Non-small-cell lung cancer (NSCLC) represents roughly 85% of lung cancers, with an incidence that increases yearly across the world. The introduction in clinical practice of several new and more ...effective molecules has led to a consistent improvement in survival and quality of life in locally advanced and metastatic NSCLC. In particular, oncogenic drivers have indeed transformed the therapeutic algorithm for NSCLC. Nearly 25% of patients are diagnosed in an early stage when NSCLC is still amenable to radical surgery. In spite of this, five-year survival rates for fully resected early stage remains rather disappointing. Adjuvant chemotherapy has shown a modest survival benefit depending on the stage, but more than half of patients relapse. Given this need for improvement, over the last years different targeted therapies have been evaluated in early-stage NSCLC with no survival benefit in unselected patients. However, the identification of reliable predictive biomarkers to these agents in the metastatic setting, the design of molecularly-oriented studies, and the availability of novel potent and less toxic agents opened the way for a novel era in early stage NSCLC treatment. In this review, we will discuss the current landscape of targeted therapeutic options in early NSCLC.
Immune checkpoint inhibitors have significantly improved overall survival with an acceptable safety profile in a substantial proportion of non-small cell lung cancer (NSCLC) patients. However, not ...all patients are sensitive to immune checkpoint blockade and, in some cases, programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors accelerate tumor progression. Several combination strategies are under evaluation, including the concomitant or sequential evaluation of chemotherapy or radiotherapy with immunotherapy. The current review provides an overview on the molecular rationale for the investigation of combinatorial approaches with chemotherapy or radiotherapy. Moreover, the results of completed clinical studies will be reported.
Summary Background An established multivariate serum protein test can be used to classify patients according to whether they are likely to have a good or poor outcome after treatment with EGFR ...tyrosine-kinase inhibitors. We assessed the predictive power of this test in the comparison of erlotinib and chemotherapy in patients with non-small-cell lung cancer. Methods From Feb 26, 2008, to April 11, 2012, patients (aged ≥18 years) with histologically or cytologically confirmed, second-line, stage IIIB or IV non-small-cell lung cancer were enrolled in 14 centres in Italy. Patients were stratified according to a minimisation algorithm by Eastern Cooperative Oncology Group performance status, smoking history, centre, and masked pretreatment serum protein test classification, and randomly assigned centrally in a 1:1 ratio to receive erlotinib (150 mg/day, orally) or chemotherapy (pemetrexed 500 mg/m2 , intravenously, every 21 days, or docetaxel 75 mg/m2 , intravenously, every 21 days). The proteomic test classification was masked for patients and investigators who gave treatments, and treatment allocation was masked for investigators who generated the proteomic classification. The primary endpoint was overall survival and the primary hypothesis was the existence of a significant interaction between the serum protein test classification and treatment. Analyses were done on the per-protocol population. This trial is registered with ClinicalTrials.gov , number NCT00989690. Findings 142 patients were randomly assigned to chemotherapy and 143 to erlotinib, and 129 (91%) and 134 (94%), respectively, were included in the per-protocol analysis. 88 (68%) patients in the chemotherapy group and 96 (72%) in the erlotinib group had a proteomic test classification of good. Median overall survival was 9·0 months (95% CI 6·8–10·9) in the chemotherapy group and 7·7 months (5·9–10·4) in the erlotinib group. We noted a significant interaction between treatment and proteomic classification (pinteraction =0·017 when adjusted for stratification factors; pinteraction =0·031 when unadjusted for stratification factors). Patients with a proteomic test classification of poor had worse survival on erlotinib than on chemotherapy (hazard ratio 1·72 95% CI 1·08–2·74, p=0·022). There was no significant difference in overall survival between treatments for patients with a proteomic test classification of good (adjusted HR 1·06 0·77–1·46, p=0·714). In the group of patients who received chemotherapy, the most common grade 3 or 4 toxic effect was neutropenia (19 15% vs one <1% in the erlotinib group), whereas skin toxicity (one <1% vs 22 16%) was the most frequent in the erlotinib group. Interpretation Our findings indicate that serum protein test status is predictive of differential benefit in overall survival for erlotinib versus chemotherapy in the second-line setting. Patients classified as likely to have a poor outcome have better outcomes on chemotherapy than on erlotinib. Funding Italian Ministry of Health, Italian Association of Cancer Research, and Biodesix.
In NSCLC, KRAS mutations occur in up to 30% of all cases, most frequently at codon 12 and 13. KRAS mutations have been linked to adenocarcinoma histology, positive smoking history, and Caucasian ...ethnicity, although differences have been described across KRAS mutational variants subtypes. KRAS mutations often concur with other molecular alterations, notably TP53, STK11, and KEAP1, which could play an important role in treatment efficacy and patient outcomes. For many years, KRAS mutations have been considered undruggable mainly due to a high toxicity profile and low specificity of compounds. Sotorasib and adagrasib are novel KRAS inhibitors that recently gained FDA approval for pre-treated KRAS mutant NSCLC patients, and other molecules such as GDC-6036 are currently being investigated with promising results. Despite their approval, the efficacy of these drugs is lower than expected and progression among responders has been reported. Mechanisms of acquired resistance to anti-KRAS molecules typically involves either on target secondary mutations (e.g., G12, G13, Q61H, R68S, H95, Y96C, V8L) or off-target alterations. Ongoing trials are currently evaluating strategies for implementing efficacy and overcoming acquired resistance to these compounds. Finally, the efficacy of immune-checkpoint inhibitors still needs to be completely assessed and responses to anti-PD-1/PD-L1 agents may strongly depend on concomitant mutations.
Patients with anaplastic lymphoma kinase rearranged (ALK+) non-small cell lung cancer (NSCLC) have a higher risk of developing brain metastases (BMs) than patients with other NSCLC sub-types. ALK ...inhibitors have activity in BMs due to ALK+ NSCLC. We performed a systematic review of the literature with the aim of assessing the efficacy of ALK inhibitors on BMs.
A systematic search of the literature was performed using the databases Pubmed, EMBASE, Web of Science, The Cochrane Library, and SCOPUS. Relevant publications reporting activity of ALK inhibitors in NSCLC BMs were retrieved. Data were pooled using the number of events/number of evaluable patients according to fixed or random effect models. Intracranial tumour response was assessed through overall response rate (ORR), disease control rate (DCR: ORR + stable disease rate), median progression-free survival (PFS), and overall survival (OS). The primary endpoint was intracranial overall response rate (IC ORR).
A total of 1,016 patients with BMs from 21 studies were analysed. In patients receiving ALK inhibitors in the first line setting, the pooled IC ORR was 39.17% (95%CI 13.1-65.2%), while the pooled IC ORR observed in further lines was 44.2% (95%CI 33.3-55.1%). Intracranial disease control rate (IC DCR) was 70.3% and 78.2% in naïve and pre-treated patients, respectively. Patients who had not received brain radiation attained an IC ORR of 49.0%.
Based on these data, ALK inhibitors are effective in both naive and pre-treated patients with similar IC ORR and IC DCR, irrespective of the line of therapy.
Background: Gefitinib is a selective inhibitor of the epidermal growth factor (EGFR) tyrosine kinase, which is overexpressed in many cancers, including non–small-cell lung cancer (NSCLC). We carried ...out a clinical study to compare the relationship between EGFR gene copy number, EGFR protein expression, EGFR mutations, and Akt activation status as predictive markers for gefitinib therapy in advanced NSCLC. Methods: Tumors from 102 NSCLC patients treated daily with 250 mg of gefitinib were evaluated for EGFR status by fluorescence in situ hybridization (FISH), DNA sequencing, and immunohistochemistry and for Akt activation status (phospho-Akt P-Akt) by immunohistochemistry. Time to progression, overall survival, and 95% confidence intervals (CIs) were calculated and evaluated by the Kaplan–Meier method; groups were compared using the log-rank test. Risk factors associated with survival were evaluated using Cox proportional hazards regression modeling and multivariable analysis. All statistical tests were two-sided. Results: Amplification or high polysomy of the EGFR gene (seen in 33 of 102 patients) and high protein expression (seen in 58 of 98 patients) were statistically significantly associated with better response (36% versus 3%, mean difference = 34%, 95% CI = 16.6 to 50.3; P<.001), disease control rate (67% versus 26%, mean difference = 40.6%, 95% CI = 21.5 to 59.7; P<.001), time to progression (9.0 versus 2.5 months, mean difference = 6.5 months, 95% CI = 2.8 to 10.3; P<.001), and survival (18.7 versus 7.0 months, mean difference = 11.7 months, 95% CI = 2.1 to 21.4; P = .03). EGFR mutations (seen in 15 of 89 patients) were also statistically significantly related to response and time to progression, but the association with survival was not statistically significant, and 40% of the patients with mutation had progressive disease. In multivariable analysis, only high EGFR gene copy number remained statistically significantly associated with better survival (hazard ratio = 0.44, 95% CI = 0.23 to 0.82). Independent of EGFR assessment method, EGFR+/P-Akt+ patients had a statistically significantly better outcome than EGFR−, P-Akt−, or EGFR+/P-Akt− patients. Conclusions: High EGFR gene copy number identified by FISH may be an effective molecular predictor for gefitinib efficacy in advanced NSCLC.
Rearrangements involving the neurotrophin kinase (
NTRK
) genes
NTRK1
,
NTRK2
and
NTRK3
with different fusion partners have been observed in both adult and pediatric solid tumors. Larotrectinib and ...entrectinib have been the first tumor-agnostic compounds approved for the treatment of NTRK fusion-positive tumors. Here, we report the first case of a female patient with a diagnosis of stage IV lung adenocarcinoma harboring the
EML4::NTRK3
gene fusion, and successfully treated with entrectinib.
Lung cancer is the leading cause of cancer deaths in the world. Surgery is the most potentially curative therapeutic option for patients with early-stage non-small cell lung cancer (NSCLC). The ...five-year survival for these patients remains poor and variable, depending on the stage of disease at diagnosis, and the risk of recurrence following tumor resection is high. During the last 20 years, there has been a modest improvement in the therapeutic strategies for resectable NSCLC. Immune checkpoint inhibitors (ICIs), alone or in combination with chemotherapy, have become the cornerstone for the treatment of metastatic NSCLC patients. Recently, their clinical development has been shifted in the neoadjuvant and adjuvant settings where they have demonstrated remarkable efficacy, leading to improved clinical outcomes. Based on the positive results from phase III trials, ICIs have become a therapeutic option in neoadjuvant and adjuvant settings. On October 2021 the Food and Drug Administration (FDA) approved atezolizumab as an adjuvant treatment following surgery and platinum-based chemotherapy for patients with NSCLC whose tumors express PD-L1 ≥ 1%. In March 2022, nivolumab in combination with platinum-doublet chemotherapy was approved for adult patients with resectable NSCLC in the neoadjuvant setting. The current review provides an updated overview of the clinical trials exploring the role of immunotherapy in patients with early-stage NSCLC, focusing on the biological rationale for their use in the perioperative setting. We will also discuss the role of potential predictive biomarkers to personalize therapy and optimize the incorporation of immunotherapy into the multimodality management of stage I-III NSCLC.
Gefitinib is an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase with activity in non–small-cell lung cancer. Diarrhea and skin toxicity are prominent gefitinib-related ...adverse events that potentially limit its use. Gefitinib is a substrate for ABCG2 (ABCP, BCRP, MXR), a polymorphic efflux transporter protein that is highly expressed in the intestines and liver. Here we investigated associations between allelic variants of EGFR, ABCG2, and the transporter protein ABCB1 with diarrhea and skin toxicity in gefitinib-treated patients. One variant, a common functional single-nucleotide polymorphism (SNP) in the ABCG2 gene, was associated with diarrhea in 124 patients treated with oral gefitinib 250 mg once daily; seven (44%) of 16 patients heterozygous for ABCG2 421C>A (Q141K) developed diarrhea, versus only 13 (12%) of 108 patients homozygous for the wild-type sequence (P = .0046). However, this SNP was not associated with skin toxicity (P = .99). The finding suggests that patients with reduced ABCG2 activity due to a common genetic variant are at increased risk for substrate drug–induced diarrhea, with implications for optimizing treatment with such agents.
Summary
Introduction
TAS-114 is a potent inhibitor of deoxyuridine triphosphatase, which is a gatekeeper protein preventing uracil and 5-fluorouracil (5-FU) misincorporation into DNA. TAS-114 has ...been suggested to enhance the antitumor activity of 5-FU. This randomized, phase 2 study investigated TAS-114 plus S-1 (TAS-114/S-1) vs. S-1 in non-small-cell lung cancer (NSCLC) patients.
Methods
Patients with advanced NSCLC, previously treated with ≥ 2 regimens, were randomized 1:1 to receive TAS-114 (400 mg)/S-1 (30 mg/m
2
) or S-1 (30 mg/m
2
). Progression-free survival (PFS, independent central review) was the primary endpoint. Secondary endpoints included disease control rate (DCR), overall survival (OS), overall response rate (ORR), and safety.
Results
In total, 127 patients received treatment. Median PFS was 3.65 and 4.17 months in the TAS-114/S-1 and S-1 groups, respectively (hazard ratio HR 1.16, 95% confidence interval CI 0.71–1.88;
P
= 0.2744). DCR was similar between groups (TAS-114/S-1 80.3%, S-1 75.9%) and median OS was 7.92 and 9.82 months for the TAS-114/S-1 and S-1 groups, respectively (HR 1.31, 95% CI 0.80–2.14;
P
= 0.1431). The ORR was higher in the TAS-114/S-1 group than the S-1 group (19.7% vs. 10.3%), and more patients with tumor shrinkage were observed in the TAS-114/S-1 group. Incidence rates of anemia, skin toxicities, and Grade ≥ 3 treatment-related adverse events were higher in the TAS-114/S-1 group compared with the monotherapy group.
Conclusions
Although the TAS-114/S-1 combination improved the response rate, this did not translate into improvements in PFS.
Clinical Trial Registration No.
NCT02855125 (ClinicalTrials.gov) registered on 4 August 2016.
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