Anti-PD-1/L1 antibody plus anti-VEGF antibody vs. plus VEGFR-targeted TKI as first-line therapy for unresectable hepatocellular carcinoma: a network meta-analysis.

Background: This article is based on our previous research, which was presented at the 2023 ASCO Annual Meeting I and published in Journal of Clinical Oncology as Conference Abstract (JCO. 2023;41:e16148. doi: 10.1200/JCO.2023.41.16_suppl.e16148). Both anti-programmed death 1/ligand-1 (PD-1/L1) antibody + anti-vascular endothelial growth factor (VEGF) antibody (A + A) and anti-PD-1/L1 antibody + VEGF receptor (VEGFR)-targeted tyrosine kinase inhibitor (A + T) are effective first-line therapies for unresectable hepatocellular carcinoma. However, there lacks evidence from head-to-head comparisons between these two treatments. We conducted a network meta-analysis on the efficacy and safety of them. Methods: After a rigorous literature research, 6 phase III trials were identified for the final analysis, including IMbrave150, ORIENT-32, COSMIC-312, CARES-310, LEAP-002, and REFLECT. The experiments were classified into three groups: A + A, A + T, and intermediate reference group. The primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and incidence of treatment-related adverse events (TRAEs). Hazard ratio (HR) with 95% confidence intervals (CI) for OS and PFS, odds ratio (OR) for ORR, and relative risk (RR) for all grade and grade ≥3 TRAEs were calculated. Under Bayesian framework, the meta-analysis was conducted using sorafenib as intermediate reference. Results: With the rank probability of 96%, A + A showed the greatest reduction in the risk of death, without significant difference from A + T (HR: 0.82, 95% CI: 0.65-1.04). A + T showed the greatest effect in prolonging PFS and improving ORR with the rank probability of 77%, but there were no statistical differences with A + A. A + A was safer than A + T in terms of all grade of TRAEs (RR: 0.91, 95% CI: 0.82-1.00) and particularly in those grade ≥3 (RR: 0.65, 95% CI: 0.54-0.77). Conclusions: A + A had the greatest probability of delivering the longest OS, while A + T was correlated with larger PFS benefits at the cost of a lower safety rate.

Management of oligometastatic and oligoprogressive epidermal growth factor receptor mutated non-small cell lung cancer patients: state of the art of a combined approach.

Recently, the development of targeted therapy approaches such as those based on tyrosine kinase inhibitor (TKI) greatly improved the clinical outcomes of patients affected by oncogene addicted advanced non-small cell lung cancer (NSCLC). Similarly, the improvement of radiation therapy techniques has permitted to deliver high radiation doses to a limited number of metastatic target lesions (oligopersistent or oligoprogressive), with limited high-dose normal tissue exposure that leads to low severe toxicity rates. The aim of this narrative review was to provide an overview of the currently established definition of oligometastatic and oligoprogressive disease, to define first line and subsequent lines targeted therapies and the role of consolidative non-invasive local ablative treatments (LATs) in these settings. The potential benefit of local treatment (LT) such as radiotherapy (RT) or surgery might be represented by an overall reduction of switching to subsequent systemic treatments lowering the risk of further systemic dissemination. Further randomized clinical trials will clarify the role of LT and their correct timing in relation to systemic targeted therapies.

Long acting delivery and therapies for neovascular age-related macular degeneration.

INTRODUCTION: Neovascular age-related macular degeneration (nAMD) represents a leading cause of severe visual impairment in individuals over 50 years of age in developed nations. Intravitreal anti-vascular endothelial growth factor (VEGF) injections have become the standard of care for treating nAMD; however, monthly or bimonthly dosing represents significant time and cost burden due to the disease's chronic nature and limited medication half-life. AREAS COVERED: This review summarizes innovative therapeutics and delivery methods for nAMD. Emerging methods for extended drug delivery include high molar concentration anti-VEGF drugs, intravitreal sustained release devices, reservoirs for intravitreal delivery, and gene therapy biofactories. In addition to VEGF-A, therapies targeting inhibition of VEGF-C and D, the angiopoetin-2 (Ang-2)/Tie-2 pathway, tyrosine kinases, and integrins are reviewed. EXPERT OPINION: The evolving therapeutic landscape of nAMD is rapidly expanding our toolkit for effective and durable treatment. Recent FDA approvals of faricimab (Vabysmo) and high dose aflibercept (Eylea HD) for nAMD with potential extension of injection intervals up to four months have been promising developments for patients and providers alike. Further research and innovation, including novel delivery techniques and pharmacologic targets, is necessary to validate the efficacy of developing therapeutics and characterize real-world outcomes. demonstrating promise in expanding treatment durability.

The challenge of running trials in advanced angiosarcoma: A systematic review of the literature from EORTC/STBSG to guide the development of angiosarcoma-specific trials.

INTRODUCTION: While available systemic treatments have modest long term efficacy in advanced angiosarcoma, immunotherapy represents an interesting new therapeutic opportunity. To establish its benefit, it is required to conduct a clinical trial assessing its efficacy and toxicity compared to standard treatments. MATERIAL AND METHODS: This is a literature review from PubMed search. RESULTS: Several systemic treatments (chemotherapy and TKI) are currently used in advanced angiosarcoma with ORR ranging from 12.5 to 68 % and PFS from 2 to 7 months. However, few randomized trials, mainly phase II, has been conducted to compare these treatments. While most centers propose doxorubicin containing regimens or paclitaxel in 1st or 2nd line, a high heterogeneity of regimens administered in this setting is observed even across sarcoma specialized centers with no consensual standard treatment. Encouraging signals of immunotherapy activity have been reported in angiosarcoma from several retrospective and phase II studies assessing anti-PD1 either alone or in combination with anti CTLA4 or TKI. Although cutaneous and head and neck location seems to benefit more from immunotherapy, response may be observed in any angiosarcoma subtype. In sarcoma in general and AS in particular, no biomarker has been clearly established to predict the efficacy of immunotherapy: high tumor mutational burden and presence of tertiary lymphoid structures are under assessment. DISCUSSION: Even essential, developing a randomized clinical trial in AS struggles with the heterogeneity of the disease, the lack of consensual standard regimen, the uncertainty on optimal immunotherapy administration and the absence of established predictive biomarkers. CONCLUSION: International collaboration is essential to run randomized trial in advanced AS and asses the efficacy of immune therapy in this rare and heterogeneous disease.

Small molecule tyrosine kinase inhibitors approved for systemic therapy of advanced hepatocellular carcinoma: recent advances and future perspectives.

Liver cancer is the sixth most commonly diagnosed cancer and the third leading cause of cancer death in the world, and hepatocellular carcinoma (HCC) is the most common form of liver cancer. More than half of the HCC patients are diagnosed at an advanced stage and often require systemic therapy. Dysregulation of the activity of receptor tyrosine kinases (RTKs) is involved in the development and progress of HCC, RTKs are therefore the potential targets for systemic therapy of advanced HCC (aHCC). Currently, a total of six small molecule tyrosine kinase inhibitors (TKIs) have been approved for aHCC, including first-line sorafenib, lenvatinib, and donafenib, and second-line regorafenib, cabozantinib, and apatinib. These TKIs improved patients survival, which are associated with disease stage, etiology, liver function, tumor burden, baseline levels of alpha-fetoprotein, and treatment history. This review focuses on the clinical outcomes of these TKIs in key clinical trials, retrospective and real-world studies and discusses the future perspectives of TKIs for aHCC, with an aim to provide up-to-date evidence for decision-making in the treatment of aHCC.

EGFR-TKI-induced Factor V deficiency in a patient with advanced non-small cell lung cancer: The first case report.

Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is routinely prescribed as first-line therapy for advanced non-small cell lung cancer, regardless of the presence of the T790M resistance mutation. This study reports a rare case of Factor V inhibitor detection during osimertinib therapy in a patient with lung adenocarcinoma. These findings underscore the importance of vigilant monitoring for coagulation abnormalities during EGFR-TKI therapy.

Narrative review of stereotactic body radiation therapy combined with tyrosine kinase inhibitors for oligometastatic EGFR-mutated non-small cell lung cancer: present and future developments.

Background and Objective: A significant number of individuals diagnosed with non-small cell lung cancer (NSCLC) have distant metastases, and the concept of oligometastatic NSCLC has shown promise in achieving a cure. Stereotactic body radiation therapy (SBRT) is currently considered a viable treatment option for a limited number of tumor metastases. It has also been demonstrated that third-generation tyrosine kinase inhibitors (TKIs) are effective in extending the survival of patients with epidermal growth factor receptor (EGFR)-mutated NSCLC. Hence, the combination of SBRT with third-generation TKIs holds the potential to enhance treatment efficacy in patients with oligometastatic EGFR-mutated NSCLC. This review aimed to assess the possibility of combining SBRT with TKIs as an optimum treatment option for patients with oligometastatic EGFR-mutated NSCLC. Methods: We performed a narrative review by searching the PubMed, Web of Science, Elsevier and ClinicalTrials.gov databases for articles published in the English language from January 2009 to February 2024 and by reviewing the bibliographies of key references to identify important literature related to combining SBRT with third-generation TKIs in oligometastatic EGFR-mutated NSCLC. Key Content and Findings: This review aimed to assess the viability of combining SBRT and EGFR-TKIs in oligometastatic EGFR-mutated NSCLC. Current clinical trials suggest that the combined therapies have better progression free survival (PFS) when using SBRT as either concurrent with EGFR-TKIs or consolidated with EGFR-TKIs. Furthermore, research with third-generation EGFR-TKIs and SBRT combinations has demonstrated tolerable toxicity levels without significant additional adverse effects as compared to prior therapies. However, further clinical trials are required to establish its effectiveness. Conclusions: The combined approach of SBRT and TKIs can effectively impede the progression of oligometastatic NSCLC in patients harboring EGFR mutations and, most notably, can prolong progression-free survival rates. However, the feasibility of combining SBRT with third-generation TKIs in clinical trials remains unclear.

Neoadjuvant aumolertinib monotherapy for EGFR-mutant lung squamous cell carcinoma: a case report.

Background: Lung cancer is the malignant tumor with high incidence and mortality in China, and more than 30% of non-small cell lung cancer (NSCLC) patients are in the locally advanced stage at the first-time diagnosis. Currently, neoadjuvant epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) combined with radical surgery is effective in the treatment of unresectable stage III EGFR-mutated NSCLC (NSCLCm), and related studies are gradually increasing. But the feasibility of neoadjuvant EGFR-TKI combined with radical surgery for unresectable stage III EGFR-mutant lung squamous cell carcinoma (LUSQm) remains controversial. Case Description: This report presented a successful case of neoadjuvant target-therapy with aumolertinib, the third-generation EGFR-TKI, combined with radical surgery for a stage IIIA LUSQm female patient. After four cycles (28 days/cycle) of neoadjuvant target-therapy, the tumor had a partial response on imaging evaluation and pathological evaluation after surgery showed complete tumor response. The neoadjuvant target-therapy was well tolerated. All adverse events (AEs) that occurred during the treatment were grade I, including decreased platelets, impaired liver function, and diarrhea. The patient was instructed to continue taking Aumolertinib for 3 years after surgery. At the cut-off date of April 1, 2024, the patient had no recurrence after 20 months of treatment. Conclusions: The result of patient treatment demonstrated the potential feasibility of neoadjuvant Aumolertinib monotherapy for locally advanced LUSQm. The report provides some support for neoadjuvant target-therapy for LUSQm.

Breaking the Barriers of Therapy Resistance: Harnessing Ferroptosis for Effective Hepatocellular Carcinoma Therapy.

Ferroptosis is a type of cell death that relies on iron and is distinguished by the occurrence of lipid peroxidation and the buildup of reactive oxygen species. Ferroptosis has been demonstrated to have a significant impact on the advancement and resistance to treatment of hepatocellular carcinoma (HCC), thereby highlighting its potential as a viable therapeutic target. Ferroptosis was observed in HCC tissues in contrast to normal liver tissue. The inhibition of ferroptosis has been found to increase the viability of HCC cells and decrease their susceptibility to various anticancer therapies, including chemotherapy, radiotherapy, and immune checkpoint blockade. The administration of drugs that directly modulate ferroptosis regulators or induce excessive production of lipid-reactive oxygen species has demonstrated the potential to enhance the responsiveness of drug-resistant HCC cells to treatment. However, the precise mechanism underlying this phenomenon remains ambiguous. This review presents a comprehensive overview of the crucial role played by ferroptosis in enhancing the efficacy of treatment for hepatocellular carcinoma (HCC). The main aim of this study is to examine the feasibility of utilizing ferroptosis as a therapeutic approach to improve the efficacy of HCC treatment and overcome drug resistance.

Stabilization of TGF-ß Receptor 1 by a Receptor-Associated Adaptor Dictates Feedback Activation of the TGF-ß Signaling Pathway to Maintain Liver Cancer Stemness and Drug Resistance.

Dysregulation of the transforming growth factor-ß (TGF-ß) signaling pathway regulates cancer stem cells (CSCs) and drug sensitivity, whereas it remains largely unknown how feedback regulatory mechanisms are hijacked to fuel drug-resistant CSCs. Through a genome-wide CRISPR activation screen utilizing stem-like drug-resistant properties as a readout, the TGF-ß receptor-associated binding protein 1 (TGFBRAP1) is identified as a TGF-ß-inducible positive feedback regulator that governs sensitivity to tyrosine kinase inhibitors (TKIs) and promotes liver cancer stemness. By interacting with and stabilizing the TGF-ß receptor type 1 (TGFBR1), TGFBRAP1 plays an important role in potentiating TGF-ß signaling. Mechanistically, TGFBRAP1 competes with E3 ubiquitin ligases Smurf1/2 for binding to TGFΒR1, leading to impaired receptor poly-ubiquitination and proteasomal degradation. Moreover, hyperactive TGF-ß signaling in turn up-regulates TGFBRAP1 expression in drug-resistant CSC-like cells, thereby constituting a previously uncharacterized feedback mechanism to amplify TGF-ß signaling. As such, TGFBRAP1 expression is correlated with TGFΒR1 levels and TGF-ß signaling activity in hepatocellular carcinoma (HCC) tissues, as well as overall survival and disease recurrence in multiple HCC cohorts. Therapeutically, blocking TGFBRAP1-mediated stabilization of TGFBR1 by selective inhibitors alleviates Regorafenib resistance via reducing CSCs. Collectively, targeting feedback machinery of TGF-ß signaling pathway may be an actionable approach to mitigate drug resistance and liver cancer stemness.

Safety and efficacy of acalabrutinib and obinutuzumab in treatment-naive chronic lymphocytic leukemia: a Japanese phase 1 study.

This report focuses on part 3 of a multicenter, open-label, phase 1 study (NCT03198650) assessing the safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of acalabrutinib plus obinutuzumab in Japanese patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL). Ten patients were included; median age was 68 years. With a median treatment duration of 27.2 months, treatment-emergent adverse events (AEs) occurred in all patients (grade ≥3, 70%), and the most common AEs were anemia and headache (40% each). One patient had a grade 4 AE of neutropenia (the only dose-limiting toxicity). PK results suggested no marked effects of concomitant obinutuzumab treatment on the exposure of acalabrutinib. PD assessment indicated that combination therapy provided >98% Bruton tyrosine kinase (BTK) occupancy. Overall response rate (ORR) was 100% with median duration of response (DoR) and median progression-free survival (PFS) not reached. Treatment with acalabrutinib plus obinutuzumab was generally safe and efficacious in adult Japanese patients with TN CLL.

Promoting reactive oxygen species accumulation to overcome tyrosine kinase inhibitor resistance in cancer.

BACKGROUND: In tumor treatment, protein tyrosine kinase inhibitors (TKIs) have been extensively utilized. However, the efficacy of TKI is significantly compromised by drug resistance. Consequently, finding an effective solution to overcome TKI resistance becomes crucial. Reactive oxygen species (ROS) are a group of highly active molecules that play important roles in targeted cancer therapy including TKI targeted therapy. In this review, we concentrate on the ROS-associated mechanisms of TKI lethality in tumors and strategies for regulating ROS to reverse TKI resistance in cancer. MAIN BODY: Elevated ROS levels often manifest during TKI therapy in cancers, potentially causing organelle damage and cell death, which are critical to the success of TKIs in eradicating cancer cells. However, it is noteworthy that cancer cells might initiate resistance pathways to shield themselves from ROS-induced damage, leading to TKI resistance. Addressing this challenge involves blocking these resistance pathways, for instance, the NRF2-KEAP1 axis and protective autophagy, to promote ROS accumulation in cells, thereby resensitizing drug-resistant cancer cells to TKIs. Additional effective approaches inducing ROS generation within drug-resistant cells and providing exogenous ROS stimulation. CONCLUSION: ROS play pivotal roles in the eradication of tumor cells by TKI. Harnessing the accumulation of ROS to overcome TKI resistance is an effective and widely applicable approach.

A pilot study of nintedanib in molecularly selected patients with advanced non-small cell lung cancer.

Background: Nintedanib is a small molecule tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR). The purpose of the study was to evaluate the response rate for patients with advanced non-small cell lung cancer (NSCLC) with mutations in TP53, VEGFR1-3, PDGFR-A, PDGFR-B, and FGFR1-3 treated with nintedanib as part of an open-label, single-arm pilot study. Methods: Patients with advanced NSCLC previously treated with platinum-doublet chemotherapy with the above mutations were enrolled. Exclusion criteria included necrotic tumors with invasion of blood vessels, history of recent thromboembolic events, increased risk of bleeding or thrombosis, myocardial infarction, and weight loss >10% within past 6 months. Nintedanib was administered at a dose of 200 mg orally twice daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Secondary endpoints included progression-free survival (PFS) and correlating outcomes with specific mutations. This study was registered with ClinicalTrials.gov, number NCT02299141. Results: Between 2015 and 2019, 20 patients were enrolled with a median age was 66 years, 15 (75%) were females, 15 (75%) had adenocarcinoma, and 17 patients had a TP53 mutation (85%). Seventeen (85%) had received prior immunotherapy and 11 (55%) had received at least three prior lines of systemic therapy. The ORR was 15% with three partial responses (PR), while 12 patients had stable disease (SD), with disease control rate (DCR) consisting of a PR and SD greater than or equal to 16 weeks of 65% (n=13). Median PFS was 4.3 months [95% confidence interval (CI): 1.8-7.9] and median overall survival (OS) was 11.3 months (95% CI: 3.5-44.2). Three patients experienced prolonged clinical benefit from nintedanib, remaining on treatment for over 1 year and all three had a TP53 mutation and received prior immunotherapy. The most common adverse events of any grade included nausea (80%), fatigue (70%), diarrhea (60%), and anorexia (60%). Conclusions: In this pilot study in heavily pretreated and molecularly selected patients with metastatic NSCLC, nintedanib showed modest activity.

Risk of hepatitis B virus reactivation in cancer patients undergoing treatment with tyrosine kinase-inhibitors.

This editorial commented on an article in the World Journal of Gastroenterology titled "Risks of Reactivation of Hepatitis B Virus in Oncological Patients Using Tyrosine Kinase-Inhibitors: Case Report and Literature Analysis" by Colapietro et al. In this editorial, we focused on providing a more comprehensive exploration of hepatitis B virus reactivation (HBVr) associated with the usage of tyrosine kinase inhibitors (TKIs). It includes insights into the mechanisms underlying HBV reactivation, the temporal relationship between TKIs and HBV reactivation, and preventive measures. The aim is to understand the need for nucleos(t)ide analogs (NAT) and serial blood tests for early recognition of reactivation and acute liver injury, along with management strategies. TKIs are considered to be an intermediate (1%-10%) of HBVr. Current guidelines stipulate that patients receiving therapy with high or moderate risks of reactivation or recent cancer diagnosis must have at least tested hepatitis B surface antigen, anti-hepatitis B core antigen (HBc), and anti-hepatitis B surface antibody. Anti-HBc screening in highly endemic areas means people with negative tests should be vaccinated against HBV. Nucleoside or nucleotide analogs (NAs) like entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) form the basis of HBV reactivation prophylaxis and treatment during immunosuppression. Conversely, lamivudine, telbivudine, and adefovir are generally discouraged due to their reduced antiviral efficacy and higher risk of fostering drug-resistant viral strains. However, these less effective NAs may still be utilized in cases where ETV, TDF, and TAF are not feasible treatment options.

Real-world treatment patterns and outcomes for patients with CLL using the Australian pharmaceutical benefits scheme (PBS) dataset.

This real-world retrospective cohort study using Australian Pharmaceutical Benefits Scheme (PBS) 10% investigated changes in chronic lymphocytic leukemia (CLL) treatment by line of therapy, time-to-next-treatment, treatment duration, and overall survival (OS). Overall, 803 patients received their first PBS-reimbursed CLL medication between 1 January 2011 to 31 July 2021 (median age: 70 years; 64.6% male), 289 post-1 August 2020. In 2011, most first-line (1 L) prescribing was fludarabine, cyclophosphamide, and rituximab (FCR). By 2021, common 1L were chlorambucil ± CD20 (26.1%), Bruton Tyrosine Kinase inhibitor (BTKi) (26.1%), and CD20 monotherapy (23.9%). In 2011, relapsed/refractory (R/R) CLL treatment was CD20 monotherapy or FCR. By 2021, BTKi (57.7%) and venetoclax ± CD20 (26.1%) were most common. Compared to FCR, 1 L treatment duration (Hazard Ratio) was shorter for CD20 monotherapy (1.7) or chlorambucil ± CD20 (2.5). In R/R CLL, median duration was 24 (ibrutinib) and 19 months (venetoclax). Median OS was 127 months. CLLtreatment pattern shave greatly changed in Australia since the introduction of novel therapies.

Histopathological Evidence for a Non-Inflammatory Mechanism in Osimertinib-Induced Myopathy: A Case Report.

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor, is the standard of care for patients with advanced NSCLC and EGFR-sensitizing mutations. Both in osimertinib pivotal trials and in the post-marketing phase, asymptomatic creatinine phosphokinase elevation and clinically relevant muscle damage have been reported. However, the mechanisms underlying these conditions remain unclear. Herein, we report the first muscle biopsy description of osimertinib-induced myopathy and hypothesize that the mechanisms underpinning muscle toxicity could be driven by hyporegenerative mechanisms and mitochondrial dysfunction with subsequent reduced metabolic endurance, both directly linked to the inhibition of downstream molecular pathways mediated by EGFR in muscle cells.

Efficacy and Safety of Immuno-Oncology Plus Tyrosine Kinase Inhibitors as Late-Line Combination Therapy for Patients with Advanced Renal Cell Carcinoma.

Background/Objectives: Immuno-oncology plus tyrosine kinase inhibitor (IO+TKI) combination therapy is an essential first-line therapy for advanced renal cell carcinoma (RCC). However, reports of its efficacy and safety as late-line therapy are lacking. This study aimed to examine the efficacy and safety of IO+TKI combination therapy as a late-line therapy for patients with RCC. Methods: We retrospectively examined 17 patients with RCC who received IO+TKI combination therapy as a second-line therapy or beyond (pembrolizumab plus axitinib, n = 10; avelumab plus axitinib, n = 5; nivolumab plus cabozantinib, n = 2). Results: The overall response and disease control rates of IO+TKI combination therapy were 29.4% and 64.7%, respectively. The median overall survival was not attained. Progression-free survival was 552 days, and 94.1% of patients (n = 16) experienced adverse effects (AEs) of any grade; moreover, 41.2% of patients (n = 7) experienced grade ≥ 3 immuno-related AEs. Conclusions: IO+TKI combination therapy may be a late-line therapy option for RCC.

Real-World Treatment Patterns and Outcomes Across Three Lines of Therapy in Patients with ALK+ NSCLC.

INTRODUCTION: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are standard first- and second-line treatment for advanced ALK+ non-small cell lung cancer (NSCLC). We evaluated outcomes in patients with ALK+ NSCLC receiving third-line ALK TKI versus non-ALK-directed therapy. METHODS: Flatiron Health OncoEMR data were extracted for patients with ALK+ NSCLC initiating first-line ALK TKI between January 2015 and March 2022 followed by second-line ALK TKI and third-line ALK TKI (group A) or non-TKI therapy (group B). Time-to-treatment discontinuation (TTD) and overall survival (OS) were analyzed using multivariate modelling. RESULTS: Among patients receiving third-line ALK TKI (A, n = 85) or non-TKI therapy (B, n = 43), most received first-line crizotinib (A/B: 64%/60%) and second-line alectinib (36%/30%), ceritinib (24%/19%), or lorlatinib (15%/30%). Common third-line treatments were lorlatinib/alectinib (41%/33%) in A and immunotherapy, chemotherapy, or chemotherapy + immunotherapy (30%/28%/21%) in B. Group A versus B had longer TTD of first-line treatment (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.41-0.93; p = 0.020) and second-line treatment (HR 0.50, 95% CI 0.33-0.75; p < 0.001) and longer OS from start of first-line treatment (HR 0.32, 95% CI 0.19-0.54; p < 0.001) and second-line treatment (HR 0.40, 95% CI 0.24-0.66; p < 0.001). For third-line treatment, median TTD (A/B) was 6.2/2.4 months (HR 0.61, 95% CI 0.37-1.00; p = 0.049) and OS was 17.6/6.5 months (HR 0.57, 95% CI 0.33-0.98; p = 0.042). CONCLUSIONS: Patients receiving third-line non-ALK-directed therapy had suboptimal outcomes on prior TKIs. Patients with longer duration of prior ALK TKI treatment appeared to benefit from third-line ALK TKIs.

The incidence of drug-induced interstitial lung disease caused by epidermal growth factor receptor tyrosine kinase inhibitors or immune checkpoint inhibitors in patients with non-small cell lung cancer in presence and absence of vascular endothelial growth factor inhibitors: a systematic review.

Interstitial lung disease (ILD) or pneumonitis caused by epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) or immune checkpoint inhibitors (ICI) is a major concern in the treatment of non-small cell lung cancer (NSCLC). Whether the addition of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) inhibitors can reduce the incidence of drug-induced ILD remains unclear. We conducted a systematic review to assess the incidence of ILD induced by EGFR-TKIs or ICIs in the presence or absence of VEGF/VEGFR inhibitors in relevant randomized trials between January 2009 and October 2023. The primary outcome was the odds ratio for the incidence of ILD in all patients worldwide and Asians. Secondary outcomes were the odds ratios (ORs) of the incidence at grade-3 or higher ILD in all patients worldwide and Asians. We identified 13 randomized studies, one sub-analysis in the EGFR-TKI group, and three randomized studies in the ICI group. In the EGFR-TKI group, the OR of ILD incidence at any grade with VEGF/VEGFR inhibitors was 0.54 (95% CI, 0.32-0.90; p = 0.02), which represented a significantly lower incidence than that without VEGF/VEGFR inhibitors. Contrarily, the OR of ILD incidence at grade ≥ 3 with VEGF/VEGFR inhibitors was 1.00 (95% CI, 0.43-2.36; p = 0.99). In all subjects in the ICI group, the OR of ILD incidence at any grade with VEGF/VEGFR inhibitors was 0.78 (95% CI, 0.51-1.21; p = 0.27). The systematic review demonstrated that the addition of VEGF/VEGFR inhibitors could reduce the incidence of drug-induced ILD at any grade caused by EGFR-TKI in patients with NSCLC but could not reduce that at grade ≥ 3. The ILD induced by ICIs remains undetermined owing to the limited number of randomized trials for which ILD data are available. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=409534, identifier CRD42023409534.

Safety of Extended Pirtobrutinib Exposure in Relapsed and/or Refractory B-Cell Malignancies.

INTRODUCTION: Pirtobrutinib, a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor, has demonstrated promising efficacy in B-cell malignancies and is associated with low rates of discontinuation and dose reduction. Pirtobrutinib is administered until disease progression or toxicity, necessitating an understanding of the safety profile in patients with extended treatment. METHODS: Here we report the safety of pirtobrutinib in patients with relapsed/refractory B-cell malignancies with extended (≥12 months) drug exposure from the BRUIN trial. Assessments included median time-to-first-occurrence of adverse events (AEs), dose reductions, and discontinuations due to treatment-emergent AEs (TEAEs) and select AEs of interest (AESIs). RESULTS: Of 773 patients enrolled, 326 (42%) received treatment for ≥12 months. In the extended exposure cohort, the median time-on-treatment was 19 months. The most common all-cause TEAEs were fatigue (32%) and diarrhea (31%). TEAEs leading to dose reduction occurred in 23 (7%) and discontinuations in 11 (3%) extended exposure patients. One patient had a fatal treatment-related AE (COVID-19 pneumonia). Infections (73.0%) were the most common AESI with a median time-to-first-occurrence of 7.4 months. Majority of TEAEs and AESIs occurred during the first year of therapy. CONCLUSIONS: Pirtobrutinib therapy continues to demonstrate an excellent safety profile amenable to long-term administration without evidence of new or worsening toxicity signals.