In this review, we report a complete and updated summary of the most recent treatment advances in the fields of oncogene-addicted disease and provide expert perspectives on the evolving paradigm of ...precision medicine in lung cancer patients.
The advent of innovative genome sequencing technologies is rapidly increasing the number of targetable molecular alterations in advanced nonsmall cell lung cancer (NSCLC), leading to the introduction of novel selective inhibitors into the clinical arena, showing unprecedent tumor responses against rare and elusive NSCLC targets. The results of the ADAURA trial suggested that targeting EGFR pathway in the adjuvant setting is a feasible and effective strategy. The routine use of next-generation sequencing (NGS) is currently recommended as new standard approach to profile advanced NSCLC samples while recent findings suggest the potential application of a plasma-based first approach for tumor genotyping. Innovative umbrella trials provide the right infrastructure to investigate the role of precision medicine in advanced NSCLC, but failed to show clinical benefit.
Implementing NGS-based molecular screening, increasing patients' access to biomarker driven-clinical trials, ensuring equal access to molecular testing and innovative treatments, overcoming disparities and preserve health systems' financial sustainability represents the main challenges of precision medicine worldwide.
PURPOSE
This meta-analysis aims to combine and analyze randomized clinical trials comparing computed tomography lung screening (CTLS) versus either no screening (NS) or chest x-ray (CXR) in subjects ...with cigarette smoking history, to provide a precise and reliable estimation of the benefits and harms associated with CTLS.
MATERIALS AND METHODS
Data from all published randomized trials comparing CTLS versus either NS or CXR in a highly tobacco-exposed population were collected, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Subgroup analyses by comparator (NS or CXR) were performed. Pooled risk ratio (RR) and relative 95% CIs were calculated for dichotomous outcomes. The certainty of the evidence was assessed using the GRADE approach.
RESULTS
Nine eligible trials (88,497 patients) were included. Pooled analysis showed that CTLS is associated with: a significant reduction of lung cancer–related mortality (overall RR, 0.87; 95% CI, 0.78 to 0.98; NS RR, 0.80; 95% CI, 0.69 to 0.92); a significant increase of early-stage tumors diagnosis (overall RR, 2.84; 95% CI 1.76 to 4.58; NS RR, 3.33; 95% CI, 2.27 to 4.89; CXR RR, 1.52; 95% CI, 1.04 to 2.23); a significant decrease of late-stage tumors diagnosis (overall RR, 0.75; 95% CI, 0.68 to 0.83; NS RR, 0.67; 95% CI, 0.56 to 0.80); a significant increase of resectability rate (NS RR, 2.57; 95% CI, 1.76 to 3.74); a nonsignificant reduction of all-cause mortality (overall RR, 0.99; 95% CI, 0.94 to 1.05); and a significant increase of overdiagnosis rate (NS, 38%; 95% CI, 14 to 63). The analysis of lung cancer–related mortality by sex revealed nonsignificant differences between men and women ( P = .21; I-squared = 33.6%).
CONCLUSION
Despite there still being uncertainty about overdiagnosis estimate, this meta-analysis suggested that the CTLS benefits outweigh harms, in subjects with cigarette smoking history, ultimately supporting the systematic implementation of lung cancer screening worldwide.
Pembrolizumab is the first-line standard of care for advanced non–small cell lung cancer (NSCLC) with a PD-L1 tumour proportion score (TPS) ≥ 50%. Eastern Cooperative Oncology Group performance ...status (PS) 2 patients may receive pembrolizumab, despite the absence of sustaining evidence.
GOIRC-2018-01 is a multicentre, retrospective, observational study. PS 2 NSCLC patients with a PD-L1 TPS ≥50% receiving first-line pembrolizumab from June 2017 to December 2018 at 21 Italian institutions were included. Clinical-pathological characteristics were correlated with disease response and survival outcomes; adverse events were recorded. The primary objective was 6-months progression-free rate (6-months PFR).
One hundred fifty-three patients (median age 70 years) were enrolled. At a median follow-up of 18.2 months, median progression-free survival (PFS) and overall survival (OS) were 2.4 (95% confidence interval, 95% CI, 1.6–2.5) and 3.0 months (95% CI 2.4–3.5), respectively. 6-months PFR was 27% (95% CI 21–35%). Patients with a PS 2 determined by comorbidities (n = 41) had significantly better outcomes compared with disease burden-induced PS 2 (n = 112). Indeed, 6-months PFR was 49% versus 19%, median PFS 5.6 versus 1.8 months and OS 11.8 versus 2.8 months, respectively. Additional potential prognostic factors (radiotherapy, antibiotics, steroids received before pembrolizumab) correlated with clinical outcomes. The determinant of PS 2 resulted the only factor independently impacting on both PFS and OS. No toxicity issues emerged.
Outcomes of PS 2 NSCLC patients with PD-L1 TPS ≥50% receiving first-line pembrolizumab were globally dismal but strongly dependent on the reason conditioning the poor PS itself.
•Evidence on first-line pembrolizumab in Eastern Cooperative Oncology Group performance status (PS) 2 non–small cell lung cancer (NSCLC) (PD-L1 ≥ 50%) are poor.•This retrospective study documented dismal outcomes in this population of interest.•Patients with disease burden-determined poor PS had poor prognosis.•Comorbidity-induced PS 2 may still benefit form pembrolizumab.•The differential determinants of PS 2 in NSCLC are relevant for clinical decisions.
The identification of reliable predictive biomarkers of efficacy or resistance to immune-oncology (I–O) agents is a major issue for translational research and clinical practice. However, along with ...PDL1 and molecular features other clinical, radiological and laboratory factors can be considered for the selection of those patients who would not be the best candidate for immune-checkpoint inhibitors (ICPIs). We examined these factors, emerging from the results of currently available studies in non-small cell lung cancer (NSCLC), aiming to provide a useful and manageable tool which can help Oncologists in their everyday clinical practice.
A thorough patient evaluation and close clinical monitoring, due to limited, early or inconclusive currently available data, should be deserved for patients with a pre-existing symptomatic chronic obstructive pulmonary disease, age >75 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥ 1, a time to progression (TTP) < three months and progressive disease (PD) as the best response to the previous treatment, hepatitis or HIV-infections, high neutrophil to lymphocyte ratio (NLR), or on treatment with high-dose steroids, when the use of ICPIs is considered. Limited data are available to consider that ICPIs are safe in patients with interstitial lung disease, bronchiolitis obliterans organizing pneumonia and autommune diseases. Early evidence on steroids, vaccinations and antibiotics suggest their possible interaction with ICPIs and need to be more investigated in clinical trials. Oncogene-addicted NSCLC harboring EGFR-mutations and low tumor-infiltrating T-lymphocytes (TILs) seems not to gain benefit from I–O.
Treatment of homologous recombination repair-deficient (HRD)-tumors with PARP inhibitors has the potential to further increase tumor immunogenicity, suggesting a synergistic effect with ...immunotherapy. Here we present the preliminary results of niraparib in combination with dostarlimab for pleural mesothelioma (PM) or non-small cell lung cancer (NSCLC) harboring HRR mutations.
UNITO-001 is a phase II, prospective, study aiming to investigate the combination of niraparib plus dostarlimab in pretreated patients with HRD and programmed death ligand-1 (PD-L1) ≥1% NSCLC and/or PM. The primary endpoint is progression-free survival (PFS).
Seventeen of 183 (10%) screened patients (12 PM and 5 NSCLC) were included. The objective response rate (ORR) was 6% 95% confidence interval (CI): 0.1-28.7 and the disease control rate (DCR) was 53% (95% CI: 27.8-77). Median PFS was 3.1 (95% CI: 2.7-N.A) and median overall survival (OS) was 4.2 (95% CI: 1.58-NA) months. The PFS was 14.1 months in one PM patient harboring a germline BAP1 mutation. The treatment duration was 9.8 months in one PM patient harboring a somatic BRCA2 mutation. The most common adverse events (AE) were grade 1-2 lymphopenia (59%), anemia (35%), hyponatremia (29%), and hypokalemia (29%). Grade ≥3 AEs were reported in 23% of the patients.
This preliminary analysis highlighted the lack of antitumor activity for the combination of niraparib and dostarlimab in patients with PM and/or advanced NSCLC harboring BAP1 somatic mutations. A potential antitumor activity emerged for PM with germline BAP1 and/or BRCA2 somatic mutations along with a good tolerability profile.
•The ADAURA study marked the advent of precision medicine and molecular biomarker testing to the early stages disease.•The IMPower-010 trial paved the way to the application of immune-checkpoint ...inhibition in the post-operative setting.•The ITACA trial definitively established no role for tailored adjuvant chemotherapy in surgically resected NSCLC.•The Lung Art data questioned the efficacy of post-operative radiotherapy for pN2 resected disease.•Growing evidence is supporting MRD as reliable prognostic biomarker in the adjuvant setting.
We are witnessing a silent revolution in the treatment of early stage non-small cell lung cancer (NSCLC), with a series of practice-changing clinical trials enriching the therapeutic perspectives of lung cancer patients with potentially curable disease. The ADAURA study marked the advent of precision medicine and biomarker testing to the early stages setting. The IMPower-010 trial interrupted the negative trend of adjuvant lung cancer immunotherapy, paving the way to the application of immune-checkpoint inhibition in the resected disease. The ITACA trial definitively established no role for tailored adjuvant chemotherapy in NSCLC, while the Lung Art data questioned the efficacy of post-operative radiotherapy for pN2 resected disease. Growing evidence is supporting MRD as effective adjuvant prognostic biomarker to stratify disease’s recurrence risk after radical interventions and select best candidates to the adjuvant strategies. This work summarizes the recent major breakthroughs in lung cancer adjuvant treatment, and provides a snapshot of the current real-world scenario, discussing the upcoming challenges and opportunities featuring the clinical management of early stage NSCLC patients.
In the last decades the approach to cancer patient management has been deeply revolutionized. We are moving from a “one-fits-all” strategy to the “personalized medicine” based on the molecular ...characterization of the tumor. In this new era it is becoming more and more clear that the monitoring of the disease is fundamental for the success of the treatment, thus there is the need of new biomarker discovery. More precisely in the last years the scientific community has started to use the term “liquid biopsy”. A liquid biopsy is a liquid biomarker that can be easily isolated from many body fluids (blood, saliva, urine, ascites, pleural effusion, etc.) and, as well as a tissue biopsy, a representative of the tissue from which it is spread. In this review we will focus our attention on circulating tumor cells, circulating tumor DNA, exosomes and secretomes with the aim to underlie their usefulness and potential application in a clinical setting for lung cancer patient management.
•The review underlies the potential impact of liquid biopsy in lung cancer patients management.•Liquid biopsy is a liquid biomarker that can be easily isolated from many body fluids.•CTC, ctDNA, exosome and secretome provide different information related to the tissue from which they originate.•Liquid biopsy can be used as predictive, prognostic and also diagnostic biomarkers in several tumor types.•The road toward the introduction of liquid biopsy in clinical setting is still long.
The present study investigated the efficacy and safety of nivolumab in pre-treated patients with advanced NSCLC harbouring KRAS mutations.
Clinical data and KRAS mutational status were analysed in ...patients treated with nivolumab within the Italian Expanded Access Program. Objective response rate, progression-free survival and overall survival were evaluated. Patients were monitored for adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events.
Among 530 patients evaluated for KRAS mutations, 206 (39%) were positive while 324 (61%) were KRAS wild-type mutations. KRAS status did not influence nivolumab efficacy in terms of ORR (20% vs 17%, P = 0.39) and DCR (47% vs 41%, P = 0.23). The median PFS and OS were 4 vs 3 months (P = 0.5) and 11.2 vs 10 months (P = 0.8) in the KRAS-positive vs the KRAS-negative group. The 3-months PFS rate was significantly higher in the KRAS-positive group as compared to the KRAS-negative group (53% vs 42%, P = 0.01). The percentage of any grade and grade 3-4 AEs were 45% vs 33% (P = 0.003) and 11% vs 6% (P = 0.03) in KRAS-positive and KRAS-negative groups, respectively.
Nivolumab is an effective and safe treatment option for patients with previously treated, advanced non-squamous NSCLC regardless of KRAS mutations.
This pooled analysis aims at evaluating the diagnostic accuracy of circulating tumor (ct) DNA for the detection of EGFR-T790M mutation in NSCLC patients who progressed after EGFR-TKIs. Data from all ...published studies, reporting both sensitivity and specificity of plasma-based EGFR-T790M mutation testing by ctDNA were collected by searching in PubMed, Cochrane Library, American Society of Clinical Oncology, European Society of Medical Oncology and World Conference of Lung Cancer meeting proceedings. A total of twenty-one studies, with 1639 patients, were eligible. The pooled sensitivity of ctDNA analysis was 0.67 (95% CI: 0.64-0.70) and the pooled specificity was 0.80 (95% CI: 0.77-0.83). The pooled positive predictive value (PPV) was 0.85 (95% CI: 0.82-0.87) and the pooled negative predictive value (NPV) was 0.60 (95% CI: 0.56-0.63). The positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were 2.67 (95% CI: 1.86-3.82) and 0.46 (95% CI: 0.38-0.54), respectively. The pooled diagnostic odds ratio (DOR) was 7.27 (4.39-12.05) and the area under the curve (AUC) of the summary receiver operating characteristics (sROC) curve was 0.77. The ctDNA analysis represents a promising, non-invasive approach to detect and monitor the T790M mutation status in NSCLC patients. Development of standardized methodologies and clinical validation are recommended.
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