Research ArticleClinical Studies

Early Serum and Hematological Responses to Pembrolizumab Therapy as Predictors of Survival in Metastatic Urothelial Cancer

MOTOHIRO FUJIWARA, RYO FUJIWARA, TETSUYA URASAKI, TOMOHIKO OGUCHI, YOSHINOBU KOMAI, NOBORU NUMAO, SHINYA YAMAMOTO, JUNJI YONESE and TAKESHI YUASA
Anticancer Research April 2022, 42 (4) 2045-2051; DOI: https://doi.org/10.21873/anticanres.15685

Abstract

Background: In order to search for predictive biomarkers of efficacy of pembrolizumab therapy for metastatic urothelial cancer (UC), we investigated the relationship between treatment outcomes and early neutrophil-lymphocyte ratio (NLR), lactate dehydrogenase (LDH), and C-reactive protein (CRP) responses. Patients and Methods: Medical records of 101 patients with metastatic UC who started pembrolizumab as a second-line or later treatment were reviewed. NLR, LDH, and CRP were recorded after 3 weeks of therapy. In addition, we investigated whether these factors had an association with prolonged progression-free (PFS) or overall (OS) survival. Results: The objective response rate, median PFS, and median OS were 25.7%, 6.3 months, and 15.2 months, respectively. PFS and OS were significantly shorter in patients with NLR>3, LDH>upper limit of normal (ULN), and CRP>0.5 mg/dl after 3 weeks of pembrolizumab treatment (p<0.05). A predictive model comprising these factors (favorable risk group: 0 risk factors; intermediate-risk group: 1-2 risk factors; poor-risk group: 3 risk factors) revealed distinct PFS and OS curves (p<0.001). In the favorable risk group, 12-month OS was 79.6%; in the poor-risk group, it was 12.8%. Harrell’s C-indices for NLR >3, LDH >ULN, CRP >0.5 mg/dl, and all three combined for predicting OS were 0.656, 0.625, 0.633 and 0.678, respectively. Early responses were also non-significantly associated with ORR (p=0.37). Conclusion: Pembrolizumab treatment outcomes are associated with early NLR, LDH, and CRP responses in metastatic urothelial cancer.

Key Words:

As a second-line treatment for platinum-refractory advanced urothelial cancer (UC), therapy with pembrolizumab, a programmed cell death-1 checkpoint inhibitor, is associated with a significantly longer overall survival (OS) than that achieved with chemotherapy (1). Due to its efficacy and acceptable toxicity, pembrolizumab therapy was rapidly introduced into clinical use in Japan, dramatically shifting the treatment strategy for metastatic UC (2). However, its associated objective response rate is only 21.1% (1). This means that about 80% of patients with metastatic UC who did not respond to first-line chemotherapy will have no response or only minimal response to pembrolizumab. Because metastatic UC is a fatal disease, with a typical OS of only 6-7 months after first-line chemotherapy, most patients have little time for second-line treatments (3). Since there is not much time left, it is preferable to know as early as possible whether the treatment is working or not by watching the response after administration of pembrolizumab. Changes in tumor size are commonly used to assess treatment response and predict patient survival (4). However, changes in tumor size alone do not provide a complete picture of a patient’s early response to the treatment because pseudoprogression may be observed in some patients receiving immune checkpoint inhibitor therapy (5). To obtain an accurate prognosis and to seek effective treatment in the time remaining for a patient, biomarkers are urgently needed to predict patient response and the effectiveness of treatment.

We reported that an early C-reactive protein (CRP) response and high serum CRP level within 1 month of starting pembrolizumab therapy are potential biomarkers of its efficacy in patients with metastatic UC (6–8). In addition to CRP, an elevated neutrophil-to-lymphocyte ratio (NLR) and lactate dehydrogenase (LDH) level, as well as the absence of an early response in these parameters after the start of immune checkpoint inhibitor therapy, have been reported as predictive factors signaling low efficacy of this type of therapy (2, 9–12). In the current study, we investigated the relationship between OS and early response of these serum and hematological markers. We hypothesized that outcomes of pembrolizumab therapy might be associated with early changes in these variables.

Patients and Methods

Patients. In this study, between January 2018 and March 2021, 101 consecutive patients diagnosed with metastatic UC and who, after first-line platinum-based chemotherapy, commenced second-line or later treatment with pembrolizumab at our Institute were included. We reviewed these patients’ medical records retrospectively. The Institutional Review Board of the Cancer Institute Hospital, Japanese Foundation for Cancer Research, approved this study (approval number #2012-1008).

Treatment and follow-up examination. As previously described, the administration schedule of pembrolizumab (200 mg) was every 3 weeks (1, 6). Patient histories, including physical examination findings, Eastern Cooperative Oncology Group Performance Status, and laboratory findings, were obtained before and after the initiation of pembrolizumab. In keeping with previous studies, for laboratory findings, 3.0 and 0.5 mg/dl were used as the cut-off values for NLR and CRP, respectively (13–15), and the upper limit of the normal range (ULN) was used as the cut-off value for LDH. Based on the Response Evaluation Criteria in Solid Tumors guideline version 1.1 (16), each patient’s response to treatment was objectively assessed by computed tomography every 2 or 3 months. Toxicities were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (17).

Statistical analysis. The progression-free survival (PFS) and OS were calculated from the initiation of pembrolizumab administration to diagnosis of progressive disease, or death, respectively. Survival curves were evaluated using the Kaplan-Meier method, and the log-rank test analyzed the differences. The predictive accuracies of risk models based on NLR, LDH, and CRP, each recorded 3 weeks after the initiation of pembrolizumab therapy, and a risk model combining all three parameters was calculated using Harrell’s concordance index (C-index). All statistical analyses were conducted using JMP, version 12.0 (SAS Institute, Cary, NC, USA) and R 4.0.1 (R Foundation for Statistical Computing, Vienna). p-Values of less than 0.05 were considered significant.

Results

Patient characteristics. Forty-four patients (43.6%) had upper urinary tract UC, while the remaining 57 (56.4%) had bladder UC. Fifty-six patients (55.4%) were given pembrolizumab as a second-line treatment, while the other 45 (44.6%) took it as a later-line of treatment (Table I).

View this table:
Table I.

Characteristics of patients treated with pembrolizumab (n=101).

Efficacy of pembrolizumab. After pembrolizumab initiation, the median follow-up time for this study was 8.6 months (interquartile range=3.9-17.6 months). The antitumor response was assessed in 84 patients. The objective response rate (ORR) was 25.7% (Figure 1A), and 36 (43.9%) patients showed reduced tumor size. Of the remaining 17 patients, nine had small lymph node metastases and no evaluable target lesions, and eight had clinical progression before the first imaging evaluation.

Figure 1.
Figure 1.

Efficacy of pembrolizumab treatment in patients with metastatic urothelial cancer (n=101). A: Waterfall plots of patient response to pembrolizumab (n=82). B: Progression-free survival. C: Overall survival.

Overall, 78 patients (77.2%) discontinued pembrolizumab therapy. The most frequent reasons for pembrolizumab discontinuation were progression of disease (n=57, 56.4%), and immune-related adverse events (AEs) (n=21, 20.8%). The remaining 23 patients (22.8%) were alive and continuing this novel therapy. During the study period, 50 patients (50.0%) died due to progression of their disease, and one patient (1.0%) died from an immune-related AE (hemophagocytic syndrome as described below). Thus, 51 patients (50.5%) died overall in this study.

The estimated median PFS period was 6.3 months (95% confidence interval=4.2-7.9 months), and the- 3, 6-, and 12-month PFS rates were 66.2%, 50.3%, and 32.8%, respectively (Figure 1B). The median OS period was 15.2 months (95% confidence interval=10.4-28.8 months), and the estimated 6-, 12-, and 18-month OS rates were 72.8%, 58.2%, and 44.8%, respectively (Figure 1C).

Adverse events. AEs occurred in 42 patients (41.6%), and severe AEs (grade 3 or more) were seen in 11 patients (10.9%), as shown in Table II. In all AEs, the rash was the most common AE (n=14, 13.9%). As previously reported, one of the patients with severe AEs died of grade 5 hemophagocytic syndrome (8). This patient had a previous history of polymyalgia rheumatica and had taken oral prednisolone (5 mg). After one course of pembrolizumab treatment, the patient complained of fatigue, general malaise and joint stiffness and was diagnosed with polymyalgia rheumatica exacerbation. Pembrolizumab was then discontinued, but 2 months later, the patient’s platelet count decreased (19,000/mm3) without other clinical signs. We immediately started steroid pulse therapy (1,000 mg for 3 days), intravenous immunoglobulin, cyclosporine, and plasma exchange, and administered appropriate antibiotics. However, on the 13th day after admission, the patient died of multiple organ failure.

View this table:
Table II.

Adverse events (AEs) of patients treated with pembrolizumab (n=101).

Analyses of NLR, LDH, and CRP at 3 weeks after starting pembrolizumab therapy. Next, we investigated predictive markers of pembrolizumab treatment. We gathered laboratory data on NLR, LDH, and CRP at 3 weeks after the start of therapy one cycle of pembrolizumab) and examined the association between these parameters and prolonged PFS or OS. In this analysis, PFS was significantly shorter in patients with NLR >3.0, LDH >ULN, and CRP >0.5 mg/dl after one cycle of pembrolizumab than in other patients (Figure 2A-C, p=0.004, p=0.030, and p<0.001, respectively).

Figure 2.
Figure 2.

Predictive model for progression-free survival (PFS) of patients treated with pembrolizumab. Three risk factors, namely a high neutrophil:lymphocyte ratio (NLR >3.0) (A), a high lactate dehydrogenase level [LDH >upper limit of normal (ULN] (B), and high C-reactive protein level (CRP >0.5 mg/dl) (C), recorded at 3 weeks after induction of pembrolizumab therapy, were associated with distinct PFS curves (p=0.004, p=0.030, and p<0.001, respectively). In addition, our predictive model, which stratified patients into three risk groups [favorable-risk: 0 risk factors, n=29 (28.7%); intermediate-risk: 1-2 risk factors, n=57 (56.4%); and poor-risk: 3 risk factors, n=15 (14.9%)], revealed that these three risk groups had distinct PFS curves (D: p<0.001).

A predictive model comprising these three factors (favorable risk group: 0 risk factors; intermediate-risk group: 1-2 risk factors; poor-risk group: 3 risk factors) revealed distinct PFS curves (Figure 2D, p<0.001). For the favorable-risk group (n=29), the median PFS and the 6-month and 1-year PFS rates were not reached, 68.0%, and 51.3%, respectively. For the intermediate-risk group (n=57), these values were 5.9 months, 47.3%, and 29.1%, respectively. For the poor-risk group (n=15), they were 1.9 months, 21.6%, and 0%, respectively (Figure 2D).

The OS was also significantly shorter for patients with NLR >3.0, LDH >ULN, and CRP >0.5 mg/dl after one cycle of pembrolizumab than for other patients (Figure 3A-C, p<0.001, p<0.001, and p=0.004, respectively). A predictive model comprising these three factors (favorable risk group: 0 risk factors; intermediate-risk group: 1-2 risk factors; poor-risk group: 3 risk factors) revealed significantly different OS curves (p<0.001). For the favorable-risk group (n=29), the median OS and the 1- and 2-year OS rates were 28.8 months, 79.6%, and 64.7%, respectively. These values were 15.1 months, 58.4%, and 40.7% for the intermediate-risk group (n=57), and 3.3 months, 12.8%, and 0% for the poor-risk group (n=15), respectively (Figure 3D). The C-indices for predicting OS using NLR >3.0 and LDH >ULN, and CRP >0.5 mg/dl after one cycle of pembrolizumab were 0.656, 0.625, and 0.633, respectively, while the C-index of a model combining all three factors was 0.678.

Figure 3.
Figure 3.

Predictive model for overall survival (OS) of patients treated with pembrolizumab. Three risk factors, namely a high neutrophil:lymphocyte ratio (NLR >3.0) (A), a high lactate dehydrogenase level (LDH >upper limit of normal) (B), and high C-reactive protein level (CRP >0.5 mg/dl) (C), recorded at 3 weeks after induction of pembrolizumab therapy, were associated with distinct OS curves (p<0.001, p<0.001, and p=0.004, respectively). Furthermore, our predictive model, which stratified patients into three risk groups [favorable-risk: 0 risk factors, n=26 (25.7%); intermediate-risk: 1-2 risk factors, n=59 (58.4%); and poor-risk: 3 risk factors, n=16 (15.9%)], revealed that these three risk groups had distinct OS curves (D: p<0.001).

Relationship between objective response and early response by hematological and serum variables. Finally, the relationship between ORR and early response by hematological and serum variables was assessed. Our mosaic plot revealed a tendency for the favorable-risk group to have higher ORR than the other two groups (Figure 4). However, this difference among the groups was not significant (p=0.37).

Figure 4.
Figure 4.

Relationship between objective response and early response by hematological and serum variables. The mosaic plot demonstrates that the favorable risk group tended to have a higher overall objective response rate than the other two groups; however, this difference was not significant (p=0.37). Partial response (PR): 28%; stable disease (SD): 24%; progressive disease (PD): 48%.

Discussion

In this study, we made a straightforward predictive model depending on an early response reflected by NLR, LDH, and CRP levels after the initiation of pembrolizumab. In this model, the median OS for the favorable-risk group (0 risk factors) was 28.8 months, and that for the poor-risk group (3 risk factors) was 3.3 months (Figure 3D). From the mosaic plot (Figure 4), our model did not significantly predict the effect of tumor shrinkage, but a trend was observed. We set a time point of 3 weeks (after one cycle) to check for an early response in this study. To our knowledge, this is the first study assessing NLR, LDH, and CRP values recorded 3 weeks after the start of pembrolizumab therapy as predictive biomarkers for the outcome of patients with metastatic UC who were treated with pembrolizumab.

The NLR is helpful as a predictive marker for various cancer types. In addition, it is cost-effective and straightforward to obtain (2, 10). For example, Sekine et al. reported that an early response of the NLR might be a valuable marker for predicted treatment response in patients with advanced non-small-cell lung cancer receiving nivolumab (18). Immune checkpoint inhibitors enhance antitumor immunity by promoting lymphocyte function and inhibiting negative regulators of T-cell functions (18–20). Therefore, it is reasonable that early changes in the relative proportions of circulating lymphocytes and neutrophils might affect the efficacy of immune checkpoint inhibitors.

An elevated LDH level has also been reported as a predictive factor indicating poor prognosis in metastatic UC (1, 2, 14). Among patients with metastatic melanoma treated with an immune checkpoint inhibitor, Diem et al. reported that high baseline serum LDH and early increase in serum LDH upon starting anti-programmed cell death-1 therapy are associated with short OS (21).

CRP, an inflammation-related acute-phase protein produced by the liver, increases following interleukin-6 secretion by macrophages and T-cells (22). Previously, we reported that a high baseline serum CRP level might be a predictor of poor response to pembrolizumab therapy for metastatic UC (6). In addition, the early response of CRP within the first month of pembrolizumab therapy has been suggested as a potential biomarker for response to pembrolizumab in patients with metastatic UC (7). In the latter report, OS differed significantly among the non-elevated, responder, and non-responder groups (p<0.01), with 1-year survival rates of 69%, 61%, and 31%, respectively (7).

It is worth noting that no significant relationship was found between radiological response and early hematological and serological responses (Figure 4). This might be related to the finding that early responders among patients with metastatic UC treated with pembrolizumab tend to have better survival, even among patients without radiological response. This relationship needs to be re-investigated when more cases have been accumulated.

In the current study, some limitations exist. This was a relatively small retrospective study with a short follow-up period at a single center. Therefore, there was a possibility of bias in the extraction of predictors. Further evaluation is needed if the findings of this study are to be used in clinical practice.

In conclusion, we created a straightforward, predictive model that combined CRP, NLR, and LDH values recorded 3 weeks after the start of pembrolizumab. Although the usefulness of this predictive model in the present population was limited by the fact that around 60% of the patients were classified into the intermediate-risk group, it stratified the remaining 40% into favorable-risk (1-year and 2-year OS rates: 79.6%, and 64.7%, respectively) and poor-risk groups (1-year and 2-year OS rates: 12.8%, and 0%, respectively). Therefore, the data described here will be helpful in decision-making in daily practice.

Acknowledgements

This work was partly supported by The Smoking Research Foundation and JSPS KAKENHI Grant Number 16K11035 (T.Y.).

Footnotes

  • Authors’ Contributions

    MF analyzed and interpreted the data and wrote the article. TY conceived and designed the present study. All Authors made substantial revisions to the article and approved the final version submitted.

  • Conflicts of Interest

    T. Yuasa lectured at a meeting organized by MSD Japan (Tokyo) and received a lecture fee. The other Authors have no conflicts of interest regarding this study.

  • Received February 6, 2022.
  • Revision received February 27, 2022.
  • Accepted March 2, 2022.

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Early Serum and Hematological Responses to Pembrolizumab Therapy as Predictors of Survival in Metastatic Urothelial Cancer
MOTOHIRO FUJIWARA, RYO FUJIWARA, TETSUYA URASAKI, TOMOHIKO OGUCHI, YOSHINOBU KOMAI, NOBORU NUMAO, SHINYA YAMAMOTO, JUNJI YONESE, TAKESHI YUASA
Anticancer Research Apr 2022, 42 (4) 2045-2051; DOI: 10.21873/anticanres.15685
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