Lung Cancer: Targets and Therapy最新文献

Immunocheckpoint inhibitors (ICIs) have altered the treatment landscape of a wide range of malignancies, including non-small cell lung cancer (NSCLC). This class of agents inhibits the interaction between PD1 and PDL1, and was shown to be efficacious in the landmark PACIFIC trial with 1 year of maintenance durvalumab (anti-PDL1 antibody). This trial demonstrated that its use as a consolidation treatment given after definitive chemoradiotherapy improved progression free survival and overall survival compared to standard-of-care treatment. In this review, we discuss both clinical trial and real-world data that have been published since PACIFIC that support the use of durvalumab for stage III unresectable NSCLC. In addition, we highlight specific populations that may require special considerations for the use of durvalumab in this setting, such as oncogene-addicted NSCLC, the toxicity of immunotherapy, and future directions in ICI research in stage III NSCLC.

Human epidermal growth factor receptor 2 (HER2) is a proto-oncogene that, when mutated or overexpressed, plays an important role in oncogenesis. The landscape of HER2-positive breast cancer has changed dramatically over the past 2 decades with the FDA approval of a growing number of agents (antibodies, tyrosine kinase inhibitors, and antibody-drug conjugates) targeting the HER2 receptor. HER2 inhibition has also been approved for HER2-positive gastric cancer. HER2 is amplified in 9% and mutated in 3% of lung cancer. Historically, HER2-targeted therapy for lung cancer with trastuzumab, pertuzumab, and trastuzumab emtansine has failed to demonstrate a survival benefit. Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug conjugate with a tetrapeptide linker, which delivers a topoisomerase I inhibitor with a drug-to-antibody ratio of 7~8. The potency of the active payload, as well as its significant bystander effect, resulted in significant anti-tumor activity. The DESTINY-Lung01 trial evaluated T-DXd in HER2-positive non-squamous non-small cell lung cancer (NSCLC) and reported a progression-free survival of 14 months in HER2-mutated NSCLC, earning its breakthrough designation by the FDA. In this review, we will discuss the structural characteristics, pharmacodynamics, and pharmacokinetics of T-DXd. We will also shed light on the preclinical and ongoing clinical trials of T-DXd along with future directions in the management of HER2 positive lung cancer.

Mutations in codon 12 of KRAS have been identified in 13% of non-small cell lung cancer patients. Developing targeted therapies against KRAS^G12C mutation has proven to be challenging due to the abundance of GTP in the cytoplasm, rapid hydrolysis of GTP, and difficulty designing small molecules to achieve sufficient concentration for KRAS inhibition. Based on promising results in both preclinical and clinical trials, sotorasib, a novel KRAS^G12C inhibitor, was given conditional approval by the FDA in May 2021. The Phase I portion of the clinical trial produced 32% confirmed response with 56% of patients with stable disease. About 91.2% of patients who received the highest dose of 960mg daily achieved disease control. The Phase II portion, which used 960mg daily dosing resulted in 37.1% of patients with confirmed response and 80.6% of patients with disease control. Both phase I and phase II had similar progression-free survival, in 6.3 months and 6.8 months, respectively. In both phases, grade 4 adverse events occurred in only one patient. The most common adverse events were elevations in LFTs, which down-trended upon dose reduction and steroid treatment. While the conditional approval of sotorasib was a major breakthrough for those patients harboring KRAS^G12C mutations, resistance mutations to sotorasib are increasingly common. Many proposals have been made to address this, such as the use of combination therapy for synthetic lethality, which are producing encouraging results. Here, we explore in further detail the development of sotorasib, its efficacy, mechanism of resistance, and strategies to overcome these resistances.

Purpose: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the preferred first-line option for patients with advanced, EGFR-mutant non-small cell lung cancer (NSCLC). Afatinib, a second-generation irreversible EGFR-TKI, has been extensively used in Greece in this setting; however, real-world data regarding molecular epidemiology and financial implications of afatinib use are lacking.

Materials and methods: This was an observational, non-interventional, multicenter, retrospective cohort study, based on real-world data collected from the medical charts/records of patients treated with afatinib between 15/03/2015 and 25/06/2020 and were recorded on a web-based data capture system. Cox models were used to assess the prognostic significance of clinicopathological parameters with respect to clinical outcomes of interest. Cost analysis was conducted from a public third-payer perspective, and only direct medical costs reimbursed by the payer were considered.

Results: A total of 59 patients were treated with afatinib for their EGFR mutation-positive advanced NSCLC; the median age was 61 years (range: 37-91). Performance status was zero in 61%, and brain metastases were present in 13.6%. Forty-four patients (74.6%) had a deletion in exon 19 only, while nine (15.3%) had a mutation in exon 21, 8 of them in L858R and one in L861Q. At a median follow-up of 41.8 months (95% CI 35.9-51.4), the median PFS was 14.3 months (95% CI 12.2-16.4), and the median OS was 29 months (95% CI 25.6-33.4). Corresponding values for patients with deletion 19 only were 14.3 months (95% CI 11.5-18.5) and 28.1 months (95% CI 21.1-32.6), respectively. The mean expenditure for the treatment of each patient equals €25,333.68; with €21,865.06 being attributed to drug acquisition costs, €3325.35 to monitoring costs and €143.27 to adverse event treatment-related costs.

Conclusion: Long-term data in the real-world setting in Greece confirm activity, tolerability and cost-effectiveness of afatinib as first-line treatment of patients with advanced EGFR-mutant NSCLC.

Clinical trial registration: Clinicaltrials.gov NCT04640870.

Lung cancer has historically been the main responsible for cancer associated deaths. Owing to this is our current inability to screen for and diagnose early pathological findings, preventing us from a timely intervention when cure is still achievable. Over the last decade, together with the extraordinary progress in therapeutical alternatives in the field, there has been an ongoing search for a biomarker that would allow for this. Numerous technologies have been developed but their clinical application is yet to come. In this review, we provide an update on volatile organic compounds, a non-invasive method that can hold the key for detecting early metabolic pathway changes in carcinogenesis. For its compilation, web-based search engines of scientific literature such as PubMed were explored and reviewed, using articles, research, and papers deemed meaningful by authors discretion. After a brief description, we depict how this technique can complement current methods and present the value of electronic noses in the identification of the "breathprint". Lastly, we bring some of the latest updates in the field together with the current limitations and final remarks.

State-of-the-art cancer precision medicine approaches involve targeted inactivation of chemically and immunologically addressable vulnerabilities that often yield impressive initial anti-tumor responses in patients. Nonetheless, these responses are overshadowed by therapy resistance that follows. AXL, a receptor tyrosine kinase with bona fide oncogenic capacity, has been associated with the emergence of resistance in an array of cancers with varying pathophysiology and cellular origins, including in non-small-cell lung cancers (NSCLCs). Here in this review, we summarize AXL biology during normal homeostasis, oncogenic development and therapy resistance with a focus on NSCLC. In the context of NSCLC therapy resistance, we delineate AXL's role in mediating resistance to tyrosine kinase inhibitors (TKIs) deployed against epidermal growth factor receptor (EGFR) as well as other notable oncogenes and to chemotherapeutics. We also discuss the current understanding of AXL's role in mediating cell-biological variables that function as important modifiers of therapy resistance such as epithelial to mesenchymal transition (EMT), the tumor microenvironment and tumor heterogeneity. We also catalog and discuss a set of effective pharmacologic tools that are emerging to strategically perturb AXL mediated resistance programs in NSCLC. Finally, we enumerate ongoing and future exciting precision medicine approaches targeting AXL as well as challenges in this regard. We highlight that a holistic understanding of AXL biology in NSCLC may allow us to predict and improve targeted therapeutic strategies, such as through polytherapy approaches, potentially against a broad spectrum of NSCLC sub-types to forestall tumor evolution and drug resistance.

The EGFR exon 20 insertion (EGFRex20ins) mutations are the third most common EGFR mutations seen in non-small cell lung cancer (NSCLC). More than 50 variants of EGFRex20ins mutations have been identified with A767_V769dupASV being the most common variant across multiple surveys. Treatment with currently available EGFR tyrosine kinase inhibitors (TKIs) including osimertinib is generally ineffective. Amivantamab (JNJ-372), a bispecific monoclonal antibody against EGFR and MET, has recently been approved by the US FDA for patients with advanced or metastatic NSCLC harboring EGFRex20ins mutations after disease progression on platinum-based chemotherapy. Among all the TKIs in clinical development, mobocertinib (TAK-788) has been granted priority review by the FDA for the same indication as amivantamab. Here, we provide a concise review on mobocertinib, with a focus on its chemical structure, preclinical data, and phase 1/2 trial results. Future directions will likely focus on combination approach such as TKI plus chemotherapy in the first-line setting, designing drugs with CNS activity, and exploring disease characteristics of various EGFRex20ins mutation variants and how they may affect treatment response.

Surgery or concurrent chemoradiation are standard of care treatments for patients with localized and locally advanced non-small cell lung cancer (NSCLC). While resection and chemoradiation are potentially curative therapies for early-stage disease, relapse rates remain high. Adjuvant or neoadjuvant chemotherapy improves cure rates 5-15% compared with surgery alone for patients with resectable disease. Immune checkpoint inhibitors (ICI) have heralded a new era for the treatment of advanced NSCLC with one-third of patients experiencing long-term survival. There is increasing interest in examining the role of ICI therapy in patients with early-stage NSCLC. Consolidation durvalumab after chemoradiation has become a part of standard of care for patients with inoperable, locally advanced disease. More recently, there is emerging evidence that neoadjuvant treatment with ICIs results in substantial rates of major pathologic response and pathologic complete response, and high rates of R0 resection with no significant delay in time to surgery. Furthermore, preliminary data show that adjuvant treatment with ICIs after adjuvant chemotherapy improves disease-free survival and may play a critical role in reducing disease recurrence in patients with resectable disease. In this review, we discuss recently reported and ongoing studies that are designed to define the role of immunotherapy in patients with non-metastatic NSCLC.

MET exon 14 skipping mutation (MET∆ex14) is present about 3% of non-small cell lung cancers (NSCLCs). NSCLC patients with MET∆ex14 are characterized by an average age of over 70 years at diagnosis, a smoking history and a higher frequency in pleomorphic carcinoma and adenosquamous cell carcinoma than in adenocarcinoma. It has also been reported that NSCLCs with MET∆ex14 often have codriver alterations such as EGFR amplification (6-28%), FGFR1 alterations (5-17%), KRAS alterations (~8%), BRAF alterations (~21%), or PIK3CA mutation/amplification (~14%). In 2020, the approval of two MET-tyrosine kinase inhibitors (TKIs), capmatinib and tepotinib, for NSCLCs carrying MET∆ex14 dawned a new era for MET-targeted therapy. These drugs yielded progression-free survival of 5.4-12.4 months in clinical trials; however, it has also been reported that one-third to half of patients show inherent resistance to MET-TKIs. In addition, the emergence of acquired resistance to MET-TKIs is inevitable. In this review, we summarize the clinical and molecular characteristics of NSCLCs with MET∆ex14, the efficacy and safety of capmatinib and tepotinib, the inherent and acquired resistance mechanisms to MET-TKIs, and new treatment strategies for NSCLCs with MET∆ex14 in the near future.

Immunotherapy plays a central role in the treatment of NSCLC and biomarkers predicting response to ICIs are valuable therapeutic tools. Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) is integral in therapy selection as its positive predictive nature to ICIs in the metastatic setting is well documented. Tumor mutational burden (TMB) has undergone much study and, while results are somewhat mixed, there is evidence for its positive predictive value with ICI use. Additional markers such as tumor-infiltrating lymphocytes (TILs), gene expression profiling (GEP), mismatch repair (MMR) and microsatellite instability (MSI), somatic mutations, neutrophil to leukocyte ratio (NLR), smoking history, medication history, and immune-related adverse event (irAE) development can further guide clinicians.