Immune Checkpoint Inhibitors for Patients With Advanced Non–Small-Cell Lung Cancer: A Systematic Review

doi:10.1016/j.cllc.2017.02.001

Clinical Lung Cancer

Volume 18, Issue 5, September 2017, Pages 444-459.e1

https://doi.org/10.1016/j.cllc.2017.02.001 Get rights and content

Abstract

Second-line treatment options are limited for patients with advanced non–small-cell lung cancer (NSCLC). Standard therapy includes the cytotoxic agents docetaxel and pemetrexed, and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors erlotinib and gefitinib. Immune checkpoint inhibitors are a new class of treatment that have shown durable overall radiologic response rates and have been well tolerated. The objective of this systematic review was to investigate the efficacy of immune checkpoint inhibitors compared with other chemotherapies in patients with advanced NSCLC. Medline, Embase, and PubMed were searched for randomized controlled trials comparing treatment with immune checkpoint inhibitors against treatment with chemotherapy in patients with stage IIIB or IV NSCLC. Nine randomized controlled trials with 15 publications were included. A significant overall survival benefit of second-line nivolumab (nonsquamous: hazard ratio [HR] = 0.72, 95% confidence interval [CI], 0.60-0.77; P < .001; squamous: HR = 0.59, 95% CI, 0.44-0.79; P < .001) or second-line atezolizumab (HR = 0.73, 95% CI, 0.62-0.87; P = .0003) or second-line pembrolizumab (in patients with programmed cell death ligand 1 [PD-L1]-positive tumors) (pembrolizumab 2 mg/kg HR = 0.71, 95% CI, 0.58-0.88; P = .0008; pembrolizumab 10 mg/kg HR = 0.61, 95% CI, 0.49-0.75; P < .0001) or first-line pembrolizumab (HR = 0.60, 95% CI, 0.41-0.89; P = .005) compared with chemotherapy was found. The adverse effects were mainly higher in the chemotherapy arms. For patients with advanced stage IIIB/IV NSCLC, the improvement in overall survival outweighed the harms and supported the use of first-line pembrolizumab (in patients with ≥ 50% PD-L1–positive tumors) or second-line nivolumab, atezolizumab, or pembrolizumab (in patients with PD-L1–positive tumors).

Introduction

Lung cancer is the leading cause of cancer-related death in Canada.¹ Non–small-cell lung cancer (NSCLC) is the most common subtype and is often diagnosed at later stages.² There are few options for second-line therapy for patients with advanced NSCLC. The current standard second-line therapies for patients with advanced NSCLC are the cytotoxic agents docetaxel and pemetrexed, and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors erlotinib and gefitinib.³

A new class of treatment that targets the immune system has shown promising results in phase 1 and 2 studies. Immune checkpoint inhibitor antibodies such as nivolumab, atezolizumab, and pembrolizumab inhibit programmed cell death 1 (PD-1)-mediated signaling by blocking PD-ligand 1 from binding to PD-1, allowing T-cell activation and immune system recognition. These antibodies assist in restoring antitumor activity. Other immune checkpoint inhibitors, such as ipilimumab, prevent the activation of CTLA-4 and thereby aid in restoring immune function. Phase 1 and 2 studies with immune checkpoint inhibitors have shown durable overall radiologic response rates in the 20% to 25% range for NSCLC and have been well tolerated.4, 5

The objective of this systematic review was to investigate the efficacy of immune checkpoint inhibitors compared with other chemotherapies in patients with incurable stage IIIB and stage IV NSCLC. Cancer Care Ontario's (CCO's) Program in Evidence-Based Care, together with CCO's Lung Cancer Disease Site Group, developed this evidentiary base to inform recommendations as part of a clinical practice guideline. Based on the objective of this systematic review, we derived the following research question: Do immune checkpoint inhibitors improve patient outcomes compared with chemotherapy in patients with advanced NSCLC?

Section snippets

Search for Existing Systematic Reviews

The recent systematic review by American Society of Clinical Oncology (ASCO) was used as the evidence base to inform the recommendations of a clinical practice guideline for systemic treatment for patients with NSCLC.⁶ A search for systematic reviews that compared the efficacy of immune checkpoint inhibitors with chemotherapy was conducted since the time of ASCO's literature search.

Literature Search Strategy

The search for primary literature was conducted to update ASCO's literature search to compare immune checkpoint

Search for Systematic Reviews

No systematic reviews were found that addressed the research question and included studies that met our inclusion and exclusion criteria.

Literature Search Results

A total of 2086 citations were identified. Twenty-one were selected for full text review. Of those, 7 fully published RCTs9, 10, 11, 12, 13, 14, 15 and 3 abstracts16, 17, 18 met the predefined eligibility criteria for this systematic review. Five abstracts were included from the European Society of Medical Oncology (ESMO) conference proceedings.19, 20, 21, 22,

Discussion

Second- or third-line therapy with immune checkpoint inhibitors appears to have a more favorable impact on patient outcomes compared with chemotherapy. There is convincing evidence that second-line therapy with nivolumab, pembrolizumab, and atezolizumab improves survival compared with docetaxel. The magnitude of benefit of all 3 agents appears similar. Improved median OS was found in patients with either squamous or nonsquamous histology who received second- or third-line nivolumab or

Conclusion

In patients with advanced-stage IIIB/IV NSCLC whose disease has progressed after receiving platinum-based chemotherapy, there is evidence from phase 3 trials for an improvement in OS that outweighs the harm to support the use of nivolumab, atezolizumab, or pembrolizumab (in patients with PD-L1–positive tumors) after failure of platinum-based chemotherapy. There is insufficient evidence to select patients on the basis of the level of PD-L1 expression and to recommend other immune checkpoint

Disclosure

P.M.E. was an author of the ASCO guideline for stage IV NSCLC and is a member of a data safety monitoring committee for Celgene for a trial evaluating maintenance therapy with Abraxane. The other authors have stated that they have no conflict of interest.

Acknowledgments

We thank Fulvia Baldasarre, Melissa Brouwers, Laurie Elit, Glenn Fletcher, Sheila McNair, Hans Messersmith, and Shailendra Verma for providing feedback on draft versions of this systematic review. Jimmy Zhang conducted a data audit. The Program in Evidence-Based Care (PEBC) is a provincial initiative of CCO supported by, and editorially independent from, the Ontario Ministry of Health and Long-Term Care.

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ReviewImmune Checkpoint Inhibitors for Patients With Advanced Non–Small-Cell Lung Cancer: A Systematic Review

Abstract

Introduction

Section snippets

Search for Existing Systematic Reviews

Literature Search Strategy

Search for Systematic Reviews

Literature Search Results

Discussion

Conclusion

Disclosure

Acknowledgments

J Clin Epidemiol

Lancet

Lancet Oncol

Eur J Cancer

Eur J Cancer

Lancet

Canadian cancer statistics, 2001

Lung cancer

Second-line therapy for advanced NSCLC

Oncologist

Update on immune checkpoint inhibitors in lung cancer

Cancer Control

Nivolumab in NSCLC: latest evidence and clinical potential

Ther Adv Med Oncol

Systemic therapy for stage IV non–small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline update

J Clin Oncol

The Cochrane Collaboration's tool for assessing risk of bias in randomised trials

BMJ

Review
Immune Checkpoint Inhibitors for Patients With Advanced Non–Small-Cell Lung Cancer: A Systematic Review