Beyond EGFR, ALK and ROS1: Current evidence and future perspectives on newly targetable oncogenic drivers in lung adenocarcinoma

Lung cancer is the leading cause of cancer death worldwide. In the past decade EGFR, ALK and ROS1 TKIs lead to an unprecedented survival improvement of oncogene-addicted NSCLC patients, with better toxicity profile compared to chemotherapy. In recent years the implementation of high-throughput sequencing platforms led to the identification of uncommon molecular alterations in oncogenic drivers, such as BRAF, MET, RET, HER2 and NTRK. Moreover, newly developed drugs have been found to be active against hard to target drivers, such as KRAS. Specific TKIs targeting these genomic alterations are currently in clinical development and showed impressive activity and survival improvement, leading to FDA-accelerated approval for some of them. However, virtually all patients develop resistance to TKIs by on-target or off-target mechanisms. Here we review the clinicopathological features, the emerging targeted therapies and mechanisms of resistance and strategies to overcome them of KRAS, BRAF, MET, RET, HER2 and NTRK-addicted advanced NSCLCs. READ ARTICLE

Critical Reviews in Oncology/Hematology DOI: 10.1016/j.critrevonc.2020.103119

Authors: Giuseppe Lamberti, Elisa Andrini, Monia Sisi, Alessandro RizzoaClaudia Parisi, Alessandro Di Federico, Francesco Gelsomino and Andrea Ardizzoni

Advances in Treatment of Locally Advanced or Metastatic Non–Small Cell Lung Cancer: Targeted Therapy

KEY POINTS:
Most epidermal growth factor receptor (EGFR)-mutated NSCLC (exon 19 del and L858R) should be
initially treated with osimertinib.
Anaplastic lymphoma kinase (ALK) fusion-positive NSCLC should be initially treated with alectinib,
brigatinib, or ceritinib; however, tolerability issues limit the use of ceritinib.
ROS1 fusion-positive NSCLC should be initially treated with entrectinib over crizotinib given central
nervous system activity.
BRAF V600E-mutated NSCLC should be initially treated with dabrafenib plus trametinib.
Neurotrophic tropomyosin receptor kinase fusion-positive NSCLC should be initially treated with
entrectinib or larotrectinib.
Patients with HER2 or EGFR exon 20 insertions, RET fusions, NRG1 fusions, MET amplification and
exon 14 skipping mutations, and KRAS G12C mutations should be initially treated with standard-ofcare chemoimmunotherapy; however, there are targeted therapies under investigation showing
promise. READ ARTICLE

Clinics in Chest Medicine DOI:10.1016/j.ccm.2020.02.003

Authors: Nicholas P. Giustini, Ah-Reum Jeong, James Buturla, Lyudmila Bazhenova

Clinical features and therapeutic options in non-small cell lung cancer patients with concomitant mutations of EGFR, ALK, ROS1, KRAS or BRAF

Background: Although oncogenic driver mutations were thought to be mutually exclusive in non-small cell lung cancer (NSCLC), certain tumors harbor co-occurring mutations and represent a rare molecular subtype. The evaluation of the clinical features and therapeutic response associated with this NSCLC subtype will be vital for understanding the heterogeneity of treatment response and improving the management of these patients. Conclusion: In this study, concomitant mutations were found in 1.7% of the NSCLC. EGFR-TKI therapy was more effective than chemotherapy for patients harboring EGFR concomitant mutation, and ROS1 concomitant mutations were more frequent in male patients. For patients harboring coalterations with an ALK or ROS1 rearrangement, we should be cautious when considering the therapeutic options. READ ARTICLE

Cancer Medicine DOI:10.1002/cam4.2183

Authors: Xibin Zhuang, Chao Zhao, Jiayu Li, Chunxia Su, Xiaoxia Chen, Shengxiang Ren, Xuefei Li, Caicun Zhou

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