Elsevier

Thoracic Surgery Clinics

Volume 30, Issue 2, May 2020, Pages 199-206
Thoracic Surgery Clinics

Combining Immunotherapy and Chemotherapy for Non–Small Cell Lung Cancer

https://doi.org/10.1016/j.thorsurg.2020.01.006 Get rights and content

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Key points

  • Adaptive immunity plays a major role in the prevention of tumor growth and development.

  • Platinum-based chemotherapy augments antitumor immunity by inducing immunogenic cell death, increasing tumor neo-antigen expression, and disturbing the immunosuppressive tumor microenvironment that prevents immune detection.

  • Antibodies targeting the PD-1 receptor-ligand interaction, which tumor cells exploit to evade immune detection, enhance the antitumor immune response.

  • Based on preclinical studies, there is

Introduction: overview of advanced non–small cell lung cancer treatment

Lung cancer remains the leading cause of cancer-related deaths worldwide.1 In the United States, there were an estimated 234,030 new lung cancer cases and 154,050 lung cancer–related deaths in 2018, with higher incidence and mortality in men compared with women. Non–small cell lung cancer (NSCLC) is the most common histologic subtype, accounting for approximately 85% of all lung cancer cases.2 Unfortunately, most patients with lung cancer are deemed incurable, with advanced disease at

Non–small cell lung cancer immunology and the use of checkpoint inhibition

Cancer is associated with a state of chronic inflammation, as well as severe systemic immune suppression.14 Cancer develops by accumulating genetic alterations and the loss of normal cellular regulation. These events lead to the expression of neo-antigens, a peptide bound to major histocompatibility class I (MHC-I) molecules, on the cancer cell surface, which differentiates them from normal cells.15 It is well established that evasion of immune surveillance is one of the hallmarks of cancer.16

Platinum-based chemotherapy immunomodulation and synergy with immunotherapy

Platinum-based chemotherapy augments antitumor immunity by inducing immunogenic cell death (ICD), increasing tumor neo-antigen expression and also by disturbing the immunosuppressive tumor microenvironment that prevents immune detection.6 ICD involves changes on the cell membrane that signal DCs to remove the dying cell followed by release of factors, which stimulates DC activation and maturation. Subsequently, DCs present tumor antigens to T cells creating tumor-specific effector cells.6

Clinical data combining chemotherapy with immunotherapy in nonsquamous non–small cell lung cancer

In patients with metastatic nonsquamous NSCLC, 3 trials, KEYNOTE-189, IMpower150, and IMpower130, have demonstrated improved overall survival (OS) with the addition of an anti-PD-1/PD-L1 antibody to standard chemotherapy (Table 1).

KEYNOTE-189 was a phase III trial of treatment-naïve patients with nonsquamous NSCLC without sensitizing epidermal growth factor receptor (EGFR) or anaplastic large-cell lymphoma kinase (ALK) mutations, who were randomized to receive a platinum and pemetrexed doublet

Role of immunotherapy in epidermal growth factor receptor and anaplastic large-cell lymphoma kinase mutated non–small cell lung cancer tumors

Earlier randomized trials in patients with EGFR or ALK sensitizing alterations, previously treated with a TKI, indicated that immunotherapy was less effective in the second line compared with patients with WT tumors.24, 25, 26 In fact, in patients with tumors harboring EGFR or ALK alterations, inferior outcomes were observed in those treated with immunotherapy compared with chemotherapy, as first line or after progression on a TKI, regardless of their PD-L1 expression.27,28 However, in the more

Trial data combining chemotherapy with immunotherapy in squamous non–small cell lung cancer

In patients with metastatic squamous NSCLC, the KEYNOTE-407 trial demonstrated improved survival in patients treated with the combination of pembrolizumab and a standard platinum doublet (see Table 1).13 This was a phase III trial in treatment-naïve patients randomized to receive carboplatin and the physician’s choice of either paclitaxel or nab-paclitaxel in addition to pembrolizumab or placebo for 4 cycles, followed by pembrolizumab or placebo maintenance. There was improvement in the

Outline of active treatment protocols

Currently, per National Comprehensive Cancer Network guidelines, platinum-based chemotherapy combined with immunotherapy is considered the preferred, category 1, treatment for most cases of advanced or metastatic NSCLC.30 Patients with metastatic adenocarcinoma, not harboring a driver mutation in EGFR, ALK, ROS1, or BRAF V600 E, and with PDL1 TPS <50%, should receive systemic triplet therapy with carboplatin or cisplatin and pemetrexed combined with pembrolizumab or quadruple therapy with

Summary

During the past decade, there has been significant advancement in the treatment of lung cancer, including the identification of targetable oncogenic driver mutations and more recently with the development of immunotherapeutic agents. It is well established that adaptive immunity plays a major role in the prevention of tumor growth. However, tumor cells exploit mechanisms of self-tolerance, including the PD1/PD-L1 interaction, causing immunosuppression. Antibodies targeting PD-1 and PD-L1 have

Disclosure

J. Judd has nothing to disclose. H. Borghaei has research support from Millennium, Merck/Celgene, and BMS/Lilly; Advisory Board role/Consultant for BMS, Lilly, Genentech, Celgene, Pfizer, Merck, EMD-Serono, Boehringer Ingelheim, Astra Zeneca, Novartis, Genmab, Regeneron, BioNTech, Cantargia AB, Amgen, AbbVie, Axiom, PharmaMar, Takeda, Huya Bio; and Data and Safety Monitoring Board role with University of Pennsylvania CAR T Program and Takeda.

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