Oncogene-addicted Non-small Cell Lung Cancer Research Articles

Proteolysis Targeting Chimera Agents (PROTACs): New Hope for Overcoming the Resistance Mechanisms in Oncogene-Addicted Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) remains a disease with a poor prognosis despite the advances in therapies. NSCLC with actionable oncogenic alterations represent a subgroup of diseases for which tyrosine kinase inhibitors (TKIs) have shown relevant and robust impact on prognosis, both in early and advanced stages. While the introduction of powerful TKIs increases the ratio of potentially curable patients, the disease does develop resistance over time through either secondary mutations or bypass activating tracks. Therefore, new treatment strategies are being developed to either overcome this inevitable resistance or to prevent it, and proteolysis targeting chimera agents (PROTACs) are among them. They consist of two linked molecules that bind to a target protein and an E3 ubiquitin ligase that causes ubiquitination and degradation of proteins of interest. In this paper, we review the rationale for PROTAC therapy and the current development of PROTACs for oncogene-addicted lung cancer. Moreover, we critically analyze the strengths and limitations of this promising technique that may help pave the way for future perspectives.

Alectinib in Early-Stage Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: Current Evidence and Future Challenges.

Targeted therapies changed the treatment of advanced oncogene-addicted non-small cell lung cancer and could also improve outcomes in resectable disease. The ALINA trial evaluated the clinical benefit of adjuvant alectinib compared with standard chemotherapy and met the primary endpoint with a significant increase in disease-free survival at 2 years among anaplastic lymphoma kinase positive patients with stage IB-IIIA disease; two phase II trials (ALNEO and NAUTIKA1) are currently evaluating perioperative treatment with alectinib, and the results of the case reports published to date are encouraging. In resectable anaplastic lymphoma kinase-positive lung cancer, adjuvant alectinib represents the new standard of care and could soon be used in perioperative treatment.

The EXcellenT Trial: Exercise in Extended Oncogene Addicted Lung Cancer in Active Treatment

IntroductionThe discovery of oncogenic mutations that drive the growth and progression of Non–small-cell lung cancer (NSCLC) led to the development of a range of molecular targeted therapies. Tyrosine kinase inhibitors (TKIs) improve the overall outcome of patients with oncogene addicted NSCLC, ensure a better compliance to treatment and few side effects compared to traditional chemotherapy. However, the treatment is still completely “drug-centric”, in a population of patients who usually survive for a long time and desire to regain their quality of life. Despite an extensive literature on the importance of complementary treatments and lifestyle promotion, the guidelines on physical exercise are general and usually refer to the entire lung cancer pathology. Methods and objectivesEXcellenT is an Italian monocentric randomized prospective study enrolling 40 patients diagnosed with oncogene-addicted advanced NSCLC in active treatment with TKIs. Patients will be randomized (1:1 ratio) to an ‘interventional’ or a ‘control’ group. In the interventional arm (arm A), participants will receive a 3-month multicomponent personalized physical activity prescription combining a supervised coaching program at the training center and an app-based physical activity schedule at patients home. In the control group (arm B) patients will receive a fitness professional-guided montly session that will result in an unsupervised home-based physical activity counselling. Prospective collection of blood metabolome and immune phenotypes will be performed to investigate the integration with genetic alterations that drive the patient's disease. The overall aim of the project is to evaluate if a tailored physical program may have a significant impact on quality of life and performances of this specific homogeneous subgroup of patients. The exploratory goal is to elucidate a potential link between metabolites, immune parameters and genetic deregulations and how this interplay may be influenced by physical exercise. ConclusionEXcellent trial aims to propose a new approach to personalized medicine in the specific subgroup of oncogene-addicted NSCLC patients, where targeted therapy is integrated with an equally tailored physical activity program. The homogeneity of this cancer population will provide insights on the influence of exercise on metabolism and immunity during treatment with TKIs.

Farnesyltransferase inhibition overcomes oncogene-addicted non-small cell lung cancer adaptive resistance to targeted therapies

Drug-tolerance has emerged as one of the major non-genetic adaptive processes driving resistance to targeted therapy (TT) in non-small cell lung cancer (NSCLC). However, the kinetics and sequence of molecular events governing this adaptive response remain poorly understood. Here, we combine real-time monitoring of the cell-cycle dynamics and single-cell RNA sequencing in a broad panel of oncogenic addiction such as EGFR-, ALK-, BRAF- and KRAS-mutant NSCLC, treated with their corresponding TT. We identify a common path of drug adaptation, which invariably involves alveolar type 1 (AT1) differentiation and Rho-associated protein kinase (ROCK)-mediated cytoskeletal remodeling. We also isolate and characterize a rare population of early escapers, which represent the earliest resistance-initiating cells that emerge in the first hours of treatment from the AT1-like population. A phenotypic drug screen identify farnesyltransferase inhibitors (FTI) such as tipifarnib as the most effective drugs in preventing relapse to TT in vitro and in vivo in several models of oncogenic addiction, which is confirmed by genetic depletion of the farnesyltransferase. These findings pave the way for the development of treatments combining TT and FTI to effectively prevent tumor relapse in oncogene-addicted NSCLC patients.

Physical activity (PA) impact on metabolome and immunity of oncogene addicted non-small cell lung cancer (NSCLC): The EXcellenT trial.

e20582 Background: Today patients (pts) with oncogene addicted advanced NSCLC receive molecular targeted therapies as first-line treatment ensuring high compliance to therapy, few side effects and long survival time. These pts are usually young and with a strong wish to regain the pre-diagnosis quality of life (QoL), including the ability to perform PA. It’s known that PA can impact significantly on metabolomic and immunity status, but to date only few studies on its role in NSCLC have been performed. The aim of the EXcellenT trial is to evaluate if a tailored PA program may have an impact on QoL and performances of this homogeneous subgroup of pts. An exploratory objective was to explore the complex interplay between PA and immune status and the influence of PA on metabolome. Methods: EXcellenT (Exercise in Extended oncogene addicted Lung Cancer in Active Treatment - NCT05306652) is an Italian monocentric prospective study enrolling 40 pts with oncogene-addicted advanced NSCLC in active treatment with tyrosine kinase inhibitors (TKI). Pts are randomized in 2 arms: an interventional arm of a personalized supervised PA program or a counselling group of home-based exercise. We explored peripheral variations of T cells subsets during TKI treatment combined with exercise training to better define the immuno-dependence of these tumors. Fatty acid composition (FA) of plasma has been carried out using gas chromatography-flame ionization detection (GC-FID) and liquid chromatography-mass spectrometry (LC-MS). Immature and mature neutrophils, monocytes, CD34+ cells and megakaryocytes (MK) precursors have been determined through flow cytometry analysis. Results: A preliminary exploratory analysis on the first patients enrolled with 3 complete time point (baseline; week 4 and 12) was performed. To date 23 out of 40 pts have been enrolled, 46% of them with pre-diagnosis leisure-time physical activity. The oncogene identified are: ALK 52%, EGFR 26%, BRAF 9%, RET 4%, ROS1 9%. 35% had stable brain metastasis (mts) and 39% bone mts not at risk of skeletal-related events. FA analysis (4 pts) showed significant increase of monounsaturated fatty acids (p = 0.0329) during the study. According to immunophenotype, we observed (3 pts) a significant reduction of CD34+ cancer stem cell (p 0.0112) and a consistent increase in mature CD66b+CD10+ neutrophils with a trend of decrease in CD66b+CD10- cells. Conclusions: The ExcellenT trial is showing that PA programs are feasible and well accepted by patients with oncogene-addicted NSCLC. The QoL analysis will be performed at the end of enrolment. The preliminary analysis on metabolomic and immunity status shows an improvement of fatty acid composition and an increase of mature cell precursors compared to immature counterpart suggesting a potential role of PA in hindering tumor immune escape strategies. Clinical trial information: NCT05306652 .

First-line immunotherapy in patients with mNSCLC with rare molecular alterations.

e20604 Background: Oncogene-addicted non-small cell lung cancer (NSCLC) is an heterogeneous group including different molecular alterations. Most single agent (IO) and combination immunotherapy (CT-IO) trials excluded specific oncogene-addicted NSCLCs such as ALK and EGFR; however, it is likely that other oncogene driven tumours were not tested for but included in these trials and could be actually treated with IO in clinical practice. Methods: Among 428 patients treated with IO or CT-IO as first-line treatment, 30 patients were identified to harbour rare molecular alterations (37% non-smokers, 63% former or current smokers): METex14 skipping mutation (n = 10), MET amplifications (n = 4), BRAF other than V600E mutations (n = 7), HER2 exon 20 insertions (n = 5), RET fusions (n = 2), EGFR exon 20 insertions (n = 2). We analyzed progression-free survival (PFS) and overall survival (OS) in patients harbouring these mutations who underwent first-line IO (if PD-L1≥50%; n = 23) or CT-IO (if PD-L1 < 1-49% n = 2 or < 1% n = 5). Results: In whole population median PFS was 5,1 months (95%CI: 2,39-11,29) and median OS 25,5 months (95%CI: 8,80-60,98); 13 patients experienced progressive disease as best response, the disease control rate (DCR) was 56,7%. Patients treated with IO (n = 22) had a mPFS of 4,7 m (95%CI: 2,13-23,48) and a mOS of 29,8 months (95%CI: 10,08-60,98); those treated with CT-IO (n = 8) had a mPFS of 5,1 m (95%CI: 2,29-6,01) and a mOS of 8,5 m (95%CI: 7,68-12,51). Among the most represented molecular alterations, MET alterations (n = 14, 3 treated with CT-IO and 11 with IO) had a mPFS of 5,1 m (95%CI: 1,67-23,90) and a mOS of 25,5 m (95%CI: 8,80-60,72). In particular METex14 skipping mutations had a mPFS of 5,1 m and a mOS of 25,5 m, while MET amplifications had a mPFS of 2,4 m and mOS of 10,3 m. BRAF nonV600E mutations (n = 7, 2 treated with CT-IO and 5 with IO) had a mPFS 5,3 m and mOS not reached. HER2 exon 20 insertions (n = 5, 2 treated with CT-IO and 3 with IO) had a similar mPFS (6,0 m) but a poorer OS outcome (8,5 m). ( Table 1) Conclusions: Our results show a limited effectiveness of both IO alone and CT-IO as first-line treatment in oncogene addicted mNSCLC, even taking into account survival outcomes of upfront CT compared to targeted agents in pivotal trials. [Table: see text]

A case series of non-small cell lung cancer patients with EGFR or HER2 exon 20 insertion in Li Fraumeni syndrome.

Germline pathogenic mutations in TP53 gene are associated with a cancer predisposition syndrome known as Li Fraumeni syndrome. Albeit infrequently, non-small cell lung cancer, especially as oncogene-addicted disease, may be diagnosed in young patients with Li Fraumeni syndrome. We report three cases of patients affected by Li Fraumeni syndrome who developed non-small cell lung cancer with EGFR or HER2 exon 20 insertions. The first patient suffered from liposarcoma and, then, brain metastases from HER2-mutated non-small cell lung cancer: after stereotactic radiotherapy, he benefited from enrollment in a clinical trial with a HER2-targeted therapy. The second young patient was a female with personal history of rhabdomyosarcoma, diagnosed with brain metastases from EGFR-mutated non-small cell lung cancer: enrollment in a clinical trial led to a temporary clinical benefit. The last case was a female diagnosed with breast carcinoma, ovarian granulosa cell tumor and advanced EGFR-mutated non-small cell lung cancer at a young age. Young patients affected by oncogene-addicted non-small cell lung cancer and with a positive familial cancer history should be referred for an accurate genetic counselling to look for Li Fraumeni syndrome. The underlying molecular connection between TP53 and HER family receptor tyrosine kinases remains unclear, but an extensive molecular characterization of tumors from patients with Li Fraumeni syndrome should always be performed, to offer patients a personalized therapeutic approach.

Rare Driver Mutations in Advanced, Oncogene-Addicted Non-Small Cell Lung Cancer: A North Italian, Real-World, Registry Experience.

The real-world, retrospective, NEROnE registry investigated the impact of next-generation sequencing (NGS) in advanced non-small-cell lung cancer (NSCLC) patients (pts) at three oncology units in the north of Italy between January 2020 and December 2022. We focused on the clinical characterization and outcomes of NSCLC with rare molecular alterations: EGFR exon 20 insertion, non-activating EGFR mutations, BRAF V600E and non-V600, ROS1 and RET rearrangements, MET, ErbB2, and FGFR mutations. Overall, these represented 6.4% (62/970) of the pts analysed with NGS in the daily practice. The most heavily represented rare alterations were ROS1 rearrangement (15 pts-24%) and MET exon 14 skipping mutation (11 pts-18%). No associations were found with the demographic and clinical features. Forty-nine pts received targeted therapies, of which 38.8% were first- and 9.8% were second-line. The remaining pts received chemotherapy and/or immunotherapy. In terms of the clinical outcomes, although not statistically significant, a tendency toward shorter OS was seen when therapies other than specific targeted therapies were used (HR: 1.84, 95% CI: 0.79-4.33, p = 0.158). The pts with co-mutations (19.4%) seemed to receive an advantage from the front-line chemotherapy-based regimen. Finally, an NLR score (a well-known inflammatory index) ≥ 4 seemed to be related to shorter OS among the pts treated with immunotherapy alone or in combination with chemotherapy (HR: 2.83, 95% CI: 1.08-7.40, p = 0.033). Prospective evaluations need to be performed to clarify whether these indexes may help to identify patients with oncogene-addicted NSCLC who could benefit from immunotherapy.

Is Immunotherapy Beneficial in Patients with Oncogene-Addicted Non-Small Cell Lung Cancers? A Narrative Review.

Over the past 20 years, there has been a paradigm shift in the care of patients with non-small cell lung cancer (NSCLC), who now have a range of systemic treatment options including targeted therapy, chemotherapy, immunotherapy (ICI), and antibody-drug conjugates (ADCs). A proportion of these cancers have single identifiable alterations in oncogenes that drive their proliferation and cancer progression, known as "oncogene-addiction". These "driver alterations" are identified in approximately two thirds of patients with lung adenocarcinomas, via next generation sequencing or other orthogonal tests. It was noted in the early clinical development of ICIs that patients with oncogene-addicted NSCLC may have differential responses to ICI. The toxicity signal for patients with oncogene-addicted NSCLC when treated with ICIs also seemed to differ depending on the alteration present and the specific targeted agent used. Developing a greater understanding of the underlying reasons for these clinical observations has become an important area of research in NSCLC. In this review, we analyze the efficacy and safety of ICI according to specific mutations, and consider possible future directions to mitigate safety concerns and improve the outcomes for patients with oncogene-addicted NSCLC.

Repotrectinib's Clinical Benefit and Its Brain Penetration in a Patient with Meningeal Carcinomatosis from G2032R-Mutated ROS-1 Positive Non-Small Cell Lung Cancer.

In this work, we report on a clinically significant response of meningeal carcinomatosis to repotrectinib in a woman with a heavily pretreated ROS1-rearranged non-small cell lung cancer (NSCLC) that harbored the concomitant solvent front G2032R mutation. Meningeal carcinomatosis has a higher incidence in oncogene addicted NSCLC due to increased life expectancy, yet no report has ever documented the activity of repotrectinib in this context. In line with its activity, we documented the presence of the drug at potentially active concentrations in the cerebrospinal fluid. Nevertheless, the short-lived response reported by our patient highlights the importance for novel ROS1-tyrosine kinase inhibitors (TKIs) to be specifically developed to be able to penetrate the blood-brain barrier.

New Generations of Tyrosine Kinase Inhibitors in Treating NSCLC with Oncogene Addiction: Strengths and Limitations.

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.

Abstract 3418: Alterations in PIK3CA/PTEN as resistance mechanisms in lung cancer patients progressing on first-line next generation EGFR/ALK tyrosine kinase inhibitors

Abstract Introduction: Advent of targeted therapies has deeply changed treatment of advanced oncogene-addicted non-small cell lung cancer (NSCLC), but development of resistance remains a main issue. Given the efficacy of next generation tyrosine kinase inhibitors (TKIs) against on-target mutations, their first-line administration could increase the relevance of off-target resistance mechanisms. Activating PIK3CA mutations and PTEN loss have been described as putative off-target resistance mechanisms across generations of EGFR TKIs. The role of these alterations in the development of resistance to ALK TKIs has been less described. MATCH-R trial (NCT02517892) is an ongoing prospective study whose objective is to understand mechanisms of acquired resistance to cancer therapies and develop strategies to overcome it. Materials and methods: We collected clinical and molecular data of patients (pts) with NSCLC enrolled in the molecular target group (MTG) of MATCH-R trial. We identified pts with EGFR mutations or ALK rearrangements who developed PIK3CA/PTEN alterations in tissue biopsy and/or circulating tumor DNA upon progression to first-line osimertinib/alectinib. We established patient-derived cell lines (PDCL) from the identified MATCH-R pts and we engineered commercial cell lines (CCL) harboring EGFR mutation (PC9) or ALK fusion (H3122) to constitutively express PIK3CA mutations and/or to have a permanent loss of PTEN. Cell viability assays and Western blot studies with different EGFR/ALK/PI3K/mTOR inhibitors were performed. Results: Of the 186 pts with advanced NSCLC included in the MTG of MATCH-R, 110 (59.1%) harbored EGFR mutations (EGFR+) and 27 (14.5%) ALK rearrangements (ALK+). Among them, 19 received first-line osimertinib and seven first-line alectinib. Five and two pts developed PIK3CA/PTEN alterations in the EGFR+ and ALK+ groups, respectively. In the EGFR+ group, PIK3CA E545K (n=2), R108H, N345K and R357Q mutations were detected. PTEN mutations (F437fs*5 and Y27C) were concomitant with E545K and R357Q mutations, respectively. In both ALK+ pts, a PIK3CA E545K mutation was identified, together with PTEN exon 5 splicing in one case. We confirmed on CCL that PIK3CA E545K mutation, alone or in combination with PTEN loss, confers resistance to second-/third-generation EGFR/ALK TKIs. PTEN loss alone had a moderate impact on TKIs sensitivity. Overcoming strategies combining EGFR/ALK TKIs with PIK3CA/mTOR inhibitors are being evaluated and will be disclosed at the meeting. Conclusions: Activating PI3KCA mutations and molecular events leading to PTEN loss are frequent events at resistance to first-line EGFR/ALK TKIs, and can be detected concomitantly. Functional assays confirmed that these alterations act as resistance mechanisms. These observations are of interest as PI3KCA/mTOR inhibitors may have a role in overcoming resistance. Citation Format: Giorgia Guaitoli, Francesco Facchinetti, Juan David Flórez-Arango, Floriane Braye, Hayato Mizuta, Santiago Ponce-Aix, Damien Vasseur, Ken André Olaussen, Stefan Michiels, Mihaela Aldea, Jordi Remon, Fabrice Barlesi, Benjamin Besse, David Planchard, Luc Friboulet. Alterations in PIK3CA/PTEN as resistance mechanisms in lung cancer patients progressing on first-line next generation EGFR/ALK tyrosine kinase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3418.

Salvage Surgery After First-Line Alectinib for Locally-Advanced/Metastatic ALK-Rearranged NSCLC: Pathological Response and Perioperative Results

BackgroundThe role of salvage surgery after tyrosine kinase inhibitors in advanced oncogene-addicted non-small cell lung cancer is largely unexplored. PatientsWe aimed to describe the pathological features and surgical early-outcomes of Anaplastic Lymphome Kinase anaplastic lymphome kinase positive non-small cell lung cancer patients undergoing surgery after first-line alectinib treatment. We retrospectively collected and analyzed multicentric data of 10 patients treated with alectinib for advanced-stage anaplastic lymphome kinase positive lung adenocarcinoma who underwent anatomical surgical resection from January 2020 to Decemeber 2021. All patients were treatment naive and received alectinib (600 mg twice daily). Surgery was always proposed after multidisciplinary discussion. The primary endpoints were pathological response and surgical feasibility (technical intraoperative complications, postoperative outcomes). ResultsAlectinib was received for a mean of 212 days before surgery (42-415 days) and was generally interrupted about one week before surgery (range: 0-32 days) with no patient experienced grade 4 toxicity. All patients received an R0 resection with surgery consisting of lobectomy in 8 cases with bilobectomy and (left) pneumonectomy in 1 case each. Intra-operative difficulties were described in 7 cases (70%), mostly due to perivascular fibrosis or thickening of mediastinal lymph nodal tissues. Major and minor complications occurred in 0 and 3 cases (30%), respectively. A pathological complete response and major pathological response (defined as 0% and < 10% viable tumor cells, respectively) were observed in 50% and 90% of cases, respectively. Despite short follow-up, only one tumor recurrence was observed (in the only patient who did not resume alectinib after surgery). InterpretationDespite some technical intraoperative difficulties, salvage surgery was safe and feasible after Alectinib for advanced lung adenocarcinoma.

At the crossroads of immunotherapy for oncogene-addicted subsets of NSCLC.

Non-small-cell lung cancer (NSCLC) has become a paradigm of precision medicine, with the discovery of numerous disease subtypes defined by specific oncogenic driver mutations leading to the development of a range of molecularly targeted therapies. Over the past decade, rapid progress has also been made in the development of immune-checkpoint inhibitors (ICIs), especially antagonistic antibodies targeting the PD-L1-PD-1 axis, for the treatment of NSCLC. Although many of the major oncogenic drivers of NSCLC are associated with intrinsic resistance to ICIs, patients with certain oncogene-driven subtypes of the disease that are highly responsive to specific targeted therapies might also derive benefit from immunotherapy. However, the development of effective immunotherapy approaches for oncogene-addicted NSCLC has been challenged by a lack of predictive biomarkers for patient selection and limited knowledge of how ICIs and oncogene-directed targeted therapies should be combined. Therefore, whether ICIs alone or with chemotherapy or even in combination with molecularly targeted agents would offer comparable benefit in the context of selected oncogenic driver alterations to that observed in the general unselected NSCLC population remains an open question. In this Review, we discuss the effects of oncogenic driver mutations on the efficacy of ICIs and the immune tumour microenvironment as well as the potential vulnerabilities that could be exploited to overcome the challenges of immunotherapy for oncogene-addicted NSCLC.

Brain metastasis screening in the molecular age.

The incidence of brain metastases (BM) amongst cancer patients has been increasing due to improvements in therapeutic options and an increase in overall survival. Molecular characterization of tumors has provided insights into the biology and oncogenic drivers of BM and molecular subtype-based screening. Though there are currently some screening and surveillance guidelines for BM, they remain limited. In this comprehensive review, we review and present epidemiological data on BM, their molecular characterization, and current screening guidelines. The molecular subtypes with the highest BM incidence are epithelial growth factor receptor-mutated non-small cell lung cancer (NSCLC), BRCA1, triple-negative (TN), and HER2+ breast cancers, and BRAF-mutated melanoma. Furthermore, BMs are more likely to present asymptomatically at diagnosis in oncogene-addicted NSCLC and BRAF-mutated melanoma. European screening standards recommend more frequent screening for oncogene-addicted NSCLC patients, and clinical trials are investigating screening for BM in hormone receptor+, HER2+, and TN breast cancers. However, more work is needed to determine optimal screening guidelines for other primary cancer molecular subtypes. With the advent of personalized medicine, molecular characterization of tumors has revolutionized the landscape of cancer treatment and prognostication. Incorporating molecular characterization into BM screening guidelines may allow physicians to better identify patients at high risk for BM development and improve patient outcomes.

ALK-driven NSCLC: A narrative review - Part I

ABSTRACT Anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is a molecularly distinct subgroup of oncogene-addicted NSCLC, accounting for 3-5% of cases. These are mainly genomic rearrangements resulting in a fusion oncoprotein, thus causing persistent constitutive signaling. Recent developments and approvals of various generations of ALK inhibitors have revamped the therapeutic and prognostic landscape of this disease entity. For the preparation of this review, we searched various databases such as PubMed, Embase, and Scopus, using the keywords “ALK,” “ALK crizotinib,” “Oncogene NSCLC,” and “Alectinib,” and we finally included 46 articles. In this review, we describe the molecular biology and pathologic and clinical characteristics of ALK-rearranged NSCLC. The detection methods, therapeutic strategies, and trials will be discussed in the next part of this biomarker review series.

Transient targeting of BIM-dependent adaptive MCL1 preservation enhances tumor response to molecular therapeutics in non-small cell lung cancer.

Despite remarkable efficacy, targeted treatments often yield a subpopulation of residual tumor cells in part due to non-genetic adaptions. Previous mechanistic understanding on the emergence of these drug-tolerant persisters (DTPs) has been limited to epigenetic and transcriptional reprogramming. Here, by comprehensively interrogating therapy-induced early dynamic protein changes in diverse oncogene-addicted non-small cell lung cancer models, we identified adaptive MCL1 increase as a new and universal mechanism to confer apoptotic evasion and DTP formation. In detail, acute MAPK signaling disruption in the presence of genotype-based tyrosine kinase inhibitors (TKIs) prompted mitochondrial accumulation of pro-apoptotic BH3-only protein BIM, which sequestered MCL1 away from MULE-mediated degradation. A small-molecule combination screen uncovered that PI3K-mTOR pathway blockade prohibited MCL1 upregulation. Biochemical and immunocytochemical evidence indicated that mTOR complex 2 (mTORC2) bound and phosphorylated MCL1, facilitating its interaction with BIM. As a result, short-term polytherapy combining antineoplastic TKIs with PI3K, mTOR or MCL1 inhibitors sufficed to prevent DTP development and promote cancer eradication. Collectively, these findings support that upfront and transient targeting of BIM-dependent, mTORC2-regulated adaptive MCL1 preservation holds enormous promise to improve the therapeutic index of molecular targeted agents.

The Effect of Intrathoracic Lesion Location on Initial Tyrosine Kinase Inhibitor Response in Advanced Oncogene-Addicted Non-Small Cell Lung Cancer: A Comparison Between RECIST 1.1 and a Novel Method of Response Assessment (MAX)

IntroductionDifferent subtypes of non-small cell lung cancer (NSCLC) are associated with different patterns of metastatic spread. Anatomic location of lesions in the chest may influence patterns of cancer growth and the shrinkage to therapy. Consequently, lesion location could affect apparent response rates per RECIST. We sought to explore this and develop, as needed, treatment response assessments less affected by the location. MethodsCases of advanced oncogene-addicted NSCLC (EGFR, ALK, and ROS1) with pre- and on-therapy imaging during initial targeted therapy were identified. Lesions located in the lung parenchyma, pleural space or intra-thoracic lymph nodes were identified and analyzed separately from each other by RECIST 1.1 (unidimensional measurements) and by a novel MAX methodology (bidimensional measurements) which takes the axis with the greatest absolute percentage change on therapy in each location as the representative measurement. ResultsThree hundred three patients with 446 unidimensional measured lesions were included for RECIST analysis. Two hundred forty nine patients with 386 bidimensional measured lesions were included for MAX analysis, as well as the analysis comparing RECIST and MAX. Intrathoracic location significantly impacted percentage shrinkage and the response rate per RECIST. The response rates for pleural, intra-parenchymal and nodal lesions were 34.1%, 49.6%, and 68.3%, respectively (P = .0002). The MAX methodology both increased the apparent treatment effect and made it consistent between intrathoracic locations. For pleural, parenchymal and nodal lesions, the MAX calculated response rate were 83.7%, 72.2%, and 75.4%, respectively (P-value = .24). ConclusionIntrathoracic lesion location affects RECIST-based treatment effectiveness estimations. The MAX methodology neutralizes location effect when examining impact of treatment and should be explored further.

Evaluation of the Molecular Landscape in PD-L1 Positive Metastatic NSCLC: Data from Campania, Italy.

Background: Immune-checkpoint inhibitors (ICIs) have increased and improved the treatment options for patients with non-oncogene-addicted advanced stage non-small cell lung cancer (NSCLC). However, the role of ICIs in oncogene-addicted advanced stage NSCLC patients is still debated. In this study, in an attempt to fill in the informational gap on the effect of ICIs on other driver mutations, we set out to provide a molecular landscape of clinically relevant oncogenic drivers in programmed death-ligand 1 (PD-L1) positive NSCLC patients. Methods: We retrospectively reviewed data on 167 advanced stage NSCLC PD-L1 positive patients (≥1%) who were referred to our clinic for molecular evaluation of five driver oncogenes, namely, EGFR, KRAS, BRAF, ALK and ROS1. Results: Interestingly, n = 93 (55.7%) patients showed at least one genomic alteration within the tested genes. Furthermore, analyzing a subset of patients with PD-L1 tumor proportion score (TPS) ≥ 50% and concomitant gene alterations (n = 8), we found that n = 3 (37.5%) of these patients feature clinical benefit with ICIs administration, despite the presence of a concomitant KRAS gene alteration. Conclusions: In this study, we provide a molecular landscape of clinically relevant biomarkers in NSCLC PD-L1 positive patients, along with data evidencing the clinical benefit of ICIs in patient NSCLC PD-L1 positive alterations.

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.