Effect of region on the Outcome of Patients Receiving PD-1/PD-L1 Inhibitors for Advanced Cancer
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.
References (38)
- et al.
Targeting T cell co-receptors for cancer therapy
Immunity
(2016) - et al.
Immune-related adverse events with immune checkpoint blockade: a comprehensive review
Eur. J. Cancer
(2016) - 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) - et al.
Immune-related adverse events from combination immunotherapy in cancer patients: a comprehensive meta-analysis of randomized controlled trials
Int. Immunopharmacol.
(2018) - et al.
Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study
Lancet Oncol.
(2010) - et al.
Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial
Lancet (London, England)
(2016) - et al.
Updated efficacy analysis including secondary population results for OAK: a randomized phase III study of atezolizumab versus docetaxel in patients with previously treated advanced non-small cell lung cancer
J. Thorac. Oncol.
(2018) - et al.
Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial
Lancet Oncol.
(2015) - et al.
Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial
Lancet (London, England)
(2017) - et al.
Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial
Lancet (London, England)
(2018)
Efficacy and safety of CTLA-4 inhibitors combined with PD-1 inhibitors or chemotherapy in patients with advanced melanoma
Int. Immunopharmacol.
The PD-1 pathway in tolerance and autoimmunity
Immunol. Rev.
Immune checkpoint blockade in cancer therapy
J. Clin. Oncol.
The future of immune checkpoint therapy
Science
The blockade of immune checkpoints in cancer immunotherapy
Nat. Rev. Cancer
Cancer immunotherapy comes of age
Nature
The PD-1/PD-L1 pathway in human pathology
Curr. Mol. Med.
Immunostimulatory monoclonal antibodies for cancer therapy
Nat. Rev. Cancer
Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer
J. Clin. Oncol.
Cited by (8)
Identification of Five m6A-Related lncRNA Genes as Prognostic Markers for Endometrial Cancer Based on TCGA Database
2022, Journal of Immunology ResearchComparison of efficacy outcomes of anticancer drugs between Japanese patients and the overall population
2021, International Journal of Clinical Oncology
- 1
These authors contributed equally to this study.