Lung Cancer: Targets and Therapy最新文献

Background: Pulmonary spindle cell carcinoma (PSCC), a highly malignant tumor, often exhibits cell pleomorphism, a histopathological characteristic. Owing to its extremely low incidence, atypical imaging and clinical presentations, and insufficient awareness among clinicians, PSCC is often misdiagnosed, which results in delays in treatment. Herein, we reported a rare case of PSCC that was initially misdiagnosed as granulomatous inflammation.

Case presentation: A 66-year-old male visited a local hospital with symptoms such as cough and hemoptysis. A computed tomography (CT) scan of the chest revealed a mass in his right lung, and no mediastinal lymphadenopathy was observed. Bronchoscopy showed no major abnormalities, and the results of fine needle aspiration biopsy showed granulomatous inflammation. Even though the patient received anti-infection treatment, his symptoms did not improve markedly. After two months, a follow-up CT scan of the lung showed a noticeably enlarged mass accompanied by multiple instances of mediastinal lymphadenopathy in the upper lobe of the right lung. Consequently, he underwent a second CT-guided lung biopsy at our hospital. The pathology report indicated PSCC. Due to financial constraints, genetic testing was not performed. Given his poor overall physical condition, the patient was unable to undergo systemic chemotherapy and instead received palliative radiotherapy. The prescribed radiotherapy dose for the right upper lobe lung cancer and multiple metastatic lymph nodes was 60 Gy, administered in 30 fractions. Unfortunately, he failed to adhere to scheduled follow-ups and succumbed to the disease 6 months later, as confirmed during a telephone follow-up.

Conclusion: PSCC is a rare but highly malignant lung cancer. Multiple pathological biopsies are necessary to accurately and promptly diagnose the disease, which is crucial for early treatment intervention as well as improving patient prognosis.

On April 18, 2024, the Food and Drug Administration approved alectinib as an adjuvant treatment for patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) after tumor resection. This approval was grounded in the outcomes of the ALINA trial, which demonstrated that alectinib significantly enhances disease-free survival compared to traditional platinum-based chemotherapy in the adjuvant setting. The ALINA trial is notable not just for advancing ALK tyrosine kinase inhibitors (TKIs) into the adjuvant setting but also for its innovative approach of comparing them to adjuvant chemotherapy, distinguishing it from other landmark trials.

Mesenchymal-epithelial transition (MET) gene has been identified as a promising target for treatments. However, different sites of the MET mutation show different effects to MET inhibition. Here, we reported a non-small cell lung cancer (NSCLC) patient harboring MET Y1003H mutation who achieved a durable partial response to crizotinib with a PFS of 22.4 months. Furthermore, we report for the first time the identification of MET D1228N as a possible mechanism of acquired resistance to crizotinib in a patient with MET Y1003H mutation during disease progression.

On December 22, 2023, the US Food and Drug Administration (FDA) approved the biologics license application for patritumab deruxtecan (HER3-DXd) for priority review. This treatment is aimed at adult patients with locally advanced or metastatic NSCLC with EGFR mutations, who have received at least two prior systemic therapies. Approval of patritumab deruxtecan would mark it as the first HER3 targeted therapy in the United States. This prioritization by the FDA is grounded in compelling results from the global Phase II HERTHENA-Lung01 trial, wherein HER3-DXd exhibited clinically meaningful efficacy, achieving a median progression-free survival (mPFS) of 5.5 months in patients with heavily treated EGFR-mutated NSCLC. A pivotal question remains: Is a mPFS of 5.5 months sufficient in the context of the evolving first-line landscape observed in the FLAURA-2 and MARIPOSA trials?

The year 2024 is the 20^th anniversary of the discovery of activating epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC). Since then, tremendous advances have been made in the treatment of NSCLC based on this discovery. Some of these studies have led to seismic changes in the concept of oncology research and spurred treatment advances beyond NSCLC, leading to a current true era of precision oncology for all solid tumors. We now routinely molecularly profile all tumor types and even plasma samples of patients with NSCLC for multiple actionable driver mutations, independent of patient clinical characteristics nor is profiling limited to the advanced incurable stage. We are increasingly monitoring treatment responses and detecting resistance to targeted therapy by using plasma genotyping. Furthermore, we are now profiling early-stage NSCLC for appropriate adjuvant targeted treatment leading to an eventual potential "cure" in early-stage EGFR+ NSCLC which have societal implication on implementing lung cancer screening in never-smokers as most EGFR+ NSCLC patients are never-smokers. All these advances were unfathomable in 2004 when the five papers that described "discoveries" of activating EGFR mutations (del19, L858R, exon 20 insertions, and "uncommon" mutations) were published. To commemorate this 20^th anniversary, we assembled a global panel of thoracic medical oncology experts to select the top 20 papers (publications or congress presentation) from the 20 years since this seminal discovery with December 31, 2023 as the cutoff date for inclusion of papers to be voted on. Papers ranked 21 to 30 were considered "honorable mention" and also annotated. Our objective is that these 30 papers with their annotations about their impact and even all the ranked papers will serve as "syllabus" for the education of future thoracic oncology trainees. Finally, we mentioned potential practice-changing clinical trials to be reported. One of them, LAURA was published online on June 2, 2024 was not included in the list of papers to be voted on but will surely be highly ranked if this consensus survery is performed again on the 25^th anniversay of the discovery EGFR mutations (i.e. top 25 papers on the 25 years since the discovery of activating EGFR mutations).

Afatinib, a second-generation covalent EGFR TKI, has been approved for the treatment of the three "uncommon" EGFR mutations (G719X, S768I, and L861Q) based on one pooled retrospective analysis of three prospective trials (LUX-Lung 2, 3 and 6). The confirmed overall response rate, as assessed by independent radiology review, was 66% (95% confidence interval: 47-81). Among the 21 responders, the proportion of patients with response duration of ≥12 months was 52% and the proportion with response durations of ≥18 months was 33%. Of note, all patients received afatinib at 40 or 50 mg once daily which is higher than the approved dose of 40 mg once daily and the usual 30 mg once daily starting dose by most thoracic oncologists. Given the approval of afatinib for "uncommon" EGFR mutations was based on the limited number of patients analyzed, the retrospective nature of the analysis, lack of randomized phase 2 or 3 trial, there remains uncertainty as to whether afatinib, chemotherapy or other next-generation EGFR TKIs is the optimal treatment. This uncertainty also hinders the development of future treatment of these "uncommon" mutations because of the uncertainty that afatinib is the optimal treatment and hence should be the standard of care control arm in future randomized trials. Finally, the ACHILLES/TORG1834 provided us with the first randomized trial result that afatinib achieved superior progression-free survival over platinum-based chemotherapy (10.6 months vs 5.7 months, HR = 0.42; 95% CI: 0.256-0.694; P = 0.0007). However, ACHILLES should mostly be considered as phase 2 trial given the limited number (N = 109) of patients enrolled. Furthermore, the PFS benefit seemed to be with the 40 mg daily dose (HR = 0.128; 95% CI: 0.050-0.327) and not with the 30 mg daily dose (HR = 0.704; 95% CI: 0.352-1.406). Further investigation of the 30 once daily dosing for the treatment of uncommon EGFR mutations is needed.

Purpose: High-mobility group box 1 protein (HMGB1) is subject to exportin 1 (XPO1)-dependent nuclear export, and it is involved in functions implicated in resistance to immunotherapy. We investigated whether HMGB1 mRNA expression was associated with response to immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC).

Patients and methods: RNA was isolated from pretreatment biopsies of patients with advanced NSCLC treated with ICI. Gene expression analysis of several genes, including HMGB1, was conducted using the NanoString Counter analysis system (PanCancer Immune Profiling Panel). Western blotting analysis and cell viability assays in EGFR and KRAS mutant cell lines were carried out. Evaluation of the antitumoral effect of ICI in combination with XPO1 blocker (selinexor) and trametinib was determined in a murine Lewis lung carcinoma model.

Results: HMGB1 mRNA levels in NSCLC patients treated with ICI correlated with progression-free survival (PFS) (median PFS 9.0 versus 18.0 months, P=0.008, hazard ratio=0.30 in high versus low HMGB1). After TNF-α stimulation, HMGB1 accumulates in the cytoplasm of PC9 cells, but this accumulation can be prevented by using selinexor or antiretroviral drugs. Erlotinib or osimertinib with selinexor in EGFR-mutant cells and trametinib plus selinexor in KRAS mutant abolish tumor cell proliferation. Selinexor with a PD-1 inhibitor with or without trametinib abrogates the tumor growth in the murine Lewis lung cancer model.

Conclusion: An in-depth exploration of the functions of HMGB1 mRNA and protein is expected to uncover new potential targets and provide a basis for treating metastatic NSCLC in combination with ICI.