•Immunotherapy changed treatment paradigm for NSCLC patients.•Real-world patients often differ from selected patients enrolled in clinical trials.•Some patient subsets are underrepresented in ...randomized clinical trials (RCTs)•Real-world studies may close this gap and overcome the intrinsic limits of RCTs.
Immune checkpoint inhibitors (ICIs) targeting programmed death 1 (PD-1) and PD-ligand 1 (PD-L1) quickly subverted the standard of treatment in Non-Small Cell Lung Cancer (NSCLC), where they were first introduced in all comers previously treated advanced/metastatic NSCLC patients and subsequently in the first line of PD-L1 selected cases of metastatic and locally advanced disease.
Treatment algorithm is an evolving landscape, where the introduction of front-line ICIs, with or without chemotherapy, unavoidably influences the following treatment lines. In this context, medical oncologists are currently facing many unclear issues, which have been not clarified so far by available data.
Effectiveness and safety in special populations underrepresented in clinical trials - such as elderly, poor PS, hepatitis or human immunodeficiency virus-affected patients - are only a part of the unexplored side of ICIs in the real world. Indeed, pivotal randomized clinical trials (RCTs) often lack of external validity because eligibility criteria exclude some patient subgroups commonly treated in real-world clinical practice. Similarly, cost-effectiveness and sustainability of these innovative agents are important issues to be considered in the real-world. Though affected by several limitations, real-world evidence (RWE) studies allow to collect data regarding overall treated patients in clinical practice according to local authority regulations, overcoming the intrinsic limits of RCTs.
The present review focuses on RWE about ICIs in lung cancer treatment, with particular reference to special patient populations, and discusses potential application of real-world data in a potential innovative drug development model.
Compound epidermal growth factor receptor (
) mutations represent a heterogeneous subgroup of non-small cell lung cancer (NSCLC) patients with uncommon
mutations. We conducted a systematic review to ...investigate the available data on this patients' subgroup. Overall, we found a high heterogeneity in the incidence of compound mutations (4-26% of total
mutant cases), which is dependent on the different testing methods adopted and the specific mutations considered. In addition, the relative incidence of distinct compound subclasses identified is reported with extreme variability in different studies. Preclinical and clinical data, excluding
exon 20 p.T790M compound mutations, show good responses with EGFR tyrosine kinase inhibitors (TKIs) (combined common mutations: response rate (RR) ≥ 75% with either first- or second-generation TKIs; combined common plus uncommon: RR 40-80% and 100% with first-generation TKIs and afatinib, respectively; combined uncommon: RR 20-70%, ~80% and ~75% with first-generation TKIs, afatinib and osimertinib, respectively). Overall, data are consistent in supporting the use of EGFR TKIs in treating compound
mutations, taking into account different sensitivity profile of accompanying
mutations for selecting the most adequate EGFR TKI for individual patients.
Uncommon (ucEGFRmuts) and rare epidermal growth factor receptor (
) mutations account for 10-15% of diagnosed cases and consist of a heterogeneous group represented by several clusters within exons ...18-21 (e.g., exon 18 point mutations, exon 21 L861X, exon 20 S768I), as well as exon 20 insertions (Ex20ins). Their incidence is under molecular and clinical investigation following recent findings that reported an increase of sensitivity and specificity of next-generation sequencing (NGS) methods. Consequently, their detection allows for the selection of emerging treatment options to significantly improve patients' outcomes in these particular subgroups of
-mutated advanced non-small cell lung cancer (NSCLC). Specifically, this commentary is focused on the notable progress of the Phase 3 PAPILLON study that showed primary efficacy results from amivantamab, a bispecific antibody with specific binding and affinity to extracellular domains of EGFR and MET, plus chemotherapy in the first-line setting for EGFR exon 20 insertion-mutated advanced or metastatic NSCLC patients, as compared with chemotherapy alone, thus becoming the new standard of care in this group of patients.
Liquid biopsy has the potential to monitor biological effects of treatment. KRAS represents the most commonly mutated oncogene in Caucasian non-small-cell lung cancer (NSCLC). The aim of this study ...was to explore association of dynamic plasma KRAS genotyping with outcome in advanced NSCLC patients.
Advanced NSCLC patients were prospectively enrolled. Plasma samples were collected at baseline (T1), after 3 or 4 weeks, according to treatment schedule (T2) and at first radiological restaging (T3). Patients carrying KRAS mutation in tissue were analysed in plasma with droplet digital PCR. Semi-quantitative index of fractional abundance of mutated allele (MAFA) was used.
KRAS-mutated cohort included 58 patients, and overall 73 treatments (N = 39 chemotherapy and N = 34 immune checkpoint inhibitors) were followed with longitudinal liquid biopsy. Sensitivity of KRAS detection in plasma at baseline was 48.3% (95% confidence interval (CI): 35.0-61.8). KRAS mutation at T2 was associated with increased probability of experiencing progressive disease as best radiological response (adjusted odds ratio: 7.3; 95% CI: 2.1-25.0, p = 0.0016). Increased MAFA (T1-T2) predicted shorter progression-free survival (adjusted hazard ratio (HR): 2.1; 95% CI: 1.2-3.8, p = 0.0142) and overall survival (adjusted HR: 3.2; 95% CI: 1.2-8.4, p = 0.0168).
Longitudinal analysis of plasma KRAS mutations correlated with outcome: its early assessment during treatment has great potentialities for monitoring treatment outcome in NSCLC patients.
Liver kinase B1 (
) is a tumor suppressor gene whose inactivation is frequent in different tumor types, especially in lung adenocarcinoma (about 30% of cases). LKB1 has an essential role in the ...control of cellular redox homeostasis by regulating ROS production and detoxification. Loss of LKB1 makes the tumor cell more sensitive to oxidative stress and consequently to stress-inducing treatments, such as chemotherapy and radiotherapy. LKB1 loss triggers complex changes in tumor microenvironment, supporting a role in the regulation of angiogenesis and suggesting a potential role in the response to anti-angiogenic treatment. On the other hand, LKB1 deficiency can promote an immunosuppressive microenvironment and may be involved in primary resistance to anti-PD-1/anti-PD-L1, as it has been reported in lung cancer. The aim of this review is to discuss interactions of LKB1 with the tumor microenvironment and the potential applications of this knowledge in predicting response to treatment in lung cancer.
In February 2020, Italy became one of the first countries to be plagued by the SARS-CoV-2 pandemic, COVID-19. In March 2020, the Italian government decreed a lockdown for the whole country, which ...overturned communication systems, hospital organization, and access to patients and their relatives and carers. This issue had a particular regard for cancer patients. Our Thoracic Oncology Division therefore reorganized patient access in order to reduce the risk of contagion and, at the same time, encourage the continuation of treatment. Our staff contacted all patients to inform them of any changes in treatment planning, check that they were taking safety measures, and ascertain their feelings and whether they had any COVID-19 symptoms. To better understand patients’ fears and expectations of during the pandemic period, we created a nine-question interview, administered from April to May 2020 to 156 patients with lung cancer. Patients were classified by age, sex, comorbidity, disease stage, prior treatment, and treatment type. The survey showed that during the pandemic period some patients experienced fear of COVID-19, in particular: women (55% vs. 33%), patients with comorbidities (24% vs. 9%), and patients who had already received prior insult (radiotherapy or surgery) on the lung (30% vs. 11%). In addition, the patients who received oral treatment at home or for whom intravenous treatment was delayed, experienced a sense of relief (90% and 72% respectively). However, only 21% of the patients were more afraid of COVID-19 than of their cancer, in particular patients with long-term (> 12 months) vs. short-term cancer diagnosis (28% vs. 12.5%, respectively). Furthermore, the quarantine period or even just the lockdown period alone, worsened the quality of life of some patients (40%), especially those in oral treatment (47%). Our data demonstrate how lung cancer patients are more afraid of their disease than of a world pandemic. Also this interview indirectly highlights the clinician’s major guiding principle in correctly and appropriately managing not just the patient’s expectations of their illness and its treatment, but also and especially of the patient’s fears.
An increasing number of driver genomic alterations with potential targeted treatments have been identified in non-small cell lung cancer (NSCLC). Much less is known about the incidence and different ...distribution of concurrent alterations, as identified by comprehensive genomic profiling in oncogene-addicted NSCLCs. Genomic data from advanced NSCLC consecutively analyzed using a broad next-generation sequencing panel were retrospectively collected. Tumors harboring at least one main actionable gene alteration were categorized according to the presence/absence of concurrent genomic aberrations, to evaluate different patterns among the main oncogene-addicted NSCLCs. Three-hundred-nine actionable gene alterations were identified in 284 advanced NSCLC patients during the study period. Twenty-five tumor samples (8%) displayed concurrent alterations in actionable genes. Co-occurrences involving any pathogenic variant or copy number variation (CNV) were identified in 82.8% of cases. Overall, statistically significant differences in the number of concurrent alterations, and the distribution of
,
, cyclines and receptor tyrosin kinase (RTK) aberrations were observed across the eight actionable gene groups. NGS analyses of oncogene-addicted NSCLCs showed a different distribution and pattern of co-alteration profiles. Further investigations are needed to evaluate the prognostic and treatment-related impact of these concurrent alterations, hooked to the main gene aberrations.
Immune checkpoint blockade has modified the treatment landscape for many types of tumors, including lung cancer. Still our knowledge on the biology of the interaction between tumor cells and the ...microenvironment is limited, preventing the optimal use of these new compounds and the maximum benefit that the patients can derive from them. We have actively worked on the role of STAT3, a transcriptional factor that causes innate resistance to targeted therapies in oncogene-addicted tumors. In this short review we take the opportunity to express our opinion and review existing knowledge on the immune role of STAT3 and the possible implications that this may have for the discovery of new biomarkers to predict response to immunotherapy, as well as new partners to combine with and increase the efficacy of immune checkpoint inhibitors.
Tyrosine kinase inhibitors (TKIs) revolutionized the treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC) harboring most driver gene alterations. Starting from the ...first generation, research rapidly moved to the development of newer, more selective generations of TKIs, obtaining improved results in terms of disease control and survival. However, the use of novel generations of TKIs is not without limitations. We reviewed the main results obtained, as well as the ongoing clinical trials with TKIs in oncogene-addicted NSCLC, together with the biology underlying their potential strengths and limitations. Across driver gene alterations, novel generations of TKIs allowed delayed resistance, prolonged survival, and improved brain penetration compared to previous generations, although with different toxicity profiles, that generally moved their use from further lines to the front-line treatment. However, the anticipated positioning of novel generation TKIs leads to abolishing the possibility of TKI treatment sequencing and any role of previous generations. In addition, under the selective pressure of such more potent drugs, resistant clones emerge harboring more complex and hard-to-target resistance mechanisms. Deeper knowledge of tumor biology and drug properties will help identify new strategies, including combinatorial treatments, to continue improving results in patients with oncogene-addicted NSCLC.
Lung cancer is the second-most commonly diagnosed cancer and the leading cause of cancer death worldwide. The most common histological type is non-small-cell lung cancer, accounting for 85% of all ...lung cancer cases. About one out of three new cases of non-small-cell lung cancer are diagnosed at a locally advanced stage-mainly stage III-consisting of a widely heterogeneous group of patients presenting significant differences in terms of tumor volume, local diffusion, and lymph nodal involvement. Stage III NSCLC therapy is based on the pivotal role of multimodal treatment, including surgery, radiotherapy, and a wide-ranging option of systemic treatments. Radical surgery is indicated in the case of hilar lymphnodal involvement or single station mediastinal ipsilateral involvement, possibly after neoadjuvant chemotherapy; the best appropriate treatment for multistation mediastinal lymph node involvement still represents a matter of debate. Although the main scope of treatments in this setting is potentially curative, the overall survival rates are still poor, ranging from 36% to 26% and 13% in stages IIIA, IIIB, and IIIC, respectively. The aim of this article is to provide an up-to-date, comprehensive overview of the state-of-the-art treatments for stage III non-small-cell lung cancer.
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