Targeted Therapy in Mesotheliomas: Uphill All the Way.

Mesothelioma (MM) is an aggressive and lethal disease with few therapeutic opportunities. Platinum-pemetrexed chemotherapy is the backbone of first-line treatment for MM. The introduction of immunotherapy (IO) has been the only novelty of the last decades, allowing an increase in survival compared to standard chemotherapy (CT). However, IO is not approved for epithelioid histology in many countries. Therefore, therapy for relapsed MM remains an unmet clinical need, and the prognosis of MM remains poor, with an average survival of only 18 months. Increasing evidence reveals MM complexity and heterogeneity, of which histological classification fails to explain. Thus, scientific focus on possibly new molecular markers or cellular targets is increasing, together with the search for target therapies directed towards them. The molecular landscape of MM is characterized by inactivating tumor suppressor alterations, the most common of which is found in CDKN2A, BAP1, MTAP, and NF2. In addition, cellular targets such as mesothelin or metabolic enzymes such as ASS1 could be potentially amenable to specific therapies. This review examines the major targets and relative attempts of therapeutic approaches to provide an overview of the potential prospects for treating this rare neoplasm.

Osimertinib in Patients With Treatment-Naive EGFR-Mutant Non-small Cell Lung Cancer: Overall Survival, Post-progression Management and Budget Impact Analysis in Real-World.

INTRODUCTION: The observational multicenter prospective FLOWER study (NCT04965701) confirmed effectiveness and safety of osimertinib in the real-world (RW) management of untreated EGFR-mutant advanced non-small cell lung cancer (aNSCLC) patients. METHODS: Herein, we report updated survival data, post-progression management, cost/effectiveness and budget impact (BI) of osimertinib compared with a RW population receiving gefitinib or erlotinib. RESULTS: Overall, 189 Caucasian patients receiving first-line osimertinib were included. After a follow-up of 20.7 months, 74(39.2%) patients discontinued osimertinib, median time-to-treatment discontinuation (mTTD) was 27.9 months, overall survival 36.8 months. At progression, tissue biopsy was performed in 29 (56.9%), liquid biopsy in 15 (29.4%) and both in 7 (13.7%) cases. The most frequent resistant mechanism was MET amplification (N = 14, 29.8%). At data cutoff, 13 (6.9%) patients were continuing osimertinib beyond progression; 52 (67.5%) received second-line treatment; no further treatments were administered in 25 (32.5%) cases. Thirty-three (63.4%) patients received chemotherapy, 12(23.1%) TKIs combination. Cost-effectiveness analysis showed a total cost per patient based on RW mTTD of 98,957.34€, 21,726.28€ and 19,637.83€ for osimertinib, erlotinib and gefitinib, respectively. The incremental cost-effectiveness ratio (ICER)/month for osimertinib was 359,806.0€/life-year-gained (LYG) and 197,789.77€/LYG compared to erlotinib and gefitinib. For osimertinib, the BI-gap between RW-TTD and theoretical-TTD was 16,501.0€ per patient. CONCLUSIONS: This updated analysis confirms the effectiveness of osimertinib in RW. Although the ICER of osimertinib seems not cost-effective, additional costs for the management of disease progression to old generation TKIs were not considered in this study. The BI-gap suggests RW mTTD as a more reliable measure for expense estimation.

Case report: First evidence of impressive efficacy of modulated dose selpercatinib in a young Caucasian with ANK3-RET fusion-positive NSCLC.

Over the past decade, molecular characterization has led to change the management of advanced non-small cell lung cancer (NSCLC) harboring driver mutations. Rearranged during transfection (RET) gene fusions, occurring in 1% to 2% of NSCLC, have emerged as an oncogenic druggable target. Systemic targeted therapies with highly selective RET inhibitors (RETi), selpercatinib and pralsetinib, represent a recent clinical breakthrough. While the development of RETi has improved survival, with their increasing use, it is crucial to be aware of the risks of rare but serious adverse events (AEs). A particular challenge for clinicians in applying targeted therapies is not only diagnosing but also interpreting rare mutations. Herein, we report a case of a 43-year-old Caucasian advanced NSCLC patient diagnosed with a rare RET gene fusion, ANK3::RET, identified with Next Generation Sequencing (NGS). Selpercatinib has been initiated at the recommended initial dose after one incomplete chemotherapy cycle due to a severe infusion reaction, but it subsequently required a dose adjustment following grade 3 (G3) AEs. During treatment, we used a particular selpercatinib dosage (160 mg in the morning and 80 mg in the evening) with good tolerance and without compromising effectiveness. Our finding broadens the range of RET fusion types in not-Asian NSCLC. To the best of our knowledge, our case demonstrates, for the first time, a clinical and radiological response to frontline highly selective RETi selpercatinib, expanding the spectrum of potential oncogenic RET fusion partners in newly diagnosed NSCLC patients. Furthermore, to our knowledge, this is the first case describing a RET fusion-positive (RET+) NSCLC patient treated with a modified selpercatinib dosage outside the drug data sheet and demonstrating a safe and effective use.

Liquid Biopsy in NSCLC: An Investigation with Multiple Clinical Implications.

Tissue biopsy is essential for NSCLC diagnosis and treatment management. Over the past decades, liquid biopsy has proven to be a powerful tool in clinical oncology, isolating tumor-derived entities from the blood. Liquid biopsy permits several advantages over tissue biopsy: it is non-invasive, and it should provide a better view of tumor heterogeneity, gene alterations, and clonal evolution. Consequentially, liquid biopsy has gained attention as a cancer biomarker tool, with growing clinical applications in NSCLC. In the era of precision medicine based on molecular typing, non-invasive genotyping methods became increasingly important due to the great number of oncogene drivers and the small tissue specimen often available. In our work, we comprehensively reviewed established and emerging applications of liquid biopsy in NSCLC. We made an excursus on laboratory analysis methods and the applications of liquid biopsy either in early or metastatic NSCLC disease settings. We deeply reviewed current data and future perspectives regarding screening, minimal residual disease, micrometastasis detection, and their implication in adjuvant and neoadjuvant therapy management. Moreover, we reviewed liquid biopsy diagnostic utility in the absence of tissue biopsy and its role in monitoring treatment response and emerging resistance in metastatic NSCLC treated with target therapy and immuno-therapy.

Therapeutical Options in ROS1-Rearranged Advanced Non Small Cell Lung Cancer.

ROS proto-oncogene 1 (ROS1) rearrangements occur in 0.9-2.6% of patients with non small cell lung cancer (NSCLC), conferring sensitivity to treatment with specific tyrosine-kinase inhibitors (TKI). Crizotinib, a first-generation TKI, was the first target-therapy approved for the first-line treatment of ROS1-positive NSCLC. Recently, entrectinib, a multitarget inhibitor with an anti-ROS1 activity 40 times more potent than crizotinib and better activity on the central nervous system (CNS), received approval for treatment-naive patients. After a median time-to-progression of 5.5-20 months, resistance mechanisms can occur, leading to tumor progression. Therefore, newer generation TKI with greater potency and brain penetration have been developed and are currently under investigation. This review summarizes the current knowledge on clinicopathological characteristics of ROS1-positive NSCLC and its therapeutic options.

Selection Criteria and Treatment Outcome for Advanced Non-Small Cell Lung Cancer (NSCLC) Patients Unfit for Platinum-Based First-Line Therapy: Results of the MOON-OSS Observational Trial.

Limited evidence is available concerning the selection criteria and the outcomes of platinum unfit newly diagnosed advanced NSCLC patients receiving single-agent chemotherapy. We retrospectively collected data on consecutive, stage IIIB-IV, EGFR/ALK negative and PD-L1 < 50% NSCLC patients treated with first-line single agent chemotherapy. Baseline characteristics, outcome measures and toxicities were recorded, as well as criteria according to which treatment selection was made and what percentage of patients did not receive a first-line platinum-based chemotherapy. Two-hundred and twenty-one patients were included. Median age was 79 (range 56−92) years, M/F 165(74.6%)/56(25.4%), ECOG performance status (PS) 0/1/ ≥ 2 23(10.9%)/94(42.5%)/103(46.6%), with a median of two serious comorbidities. A median of 25% (range 10%-30%) of newly diagnosed NSCLC did not receive a first-line platinum combination. Clinical criteria according to which decision was made were older age (76.5%), comorbidities (72%), poor PS (55.2%) and familiar or social issues (10%). Single-agent treatment consisted of oral metronomic vinorelbine (MetV 78.6%), gemcitabine (Gem 10%), oral standard vinorelbine (Vin 8.2%) and other (O 3.2%). Median progression-free survival (PFS) and overall survival (OS) of single agent treatments ranged from 4.5 to 5 months and from 9 to 10.5 months, respectively. All grade toxicities did not differ among single agents, while grade 3−4 toxicities were less frequent with MetV. Up to 30% of newly diagnosed advanced EGFR/ALK negative and PD-L1 < 50% NSCLC patients do not receive a first-line platinum doublet. Main clinical selection criteria were older age (>70 years), comorbidities and poor PS. An oral treatment was frequently proposed with MetV being the most frequent choice according to its safety profile.

Detection of ALK fusion variants by RNA-based NGS and clinical outcome correlation in NSCLC patients treated with ALK-TKI sequences.

INTRODUCTION: Anaplastic lymphoma kinase (ALK) fusions identify a limited subset of non-small cell lung cancer (NSCLC) patients, whose therapeutic approach have been radically changed in recent years. However, diagnostic procedures and clinical-radiological responses to specific targeted therapies remain heterogeneous and intrinsically resistant or poor responder patients exist. METHODS: A total of 290 patients with advanced NSCLC defined as ALK+ by immunohistochemistry (IHC) and/or fluorescent in situ hybridisation (FISH) test and treated with single or sequential multiple ALK inhibitors (ALKi) from 2011 to 2017 have been retrospectively retrieved from a multicentre Italian cancer network database. In 55 patients with enough leftover tumour tissue, specimens were analysed with both targeted and customised next generation sequencing panels. Identified fusion variants have been correlated with clinical outcomes. RESULTS: Of the 55 patients, 24 received crizotinib as first-line therapy, 1 received ceritinib, while 30 received chemotherapy. Most of the patients (64%) received ALKi in sequence. An ALK fusion variant was identified in 73% of the cases, being V3 variant (E6A20) the most frequent, followed by V1 (E13A20) and more rare ones (e.g. E6A19). In three specimens, four new EML4-ALK fusion breakpoints have been reported. Neither fusion variants nor brain metastases were significantly associated with overall survival (OS), while it was predictably longer in patients receiving a sequence of ALKi. The presence of V1 variant was associated with progression-free survival (PFS) improvement when crizotinib was used (p = 0.0073), while it did not affect cumulative PFS to multiple ALKi. CONCLUSION: Outcomes to sequential ALKi administration were not influenced by fusion variants. Nevertheless, in V1+ patients a prolonged clinical benefit was observed. Fusion variant identification by NGS technology may add relevant information about rare chromosomal events that could be potentially correlated to worse outcomes.

Acquired Resistance to Osimertinib in EGFR-Mutated Non-Small Cell Lung Cancer: How Do We Overcome It?

Osimertinib is currently the preferred first-line therapy in patients with non-small cell lung cancer (NSCLC) with common epidermal growth factor receptor (EGFR) mutation and the standard second-line therapy in T790M-positive patients in progression to previous EGFR tyrosine kinase inhibitor. Osimertinib is a highly effective treatment that shows a high response rate and long-lasting disease control. However, a resistance to the treatment inevitably develops among patients. Understanding the secondary mechanisms of resistance and the possible therapeutic options available is crucial to define the best management of patients in progression to osimertinib. We provide a comprehensive review of the emerging molecular resistance mechanism in EGFR-mutated NSCLC pre-treated with osimertinib and its future treatment applications.

Targeted Therapy and Immunotherapy in Early-Stage Non-Small Cell Lung Cancer: Current Evidence and Ongoing Trials.

The scenario of neoadjuvant and adjuvant settings in non-small cell lung cancer (NSCLC) is rapidly evolving. As already happened for the advanced disease, also early stages have entered the era of precision medicine, with molecular analysis and Programmed death-ligand 1 (PD-L1) evaluation that by now can be considered a routine assessment. New treatment options have been recently approved, with osimertinib now part of clinical practice for Epidermal Growth Factor Receptor mutated (EGFRm) patients, and immune checkpoint inhibitors (ICIs) available after FDA approval both in the adjuvant (atezolizumab) and neoadjuvant (nivolumab) setting. No mature data on overall survival benefits are available yet, though. Several clinical trials with specific-tyrosine kinase inhibitors (TKIs) and ICIs are currently ongoing, both with and without concomitant chemotherapy. As therapeutic strategies are rapidly expanding, quite a few questions remain unsettled, such as the optimal duration of adjuvant targeted therapy or the effective benefit of ICIs in early-stage EGFRm or ALK (Anaplastic Lymphoma Kinase) rearranged patients, or the possibility to individuate high-risk patients after surgical resection assessing minimal residual disease (MRD) by ctDNA evaluation. We hereby report already available literature data and summarize ongoing trials with targeted therapy and immunotherapy in early-stage NSCLC, focusing on practice-changing results and new perspectives for potentially cured patients.

The Change in Paradigm for NSCLC Patients with EML4-ALK Translocation.

The severe prognosis linked with a lung cancer diagnosis has changed with the discovery of oncogenic molecularly driven subgroups and the use of tailored treatment. ALK-translocated advanced lung cancer is the most interesting model, having achieved the longest overall survival. Here, we report the most important paradigmatic shifts in the prognosis and treatment for this subgroup population occurred among lung cancer.

Brain Metastases Management in Oncogene-Addicted Non-Small Cell Lung Cancer in the Targeted Therapies Era.

The therapeutic landscape in patients with advanced non-small-cell lung cancer harboring oncogenic biomarkers has radically changed with the development of targeted therapies. Although lung cancers are known to frequently metastasize to the brain, oncogene-driven non-small-cell lung cancer patients show a higher incidence of both brain metastases at baseline and a further risk of central nervous system progression/relapse. Recently, a new generation of targeted agents, highly active in the central nervous system, has improved the control of intracranial disease. The intracranial activity of these drugs poses a crucial issue in determining the optimal management sequence in oncogene-addicted non-small-cell lung cancer patients with brain metastases, with a potential change of paradigm from primary brain irradiation to central nervous system penetrating targeted inhibitors.

NSCLC as the Paradigm of Precision Medicine at Its Finest: The Rise of New Druggable Molecular Targets for Advanced Disease.

Standard treatment for advanced non-small cell lung cancer (NSCLC) historically consisted of systemic cytotoxic chemotherapy until the early 2000s, when precision medicine led to a revolutionary change in the therapeutic scenario. The identification of oncogenic driver mutations in EGFR, ALK and ROS1 rearrangements identified a subset of patients who largely benefit from targeted agents. However, since the proportion of patients with druggable alterations represents a minority, the discovery of new potential driver mutations is still an urgent clinical need. We provide a comprehensive review of the emerging molecular targets in NSCLC and their applications in the advanced setting.

Bone Metastasis and Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer (NSCLC): Microenvironment and Possible Clinical Implications.

Patients with non-small cell lung cancer (NSCLC) develop bone metastasis (BoM) in more than 50% of cases during the course of the disease. This metastatic site can lead to the development of skeletal related events (SREs), such as severe pain, pathological fractures, spinal compression, and hypercalcemia, which reduce the patient's quality of life. Recently, the treatment of advanced NSCLC has radically changed due to the advent of immunotherapy. Immune checkpoint inhibitors (ICI) alone or in combination with chemotherapy have become the main therapeutic strategy for advanced or metastatic NSCLC without driver gene mutations. Since survival has increased, it has become even more important to treat bone metastasis to prevent SRE. We know that the presence of bone metastasis is a negative prognostic factor. The lower efficacy of immunotherapy treatments in BoM+ patients could be induced by the presence of a particular immunosuppressive tumor and bone microenvironment. This article reviews the most important pre-clinical and clinical scientific evidence on the reasons for this lower sensitivity to immunotherapy and the need to combine bone target therapies (BTT) with immunotherapy to improve patient outcome.

First-Line Osimertinib in Patients with EGFR-Mutant Advanced Non-Small Cell Lung Cancer: Outcome and Safety in the Real World: FLOWER Study.

BACKGROUND: Osimertinib became the standard treatment for patients with untreated EGFR-mutant advanced non-small cell lung cancer (aNSCLC) following results reported in the phase III randomized FLAURA trial. Because of strict exclusion criteria, patient populations included in pivotal trials are only partially representative of real-world patients. METHODS: We designed an observational, prospective, multicenter study enrolling patients with EGFR-mutant aNSCLC receiving first-line osimertinib to evaluate effectiveness, safety, and progression patterns in the real-world. RESULTS: At data cutoff, 126 White patients from nine oncology centers were included. At diagnosis, 16 patients (12.7%) had a performance status (PS) ≥2 and 38 (30.2%) had brain metastases. Overall response rate (ORR) was 73%, disease control rate (DCR) 96.0%. After a median follow-up of 12.3 months, median time to treatment discontinuation (mTTD) was 25.3 months, median progression-free-survival (mPFS) was 18.9 months and median overall survival (mOS) was not reached (NR). One hundred and ten patients (87%) experienced adverse events (AEs), 42 (33%) of grade 3-4, with venous thromboembolism (VTE) as the most common (n = 10, 7.9%). No difference in rates of VTE was reported according to age, PS, comorbidity, and tumor load. We observed longer mTTD in patients without symptoms (NR vs. 18.8 months) and with fewer than three metastatic sites at diagnosis (NR vs. 21.4 months). Patients without brain metastases experienced longer mPFS (NR vs. 13.3 months). No difference in survival outcome was observed according to age, comorbidity, and type of EGFR mutation. Isolated progression and progression in fewer than three sites were associated with longer time to treatment discontinuation (TTD). CONCLUSION: Osimertinib confirmed effectiveness and safety in the real world, although thromboembolism was more frequent than previously reported.

Acquired EGFR C797G Mutation Detected by Liquid Biopsy as Resistance Mechanism After Treatment With Osimertinib: A Case Report.

BACKGROUND: Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor approved for the treatment of T790M-positive non-small-cell lung cancer. More recently, osimertinib demonstrated improved disease control compared to other EGFR-TKIs. Multiple mechanisms of resistance have been described in T790M-positive patients who experienced treatment failure with osimertinib. CASE REPORT: We report the case of a 78-year-old non-smoker woman with stage IV EGFR L858R-positive lung adenocarcinoma presented with T790M mutation after five years of treatment with gefitinib. The patient was started on osimertinib, but after two and a half years of treatment experienced disease progression. The analyses of circulating tumor DNA using next-generation sequencing showed, together with the pre-existing T790M and exon 21 L858R, the presence of the EGFR C797G resistance mutation. CONCLUSION: Our case report revealed a rare EGFR-dependent acquired resistance mutation to osimertinib in circulating tumor DNA. Liquid biopsy appears to be a promising resource to understand the biology of osimertinib resistance by clonal evolution monitoring and the identification of novel resistance mechanisms.

Real-world data on treatment outcomes in EGFR-mutant non-small-cell lung cancer patients receiving osimertinib in second or further lines.

Aims: This study describes real-world outcomes of pretreated EGFR T790M-positive (T790M+) advanced non-small-cell lung cancer patients progressing after first- or second-generation tyrosine kinase inhibitors and receiving osimertinib, compared with T790M-negative (T790M-) patients. We have also described progression patterns and treatment sequences. Patients & methods: This is a retrospective multicenter Italian observational study including consecutive Caucasian patients referred between 2014 and 2018. Results: 167 patients were included. Median progression-free survival was 9.8 months (95% CI: 8.3-13.3) for T790M+ and 6.0 months (95% CI: 4.9-7.2) for T790M- patients, respectively. Median overall survival was 20.7 months (95% CI: 18.9-28.4) for T790M+ and 10.6 months (95% CI: 8.6-23.6) for T790M- patients, respectively. The T790M mutation correlated with absence of new sites of disease. After progression, most T790M+ patients continued osimertinib, whereas most T790M- patients received a different treatment line. Conclusion: Better outcomes were shown in patients receiving osimertinib. A more limited progression pattern for T790M+ was suggested.

Lay abstract Osimertinib is an oral drug that inhibits the growth of non-small-cell lung cancer (NSCLC) tumors with a specific mutation in EGFR. Osimertinib is given to patients with advanced EGFR-mutant NSCLC as initial therapy or after the failure of prior first- or second-generation tyrosine kinase inhibitors in patients who develop the EGFR T790M resistance mutation. Real-world data about the efficacy of EGFR-mutant NSCLC patients receiving osimertinib are needed to confirm the findings of large randomized clinical trials. Most real-world studies have investigated outcomes in Asian populations. This study aims to describe outcomes in EGFR T790M-positive patients receiving osimertinib after the failure of first- or second-generation tyrosine kinase inhibitors, compared with T790M-negative patients receiving a systemic treatment, in a Caucasian population. In addition, the study aims to describe how the disease spreads once it starts progressing again and any subsequent treatment lines. 167 patients were included. The results of this study suggest that EGFR T790M-positive patients receiving osimertinib as second- or further-line treatment had better outcomes and a more limited progression compared with T790M-negative cases.

Radical Hemithoracic Radiotherapy Versus Palliative Radiotherapy in Non-metastatic Malignant Pleural Mesothelioma: Results from a Phase 3 Randomized Clinical Trial.

PURPOSE: We conducted a phase 3 randomized clinical trial to assess whether radical hemithoracic radiation therapy (RHR) compared with palliative radiation therapy (PR) can achieve overall survival (OS) advantages in patients with malignant pleural mesothelioma (MPM). METHODS AND MATERIALS: From August 2014 to May 2018, patients with histologically diagnosed nonmetastatic MPM, who underwent nonradical lung-sparing surgery and chemotherapy (CHT), were randomly assigned (1:1) to receive RHR or PR. RHR total dose to the involved pleural cavity was 50 Gy in 25 fractions, and the gross residual disease received a simultaneous integrated boost of 60 Gy. The primary endpoint was OS. Secondary endpoints were local control, distant metastasis-free survival, progression-free survival, and acute and late toxicity rates. A sample size of 108 patients considering a type I error (α) of 0.05 and a statistical power of 80% was calculated to prove that RHR could improve the 2-year OS. OS was estimated with the Kaplan-Meier method and the log-rank test (2-sided) tested differences between arms. The univariate and multivariate analyses were performed using Cox proportional hazard model. Possible prognostic factors investigated: age, sex, performance status, lung surgery, gross residual disease, and histology. RESULTS: One hundred eight patients were randomized: 53 to the PR arm and 55 to the RHR arm. Median follow-up was 14.6 months. The 2-year OS rate was 58% in the RHR arm versus 28% in the PR arm (hazard ratio, 0.54; 95% confidence interval, 0.31-0.95; P = .031). In the RHR arm: 11 patients experienced acute toxicity grade ≥3, 17 patients had grade 3 to 4 late toxicity. Nine patients experience a grade ≥2 pneumonitis, including 1 patient with grade 5. CONCLUSIONS: RHR significantly improves survival in patients with MPM treated with nonradical lung-sparing surgery and CHT compared with palliative treatments, although it is associated with a nonnegligible toxicity profile.

A Multi-Center, Real-Life Experience on Liquid Biopsy Practice for EGFR Testing in Non-Small Cell Lung Cancer (NSCLC) Patients.

BACKGROUND: circulating tumor DNA (ctDNA) is a source of tumor genetic material for EGFR testing in NSCLC. Real-word data about liquid biopsy (LB) clinical practice are lacking. The aim of the study was to describe the LB practice for EGFR detection in North Eastern Italy. METHODS: we conducted a multi-regional survey on ctDNA testing practices in lung cancer patients. RESULTS: Median time from blood collection to plasma separation was 50 min (20-120 min), median time from plasma extraction to ctDNA analysis was 24 h (30 min-5 days) and median turnaround time was 24 h (6 h-5 days). Four hundred and seventy five patients and 654 samples were tested. One hundred and ninety-two patients were tested at diagnosis, with 16% EGFR mutation rate. Among the 283 patients tested at disease progression, 35% were T790M+. Main differences in LB results between 2017 and 2018 were the number of LBs performed for each patient at disease progression (2.88 vs. 1.2, respectively) and the percentage of T790M+ patients (61% vs. 26%).