Updates on Molecular Targeted Therapies for Intraparenchymal CNS Metastases

Central nervous system (CNS) metastases can occur in a high percentage of systemic cancer patients and is a major cause of morbidity and mortality in these patients. Almost any histology can find its way to the brain, but lung, breast, and melanoma are the most common pathologies seen in the CNS from metastatic disease. Identification of many key targets in the tumorigenesis pathway has been crucial to the development of a number of drugs that have demonstrated successful penetration of the blood–brain, blood–cerebrospinal fluid, and blood–tumor barriers. Targeted therapy and immunotherapy have dramatically revolutionized the field with treatment options that can provide successful and durable control of even CNS disease. In this review, we discuss major targets with successful treatment options as demonstrated in clinical trials. These include tyrosine kinase inhibitors, monoclonal antibodies, and antibody–drug conjugates. We also provide an update on the state of the field and highli..... READ ARTICLE

Cancers DOI:10.3390/cancers14010017

Authors: Akanksha Sharma, Lauren Singer, Priya Kumthekar

Immunotherapy and Vaccination in Surgically Resectable Non-Small Cell Lung Cancer (NSCLC)

Early-stage NSCLC (stages I and II, and some IIIA diseases) accounts for approximately 30% of non-small cell lung cancer (NSCLC) cases, with surgery being its main treatment modality. The risk of disease recurrence and cancer-related death, however, remains high among NSCLC patients after complete surgical resection. In previous studies on the long-term follow-up of post-operative NSCLC, the results showed that the five-year survival rate was about 65% for stage IB and about 35% for stage IIIA diseases. Platinum-based chemotherapy with or without radiation therapy has been used as a neoadjuvant therapy or post-operative adjuvant therapy in NSCLC, but the improvement of survival is limited. Immune checkpoint inhibitors (ICIs) have effectively improved the 5-year survival of advanced NSCLC patients. Cancer vaccination has also been explored and used in the prevention of cancer or reducing disease recurrence in resected NSCLC. Here, we review studies that have focused on the use of immunotherapies (i.e., ICIs and vaccination) in surgically resectable NSCLC. We present the results of completed clinical trials that have used ICIs as neoadjuvant therapies in pre-operative NSCLC. Ongoing clinical trials investigating ICIs as neoadjuvant and adjuvant therapies are also summarized. READ ARTICLE

Vaccines DOI: 10.3390/vaccines9070689

Authors: Chiu L.-C., Lin S.-M., Lo Y.-L., Kuo S.C.-H., Yang C.-T. and Hsu P.-C.

Lung Cancer Stem Cells—Origin, Diagnostic Techniques and Perspective for Therapies

Lung cancer is still a serious oncological problem worldwide. Thus, the biology of this cancer is of interest. Cancer stem cells (CSCs) are involved in tumor initiation and progression. Spontaneously occurring mutations accumulate in stem cells or/and progenitor cells throughout a person’s lifetime resulting in the formation of CSCs. In this review, we discuss the CSC hypothesis with an emphasis on age-associated changes that govern carcinogenesis. The evidence from the scientific literature, as well as our own results and observations, has been presented. READ ARTICLE

Cancers DOI: 10.3390/cancers13122996

Authors: Agata Raniszewska, Iwona Kwiecie, Elzbieta Rutkowska, Piotr Rzepecki and Joanna Domagała-Kulawik

Review Paper, group5Kirk SmithJune 15, 2021NSCLC, cancer stem cells, liquid biopsy, immunotherapy, aging, biopsy

Immunotherapy for ALK-Rearranged Non-Small Cell Lung Cancer: Challenges Inform Promising Approaches

Review Paper describing the mechanisms of ALK aberrations in non-small cell lung cancer by which an immunosuppressed tumor microenvironment is created, leading to host immune evasion. Reports pre-clinical and clinical studies evaluating novel immunotherapeutic approaches and describes the promises and challenges of incorporating immune-based treatments for ALK-rearranged non-small cell lung cancer. READ ARTICLE

Cancers DOI: 10.3390/cancers13061476

Authors: Kamya Sankar, Sunitha Nagrath, Nithya Ramnath

Review PaperKirk SmithMarch 1, 2021ALK, ALK-rearrangements, NSCLC, TKI, immune evasion, immunotherapy, cancer vaccine

Therapeutic Strategies to Overcome ALK Resistance in Cancer

Therapeutic Strategies to Overcome ALK Resistance in Cancer, Volume 13, presents current strategies to improve and prolong clinical benefit in ALK driven cancers. Most patients with ALK-driven cancer are sensitive to tyrosine kinase inhibitor (TKI) therapy, but resistance invariably develops. This book discusses topics such as structure and function of ALK, ALK rearranged lung cancer, resistance mechanisms to ALK TKI tumors, and novel therapeutic strategies to enhance crizotinib anti-tumor efficacy in ALCL. Additionally, it encompasses information on drug combinations to enhance ALK TKI anti-tumor efficacy in neuroblastoma and future perspectives in the field. This book is a valuable resource for cancer researchers, clinicians and several members of biomedical field who need to understand more about how to fight ALK resistance in cancer treatment. READ ARTICLE

Academic Press DOI: 10.1016/C2019-0-03295-5

Edited by: Luc Friboulet

Treatment of Brain Metastases of Non-Small Cell Lung Carcinoma

Lung cancer is one of the most common malignant neoplasms. As a result of the disease’s progression, patients may develop metastases to the central nervous system. The prognosis in this location is unfavorable; untreated metastatic lesions may lead to death within one to two months. Existing therapies—neurosurgery and radiation therapy—do not improve the prognosis for every patient. The discovery of Epidermal Growth Factor Receptor (EGFR)—activating mutations and Anaplastic Lymphoma Kinase (ALK) rearrangements in patients with non-small cell lung adenocarcinoma has allowed for the introduction of small-molecule tyrosine kinase inhibitors to the treatment of advanced-stage patients. The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein with tyrosine kinase-dependent activity. EGFR is present in membranes of all epithelial cells. In physiological conditions, it plays an important role in the process of cell growth and proliferation. Binding the ligand to the EGFR causes ..... READ ARTICLE

International Journal of Molecular Science DOI:10.3390/ijms22020593

Authors: Agnieszka Rybarczyk-Kasiuchnicz, Rodryg Ramlau, and Katarzyna Stencel

Immunotherapy in EGFR-Mutant and ALK-Positive Lung Cancer

Non-small cell lung cancer (NSCLC) is a heterogeneous disease, commonly
defined by genetic alterations in oncogenic drivers. Targeted therapies
have transformed the management of oncogene-driven lung cancers, with
targeted agents now approved in the United States for 7 distinct
molecular alterations. Nonetheless, acquired resistance remains an
ongoing challenge, underscoring the need for alternative therapeutic
approaches. Immune checkpoint inhibitors targeting the programmed cell
death 1 (PD-1) axis have emerged as important therapies in the
management of advanced NSCLC, but the role of these agents in patients
with oncogenic driver mutations remains unclear. Here, we focus on
epidermal growth factor receptor-mutant and anaplastic lymphoma
kinase-rearranged NSCLC as paradigms to explore the role of immune
checkpoint inhibitors in oncogene-driven NSCLC. We provide an overview
of the clinical data examining programmed death ligand 1 (PD-L1)
inhibitor monotherapy, PD-(L)1 inhibitors, and tyrosine kinase inhibitor
combinations, as well as combinations of PD-(L)1 inhibitors and
chemotherapy. READ ARTICLE

Cancer Journal DOI:10.1097/PPO.0000000000000491

Authors: Gavralidis A, Gainor JF

Review PaperKirk SmithDecember 1, 2020ALK, EGFR, immunotherapy, oncogenic-driver, PD-1

Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) patients bearing targetable oncogene alterations typically derive limited benefit from immune checkpoint blockade (ICB), which has been attributed to low tumor mutation burden (TMB) and/or PD-L1 levels. We investigated oncogene-specific differences in these markers and clinical outcome.
We concluded that high TMB and PD-L1 expression are predictive for benefit from ICB treatment in oncogene-driven NSCLCs. NSCLC harboring BRAF mutations demonstrated superior benefit from ICB that may be attributed to higher TMB and higher PD-L1 expression in these tumors. Meanwhile EGFR and HER2 mutations and ALK, ROS1, RET, and MET fusions define NSCLC subsets with minimal benefit from ICB despite high PD-L1 expression in NSCLC harboring oncogene fusions. These findings indicate a TMB/PD-L1-independent impact on sensitivity to ICB for certain oncogene alterations. READ ARTICLE

Journal for ImmunoTherapy of Cancer DOI:10.1136/jitc-2021-002891

Authors: Marcelo V Negrao, Ferdinandos Skoulidis, Meagan Montesion, Katja Schulze, Ilze Bara, Vincent Shen, Hao Xu, Sylvia Hu, Dawen Sui, Yasir Y Elamin, Xiuning Le, Michael E Goldberg, Karthikeyan Murugesan, Chang-Jiun Wu, Jianhua Zhang, David S Barreto, Jacqulyne P Robichaux, Alexandre Reuben, Tina Cascone, Carl M Gay, Kyle G Mitchell, Lingzhi Hong, Waree Rinsurongkawong, Jack A Roth, Stephen G Swisher, Jack Lee, Anne Tsao, Vassiliki Papadimitrakopoulou, Don L Gibbons, Bonnie S Glisson, Gaurav Singal, Vincent A Miller, Brian Alexander, Garrett Frampton, Lee A Albacker, David Shames, Jianjun Zhang, and John V Heymach

Real-World OutcomesKirk SmithAugust 10, 2020immunotherapy, lung neoplasms, tumor biomarker

Differences Between the East and the West in Managing Advanced-Stage Non-small Cell Lung Cancer

Lung cancer is a common cancer associated with high mortality rates worldwide. Unfortunately, it usually presents at a late stage, precluding the chance of curative therapy. The discovery of oncogenic driver mutations in patients with non-small cell lung cancer over the past 20 years has led to new molecular targeted therapies that have dramatically improved treatment efficacy and quality of life. New generations of therapy that target the drug-resistant mutations have also quickly evolved, benefiting patients who are refractory or intolerant to first-line targeted therapy. Eastern patients, from Southeast Asia, Japan and China, are known to have a higher incidence of epidermal growth factor receptor mutation. Therefore, compared with the West, more patients would benefit from these recent advances. In contrast, survival of patients without driver mutations has benefited from advances in novel therapeutics, including the immune checkpoint inhibitors. The current review aims to highligh..... READ ARTICLE

Clinical Oncology DOI:10.1016/j.clon.2019.07.014

Authors: V. H. F. Lee, T. S. K. Mok, Y. Goto, V. C. C. Hsue, L. Yang, Y. Jiang, D. K. C. Leung, K. S. Lau, P. Y. Tse

Life Threatening haemoptysis in primary lung cancer-signet ring cell carcinoma

Primary signet ring cell carcinoma of the lung is a rare non-small cell carcinoma of the lung with extremely aggressive features and poor prognosis. The diagnosis mainly required tissue biopsy with immunohistochemical analysis and gene mutation studies. We describe a unique case of primary signet ring cell carcinoma of the lung presenting with life threatening haemoptysis along with literature review of prognosis and management of this rare clinical entity. READ ARTICLE

Respiratory Medicine Case Reports DOI:10.1016/j.rmcr.2020.101195

Authors: Shamsuddin Anwar, Sudeep Acharya, Dany Elsayegh, Alisa Sokoloff, Maryam Rehan

Refinement of diagnosis and supporting evidence for the use of immunotherapy through sequential biopsies in a case of EML4-ALK positive lung cancer

In this case report, we describe a tortuous, yet rare, treatment process of the patient. The first biopsy of the patient suggested inflammatory myofibroblastic tumor, ALK (D5F3) positive. Considering the benign progression of the disease, and no indication for surgical resection, oral prednisone was given first. However, the disease rapidly progressed, and a second biopsy revealed a pulmonary sarcomatoid cancer. Since the biopsy was ALK (D5F3) positive, the effect of crizotinib treatment was significant, though crizotinib resistance unfortunately only occurred after 4 months. The third biopsy pathology was performed and confirmed lung adenocarcinoma. After switching to pembrolizumab treatment, the lesions were significantly reduced after four courses of treatment. The current condition of patient persisted in partial response. READ ARTICLE

OncoTargets and Therapy DOI:10.2147/OTT.S203192

Authors: Peng Song, Jingcheng Zhang, and Li Zhang

Case StudyKirk SmithApril 17, 2019Sequential biopsies, EML4-ALK, immunotherapy, lung adenocarcinoma

Immunotherapy for oncogenic-driven advanced non-small cell lung cancers: Is the time ripe for a change?

Immune checkpoint inhibitors (ICIs) have been incorporated in the treatment strategy of advanced non-small cell lung cancer (NSCLC) in first- and second-line setting improving the prognosis of these patients. However, the treatment landscape has been also drastically overturned with the advent of targeted therapies in oncogenic-addicted advanced NSCLC patients. Despite ICIs represent an active and new treatment option for a wide range of advanced NSCLC patients, the efficacy and the optimal place of ICI in the treatment strategy algorithm of oncogenic-addicted tumors remains still controversial, as only a minority of trials with ICI enrol oncogenic-addicted NSCLC patients previously treated with standard therapy. Therefore, there are still several open questions about ICI in oncogenic-driven NSCLC, such as the efficacy and toxicities, which need to be addressed before considering treatment with ICI as a standard approach in this population. It is in this framework, we provide a thoroug..... READ ARTICLE

Cancer Treatment Reviews DOI:10.1016/j.ctrv.2018.10.006

Authors: J. Remon, L.E. Hendriks, C. Cabrera, N. Reguart, B. Besse

Review PaperKirk SmithDecember 1, 2018immunotherapy, EGFR, ALK, ROS1, BRAF, advanced nonsmall cell lung cancer

Tobacco smoking and cessation and PD-L1 inhibitors in non-small cell lung cancer (NSCLC): a review of the literature

Background: Programmed death ligand 1 (PD-L1) targeting immunotherapies, as pembrolizumab and nivolumab, have significantly improved outcome in patients with non-small cell lung cancer (NSCLC). Tobacco smoking is the number one risk factor for lung cancer and is linked to 80%–90% of these cancers. Smoking during cancer therapy may influence on radiotherapy and chemotherapy outcome. We aimed to review the knowledge in immunotherapy... Conclusions: Tobacco smoking patients with NSCLC generally have a higher PD-L1 tumour proportion score and experience a better ORR of immunotherapy than no smokers. There is little evidence on the effect of smoking during immunotherapy, but one study (KEYNOTE-024) may indicate survival gains of smoking cessation. READ ARTICLE

ESMO Open DOI:10.1136/esmoopen-2018-000406

Authors: Jan Norum, Carsten Nieder

Review PaperKirk SmithJuly 1, 2018Lung cancer, PD-L1, immunotherapy, tobacco, smoking, cessation