Lung Cancer: Targets and Therapy最新文献

Objective: Extensive stage Small-Cell Lung Cancer (ES-SCLC) is the most lethal lung cancer, and the addition of immunotherapy conferred a slight survival benefit for patients. Extensive molecular profiling of patients treated with chemotherapy (CT) or chemotherapy plus immunotherapy (CT+IO) would be able to identify molecular factors associated with patients' survival.

Material and methods: In this retrospective study, 99 ES-SCLC patients were considered. Of the 79 includible patients, 42 received CT (median age 71 y/o, I-IIIQ: 65-76), and 37 received CT+IO (median age 71 y/o, I-IIIQ 66-75). The FoundationOne CDx assay was performed on patients' tumor tissues.

Results: The most mutated genes were TP53 (99%), RB1 (78%), PTEN (23%) and MLL2 (20%), with no significant differences between the treatment groups. As a continuous variable, Tumor Mutation Burden (TMB) had an effect on patients' progression-free survival (PFS) by type of treatment (HR 1.81 (95%, CI: 0.99-3.31) and HR 0.84 (95%, CI: 0.56-1.26) for patients treated with CT and CT+IO, respectively). TMB was also computed and dichotomized using two different cut-offs: considering cut-offs of 10 mut/Mb and >16 mut/Mb, 45 patients (57%) and 68 patients (86.1%) had a low TMB, respectively. A high TMB (cut-off 10 mut/Mb) predicted worse PFS in patients treated with CT (p=0.046); even though not statistically significant, a high TMB (cut-off 16 mut/Mb) predicted a better survival in patients treated with CT+IO. Moreover, at univariate analysis, MLL2 mutations were associated with better prognosis in the overall case series (HR_PFS = 0.51, 95% CI: 0.28-0.94), and overall survival (HR_OS = 0.52, 95% CI: 0.28-0.97).

Conclusion: In ES-SCLC, TMB is associated with worse survival in patients treated with CT alone, and with better survival in patients treated with CT+IO, whether considered as a continuous or a dichotomized variable, at different cut-offs. Alterations in epigenetic factors are also associated to better patient prognosis.

Background: BRAF mutations are generally divided into three classes based on the different altered mechanism of activation.

Methods: We queried the public AACR GENIE database (version 13.1), which includes tumor mutation burden (TMB) data, to explore potential molecular differences among the three classes of non-small cell lung cancer (NSCLC).

Results: Out of 20,713 unique NSCLC patients, 324 (1.6%) were BRAF mutations positive (BRAF+) class I, 260 (1.3%) class II, and 236 (1.1%) class III. The distribution of patient characteristics, including sex, age, and race, remains uniform across the three classes. The median TMB (mt/MB) was 6.5, 9.5, and 10.3 for class I, II, and III, respectively. The mean TMB was 61.5 ± 366.1 for class I, 40.5 ± 156.2 for class II, and 129.4 ± 914.8 for class III. About 30.5% of BRAF V600E+ patients had TMB ≥ 10; 47.7% of class II had TMB ≥ 10; and 52.5% of class III had TMB ≥ 10. For those patients with TMB ≥ 10, the median TMB was 45, 28.9, 18.4 for class I, II, and III, respectively. For TMB ≥ 10 patients, TP53 mutation was the most common co-alterations across all 3 classes.

Conclusion: A substantial proportion of BRAF+ NSCLC patients exhibited a TMB ≥ 10, among all three classes of BRAF mutation classification, including BRAF V600E+ NSCLC. Class III mutations appeared to have the highest median TMB, followed by class II, and then class I.

Mutations in KRAS G12C are among the more common oncogenic driver mutations in non-small cell lung cancer (NSCLC). In December 2022, the US Food and Drug Administration (FDA) granted accelerated approval to adagrasib, a small molecule covalent inhibitor of KRAS G12C, for the treatment of patients with locally advanced or metastatic KRAS G12C mutant NSCLC who received at least one prior systemic therapy based on promising results from phase 1 and 2 trials wherein adagrasib demonstrated a median PFS of 6.5 months. Results from the phase 3 KRYSTAL-12 trial were recently presented, showing benefit with adagrasib compared to docetaxel, with participants in the adagrasib group demonstrating a PFS of 5.5 months compared to 3.8 months in the docetaxel group. However, these results fall short of the 6-month PFS benchmark that had seemed achievable from what had been seen in phase 1 and 2 trials, mirroring similarly disappointing results from the CodeBreaK 200 trial wherein sotorasib, the first-in-class KRAS G12C inhibitor, also failed to meet the 6-month benchmark also thought to be possible when examining earlier trials. These results raise the question of adagrasib's true value in the second-line treatment setting and compel us to explore more potent novel therapies, combination therapies, and more as we seek to break the 6-month PFS barrier in the treatment of KRAS G12C mutant NSCLC.

Kirsten rat sarcoma viral oncogene homolog (KRAS) ^G12C-mutant non-small cell lung carcinoma (NSCLC) accounts for approximately 10-13% of advanced nonsquamous NSCLC cases in Western populations, presenting a significant therapeutic challenge owing to the difficulty of directly targeting KRAS. Adagrasib, an oral small-molecule covalent inhibitor, irreversibly and selectively targets KRAS^G12C in its inactive state. It received accelerated Food and Drug Administration (FDA) approval on December 12, 2022, following the KRYSTAL-1 Phase II trial. The Phase III KRYSTAL-12 trial demonstrated that adagrasib significantly improved median progression-free survival (mPFS) compared with docetaxel (HR, 0.58; 95% CI: 0.45-0.76; P<0.0001) and increased the intracranial objective response rate (ORR) to 40% in the central nervous system (CNS) evaluable population. This paper evaluates the clinical efficacy of adagrasib in KRAS ^G12C-mutated advanced NSCLC discussing its potential advantages over other inhibitors such as sotorasib. Despite not reaching the 6-month mPFS benchmark, adagrasib offers significant clinical benefits, particularly for the management of CNS metastases. In this pros and cons debate, we argue that adagrasib has broken the KRAS ^G12C enigma code in NSCLC.

Purpose: Small-cell lung cancer (SCLC) accounts for approximately 10-15% of all lung cancers and is characterized by a high recurrence rate, early metastasis, and poor prognosis. Before the FDA approved lurbinectedin for SCLC that progressed on or after platinum-based chemotherapy in 2020, topotecan was the sole second-line option associated with hematological toxicities and modest efficacy. Lurbinectedin received conditional approval in Korea in September 2022 for metastatic SCLC progression, with the same indications. Real-world data on its efficacy remains scarce owing to its recent implementation.

Patients and methods: Patients with metastatic SCLC who progressed on or after first-line therapy (n = 51) at Yonsei Cancer Center, Seoul, received lurbinectedin at 3.2 mg/m². Efficacy data, including tumor response, progression, survival, and demographics, were recorded.

Results: A total of fifty-one patients received lurbinectedin between April 2023 and March 2024, with thirty-four patients being eligible for the assessment. At diagnosis, approximately one-third of the patients were female, 3% had a poor performance status with an Eastern Cooperative Oncology Group Performance Score (ECOG PS ≥ 2), and the median age was 68. Most patients (80%) had extensive disease. Overall objective response rate (ORR) and disease control rate (DCR) were 20% and 47%, respectively. The median progression-free survival (PFS) was 2.8 months, and the median overall survival (OS) was 3.3 months. Never smokers showed prolonged OS compared with current/former smokers (Smokers; 3.0 vs 7.3 months). Common adverse effects were nausea (53%), loss of appetite (24%), general weakness (18%), anemia (29%), neutropenia (12%), dizziness (6%), alopecia (6%), thrombocytopenia (3%), and pneumonia (3%). Overall, 24% of the patients experienced grade ≥3 adverse events (AEs), with the most common being anemia (9%) and neutropenia (9%).

Conclusion: Real-world data suggest that lurbinectedin is a viable option for patients with SCLC who have progressed on or after platinum-based chemotherapy.

Fusions in neuregulin 1 (NRG1) are rare oncogenic drivers that occur across a number of tumor types, including non-small cell lung cancer (NSCLC). NRG1 has an EGF-like domain that serves as a ligand for HER3 receptors, inducing heterodimerization, usually with HER2, and subsequent activation of oncogenic downstream signaling pathways. Emerging evidence suggests that NSCLC harboring NRG1 fusions do not respond as well to standard therapeutic options including chemotherapy and immunotherapy, and prognosis is poor. Novel treatment approaches targeting the HER2/HER3 pathway are under investigation. Here, we discuss the biology and detection of NRG1 fusions in NSCLC and promising targeted treatment strategies for tumors harboring the mutation.

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?