Characterizing the immune tumor microenvironment in ALK fusion-positive lung cancer: state-of-the-art and therapeutical implications.

INTRODUCTION: Approximately 5% of non-small cell lung cancer (NSCLC), exhibits anaplastic lymphoma kinase (ALK) rearrangements. EML4-ALK fusions account for over 90% of ALK rearrangements in NSCLC. The advent of treatment targeting ALK has significantly improved survival rates in patients with advanced ALK-positive NSCLC. However, the emergence of resistance mechanisms and the subsequent progression disease inevitably occurs. The tumor immune microenvironment (TIME) plays a pivotal role in lung cancer, influencing disease development, patient's outcomes, and response to treatments. AREAS COVERED: The aim of this review is to provide a comprehensive characterization of the TIME in ALK rearranged NSCLC and its intrinsic plasticity under treatment pressure. EXPERT OPINION: Recognizing the fundamental role of the TIME in cancer progression has shifted the paradigm from a tumor cell-centric perspective to the understanding of a complex tumor ecosystem. Understanding the intricate dynamics of the TIME, its influence on treatment response, and the potential of immunotherapy in patients with ALK-positive NSCLC are currently among the primary research objectives in this patient population.

Exceptional Response in BRAF p.V600E-Mutant Enteric-Type Adenocarcinoma of the Lung With Cutaneous Spread: A Case Report.

Background: Enteric-type adenocarcinoma of the lung (lung-ETAC) is a rare form of lung cancer with histologic similarities to colorectal cancer, with aggressive behavior and unfavorable prognosis. Case Presentation: An 81-year-old man presented with discolored skin lesions on the chest and abdomen. After comprehensive evaluation, including skin biopsy and molecular profiling, the patient was diagnosed with having lung-ETAC with a BRAF p.V600E mutation. Treatment with dabrafenib and trametinib initially resulted in positive results, with improvement in skin lesions and overall clinical condition. Nevertheless, approximately 6 months after, the disease had progression with new skin lesions reappearing. Conclusions: We reported a unique case of a patient with BRAF p.V600E-mutant lung-ETAC with metastatic skin lesions achieving complete cutaneous response after targeted treatment with dabrafenib and trametinib, highlighting the potential for targeted therapy in patients with lung-ETAC harboring a BRAF p.V600E mutation.

Selpercatinib in RET-fusion positive metastatic non-small cell lung cancer: achievements and gray areas.

INTRODUCTION: Selpercatinib is a RET selective tyrosine kinase inhibitor with nanomolar potency against diverse RET alterations, including fusions, activating point mutations, and acquired resistance mutations. Rearranged during transfection (RET) gene is a validated target in non-small-cell lung cancer (NSCLC). Selpercatinib is currently approved for adult patients with metastatic RET fusion-positive NSCLC. AREAS COVERED: This review summarizes the efficacy and safety data of selpercatinib in the treatment landscape of RET fusion-positive NSCLC. EXPERT OPINION: Globally considered, selpercatinib is an optimal treatment choice, in terms of both (systemic and intracranial) efficacy and safety, in patients affected by advanced NSCLC harboring RET fusions as a driver mechanism. Future challenges include the identification of the most appropriate placement for selpercatinib in the treatment algorithm of RET fusion-positive NSCLC (including early stages), the clarification of resistance mechanisms, as well as of its role in EGFR-mutant NSCLC undergoing progression during osimertinib driven by RET alterations.