Lung Cancer: Targets and Therapy最新文献

Purpose: Surgery is the standard treatment for early-stage non-small cell lung cancer (NSCLC), including ground-glass opacity (GGO)-type lung cancer. However, some patients are inoperable or refuse to undergo surgery. To explore whether proton beam therapy (PBT) can be an alternative to surgical resection in these patients, this study aimed to examine the retrospective treatment outcomes of patients with GGO-type lung cancer who underwent PBT.

Patients and methods: Patients with stage I NSCLC and GGOs who underwent PBT at the Medipolis Proton Therapy and Research Center (Kagoshima, Japan) between April 2011 and September 2015 were included. Patients were treated with a total dose of 66 GyE delivered in 10 fractions. Survival curves were calculated using the Kaplan-Meier method, and treatment-related adverse events (AEs) were assessed.

Results: A total of 48 patients (median age: 70.9 ± 9.2 years; men: 54.2%) were analyzed, among whom 53 tumors were observed. The 3-year overall survival rate after PBT was 91.7% (95% confidence interval [CI], 79.3-96.8%), the 3-year disease-free survival rate was 85.4% (95% CI: 71.8-92.8%), and the 3-year local control rate among 53 tumors was 92.5% (95% CI: 81.1-97.1%). During the 3-year follow-up period, 4 patients died, and 3 survived despite recurrence or metastasis. Common AEs were radiation pneumonitis (89.6%), rib fracture (27.1%), and cough (27.1%). None of the patients developed grade ≥3 treatment-related AEs.

Conclusion: The results of this study suggest that PBT may be a promising alternative for patients with GGO-type lung cancer when surgical resection is not feasible, with excellent survival outcomes and tolerable treatment-related AEs.

Purpose: The effects of immune checkpoint inhibitors have been reported to be linked with immune-related adverse events (irAEs). In patients with advanced non-small-cell lung cancer, who tested positive for programmed death-ligand 1 (PD-L1), pembrolizumab, an immune checkpoint inhibitor can be used as a treatment, and it was found to improve overall survival. However, there are only a few reports on the relationship between the therapeutic effects of pembrolizumab in patients with lung cancer and the irAEs of pembrolizumab. The purpose of this study was to determine the correlation between immune-related adverse events and the effects of pembrolizumab monotherapy in patients with non-small-cell lung cancer.

Patients and methods: From February 2017 to August 2019, we conducted a retrospective analysis of the effects of pembrolizumab treatment and immune-related adverse events in 94 patients with non-small-cell lung cancer treated with pembrolizumab only.

Results: In 63 cases, irAEs were observed. The most common irAE was rash. PD-L1 positivity ≥ 50% tended to cause irAEs. The median progression-free survival (PFS) rates with and without irAEs were 371 days (95% CI, 184-NR) and 67 days (95% CI, 51-87 days), respectively. In a multivariate analysis, irAEs and Eastern Cooperative Oncology Group performance status (PS) were the factors related to PFS.

Conclusion: In patients with lung cancer, who were treated with pembrolizumab monotherapy, the development of irAEs was likely indicative of the positive effects of pembrolizumab. This novel finding appears to be useful for clinicians who work with pembrolizumab for lung cancer treatment.

Neuroendocrine tumors (NETs) of the lung are well-differentiated neuroendocrine neoplasms (NENs) with a heterogeneous clinical behaviour. Unlike gastroenteropancreatic NENs where therapeutic armamentarium clearly increased over the last decade, everolimus represented the only clinical practical innovation for lung NET patients over the last years. Therefore, for lung NETs, a multidisciplinary discussion within a dedicated team remains critical for an adequate decision-making. Although the main regulatory authorities considered the everolimus-related evidence is enough to approve the drug in advanced lung NETs, several clinical features deserve to be discussed. In this review, we systemically and critically analysed the main clinical studies including patients with advanced lung NETs receiving everolimus. Furthermore, we reported the biological and clinical background of everolimus in lung NET setting. The purpose of this review is to help clinical community to contextualize evidence and experience for a personalised use of this drug in clinical practice in the context of advanced lung NET patients.

Background: ALK fusions are targetable drivers in non-small-cell lung cancer (NSCLC). However, patients with NSCLC harboring ALK rearrangements without a fusion partner identified in DNA have also been shown to respond to ALK inhibitors. We aimed to characterize complex ALK variants that may predict sensitivity to multiple approved ALK inhibitors.

Methods: Comprehensive genomic profiling (CGP) of DNA isolated from formalin-fixed paraffin-embedded (FFPE) tumor tissue or blood-based circulating tumor DNA was performed for 39,159 NSCLC patients during routine clinical care. For a subset of cases, RNA sequencing was performed, and prior ALK test results and clinical treatment information were collected from treating physicians.

Results: We queried the Foundation Medicine NSCLC database and identified ALK internal inversions, as well as internal deletions, as the sole ALK rearrangements in 6 (0.02%) and 3 (0.01%) of cases, respectively. In cases with ALK internal inversions, RNA testing identified an EML4-ALK fusion in 2/2 cases evaluated, and 3/3 patients treated with ALK inhibitors had durable responses. A single patient with an ALK internal deletion and clinical data available responded to multiple ALK inhibitors. RNA data available for a subset of non-NSCLC cases suggest that ALK internal deletions removing a portion of the N-terminus are drivers themselves and do not result in ALK fusions. Fluorescence in situ hybridization (FISH) results were inconsistent for both classes of DNA events.

Conclusion: Rare internal inversions of ALK appear to be indicative of ALK fusions, which can be detected in RNA, and response to ALK inhibitors in patients with NSCLC. In contrast, ALK internal deletions are not associated with ALK fusions in RNA but likely represent targetable drivers themselves. These data suggest that CGP of DNA should be supplemented with immunohistochemistry or RNA-based testing to further resolve these events and match patients to effective therapies.

Lung cancer is the leading cause of death of all cancer entities and small-cell lung cancer (SCLC) is the most malignant subtype. Despite good initial response to chemotherapy, many patients relapse early and success of second line treatment remains poor. For years, no relevant improvement of second line treatment has been achieved in the field of SCLC. Lurbinectedin, a novel RNA-polymerase II inhibitor has shown promising results in pretreated SCLC patients as single agent and in combination with other chemotherapeutic drugs leading to an orphan drug designation from the FDA. This article reviews the current data on this emerging substance and its impact on the treatment of SCLC.

Central nervous system (CNS) metastasis carries a significant morbidity and mortality in anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). Next-generation ALK tyrosine kinase inhibitors (TKIs) are highly CNS-penetrant and have demonstrated remarkable intracranial activity across clinical studies, and yet radiation remains the mainstay of treatment modality against CNS metastasis. We have previously reported alectinib can induce CNS radiation necrosis even after a remote history of radiation (7 years post-radiation). Lorlatinib is another potent next-generation ALK TKI that can overcome many ALK resistance mutations and has been shown to have excellent activity in patients with baseline CNS metastasis. Here we report two ALK-rearranged NSCLC patients who developed radiation necrosis shortly after initiating lorlatinib following progression on the sequential treatment of crizotinib, alectinib, and brigatinib. In both cases, radiation necrosis is evidenced by serial MRI images and histological examination of the resected CNS metastasis that had previously been radiated. Our cases highlight the importance of recognizing CNS radiation necrosis that may mimic disease progression in ALK-rearranged NSCLC treated with and potentially precipated by next-generation ALK TKIs.

There has been no improvement in outcome for patients with unresectable locally advanced (stage III) non-small cell lung cancer (NSCLC) for more than 10 years. The standard treatment for these patients is definitive concurrent chemotherapy and radiation (CCRT). Although the goal of treatment in this setting is to achieve a cure, most patients progress and their prognosis is poor, with a 5-year survival rate of 15-30%. There is thus an urgent need for the development of novel anticancer treatments in this patient population. Recent advances in cancer immunotherapy have led to a marked improvement in clinical outcome for advanced NSCLC. Such immunotherapy mainly consists of the administration of immune checkpoint inhibitors (ICIs) such as antibodies to cytotoxic T lymphocyte-associated protein-4 (CTLA-4) or to either programmed cell death-1 (PD-1) or its ligand PD-L1. Durvalumab (MEDI4736) is a high-affinity human immunoglobulin G1 monoclonal antibody that blocks the binding of PD-L1 on tumor cells or antigen-presenting cells to PD-1 on T cells. The PACIFIC study recently evaluated consolidation immunotherapy with durvalumab versus placebo administered after concurrent chemoradiotherapy (CCRT) in patients with unresectable stage III NSCLC. It revealed a significant improvement in both progression-free and overall survival with durvalumab, and this improvement was associated with a favorable safety profile. This achievement has made durvalumab a standard of care for consolidation after CCRT in patients with unresectable stage III NSCLC, and it has now been approved in this setting by regulatory agencies in the United States, Canada, Japan, Australia, Switzerland, Malaysia, Singapore, India, and the United Arab Emirates. In this review, we briefly summarize the results of the PACIFIC trial, including those of post hoc analysis, and we address possible molecular mechanisms, perspectives, and remaining questions related to combined treatment with CCRT and ICIs in this patient population.

Introduction: The treatment techniques used for stereotactic body radiation therapy (SBRT) for early-stage lung cancer continue to evolve. In this study, clinical outcomes following SBRT were evaluated according to the use of either 3D conformal radiotherapy (3DCRT) or intensity-modulated radiation therapy (IMRT).

Patients and methods: Patients with stage I NSCLC who received SBRT from 2007 to 2015 were retrospectively reviewed. Disease control and survival were assessed using Kaplan-Meier estimates. Dosimetric analyses for target dose heterogeneity and coverage were performed.

Results: A total of 297 patients with 351 lesions were included. 3DCRT was used in 52% and IMRT in 48%. IMRT was utilized at a higher rate in more recent years. The most common regimens were 48 Gy in 4 fractions and 54-60 Gy in 3 fractions. With a median follow up of 22.7 months, there were 17 local failures for a crude relapse rate of 5.7%. Local failure did not differ in patients treated with 3DCRT and IMRT (4.9% vs 6.5%, p=0.573). Mean dose to gross tumor volume (GTV) as a percent of prescription dose was higher with 3DCRT compared with IMRT (107.7% vs 103.6%, p < 0.0001). Tumor stage, histology, and SBRT regimen did not correlate with local tumor control. Overall survival for the entire population approximated 72% at 2 years. Treatment was well tolerated with 6 documented grade 3+ events.

Conclusion: In this single-institution cohort of SBRT for early-stage NSCLC, there was no discernible difference in clinical outcomes between those treated with 3DCRT and IMRT.

Pulmonary sarcomatoid carcinoma (PSC) is a heterogeneous category of primary lung cancer accounting from 0.3% to 3% of all primary lung malignancies. According to the most recent 2015 World Health Organization (WHO) classification, PSC includes several different variants of malignant epithelial tumors (carcinomas) histologically mimicking sarcomas showing or entirely lacking a conventional component of non-small cell lung cancer (NSCLC). Thus, this rare subheading of lung neoplasms includes pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, pulmonary blastoma, and carcinosarcoma. A diagnosis of PSC may be suspected on small biopsy or cytology, but commonly requires a surgical resection to reach a conclusive definition. The majority of patients with PSC consists of elderly, smoking men with a large, peripheral mass characterized by well-defined margins. However, presentation with a central, polypoid endobronchial lesion is well-documented, particularly in pleomorphic carcinoma and carcinosarcoma showing a squamous cell carcinoma component. As expected, PSC may pose diagnostic problems and immunohistochemistry is largely used when pathologists deal these tumors in routine practice. Indeed, PSC tends to overexpress molecules associated with the epithelial-to-mesenchymal transition, such as vimentin, but the panel of immunostains also includes epithelial markers (cytokeratins, EMA), TTF-1, p40 and negative markers (e.g., melanocytic, mesothelial and sarcoma-related primary antibodies). Although rare, PSC has increased their interest among oncologist community for different reasons: a. identification of the epithelial-to-mesenchymal phenomenon as a major mechanism of secondary resistance to tyrosine kinase inhibitors; b. over-expression of PD-L1 and effective treatment with immunotherapy; c. identification of c-MET exon 14 skipping mutation representing an effective target to crizotinib and other specific inhibitors. In this review, the feasibility of the diagnosis of PSC, its differential diagnosis and novel molecular findings characterizing this group of lung tumor are discussed.