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Immune checkpoint inhibitors for small cell lung cancer: opportunities and challenges.

ABSTRACT: Lung cancer is the most common cancer and the leading cause of cancer death worldwide, with an estimated 2.1 million new cases and 1.8 million deaths in 2018. Although small cell lung cancer (SCLC) is the most aggressive type of lung cancer, it shows high response rates to chemotherapy in early lines of therapy. Unfortunately, it is associated with rapid recurrence and relatively poor prognosis. Over the last few years, considerable progress has been made in cancer immunotherapy. One of the most promising ways to activate therapeutic antitumor immunity is via blockade of immune checkpoints, such as cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein-1/programmed cell death ligand-1 (PD-1/PD-L1). Immune checkpoint inhibitors show promise as SCLC therapeutics. The overall expectation for immuno-oncology is high, and the outcomes of trials will hopefully reveal a variety of treatment options for SCLC patients. In this review, we discuss the discovery of new immune inhibitory and stimulatory pathways and rational combination strategies to explain the role of immunotherapy in SCLC and its future opportunities and challenges.

SUBMITTER: Regzedmaa O

PROVIDER: S-EPMC6580132 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Immune checkpoint inhibitors for small cell lung cancer: opportunities and challenges.

Regzedmaa Orgilmaa O Zhang Hongbing H Liu Hongyu H Chen Jun J

OncoTargets and therapy 20190613

Lung cancer is the most common cancer and the leading cause of cancer death worldwide, with an estimated 2.1 million new cases and 1.8 million deaths in 2018. Although small cell lung cancer (SCLC) is the most aggressive type of lung cancer, it shows high response rates to chemotherapy in early lines of therapy. Unfortunately, it is associated with rapid recurrence and relatively poor prognosis. Over the last few years, considerable progress has been made in cancer immunotherapy. One of the most ...[more]

PMID: 31354294

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Project description:Hepatocellular carcinoma (HCC) is the most common malignancy worldwide, and is especially common in China. A total of 70%-80% of patients are diagnosed at an advanced stage and can receive only palliative care. Sorafenib has been the standard of care for a decade, and promising results for regorafenib as a second-line and lenvatinib as a first-line treatment were reported only 1 or 2 years ago. FOLFOX4 was recently recommended as a clinical practice guideline by the China Food and Drug Administration. All approved systemic therapies remain unsatisfactory, with limited objective response rates and poor overall survival. Immune checkpoint inhibitors (CPIs) offer great promise in the treatment of a rapidly expanding spectrum of solid tumors. Immune checkpoint molecules are involved in almost the whole process of viral-related hepatitis with cirrhosis and HCC and in the most important resistance mechanism of sorafenib. The approval of nivolumab by the U.S. Food and Drug Administration on September 23, 2017, for the treatment of patients with HCC, based only on a phase I/II clinical trial, is a strong hint that immunotherapy will introduce a new era of HCC therapy. CPI-based strategies will soon be a main approach in anticancer treatment for HCC, and we will observe the rapid advances in the therapeutic use of CPIs, even in an adjuvant setting, with great interest. How shall we face the opportunities and challenges? Can we dramatically improve the prognosis of patients with HCC? This review may provide some informed guidance. IMPLICATIONS FOR PRACTICE: Immune checkpoint molecules are involved in almost the whole process of viral-related hepatitis with cirrhosis and hepatocellular carcinoma (HCC) and in the most important resistance mechanism of sorafenib. As all approved systemic therapies in HCC remain unsatisfactory, checkpoint inhibitor (CPI)-based strategies will soon be a main approach in anticancer treatment for advanced stage of HCC, even in an adjuvant setting. In virus-related HCC, especially hepatitis B virus-related HCC, whether CPIs can control virus relapse should be further investigated. Combination strategies involving conventional therapies and immunotherapies are needed to increase clinical benefit and minimize adverse toxicities with regard to the underlying liver disease.

Project description:Histological transformation of oncogene-driven lung adenocarcinoma to small cell lung cancer (SCLC) following treatment with tyrosine kinase inhibitors (TKIs) is a well-described phenomenon. Whether a similar transformation may drive acquired resistance to immune checkpoint inhibitors (ICPIs) in non-SCLC (NSCLC) is uncertain. Hence, tissue biopsies are not universally recommended at progression of NSCLC on ICPIs, unlike TKIs. We report a case of a woman in her mid-60s with a 35 pack-years tobacco history and stage IV squamous cell lung carcinoma with no targetable genomic alterations, whose disease progressed within 4 months of first line carboplatin/gemcitabine therapy. Her treatment was switched to second line nivolumab monotherapy which resulted in sustained partial response lasting 21 months. She subsequently developed rapid, bulky progression of mediastinal disease. Biopsy showed transformation to SCLC. Comparison of genomic profiling results from the initial NSCLC diagnosis and SCLC transformation revealed near-identical tumor profiles. Her disease responded to next line carboplatin/etoposide, though lasting for only 10 months. She died 14 months after detection of neuroendocrine transformation of her NSCLC. We performed a systematic review of the literature to identify similar cases of NSCLC-to-small cell transformation on ICPIs. Nine patients, including our index case, were identified, with seven (77.8%) on nivolumab and two (22.2%) on pembrolizumab monotherapy. Median survival time since small cell transformation was 13.0 months (95% CI 2.0 to 16.0). Using our patient case as a framework, we further discuss the lack of consensus criteria to distinguish small cell transformation from de novo metachronous SCLC. Histological transformation to SCLC is a potential mechanism of acquired resistance to ICPIs in NSCLC. Repeat tissue biopsies should be considered at the time of progression, similar to oncogene-directed therapies. Prospective larger studies are warranted to further characterize NSCLC-to-small cell transformation on ICPIs using molecular fingerprinting with paired tumor genomic profiles, evaluation of neuroendocrine features at baseline and consideration of initial response.

Dataset Information

Immune checkpoint inhibitors for small cell lung cancer: opportunities and challenges.

Publications

Immune checkpoint inhibitors for small cell lung cancer: opportunities and challenges.

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