression was performed to estimate the hazard ratios (HRs) and 95% CI. p < .05 was considered statistically significant. The follow-up deadline is January 18, 2021. All statistical analyses were performed using SPSS 25.0 software.

| Patient characteristics
A total of 90 patients were enrolled in the study, including 58 males (64.4%) and 32 females (35.6%). The mean age was 61.97 ± 8.44 years old, ranging from 31 to 77 years old. The baseline characteristics of the patients are shown in Table 1
Immune-related adverse events (irAEs) were developed in patients who received monotherapy and combination. In monotherapy group, two (10.00%) patients developed grade 1-2 rash, and no patients developed grade ≥3 irAEs. In combination therapy group, 7 (10.00%) patients developed pneumonia in grades 1-2, one patient developed grade ≥3 rash. Many other adverse events were also developed in monotherapy and combination therapy which were shown in Table 2. And six patients discontinued therapy due to any grade 3-5 adverse events.

| Multivariate analyses
Multivariate Cox regression showed that ECOG PS score, smoking state, liver metastasis, NLR were independently correlated with PFS, and liver metastasis, LDH level were independently correlated with OS, as shown in Table 3.

| Efficacy analysis according to tumor types
Tumor types of more than 10 patients were analyzed including 22   efficacy and controllable safety. 10 However, there are strict inclusion criteria for clinical trials. It is inevitable for the wider use of new regimes out of the eligibility criteria for clinical trials after the approval of authorities, especially when there are not attractive choice and standard treatment has considerable toxicity and poor efficacy. Therefore, real-world evidence is necessary to prove the efficacy of a newly approved drug.
Our single-center retrospective study assessed the efficacy of PD-1/PD-L1 inhibitors monotherapy or in combination with other treatment strategies (chemotherapy or antiangiogenesis inhibitor) for 90 patients with advanced  solid tumors. 11 We collected the irAEs and other adverse events of 90 patients and classified different occurrence frequencies in monotherapy and combination therapy. And more study should be conducted to explore the management of these adverse events. We respectively analyzed the major tumor types involved in the study. For NSCLC, previous published clinical trials showed that ORR ranged from 27.2% to 62.6%, PFS ranged from 5.1 to 9.0 months, and OS ranged from 16.4 to 26.3 months. [12][13][14] Our study showed that ORR was 27.3%, PFS was 5.5 months (95% CI: 0.96-10.10) and the median OS was not reached. It was shown that ORR ranged from 9.9% to 46%, PFS ranged from 1.7 to 6.3 months, and OS ranged from 7.1 to 12.4 months for esophageal cancer in previous study 4,15,16 and they were 36.8%, 5.0 months (95% CI: 1.07-8.87) and 9.4 months (95% CI: 1.53-17.33), respectively in our study. For GC patients, ORR, mPFS, and mOS were 25.0%, 5.7 months, and NR in the study, compared with 2.2%-57.5% for ORR, 1.4-10.45 months for PFS, and 4.6-9.1 months for OS in published studies. [17][18][19] Furthermore, we explored the effect of clinical characteristics (gender, smoking status, liver metastasis status, inflammatory response, etc.) on PFS and OS. One of the most interesting finding in the study was that patients who smoked had significantly longer PFS and OS compared with patients who never smoked, which was consistent with previous study. 20 It is demonstrated that smoking can cause many genetic mutations and higher PD-L1 expression level, 21 which may account for the difference of efficacy between different smoking status.
We also explored the relationship between inflammation and the PFS of PD-1/PD-L1 inhibitors based on the phenomenon that inflammation is known as the main driver of tumor development and has prognostic value in several kinds of malignant tumors. 22 Among all the simple and easily detected biomarkers, NLR and PLR reflect the level of systemic inflammatory response, which is significantly correlated with the occurrence, development, and prognosis of various malignant tumors such as lung cancer, gastric cancer, colorectal cancer, breast cancer, and thyroid cancer, and can predict the risk of tumor recurrence and metastasis. In addition, several studies showed that there was also a significant correlation between NLR, PLR and the efficacy PD-1/PD-L1 inhibitors. 23 Our retrospective study showed that NLR was associated with the PFS and OS of PD-1/PD-L1 inhibitors, while PLR was not. Therefore, NLR may be taken into consideration for the use of PD-1/PD-L1 inhibitors.
There were no statistically significant different between PFS, OS and other factors such as gender, age, stage, monotherapy/combination therapy, history of drinking, family history of tumor, brain metastasis, lung metastasis, bone metastasis, PLR, and LDH, etc., which was consistent with previous studies. [24][25][26][27][28] Although the discovery was interesting, the explanation for the results should be carefully, given the fact that there were several inevitable limitations. The main limitation was that it may introduce unexpected deviation because it was a retrospective design such as the bias in the doctor's decision. Secondly, the power of the study to a certain extent is limited to the limited sample size and follow-up time, which may lead to some errors in our results. Therefore, additional investigations will be required to verify the results. In addition, the heterogeneity of the study was relatively large, which is acceptable considering that we are trying to explore the efficacy of PD-1/PD-L1 inhibitors and its effect on solid tumors from an overall perspective.
In summary, this study showed that PD-1/PD-L1 inhibitors showed comparable efficacy in the real world compared with studies for advanced solid tumors. ECOG status, smoking status, liver metastasis status, and NLR might predict the recurrence of between PD-1/PD-L1 inhibitors treatment and liver metastasis, LDH might predict the survival. This finding has great significance and value of the guidance for the application of immunotherapy.