Effect of region on the Outcome of Patients Receiving PD-1/PD-L1 Inhibitors for Advanced Cancer

https://doi.org/10.1016/j.intimp.2019.105709Get rights and content

Highlights

  • This is the first study to explore the potential effect of regional difference on cancer immunotherapy efficacy.

  • PD-1/L1 inhibitors significantly improved OS and PFS in both North American and European patients.

  • North American patients benefited more PD-1/L1 inhibitors than European patients.

Abstract

Background

Regional differences were associated with cancer incidence and mortality. However, the correlation between regional differences and cancer immunotherapy efficacy was still not evaluated. In this study, we performed a meta-analysis to investigate whether regional differences play a role in efficacy of PD-1/L1 inhibitors in cancer patients.

Methods

A meticulous review of relevant randomized controlled trials that were sourced from the PubMed, Embase and MEDLINE databases. Overall survival (OS) and progression-free survival (PFS) were the primary outcome and secondary outcome in our study, respectively. We also assessed difference on the hazard ratio (HR) between European and North American groups.

Results

A total of 14 randomized clinical trials including 9387 patients were finally eligible for meta-analysis in our study. With respect to the pooled HR in treatment with PD-1/L1 inhibitors, North American patients presented OS as 0.60 (95% CI 0.53 to 0.67), and PFS as 0.49 (95% CI 0.40 to 0.59), whereas European patients presented OS as 0.76 (95% CI 0.62 to 0.90), and PFS as 0.58 (95% CI 0.44 to 0.72), relative to their corresponding control groups. OS efficacy thus varied significantly (Pheterogeneity = 0.028) between North American and European patients when treated with PD-1/L1 inhibitors.

Conclusions

Our findings were very surprising especially considering the higher prevalence of cancer in Europe. Although PD-1/L1 inhibitors improved OS and PFS in both North American and European patients compared with controls, the magnitude of benefit was region-dependent. North American patients can benefit more from PD-1/L1 inhibitors than European patients. More researches were urgently demanded to explore its potential molecular mechanisms.

Introduction

Over the past decades, the development of immunology and cancer biology has brought hope to decipher the mechanisms of tumor-induced immune tolerance [[1], [2], [3], [4]]. The passive immunotherapy has shown significant clinical benefits against multiple solid and hematological malignancies, such as the transfer of tumor-targeted mono-antibodies and donor T cells. While active immunotherapy aim to improve anti-tumor effects through enhancing self-immunity [[5], [6], [7]]. Unfortunately, cancer cells always continuously exploit a variety of pathways to evade immune attack. Of these, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein-1 (PD-1) receptor pathways were considered as the two most important immunosuppressive pathways, which are referred to as “immune checkpoints” [8,9]. Several immune checkpoint inhibitors (ICIs) have been developed to block these immunosuppressive pathways to enhance anti-tumor immune responses, and have demonstrated a significantly prolonged survival in cancer patients compared to traditional therapies. The discovery of PD-1/L1 and CTLA-4 inhibitors has been undoubtedly a definitive breakthrough in cancer immunotherapy [[11], [12], [13], [14], [15]]. It is estimated that nearly half of all cases and more than half of all cancer deaths will occur in Asia by 2018, partly because nearly 60% of the global population lives there. Although European population accounts for only 9% of the global population, the incidence of cancer accounts for 23.4% of all cancer cases and 20.3% of all cancer deaths. Furthermore, The Americas regions have 21% morbidity and 14.4% mortality among all cancers. Regional differences on cancer morbidity and mortality are mainly related to economic levels and lifestyles in different regions [16]. However, the correlation between regional differences and immunotherapy efficacy in cancer patients was still not evaluated. In this study, we performed a meta-analysis based on existed clinical data to systemically explore whether regional differences have potential effect on efficacy of PD-1/L1 inhibitors.

Section snippets

Search strategy and study selection

Our meta-analysis was based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. We comprehensively searched for relevant clinical trials which compared immune checkpoint inhibitors with control group on PubMed, Medline, Embase, Google Scholar and Web of Science. September 2018 was the cut-off date. Key words included “nivolumab”, “pembrolizumab”, “atezolizumab”, “avelumab”, “durvalumab”, and “PD-1”. Two investigators, ZHW and SQR, independently reviewed

Search results and patient characteristics

In total, 10,256 publications were selected via searching the above-mentioned database and reference lists, eventually identifying 56 potentially relevant studies. A full review of abstracts and articles, as per the selection criteria, further condensed this to a final of 14 studies for evaluation, which comprised twelve 3-phased, and two 2-phased trials. The number of studies, with the drug investigated, are respectively listed herewith: 4, nivolumab; 4, pembrolizumab; 2, atezolizumab; 1,

Discussion

Although immune checkpoint inhibitors targeting CTLA-4 and PD-1 have demonstrated higher efficacy compared to standard of care chemotherapeutic approaches in several solid and hematologic malignancies, not all patients benefit from this promising therapy, with objective response rate lower than 30% [[34], [35]]. Recent studies revealed that the efficacy of immune checkpoint inhibitors could correlate with special patient population, such as older patients and smoking patients [[36], [37]].

Conclusions

In conclusion, our meta-analysis showed that PD-1/L1 inhibitors can significantly prolong patients' OS and PFS compared to controls, but the magnitude of benefit was region-dependent. North American patients benefited more from PD-1/L1 inhibitors than European patients. More studies were urgently demanded to explore its potential molecular mechanisms.

Funding

Scientific Research Projects of Wuxi Health Planning Commission (Z201703Z201703), Wuxi, Jiangsu, China; The National Undergraduate Training Programs for Innovation (Nantong university, 201910304030Z; 201910304028Z), China; Training Program of Innovation and Entrepreneurship for College Students in Jiangsu (NO. 201913993001Y and 201913993021H), Jiangsu, China.

Declaration of Competing Interest

None.

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  • 1

    These authors contributed equally to this study.

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