Cancer Letters

Cancer Letters

Volume 405, 1 October 2017, Pages 29-37
Cancer Letters

Mini-review
PD-1/PD-L1 checkpoint blockades in non-small cell lung cancer: New development and challenges

https://doi.org/10.1016/j.canlet.2017.06.033Get rights and content

Highlights

  • PD-1/PD-L1 blockades present a new paradigm shift in treating NSCLC.

  • Pembrolizumab achieved great success over chemotherapy in first-line setting.

  • Combination with other treatments has the potential to achieve higher efficacy.

  • A lot of challenges need to be overcome before PD-1/PD-L1 blockades are widely used.

Abstract

PD-1/PD-L1 checkpoint blockades have dramatically changed the landscape for second-line treatment of non-small cell lung cancer (NSCLC). Based on the promising results of Keynote-024 presented so far, pembrolizumab has been approved as first-line treatment for advanced PD-L1 positive NSCLC patients. However, overall response rate (ORR) is limited to PD-1/PD-L1 checkpoint blockades when used as single agent. Combining with chemotherapy, anti-CTLA-4 antibodies, targeted therapy, radiotherapy or other treatment options is perceived as an appealing method aimed at achieving higher efficacy. There are many clinical trials on going or finished assessing the efficacy and safety of the PD-1/PD-L1 blockades alone or combining with other approaches in first-line or second-line treatments. A lot of challenges need to be overcome before PD-1/PD-L1 checkpoint blockades are widely used in the patients with NSCLC including the identification of optimal combination, treatment-related adverse effects, the high cost and lack of effective predictive markers. In this review, we focus on outlining current clinical trials and challenges for future research of PD-1/PD-L1 pathway checkpoint blockades in NSCLC.

Introduction

Immune-checkpoint blockades targeting programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) showed durable response rate and long-term survival in advanced non-small-cell lung cancer (NSCLC) [1], [2], [3], [4]. Base on the prominent results, PD-1/PD-L1 checkpoint blockades become powerful new treatment options. There are many clinical trials on going or finished assessing the efficacy and safety of the PD-1/PD-L1 blockades alone or combining with other approaches in first-line or second-line treatment. This review is focused on outlining current clinical trials and challenges for future research of PD-1/PD-L1 checkpoint blockades in NSCLC.

Section snippets

PD-1/PD-L1 blockades

PD-1 is a negative stimulatory receptor on the surface of activated T cells [5]. The binding of PD-1 to one of its ligands, PD-L1 or PD-L2 on tumor cells or tumor infiltrating immune cells, can inhibit a cytotoxic T-cell response and help tumor cells avoid T cell cytolysis and facilitate cancer formation [6], [7]. Inhibiting the interaction of PD-1 and its ligands can significantly enhance T cell function, resulting in anti-tumor activity [8], [9], [10]. Anti-PD-1 antibodies, such as nivolumab

PD-1/PD-L1 blockades in the second line

Clinical outcomes remain poor for patients with previously treated, advanced NSCLC [18]. PD-1/PD-L1 blockades were explored as an approach to improve the survival of those patients (Table 1). International, open-label, randomized trials showed superior survival and an improved safety profile versus standard docetaxel in patients with advanced, previously treated NSCLC [1], [2], [3], [4].

In CheckMate 017 trial, the overall response rate (ORR) was 20% with nivolumab versus 9% with docetaxel (p

PD-1/PD-L1 blockades in the first line

Platinum-based chemotherapy has been the standard first-line treatment for metastatic NSCLC without targetable mutations. However, the responses are rarely durable with moderate to severe toxicities [24]. A profound need exists for new treatment strategy to improve outcome with low toxicity. Nivolumab showed significant improvement of PFS and OS over dacarbazine and was approved by FDA in 2015 as a single agent for the first-line treatment of patients with BRAFV600 wild-type, unresectable or

Strategies to improve the efficacy

Up to date, the ORRs were limited to PD-1/PD-L1 checkpoint antibodies when used as single agent. Combining with other treatment was perceived as an appealing method aimed at achieving higher efficacy. Such a strategy would involve initiating the immune response enhanced by checkpoint blockades, including cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors, chemotherapy, targeted therapy, radiotherapy or other treatment options (Table 3). The combinations demonstrated antitumor activity, but

Challenges for future directions

PD-1/PD-L1 checkpoint blockade is rapidly becoming an effective therapeutic option for second line setting in NSCLC. Pembrolizumab showed promising results over standard chemotherapy in the first-line setting. However, there are a lot of challenges to be overcome before PD-1/PD-L1 checkpoint blockades are widely used in the patients with NSCLC.

Conclusion

PD-1/PD-L1 checkpoint blockades have showed promising efficacy in NSCLC. Many trials are ongoing to assess the efficacy and safety of PD-1/PD-L1 checkpoint blockades combining with chemotherapy, anti-CTLA-4 antibodies, targeted therapy, radiotherapy or other approaches. However, there are a lot of considerations to be adequately addressed. First, nivolumab did not show better efficacy over chemotherapy and only a part of PD-L1 high expression patients benefit from pembrolizumab in first line.

Funding

This work was supported by the National Natural Science Foundation of China (grant numbers 81301868, 81572970), the Special Fund for Scientific Research in the Public Interest (grant number 201402011).

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