Tyrosine Kinase Inhibitors In Patients Research Articles

Additive toxicity arising from combined use of immune checkpoint inhibitors and tyrosine kinase inhibitors in patients with renal or endometrial carcinoma: Protocol for a rapid systematic review

The combined use of immune checkpoint inhibitors and tyrosine kinase inhibitors (ICI/TKI) is an effective treatment strategy for some cancers. A better understanding of the potential additive toxicity for ICI/TKI combinations is needed to inform patient and provider treatment decisions. We aim to evaluate the safety of ICI/TKI combinations for individuals with renal cell or endometrial carcinoma. This rapid systematic review (SR) protocol follows PRISMA guidelines. A systematic search will be designed, peer reviewed and executed by experienced information specialists (Cochrane Central, MEDLINE, Embase) to identify published SRs and primary studies published since the most recent SR search. Randomized, quasi- or non-randomized controlled trials and comparative cohort studies are eligible if they compare ICI/TKI combinations to monotherapy or standard of care in participants with renal cell or endometrial carcinoma. The primary outcome is grade ≥ 3 treatment-related adverse-effects. Studies will be screened, selected, extracted and assessed for risk of bias by a single reviewer and checked completely by a second. Where feasible and appropriate, we will pool studies separately by design and indication using meta-analysis and test robustness of effects using prespecified subgroup and sensitivity analyses. Results will be summarized descriptively and presented in tables and figures. (PROSPERO ID: CRD42023416388).

Circulating tumor DNA (ctDNA) as a biomarker for lung cancer: Early detection, monitoring and therapy prediction.

Circulating tumor DNA (ctDNA), i.e., DNA shed from tumor cells into the bloodstream, is emerging as one of the most useful plasma biomarkers in patients with multiple types of cancer, including patients with non-small cell lung cancer (NSCLC). Indeed, NSCLC was the first malignancy in which measurement of ctDNA was approved for clinical use, i.e., mutational testing of EGFR for predicting response to EGFR tyrosine kinase inhibitors in patients with advanced disease. Although historically the gold standard method for EGFR mutational analysis required tumor tissue, the use of ctDNA is more convenient and safer for patients, results in a faster turn-around-time for return of results, provides a more complete representation of genetic alteration in heterogeneous tumors and is less costly to perform. Emerging uses of ctDNA in patients with lung or suspected lung cancer include screening for early disease, surveillance following initial treatment and monitoring response to therapy in metastatic disease. For evaluating therapy response, ctDNA appears to be especially useful in patients receiving targeted therapies against driver oncogenes or immunotherapy. Further work should not only validate these emerging findings but also aim to optimize and standardize ctDNA assays.

Efficacy of tyrosine kinase inhibitors in patients with advanced or metastatic sarcomas after prior chemotherapy: A meta-analysis.

Sarcoma is a heterogeneous malignancy arising from interstitial tissue. Anthracycline-based therapy is the first-line treatment recommended by guidelines for patients with locally advanced or metastatic unresectable sarcoma. Recently, targeted therapies, in particular tyrosine kinase inhibitors (TKIs), have made significant progress in the treatment of sarcoma, and their efficacy has been investigated in randomized controlled trials. The aim of this meta-analysis is to evaluate the efficacy of TKIs in patients with advanced or metastatic sarcoma who have previously received chemotherapy. We completed a meta-analysis after conducting literature searches in PubMed, Embase, and Cochrane. The single-drug, placebo-controlled, randomized controlled clinical trials of TKIs in patients with advanced or progressive sarcoma who have previously received chemotherapy are available for inclusion in the study. The observation results were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The subgroup analysis was performed according to histological subtypes of sarcoma. This study included 6 studies, including 1033 patients. The ORR (OR: 7.99, 95% CI: 3.62-19.61, P < .00001), DCR (OR: 2.54, 95% CI: 1.27-5.08, P = .009), PFS (HR: 0.46, 95% CI: 0.34-0.62, P < .00001), and OS (HR: 0.80, 95% CI: 0.67-0.96, P = .02) of patients treated with TKIs were better than those in the placebo group. In patients with advanced sarcoma, TKIs have been shown to have advantages in terms of ORR, DCR and PFS and OS. Multi-targeted TKIs may be considered as one of the second-line treatment options for sarcoma patients who have received prior chemotherapy.

EfficientNet-Based System for Detecting EGFR-Mutant Status and Predicting Prognosis of Tyrosine Kinase Inhibitors in Patients with NSCLC.

We aimed to develop and validate a deep learning-based system using pre-therapy computed tomography (CT) images to detect epidermal growth factor receptor (EGFR)-mutant status in patients with non-small cell lung cancer (NSCLC) and predict the prognosis of advanced-stage patients with EGFR mutations treated with EGFR tyrosine kinase inhibitors (TKI). This retrospective, multicenter study included 485 patients with NSCLC from four hospitals. Of them, 339 patients from three centers were included in the training dataset to develop an EfficientNetV2-L-based model (EME) for predicting EGFR-mutant status, and the remaining patients were assigned to an independent test dataset. EME semantic features were extracted to construct an EME-prognostic model to stratify the prognosis of EGFR-mutant NSCLC patients receiving EGFR-TKI. A comparison of EME and radiomics was conducted. Additionally, we included patients from The Cancer Genome Atlas lung adenocarcinoma dataset with both CT images and RNA sequencing data to explore the biological associations between EME score and EGFR-related biological processes. EME obtained an area under the curve (AUC) of 0.907 (95% CI 0.840-0.926) on the test dataset, superior to the radiomics model (P = 0.007). The EME and radiomics fusion model showed better (AUC, 0.941) but not significantly increased performance (P = 0.895) compared with EME. In prognostic stratification, the EME-prognostic model achieved the best performance (C-index, 0.711). Moreover, the EME-prognostic score showed strong associations with biological pathways related to EGFR expression and EGFR-TKI efficacy. EME demonstrated a non-invasive and biologically interpretable approach to predict EGFR status, stratify survival prognosis, and correlate biological pathways in patients with NSCLC.

Effectiveness of immune checkpoint inhibitors in combination with tyrosine kinase inhibitors in patients with advanced or metastatic colorectal carcinoma with either mismatch repair proficient or metastatic microsatellite stable disease: A systematic review and meta‑analysis.

Immune checkpoint inhibitors (ICIs) have limited efficacy in mismatch repair proficient (pMMR) or metastatic microsatellite stable (MSS) advanced or metastatic colorectal cancer (mCRC). ICIs, in conjunction with tyrosine kinase inhibitors (TKIs) possessing anti-angiogenic properties, serve as a potential strategy for circumventing the resistance exhibited by MSS or pMMR mCRC to immunotherapeutic interventions. The present study aimed to evaluate efficacy and safety of ICIs + TKIs and provide a reference for the treatment of CRC. The present systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Embase, Cochrane, Web of Science and ClinicalTrials.gov databases were screened from January 1, 2003 to July 28, 2023. A total of 14 studies were included in qualitative and quantitative analyses, with a total of 819 patients enrolled. The Newcastle-Ottawa scale scores of the 14 cohort studies included were ≥7, indicating they were of a high quality. The objective response rate (ORR) of ICIs + TKIs was 14% [95% confidence interval (CI), 0.08-0.24; P=0.132] in patients with advanced or metastatic MSS/pMMR CRC. The disease control rate (DCR) was 65% (95% CI, 0.58-0.74; P<0.0001). The overall incidence of adverse events of varying severity linked to combination of ICIs and TKIs in patients with advanced or metastatic MSS/pMMR CRC was 64% (95% CI, 0.52-0.78; P<0.0001). The incidence of grade ≥3 adverse reactions was 24% (95% CI, 0.14-0.4; P<0.0001). The sensitivity analysis indicated that the exclusion of individual studies did not yield statistically significant variations in combined analysis results. Based on the examination of publication bias, ORR and DCR, Begg's and Egger's tests had P-values of 0.114 and 0.395, respectively. Overall publication bias overall was absent in the Begg's funnel plot, as there was no apparent asymmetry. Nonetheless, the P-values of the Egger's and Begg's tests for adverse reactions and adverse reactions grade ≥3 were P=0.008 and P=0.048, respectively. The asymmetry of the Begg's funnel plots was evident, suggesting the presence of potential publication bias regarding adverse event results. In conclusion, the combination of ICIs and TKIs demonstrates a favorable effectiveness and notable safety profile in the management of patients with advanced or metastatic MSS/pMMR CRC.

Mechanisms of Resistance in Non-Small Cell Lung Cancer

Objectives: Treatment of patients with non-small cell lung cancer continues to evolve and the discovery and approval of tyrosine kinase inhibitors in patients with NSCLC and targetable alterations brought an important contribution in treating these patients. Material and Methods: This review aims to describe the main alterations that can affect the signaling pathways involved in NSCLC, present the therapy that can target these alterations and describe the mechanisms that can determine resistance to targeted therapy. Literature research was performed on PubMed and Google Scholar and 60 relevant articles were selected for the purpose of our review. Discussion: The data of the present research were structured in nine paragraphs, each one presenting the main alterations that can affect the signaling pathways in patients diagnosed with NSCLC, targeted therapy used in managing these cases and mechanisms of resistance to targeted therapy. Conclusions: Testing for molecular biomarkers should be mandatory for every newly diagnosed NSCLC patient in order to offer the most appropriate treatment.

Cardiovascular adverse events in patients with hepatocellular carcinoma receiving vascular endothelial growth factor inhibitors.

Vascular endothelial growth factor inhibitors, including tyrosine kinase inhibitors (TKIs) and anti-angiogenics, are first-line therapies for advanced and metastatic hepatocellular carcinoma. Although TKIs have a greater potential for off-target adverse effects compared with bevacizumab (anti-angiogenics), a direct comparison of the risk of cardiovascular adverse events between these two types of therapies has not been performed. To compare the incidence of and characterize cardiovascular adverse events in patients with hepatocellular carcinoma receiving TKIs versus bevacizumab. This cohort study included adult patients with hepatocellular carcinoma who received first-line TKIs (sorafenib or lenvatinib) or bevacizumab at two academic medical centers and one community cancer center from September 2018 to August 2021. The primary outcome was risk of cardiovascular adverse events. Major secondary outcomes included the incidence of individual types of cardiovascular adverse events and risk factors associated with major adverse cardiovascular events (MACE). The study included 221 patients (159 TKI patients; 62 bevacizumab patients). At a median follow-up of 5 months, the probability of cardiovascular adverse events was not significantly different between the two groups (hazard ratio [HR]: 0.85; 95% confidence interval [95% CI]: 0.58-1.24; p = 0.390). The cumulative incidence of cardiovascular events was highest in patients receiving lenvatinib (sub-distribution hazard ratio [SHR]: 1.53; 95% CI: 1.02-2.30) compared with those receiving sorafenib (reference) or bevacizumab (SHR: 1.05; 95% CI: 0.68-1.64) after adjustment for comorbidities, liver transplant status, and presence of portal vein thrombosis at baseline. Cardiovascular adverse events were observed in 151 (68%) patients, and MACE were observed in 27 (12%) patients. Risk factors associated with MACE were hypertension (SHR: 3.5; 95% CI: 0.9087-15.83; p = 0.086), prior history of MACE (SHR: 2.01; 95% CI: 0.83-4.87; p = 0.124), and tobacco use (SHR: 2.85; 95% CI: 0.90-8.97; p = 0.074). Cardiovascular risk was not significantly different between TKIs and bevacizumab. Lenvatinib appears to have the highest risk of cardiovascular adverse events among these first-line VEGF inhibitors.

A Predictive Scoring System for Therapy Failure of Tyrosine-Kinase Inhibitors in Patients with Chronic-Phase Chronic Myeloid Leukemia

Background In the latest version of WHO criteria (5th edition, 2022), accelerated-phase chronic myeloid leukemia (CML-AP) was re-defined as “high-risk” chronic-phase chronic myeloid leukemia (CML-CP). However, there is no robust predictive scoring system for therapy failure of tyrosine-kinase inhibitors (TKIs) in these newly-defined CML-CP patients. Objectives To develop and validate a predictive scoring system for TKI-therapy failure in CML-CP patients. Methods Data from 2,038 consecutive CML-CP patients according to the WHO 2022 criteria receiving initially TKI-therapy at one centre were interrogated as the training dataset to develop a predictive scoring system which was subsequently-validated in 4,640 patients from 76 other centres (validation dataset). TKI-therapy failure was defined by the 2020 European LeukemiaNet recommendation. Results In the training dataset, 1,591 patients (78%) initially received imatinib; 326 (16%), nilotinib; 85 (4%), dasatinib; and 36 (2%), flumatinib (a novel 2G-TKI made in China). Median TKI-therapy duration was 58 months (IQR, 33-90 months). 515 patients (27%) experienced therapy failure at a median of 9 months (IQR 3-12 months) on TKI-therapy. Multi-variable analysis indicated that older age, male sex, lower hemoglobin concentration, higher proportion of blood blasts and basophils, larger spleen size below the costal margin and high-risk additional cytogenetic abnormalities (ACAs) in Ph + cells were significantly-associated with higher cumulative incidence of therapy failure. Based on the optimal Fine-Gray regression model, a formula to calculate the therapy-failure risk score was established: “ Initial TKI-therapy failure risk score = 1.9321 × (Age/100) + 0.2950 × Sex (male = 1, female = 0) - 0.8589 × (HGB/100) 2 + 0.0979 × Blood blasts + 0.023× Blood basophils + 0.0521 × Spleen size below the costal margin + 0.5075 × high-risk ACAs (existing = 1, no = 0)” which divided patients into low- (score ≤ 0.0545; n = 908; 47%), intermediate- (0.0545 &amp;lt; score &amp;lt; 1.1662; n = 791; 41%) and high-risk (score ≥ 1.1662; n = 216; 12%) cohorts with 7-year cumulative incidences of therapy failure of 8% (95%CI, 4, 12%), 39% (35, 43%) and 80% (76, 84%; p &amp;lt; 0.001; Figure 1A). Sub-distribution hazard ratios (sHRs) for therapy failure (low-risk cohort as reference) were 3.2 (2.6, 4.1, p &amp;lt; 0.001) and 9.5 (7.4, 12.2; p &amp;lt; 0.001) for the intermediate- and high-risk cohorts. In the validation dataset, 4,640 patients were classified into the low- (n = 2,168; 47%), intermediate- (n = 2,093; 45%) and high-risk (n = 379; 8%) cohorts using the scoring system. 7-year cumulative incidences of therapy-failure were 10% (7, 13%), 36% (33, 39%) and 70% (66, 74%; p &amp;lt; 0.001; Figure 1B). sHRs (low-risk cohort as reference) were 3.4 (3.0, 3.9; p &amp;lt; 0.001) and 8.8 (7.5, 10.3; p &amp;lt; 0.001) for the intermediate- and high-risk cohorts. Time-dependent AUROC values for therapy failure using the predictive scoring system were 0.84-0.92 and 0.79-0.86 in the training and validation datasets. Moreover, patients identified as intermediate- or high-risk cohorts by the predictive scoring system receiving initial 2G-TKI-therapy had significantly-lower therapy failure rate than those receiving imatinib-therapy ( p-values = 0.002 and 0.017) both in the training and validation datasets. Conclusions We developed and validated a robust predictive scoring system for TKI-therapy failure in newly-defined CML-CP patients according to the WHO criteria (5th edition, 2022), which might help physicians decide appropriate therapy strategy.

ASC4START and ASC4FIRST: Two Ongoing Phase 3 Trials Investigating Asciminib Monotherapy As First-Line Therapy Versus Tyrosine Kinase Inhibitors in Patients with Newly Diagnosed Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase

Background: The current standard of care (SoC) for newly diagnosed patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) is treatment with 1 of the 4 tyrosine kinase inhibitors (TKIs) approved for this use (first generation [1G] imatinib [IMA] and second generation [2G] bosutinib [BOS], dasatinib [DAS], and nilotinib [NIL]). Although TKIs have vastly improved treatment outcomes, pts with newly diagnosed CML-CP experience lack of efficacy and intolerance to available treatments. A large number of pts treated with IMA do not achieve major molecular response (MMR) and even fewer pts achieve deep molecular response, a key requirement to attempt treatment-free remission. Treatment with 2G TKIs results in larger proportions of pts achieving deep responses albeit still with a sizeable minority not reaching this goal. Also, many pts are intolerant to 2G TKIs, resulting in therapy switching, frequently multiple times. For pts who remain on treatment, even low-grade adverse events (AEs) may significantly impact quality of life (QoL) given the long-term nature of treatment. Improved treatments with high efficacy and improved tolerability are needed to limit therapy switching, reduce treatment discontinuation, maintain, or improve pt QoL, and allow pts to remain on treatment at an optimal dose for longer duration to achieve deep responses. Asciminib is the first and only approved BCR::ABL1 inhibitor that works by specifically targeting the ABL myristoyl pocket (STAMP). This unique mechanism of action (MoA) has no confirmed overlapping mutation-driven resistance profile with ATP-competitive TKIs. Asciminib shows better selectivity compared to other TKIs, with no known off-target kinase-mediated effects due to its MoA; this translates into improved tolerability. In clinical trials (Hughes et al. N Engl J Med. 2019; Rea et al. Blood 2021), asciminib has demonstrated sustained efficacy and a favorable safety profile over time in pts with Philadelphia chromosome positive (Ph+) CML-CP previously treated with ≥2 TKIs as well as in pts with T315I mutation. Asciminib as monotherapy and in combination with ATP-competitive TKIs is being studied as first-line (1L) treatment in CML. The ongoing ASC4FIRST (NCT04971226) study is investigating the efficacy and safety of asciminib 80 mg once daily (QD) monotherapy vs investigator-selected 1G or 2G TKI in adults with newly diagnosed Ph+ CML-CP ( Table 1). The primary endpoint of ASC4FIRST is MMR rate at 48 weeks. The ongoing ASC4START (NCT05456191) study is focused on pt-centric objectives, assessing the tolerability and efficacy of asciminib vs 2G TKI NIL in adults with newly diagnosed Ph+ CML-CP. The primary endpoint of ASC4START is time to treatment discontinuation due to an AE ( Table 1). Current Status: As of December 20, 2022, the ASC4FIRST study completed recruitment, with 405 pts enrolled worldwide. The end of study (EOS) will occur 5 years from the last pt first treatment in the study. Pts will continue to receive the assigned treatment until the EOS, or until premature discontinuation due to treatment failure, disease progression or intolerance, or due to investigator or participant decision. Between 21 November 2022 and 25 July 2023, 180 pts have been screened for the ASC4START study, with 147 pts randomized to treatment (n=52 France, n=40 Germany, n=9 Bulgaria, n=7 Czechia, n=7 Hungary, n=6 Korea, n=6 Singapore, n=2 Slovakia, n=5 Argentina, n=3 Greece, n=2 each from Slovakia, Malaysia, and Oman, and n=1 each from the USA, Italy, Romania, UK, Jordan, and Canada). Recruitment is ongoing. Patients will be treated until approximately 64 discontinuations of either study treatment due to an AE have been recorded. Conclusions: With demonstrated efficacy and improved tolerability compared to ATP-binding TKIs, asciminib has the potential to become the therapy of choice for CML in 1L, enabling newly diagnosed patients to remain on therapy with improved QoL and overall survival, and reducing the need for therapy switching, ultimately allowing patients to achieve optimal milestone responses and reach treatment goals. Findings from these two trials will provide comprehensive evidenceon the use of asciminib as 1L therapy for newly diagnosed pts with Ph+ CML-CP.

Brief Report: Circular Runt-related transcription factor (circRUNX1) as potential biomarker for cancer recurrence in EGFR mutation-positive surgically resected NSCLC

IntroductionAs recently evidenced by the ADAURA trial, most patients with stages IB to IIIA of resected EGFR-mutant lung adenocarcinoma benefit from osimertinib as adjuvant therapy. Nevertheless, predictive markers of response and recurrence are still an unmet need for more than 10% of these patients. Some circular RNAs (circRNAs) have been reported to play a role in tumor growth and proliferation. In this project, we studied circRNA expression levels in formalin-fixed, paraffin-embedded lung tumor samples to explore their biomarker potential and develop a machine learning (ML)-based signature that could predict the benefit of adjuvant EGFR tyrosine kinase inhibitors in patients with EGFR-mutant NSCLC. MethodsPatients with surgically resected EGFR mutant-positive, stages I to IIIB NSCLC were recruited from February 2007 to December 2015. Formalin-fixed, paraffin-embedded tumor samples were retrospectively collected from those patients with a follow-up period of more than or equal to 36 months (N = 76). Clinicopathologic features were annotated. Total RNA was purified and quantified prior nCounter processing with our circRNA custom panel. Data analysis and ML were performed taking into consideration circRNA expression levels and recurrence-free survival (RFS). RFS was defined from the day of surgery to the day when recurrence was detected radiologically or the death owing to any cause. ResultsOf the 76 patients with EGFR mutation-positive NSCLC included in the study, 34 relapsed within 3 years after resection. The median age of the relapsing cohort was 71.5 (range: 49–89) years. Most patients were nonsmokers (n = 21; 61.8%) and of female sex (n = 21; 61.8%). Most cases (n = 17; 50%) presented an exon 21 mutation, whereas 15 and four patients had an exon 19 and exon 18 mutation, respectively. Differential expression analysis revealed that circRUNX1, along with circFUT8 and circAASDH, was up-regulated in relapsing patients (p < 0.05 and >2 fold-change). A ML-based circRNA signature predictive of recurrence in patients with EGFR mutation-positive NSCLC, comprising circRUNX1, was developed. Our final model including selected 6-circRNA signature with random forest algorithm was able to classify relapsing patients with an accuracy of 83% and an area under the receiver operating characteristic curve of 0.91.RFS was significantly shorter not only for the subgroup of patients with high versus low circRUNX1 expression but also for the group classified as recurrent by the ML circRNA signature when compared with those classified as nonrecurrent. ConclusionsOur findings suggest that circRUNX1 and the presented ML-developed signature could be novel tools to predict the benefit of adjuvant EGFR tyrosine kinase inhibitors with regard to RFS in patients with EGFR-mutant NSCLC. The training and validation phases of our ML signature will be conducted including bigger independent cohorts.

Treatment outcomes of non-small cell lung cancers treated with EGFR tyrosine kinase inhibitors: a real-world cohort study

Background Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are a standard of care treatment options in non-small cell lung cancer (NSCLC). The present study investigated real-world EGFR TKI use and patient outcomes in NSCLC. Material and methods We collected all the patients who had reimbursement for EGFR TKIs in Finland 2011–2020 and had data available at Finnish Cancer Registry. Survival and time-on-treatment (ToT) were analyzed from the first EGFR TKI purchase and patients were stratified according to the TKIs. Results Whole patient cohort consisted of 1498 individuals who were treated with erlotinib (n = 998), afatinib (n = 258), or gefitinib (n = 238). In the EGFR mutant cohort (all gefitinib users and afatinib users with non-squamous histology; n = 466), survival was comparable to registrational trials while patients treated with afatinib had improved survival (HR 0.67 CI 95% 0.53–0.85) and longer ToT (13.9 vs 11.9 months, NS) compared to those treated with gefitinib. Females treated with afatinib had improved survival (HR 0.61 CI 95% 0.44–0.83) and longer ToT (15.1 vs 12.5 months, NS) compared to gefitinib while similar was not observed in males. Later line osimertinib treatment was applied for 78 patients. Approximately 20% of the individuals treated with previous gefitinib or afatinib had later line osimertinib treatment. Efficacy analysis of osimertinib treated showed similar ToT and survival regardless of the first line EGFR TKI. Conclusions EGFR mutants treated with afatinib have improved outcomes compared to gefitinib while later-line osimertinib was applied only for around 20% of the individuals. The study further highlights the good real-world performance of EGFR TKIs and sheds light on therapy sequencing.

Siglec 15 as a biomarker or a druggable molecule for non-small cell lung cancer.

Lung cancer has been the main cause of cancer mortality worldwide. Furthermore, lung cancer rates of new cases per year evidenced a large incidence of this neoplasm in both men and women. Because there is no biomarker for early detection, it is frequently detected late, at an advanced state. The introduction of multiple lines of tyrosine kinase inhibitors in patients with EGFR, ALK, ROS1, and NTRK mutations has modified the therapy of lung cancer. Immunotherapy advances have resulted in substantial improvements in overall survival and disease-free survival, making immune checkpoint inhibitors (ICIs) a potential option for lung cancer treatment. Current PD-1/PD-L1/CTLA-4 immunotherapies have resulted in important response and survival rates. However, existing medicines only function in around 20% of unselected, advanced NSCLC patients, and primary and acquired resistance remain unsolved obstacles. Therefore, precise predictive indicators must be identified to choose the best patients for ICI treatment. Thus, Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) stands out as a potential tumor biomarker, with distinctive expression in normal tissues, in tumor immune involvement, and a high structural similarity to PD-L1. Understanding the tumor immune response and the search for new therapeutic targets leads to the improvement of therapeutic pathways directed at the tumor microenvironment. The present review aims to analyze Siglec-15 potential as a diagnostic, prognostic, and response biomarker in lung cancer, considering its results evidenced in the current literature.

Safety and Efficacy of Hypofractionated Radiotherapy Combined with Tyrosine Kinase Inhibitors in Patients with Lung Metastases after Liver Transplantation for Hepatocellular Carcinoma

We evaluated the safety and efficacy of hypofractionated radiotherapy (HFRT) combined with tyrosine kinase inhibitors (TKIs) in patients with pulmonary metastases after orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC). Twenty-five patients with lung metastases after OLT for HCC who underwent HFRT using helical tomotherapy concomitantly with TKIs (sorafenib or lenvatinib) were retrospectively. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), local control rate (LCR), objective response rate (ORR), and treatment-related side effects. The median follow-up time was 35.5 months, with a median interval from OLT to lung metastasis of 15.3 months. The median PFS and OS were 9.9 and 32.7 months, respectively. The 1-, 2-, and 3-year PFS and OS rates were 36.0%, 16.0%, and 12.0%, and 84.0%, 52.0%, and 20.0%, respectively. The LCR of pulmonary metastases at 1 year was 100%, whereas the two-year LCR was 76.9%. The 1- and 2- year ORRs were 95.2% and 69.2%, respectively, with no grade > 2 adverse events. Radiation pneumonitis was observed in 17 patients (68.0%). Grade 1 pneumonitis occurred in 15 patients (60.0%), and grade 2 pneumonitis occurred in 2 patients (8.0%). The combination therapy of HFRT with TKIs is a feasible, safe, and promising approach in the treatment of pulmonary metastases for HCC after OLT.

Efficacy of tyrosine kinase inhibitors in patients with non-small-cell lung cancer with performance status 4: a case series and review of the literature

BackgroundCurrent guidelines for non-small-cell lung cancer (NSCLC) recommend that each tyrosine kinase inhibitor (TKI) is indicated even for driver mutation-positive patients with a poor performance status (PS). In previous studies, most patients had a PS of 2–3, but those with a PS of 4 were very few. Therefore, the efficacy of TKIs in patients with NSCLC with a PS of 4 remains unclear.Case presentationWe retrospectively reviewed the clinical records of four patients with NSCLC with PS 4 treated with TKIs: an 89-year-old Japanese woman (Case 1), a 80-year-old Japanese woman (Case 2), an 50-year-old Japanese man (Case 3), and a 81-year-old Japanese woman (Case 4). Genetic alterations were epidermal growth factor receptor (EGFR), MET exon 14 skipping, BRAFV600E, and ROS1 proto-oncogene receptor tyrosine kinase (ROS1). One case with ROS1 fusion showed a significant response with the recovery of PS. However, in the remaining three cases (i.e., EGFR, MET exon 14 skipping, and BRAFV600E mutations), patients died despite the administration of TKIs. These three patients had to be hospitalized at the end of their life to receive treatment.ConclusionsThis is the first case series to summarize the efficacy of TKIs in patients with NSCLC with a PS of 4. Additionally, this case series poses a question concerning the indication of TKIs for older patients with a PS of 4.

A rare FBXO25–SEPT14 fusion in a patient with chronic myeloid leukemia treatment to tyrosine kinase inhibitors: a case report

Abstract Objectives Exploring the pathogenesis of resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia. Case presentation This case report describes a rare fusion of FBXO25 and SEPT14 genes in a 58-year-old male patient with chronic myeloid leukemia. The patient had been treated with tyrosine kinase inhibitors for one year. After 6 months of imatinib treatment, the patient's symptoms improved significantly and the complete blood count returned to normal, but the optimal ratio of BCR::ABL transcripts to ABL transcripts is greater than 10 % indicating treatment failure. Then we switched to a second generation TKIs to continue treatment, During the Flumatinib treatment period, the patient developed severe bone marrow suppression and exhibited additional cytogenetic abnormalities involving chromosome aberration: 47, XY,+8[5]/47, idem, inv(Y)(p11.2q11.23)[15]. By adjusting the drug dose and elevating blood cells, the patient’s BCR::ABL P210/ABL was 2.56 % after six months of Flumatinib treatment. The patient’s BCR::ABL P210/ABL consistently remained above 1 % throughout the treatment, and additional cytogenetic abnormalities were present. Next-generation sequencing revealed the recombination of exon 4 of the FBXO25 and exon 10 of the SEPT14, and this mutation has not been previously reported. Conclusions Our findings suggest that the FBXO25-SEPT14 fusion may be associated with tyrosine kinase inhibitors resistance in chronic myeloid leukemia.

Inactivating mutations of TP53 and resistence to tyrosine-kinase inhibitors in patients affected with aggressive thyroid cancer

Inactivating mutations of TP53 and resistence to tyrosine-kinase inhibitors in patients affected with aggressive thyroid cancer

Early Circulating Tumor DNA Dynamics and Efficacy of Lorlatinib in Patients With Treatment-Naive, Advanced, ALK-Positive NSCLC

IntroductionCirculating tumor DNA (ctDNA) has been used as a biomarker for prognostication and response to treatment. Here, we evaluate ctDNA as a potential biomarker for response to lorlatinib, a third-generation ALK tyrosine kinase inhibitor in patients with treatment-naive, advanced, ALK-positive NSCLC in the ongoing phase 3 CROWN study (NCT03052608). MethodsMolecular responses were calculated using mean variant allele frequency (VAF), longitudinal mean change in VAF (dVAF), and ratio to baseline. Efficacy assessments (progression-free survival [PFS] and objective response rate) were paired with individual patient ctDNA and analyzed for association. ResultsCompared with baseline, mean VAF at week 4 was decreased in both treatment arms. Considering all detected somatic variants, a reduction in dVAF (≤0) was associated with a longer PFS in the lorlatinib arm. The hazard ratio (HR) for a dVAF less than or equal to 0 versus more than 0 was 0.50 (95% confidence interval [CI]: 0.23–1.12) in the lorlatinib arm. A similar association was not observed for crizotinib (HR = 1.00, 95% CI: 0.49–2.03). Comparing molecular responders with nonresponders, patients treated with lorlatinib who had a molecular response had longer PFS (HR = 0.37, 95% CI: 0.16–0.85); patients treated with crizotinib who had a molecular response had similar PFS as those without a molecular response (HR = 1.48, 95% CI: 0.67–3.30). ConclusionsIn patients with treatment-naive, advanced, ALK-positive NSCLC, early ctDNA dynamics predicted better outcome with lorlatinib but not with crizotinib. These results suggest that ctDNA may be used to monitor and potentially predict efficacy of lorlatinib treatment.

Enhanced anti-tumor activity of CD5 CAR T cells manufactured with tyrosine kinase inhibitors in patients with relapsed/refractory T-ALL.

7002 Background: An effective CAR T cell platform for the therapy of T-ALL requires minimizing CAR-driven fratricide of normal T cells. CD5 is a pan-T-cell surface protein present in ~85% of T-ALL. We developed a 2nd generation CD5 CAR that produces minimal T cell fratricide without additional engineering. Tonic CAR signaling accelerated terminal differentiation of CD5 CAR T cells potentially reducing their potency. In this study, we evaluated whether blocking tonic signaling with tyrosine kinase inhibitors (TKI) ibrutinib and dasatinib improves anti-leukemic activity of CD5 CAR T cells in patients with r/r T-ALL (NCT03081910). Methods: In the initial cohort of patients (CH1, n = 8), we generated CD5 CAR T cells from autologous PBMCs followed by expansion in the presence of IL-7 and IL-15 without TKI. In the subsequent cohort (CH2, n = 7) we manufactured cells from autologous (Arm A; n = 4) or HSC donor-derived (Arm B; n = 3) PBMCs in the presence of TKI. A total of 14 pts were treated (9 adult and 5 pediatric; age 11-70 years [median 36 yrs]); one pediatric pt was treated on both cohorts. Results: In CH1, all pts received autologous CAR T cells: 1 pt on DL1 (1x107 CAR T cells/m2), 5 on DL2 (5x107 CAR T cells/m2), and 2 on DL3 (1x108 CAR T cells/m2). In CH2, we treated 4 pts on Arm A (one on DL2; 3 on DL3) and 3 pts on Arm B (all on DL1). The overall expansion of CAR T cells was comparable between cohorts, but we observed more sustained persistence of CD5 CAR T cells in pts on CH2. In CH1, one pt experienced a morphologic CR. Of 7 pts treated on CH2, we observed 4 MRD-negative CRs (2 on Arm A and 2 on Arm B). The CAR T cells produced minimal early toxicity with most grade ≥3 AEs related to cytopenias, febrile neutropenia and transient abnormal laboratory values. CRS occurred in 3 pts on CH1 and 4 on CH2 (Arm A: n = 1; Arm B: n = 3); all ≤ grade 2. No pts developed ICANS. Two pts in CH2 (one on Arm A and Arm B) developed EBV viremia and post-transplant/immunodeficient lymphoproliferative disease (LPD) at wks 5 and 7 post-infusion, respectively. Both were treated with intensive multiagent chemotherapy, and one pt also received EBV specific T cells (EBVSTs) with significant reduction in viral load. Unfortunately, both passed away from complications of treatment for PTLD (unrelated to EBVSTs) with no evidence of residual T-ALL. No other significant infections occurred. Conclusions: These results demonstrate CD5 CAR T cells can induce clinical responses in heavily treated patients with r/r T-ALL. Manufacturing CD5 CAR T cells with TKI improved their potency and anti-tumor activity but also possibly suppressed CD5+ virus-specific T-cells thus leading to 2 cases of EBV associated LPD. We have subsequently modified our clinical protocol to administer prophylactic rituximab to EBV seropositive pts and identify a partially matched EBVST line prior to CAR T cell infusion as a strategy to prevent additional cases of LPD in future subjects. Clinical trial information: NCT03081910 .

Real‐world outcomes among patients with EGFR‐mutated non‐small cell lung cancer treated with EGFR tyrosine kinase inhibitors versus immunotherapy or chemotherapy in the first‐line setting

AbstractBackgroundDespite national guideline recommendations, epidermal growth factor receptor mutated (EGFRm) metastatic non‐small cell lung cancer (mNSCLC) patients may still receive suboptimal treatment in the first line (1L). This study evaluated 1L therapy initiation in relation to biomarker testing results and time to next‐treatment or death (TTNTD) in patients receiving EGFR tyrosine kinase inhibitors (TKIs) versus immunotherapy (IO) or chemotherapy.MethodsStage IV EGFRm mNSCLC adults that initiated 1L EGFR TKI (first, second, or third generation), IO ± chemotherapy (IO users), or chemotherapy alone from 5/2017–12/2019 were identified from the Flatiron database. Logistic regression estimated the likelihood of initiating treatment before receiving testing results for each therapy. Median TTNTD was evaluated via Kaplan–Meier analysis. Adjusted hazards ratios (HRs) and 95% CI examining the association of 1L therapy with TTNTD were reported from multivariable Cox proportional‐hazards models.ResultsAmong 758 EGFRm mNSCLC patients, EGFR TKI was used as 1L therapy for 87.3% of patients (n = 662), IO in 8.3% (n = 63), and chemotherapy only in 4.4% (n = 33). The majority of IO (61.9%) and chemotherapy only patients (60.6%) initiated therapy before test results were available, compared to 9.7% of EGFR TKIs. The odds of initiating therapy before receiving test results were higher for IO (OR: 19.6, p &lt; 0.001) and chemotherapy alone (OR: 14.1, p &lt; 0.001) in comparison to EGFR TKIs. Compared to IO and chemotherapy, EGFR TKIs had longer median TTNTD (EGFR TKI: 14.8 months, 95% CI: 13.5–16.3; IO: 3.7 months, 95% CI 2.8–6.2; chemotherapy: 4.4 months, 95% CI 3.1–6.8, p &lt; 0.001). EGFR TKI patients had significantly lower risk of initiating second‐line therapy or death compared to patients on 1L IO (HR: 0.33, p &lt; 0.001) or 1L chemotherapy (HR: 0.34, p &lt; 0.001).ConclusionsA portion of biomarker testing results were not used to guide 1L therapy. Patients initiating EGFR TKI as 1L therapy had longer TTNTD than IO or chemotherapy.

Analysis of Tumor Heterogeneity Through AXL Activation in Primary Resistance to EGFR Tyrosine Kinase Inhibitors

IntroductionEGFR tyrosine kinase inhibitors are standard therapeutic agents for patients with advanced NSCLC harboring EGFR mutations. Nevertheless, some patients exhibit primary resistance to EGFR tyrosine kinase inhibitors in the first-line treatment setting. AXL, a member of the TYRO3, AXL, and MERTK family of receptor tyrosine kinases, is involved in primary resistance to EGFR tyrosine kinase inhibitors in EGFR-mutated NSCLC. MethodsWe investigated spatial tumor heterogeneity using autopsy specimens and a patient-derived cell line from a patient with EGFR-mutated NSCLC having primary resistance to erlotinib plus ramucirumab. ResultsQuantitative polymerase chain reaction analysis revealed that AXL mRNA expression differed at each metastatic site. In addition, AXL expression levels were likely to be negatively correlated with the effectiveness of erlotinib plus ramucirumab therapy. Analysis of a patient-derived cell line established from the left pleural effusion before initiation of treatment revealed that the combination of EGFR tyrosine kinase inhibitors and an AXL inhibitor remarkably inhibited cell viability and increased cell apoptosis in comparison with EGFR tyrosine kinase inhibitor monotherapy or combination therapy of these inhibitors with ramucirumab. ConclusionsOur observations suggest that AXL expression may play a critical role in the progression of spatial tumor heterogeneity and primary resistance to EGFR tyrosine kinase inhibitors in patients with EGFR-mutated NSCLC.