KEYNOTE-028: how do we use immunotherapy in small cell lung cancer?
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ABSTRACT:
SUBMITTER: Pacheco JM
PROVIDER: S-EPMC5750157 | biostudies-literature | 2017 Dec
REPOSITORIES: biostudies-literature
Publications
KEYNOTE-028: how do we use immunotherapy in small cell lung cancer?
Pacheco Jose M JM Camidge D Ross DR
Translational lung cancer research 20171201 Suppl 1
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Project description:Small-cell lung cancer (SCLC) is an aggressive tumor type with limited therapeutic options and poor prognosis. Chemotherapy regimens containing platinum represent the cornerstone of treatment for patients with extensive disease, but there has been no real progress for 30 years. The evidence that SCLC is characterized by a high mutational burden led to the development of immune-checkpoint inhibitors as single agents or in combination with chemotherapy. Randomized phase III trials demonstrated that the combination of atezolizumab (IMpower-133) or durvalumab (CASPIAN) with platinum-etoposide chemotherapy improved overall survival of patients with extensive disease. Instead, the KEYNOTE-604 study demonstrated that the addition of pembrolizumab to chemotherapy failed to significantly improve overall survival, but it prolonged progression-free survival. The safety profile of these combinations was similar with the known safety profiles of all single agents and no new adverse events were observed. Nivolumab and pembrolizumab single agents showed anti-tumor activity and acceptable safety profile in Checkmate 032 and KEYNOTE 028/158 trials, respectively, in patients with SCLC after platinum-based therapy and at least one prior line of therapy. Future challenges are the identification predictive biomarkers of response to immunotherapy in SCLC and the definition of the role of immunotherapy in patients with limited stage SCLC, in combination with radiotherapy or with other biological agents.
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Project description:Small cell lung cancer (SCLC) is a "refractory cancer" characterized by rapid growth and extensive early metastasis. About 70% of patients are already in the extensive stage at the time of diagnosis. Despite the high response rate to platinum-contained first-line chemotherapy, almost all patients subsequently experienced inevitable recurrence and had poor response to second-line treatment. The high mutation load and immunogenicity of SCLC suggest that immunotherapy may be effective for SCLC patients. Over the past few years, several clinical trials have evaluated the efficacy of checkpoint inhibitors [mainly cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed death 1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors] in SCLC patients and demonstrated promising survival prospects. This article reviewed the clinical studies of immune checkpoint inhibitors (ICIs) in the first-line, maintenance and second or more line treatment of SCLC. Besides, predictive biomarkers were discussed to select suitable patients for immunotherapy effectively.
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Project description:Small cell lung cancer (SCLC) remains a poorly understood disease with aggressive features, high relapse rates, and significant morbidity as well as mortality, yet persistently limited treatment options. For three decades, the treatment algorithm of SCLC has been stagnant despite multiple attempts to find alternative therapeutic options that could improve responses and increase survival rates. On the other hand, immunotherapy has been a thriving concept that revolutionized treatment options in multiple malignancies, rendering previously untreatable diseases potentially curable. In extensive stage SCLC, immunotherapy significantly altered the course of disease and is now part of the treatment algorithm in the first-line setting. Nevertheless, the important questions that arise are how best to implement immunotherapy, who would benefit the most, and finally, how to enhance responses.
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Project description:Small cell lung cancer (SCLC) is an aggressive malignancy. Until recently the standard of care for newly diagnosed patients with extensive-stage disease was chemotherapy consisting of etoposide plus a platinum (EP). The median overall survival (OS) was only about 10 months with this systemic therapy. Immune checkpoint inhibitors were first evaluated as second or subsequent line treatments in extensive stage disease and later in combination with EP in the first-line setting. Recently two randomized phase III trials have demonstrated statistically improved OS with addition of a programmed death ligand-1 (PD-L1) inhibitor to EP. As a result, the standard of care for newly diagnosed patients with extensive-stage SCLC has changed for the first time in decades. However, many patients do not derive benefit from the addition of a PD-L1 inhibitor to EP. In this review we discuss first-line trials of chemoimmunotherapy in extensive stage SCLC and summarize data on second and subsequent line treatment with immune checkpoint inhibitors in immunotherapy-naïve patients. Additionally, we discuss potential biomarkers that could be utilized to select for which patients derive benefit from addition of a PD-L1 inhibitor to EP and propose ways to improve on first-line chemoimmunotherapy.
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Project description:Small cell lung cancer (SCLC), composing 15-20% of lung cancer, is a fatal disease with extremely poor prognosis. In the past two decades, etoposide platinum doublet chemotherapy remained the only choice of therapy, with disappointing overall survival ≤1 year for the metastatic disease. Novel treatments including immunotherapy are urgently needed and extensively explored. Recently, in two phase III trials, atezolizumab and durvalumab were shown to bring survival benefit to patients. While immunotherapy brings better outcome, it is accompanied by adverse events different from traditional treatments. Although these immune-related adverse events (irAEs) are generally mild and can be managed, some irAEs (myocarditis, pneumonitis) may be severe and even life-threatening. Accompanying with the increasing application of immunotherapy in clinical practice, the irAEs should not be overlooked. In this review, the irAEs profile in clinical trials of immunotherapy for SCLC will be summarized, also its unique features compared with irAEs in other malignancies will be explored. This review may be helpful for the appropriate clinical use of immunotherapy for SCLC.
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Project description:Small-cell lung cancer (SCLC) is a special type of lung cancer that belongs to highly aggressive neuroendocrine tumors. At present, radiotherapy and chemotherapy remain the mainstay of treatment for SCLC. Progress in targeted therapies for SCLC with driver mutations has been slow, and these therapies are still under investigation in preclinical or early-phase clinical trials, and research on antiangiogenic tyrosine kinase inhibitors (e.g., anlotinib) has achieved some success. Immunotherapy is becoming an important treatment strategy for SCLC after radiotherapy and chemotherapy. In this article we review the recent advances in immunotherapy for SCLC.
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Project description:Targeted therapies that deliver the expected anti-tumor effects while mitigating the adverse effects are taking the cancer world by storm. The need for such therapies in non-small cell lung cancer (NSCLC), where systemic cytotoxic chemotherapies still remain the backbone of management, is felt more than ever before. Runway success of immunotherapies such as Ipilimumab for melanoma has brought excitement among oncologists. Immune-based treatments are in various stages of evaluation for NSCLC as well. Immunotherapies using strategies of antigen based or cell based vaccines, and blocking immune checkpoints are of substantial interest. Meaningful clinical responses are yet to be reaped from these new treatment modalities.
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Project description:Immunotherapy has markedly improved the survival rate of patients with non-small cell lung cancer (NSCLC) and has introduced a new era in lung cancer treatment. However, not all patients with lung cancer benefit from checkpoint blockade, and some suffer from notable immunotoxicities. Thus, it is crucial to identify potential biomarkers suitable for screening the population that may benefit from immunotherapy. Based on the current clinical trials, the aim of the present study was to review the biomarkers for immune checkpoint inhibition, as well as other effective, invalid and hyperprogression markers that may have the potential to better predict responders to immunotherapy among patients with NSCLC. All these biomarkers may be incorporated into the predictive utility of bio-score systems and decision-making algorithms, to better guide the application of immunotherapy in the clinical setting.
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