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Clinical Cancer Research : An Official... Dec 2023On December 10, 2021, the FDA expanded the indications for ribociclib to include male patients for the treatment of hormone receptor-positive, HER2-negative advanced or...
On December 10, 2021, the FDA expanded the indications for ribociclib to include male patients for the treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer. Ribociclib is now indicated in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy in adult patients, or with fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy (ET), in postmenopausal women or in men. The efficacy of ribociclib + AI for male patients was primarily based on previous favorable benefit-risk assessments of ribociclib from MONALEESA-2 and MONALEESA-7 trials, and supported by COMPLEEMENT-1, an open-label, single-arm, multicenter clinical trial, in which 39 male patients (n = 3,246 total patients) received ribociclib + letrozole + goserelin/leuprolide. The overall response rate (ORR) based on confirmed responses in male patients with measurable disease at baseline was 46.9% [95% confidence interval (CI), 29.1-65.3], consistent with an ORR of 43.6% (95% CI, 41.5-45.8) in the overall population. Overall, adverse reactions occurring in male patients were similar to those occurring in female patients treated with ribociclib + ET. The efficacy of ribociclib + fulvestrant for male patients was primarily based on the previous findings of a favorable benefit-risk assessment from the MONALEESA-3 trial, supported by FDA review of clinical data of a limited number of male patients treated in clinical practice receiving ribociclib + fulvestrant. The known mechanism of action, biologic rationale, and clinical information available adequately demonstrate that the efficacy and safety of ribociclib + AI/fulvestrant are similar in male and female patients. This article summarizes the FDA's decision-making and data supporting the approval of ribociclib in male patients with breast cancer, and discusses regulatory insights.
Topics: Adult; Female; Humans; Male; Letrozole; Fulvestrant; Receptors, Estrogen; Breast Neoplasms; Aminopyridines; Aromatase Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Receptor, ErbB-2
PubMed: 37594723
DOI: 10.1158/1078-0432.CCR-23-1133 -
Frontiers in Public Health 2024The ALTA-1 L trial and EXP-3B arm of NCT01970865 trial found that both brigatinib and lorlatinib showed durable and robust responses in treating ALK-positive non-small...
BACKGROUND
The ALTA-1 L trial and EXP-3B arm of NCT01970865 trial found that both brigatinib and lorlatinib showed durable and robust responses in treating ALK-positive non-small cell lung cancer (NSCLC) patients. However, brigatinib and lorlatinib treatments are costly and need indefinite administration until the disease progression. Thus, it remains uncertain whether using brigatinib followed by lorlatinib before chemotherapy is cost-effective compared to reserving these two drugs until progression after chemotherapy.
METHODS
We used a Markov model to assess clinical outcomes and healthcare costs of treating ALK-positive NSCLC individuals with brigatinib followed by lorlatinib before chemotherapy versus a strategy of reserving these drugs until progression after chemotherapy. Transition probabilities were estimated using parametric survival modeling based on multiple clinical trials. The drug acquisition costs, adverse events costs, administration costs were extracted from published studies before and publicly available data. We calculated lifetime direct healthcare costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios from the perspective of a United States payer.
RESULTS
Our base-case analysis indicated that the incremental cost-effectiveness ratios of using first-line brigatinib followed by lorlatinib compared with second-line brigatinib followed by lorlatinib is $-400,722.09/QALY which meant that second-line brigatinib followed by lorlatinib had less costs and better outcomes. Univariate sensitivity analysis indicated the results were most sensitive to the cost of brigatinib. Probability sensitivity analysis revealed that using brigatinib followed by lorlatinib before chemotherapy had a 0% probability of cost-effectiveness versus delaying these two drugs until progression after chemotherapy at a willingness-to-pay threshold of $150,000 per QALY. Sensitivity analyses conducted revealed the robustness of this result, as incremental cost-effectiveness ratios never exceeded the willingness-to-pay threshold.
CONCLUSION
Using brigatinib as first-line treatment followed by lorlatinib for ALK-positive NSCLC may not be cost-effective given current pricing from the perspective of a United States payer. Delaying brigatinib followed by lorlatinib until subsequent lines of treatment may be a reasonable strategy that could limit healthcare costs without affecting clinical outcomes. More mature data are needed to better estimate cost-effectiveness in this setting.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Cost-Benefit Analysis; Lung Neoplasms; Lactams, Macrocyclic; Receptor Protein-Tyrosine Kinases; Pyrimidines; Aminopyridines; Lactams; Pyrazoles; Organophosphorus Compounds
PubMed: 38435286
DOI: 10.3389/fpubh.2024.1213318 -
Journal of Thoracic Oncology : Official... Apr 2024Variable partners and breakpoints have been reported in patients with ROS1-rearranged NSCLC. Here, we investigated the association of fusion partners and breakpoints...
INTRODUCTION
Variable partners and breakpoints have been reported in patients with ROS1-rearranged NSCLC. Here, we investigated the association of fusion partners and breakpoints with crizotinib efficacy in NSCLCs with common ROS1 fusions.
METHODS
DNA and RNA next-generation sequencing (NGS) and immunohistochemistry were performed to characterize ROS1 fusions.
RESULTS
Using DNA NGS, we identified ROS1 fusions in 210 cases, comprising 171 common (CD74/EZR/TPM3/SDC4/SLC34A2-ROS1) and 39 uncommon (variants identified in <5%) ROS1 fusion cases. DNA NGS detected variable ROS1 genomic breakpoints in common ROS1 fusions, whereas RNA NGS found ROS1 breakpoints mainly occurring in exons 32, 34 and 35, resulting in long (exon 32) and short (exon 34 or 35) ROS1 fusions. ROS1 immunohistochemistry revealed that membranous and cytoplasmic staining was predominant in long ROS1 fusions, whereas cytoplasmic staining was predominant in short ROS1 fusions (p = 0.006). For patients who received first-line crizotinib, median progression-free survival (mPFS) was lower in patients with long ROS1 fusions than those with short ROS1 fusions (8.0 versus 24.0 mo, p = 0.006). Moreover, mPFS for patients with and without TP53 mutations was 8.0 and 19.0 months, respectively (p = 0.159); mPFS for patients with and without BIM deletion polymorphism was 5.0 and 22.0 months, respectively (p = 0.003). When analyzing together with fusion partners, patients with long CD74/SLC34A2-ROS1 fusions were found to have shorter PFS than those with other ROS1, regardless of the presence or absence of TP53 mutations (p < 0.001 and p = 0.002, respectively).
CONCLUSIONS
Long CD74/SLC34A2-ROS1 fusions, which retain transmembrane regions in ROS1 and fusion partners, are associated with poor response to crizotinib independent of TP53 mutations.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Crizotinib; DNA; Lung Neoplasms; Mutation; Oncogene Proteins, Fusion; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; RNA; Sodium-Phosphate Cotransporter Proteins, Type IIb; Tumor Suppressor Protein p53; Histocompatibility Antigens Class II; Antigens, Differentiation, B-Lymphocyte
PubMed: 38070598
DOI: 10.1016/j.jtho.2023.12.009 -
Cancer Science Mar 2024Alectinib is the first-line therapy for anaplastic lymphoma kinase-positive non-small-cell lung cancer. Although some guidelines have recommended using other anaplastic...
Alectinib is the first-line therapy for anaplastic lymphoma kinase-positive non-small-cell lung cancer. Although some guidelines have recommended using other anaplastic lymphoma kinase inhibitors after alectinib failure, evidence for such regimens in patients who fail to respond to alectinib is limited. This study involved using administrative claims data from acute care hospitals in Japan. We extracted the data of 634 patients diagnosed with lung cancer between September 1, 2014, and January 31, 2023, who received alectinib treatment before treatment with another anaplastic lymphoma kinase inhibitor. We assessed distributions of patients according to their treatment sequencing and prognosis among three periods defined based on the initial marketing dates of lorlatinib and brigatinib. The type of anaplastic lymphoma kinase inhibitors after alectinib failure changed over time. In the most recent period, lorlatinib (58%) and brigatinib (40%) became predominant. Two-year overall survival improved over time (47%-84%), accompanied by an increased 2-year proportion of patients who continuously used anaplastic lymphoma kinase inhibitors after alectinib failure (13%-44%). The times to treatment discontinuation of the regimen between patients treated with lorlatinib and brigatinib were similar, with a hazard ratio of 1.02 (95% confidence interval, 0.64-1.64) in the period after marketing brigatinib. This study provides insights into the evolving treatment landscape for patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer who experience failed alectinib treatment and highlights the need for further studies and data accumulation to determine the optimal treatment strategy.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Anaplastic Lymphoma Kinase; Carbazoles; Protein Kinase Inhibitors; Lactams, Macrocyclic; Pyrimidines; Aminopyridines; Lactams; Piperidines; Pyrazoles; Organophosphorus Compounds
PubMed: 38148717
DOI: 10.1111/cas.16056 -
Cancer Medicine Apr 2024Combination of chidamide and anti-PD-L1 inhibitor produce synergistic anti-tumor effect in advanced NSCLC patients resistant to anti-PD-1 treatment. However, the effect...
Chidamide plus envafolimab as subsequent treatment in advanced non-small cell lung cancer patients resistant to anti-PD-1 therapy: A multicohort, open-label, phase II trial with biomarker analysis.
BACKGROUND
Combination of chidamide and anti-PD-L1 inhibitor produce synergistic anti-tumor effect in advanced NSCLC patients resistant to anti-PD-1 treatment. However, the effect of chidamide plus envafolimab has not been reported.
AIMS
This study aimed to evaluate the efficacy of chidamide plus envafolimab in advanced NSCLC patients resistant toanti-PD-1 treatment.
MATERIALS AND METHODS
Eligible advanced NSCLC patients after resistant to anti-PD-1 therapy received chidamide and envafolimab. The primary endpoint was objective response rate (ORR). The secondary end points included disease control rate (DCR), progression-free survival (PFS), and safety. The expression of histone deacetylase 2 (HDAC2), PD-L1, and blood TMB (bTMB) was also analyzed.
RESULTS
After a median follow-up of 8.1 (range: 7.6-9.2) months, only two patients achieved partial response. The ORR was 6.7% (2/30), DCR was 50% (15/30), and median PFS (mPFS) was 3.5 (95% confidence interval: 1.9-5.5) months. Biomarker analysis revealed that patients with high-level HDAC2 expression had numerically superior ORR (4.3% vs. 0), DCR (52.2% vs. 0) and mPFS (3.7 vs. 1.4m). Patients with negative PD-L1 had numerically superior DCR (52.2% vs. 33.3%) and mPFS (3.7m vs. 1.8m), so were those with low-level bTMB (DCR: 59.1% vs. 16.7%, mPFS: 3.8 vs.1.9m). Overall safety was controllable.
DISCUSSION
High HDAC2patients showed better ORR, DCR, and PFS. In addition, patient with negative PD-L1 and low-level bTMB had better DCR and PFS. This may be related to the epigenetic function of chidamide. However, the sample size was not big enough, so it is necessary to increase sample size to confirm the conclusion.
CONCLUSION
Combination of chidamide and envafolimab showed efficacy signals in certain NSCLC patients. But further identification of beneficial population is necessary for precision treatment.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; B7-H1 Antigen; Antineoplastic Agents, Immunological; Biomarkers; Aminopyridines; Benzamides; Antibodies, Monoclonal, Humanized
PubMed: 38597130
DOI: 10.1002/cam4.7175 -
Journal of Enzyme Inhibition and... Dec 2023The effect of the combination of 10-Hydroxycamptothecin (HCPT) and crizotinib (CRI) on EGFR- and KRAS-mutant lung cancer cells was investigated and the conjugates of the...
The effect of the combination of 10-Hydroxycamptothecin (HCPT) and crizotinib (CRI) on EGFR- and KRAS-mutant lung cancer cells was investigated and the conjugates of the two drugs were synthesised. HCPT combined with CRI synergistically inhibited the cell growth and proliferation of H1975, HCC827, and H460 without aggravating adverse effect on the normal cells. The combination synergistically enhanced the cell apoptosis rate through releasing Cyto-C by activation of Bcl-2 family-mediated mitochondrial signalling, which was associate with inactivating of EGFR related downstream signalling pathways including AKT, ERK, JNK, and p38 MAPK. Based on this synergy, the conjugates of HCPT and CRI (compounds and ) with different chemical bonds were synthesised. Compound exhibited stronger cytotoxicity than HCPT and CRI alone or in combination. The combination of HCPT and CRI might be a promising therapeutic regimen and the conjugate was a potential target drug for the treatment of lung cancer.
Topics: Humans; Crizotinib; Cell Line, Tumor; Lung Neoplasms; Apoptosis; ErbB Receptors
PubMed: 36305251
DOI: 10.1080/14756366.2022.2132487 -
Pulmonology 2023To evaluate the prognostic utility of inflammation-based prognostic scores in patients with ALK-positive metastatic or non-resectable non-small-cell lung cancer (NSCLC)...
OBJECTIVES
To evaluate the prognostic utility of inflammation-based prognostic scores in patients with ALK-positive metastatic or non-resectable non-small-cell lung cancer (NSCLC) treated with crizotinib.
PATIENTS AND METHODS
A total of 82 patients with ALK-positive metastatic or non-resectable NSCLC who received ALK TKI crizotinib were included. Pre-treatment modified Glasgow prognostic score (mGPS), prognostic nutritional index (PNI), and systemic immune-inflammation index (SII) were calculated. Multivariable logistic regression and Cox proportional hazards models were used to assess the impact of pretreatment mGPS, PNI, and SII on overall survival (OS), progression-free survival (PFS), and objective response rate (ORR).
RESULTS
The ORR was 77.2%, while 1-year OS and PFS rates were 95.0% and 93.5%, respectively. The univariate analysis revealed significantly higher 1-year PFS (89.4 vs. 64.4%, p=0.043) and OS (92.0 vs. 83.3%, p=0.01) rates in patients with low (<934.7) vs. high (≥934.7) SII scores. Multivariate analysis revealed that PNI ≥0.09 was a significant determinant of poorer 1-year OS rates (hazard ratio [HR]: 2.46, 95% confidence interval [CI] 0.88-4.85, p=0.035). No significant difference was observed in survival rates according to gender, age, smoking status, prior lines of therapy, or mGPS scores, while higher mGPS scores (odds ratio [OR]: 0.1, 95%CI 0.16-1.04; p=0.009) and higher PNI scores (OR: 0.16, 95% CI 0.02-0.55; p=0.035) were associated with poorer ORR.
CONCLUSION
Our findings indicate the prognostic significance of PNI and SII in terms of survival outcome and the impact of mGPS and PNI on treatment response in patients with ALK-positive NSCLC treated with crizotinib.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Crizotinib; Lung Neoplasms; Antineoplastic Agents; Inflammation; Receptor Protein-Tyrosine Kinases
PubMed: 36564237
DOI: 10.1016/j.pulmoe.2022.11.006 -
Journal of Thoracic Oncology : Official... Jun 2024Iruplinalkib (WX-0593) is a new-generation, potent ALK tyrosine kinase inhibitor (TKI) that has been found to have systemic and central nervous system (CNS) efficacy in... (Randomized Controlled Trial)
Randomized Controlled Trial
Iruplinalkib (WX-0593) Versus Crizotinib in ALK TKI-Naive Locally Advanced or Metastatic ALK-Positive NSCLC: Interim Analysis of a Randomized, Open-Label, Phase 3 Study (INSPIRE).
INTRODUCTION
Iruplinalkib (WX-0593) is a new-generation, potent ALK tyrosine kinase inhibitor (TKI) that has been found to have systemic and central nervous system (CNS) efficacy in ALK-positive NSCLC. We compared the efficacy and safety of iruplinalkib with crizotinib in patients with ALK TKI-naive, locally advanced or metastatic ALK-positive NSCLC.
METHODS
In this open-label, randomized, multicenter, phase 3 study, patients with ALK-positive NSCLC were randomly assigned to receive iruplinalkib 180 mg once daily (7-d run-in at 60 mg once daily) or crizotinib 250 mg twice daily. The primary end point was progression-free survival (PFS) assessed by Independent Review Committee (IRC) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included PFS by investigator, objective response rate (ORR), time to response, duration of response, intracranial ORR and time to CNS progression by IRC and investigator, overall survival, and safety. An interim analysis was planned after approximately 70% (134 events) of all 192 expected PFS events assessed by IRC were observed. Efficacy was analyzed in the intention-to-treat population. Safety was assessed in the safety population, which included all randomized patients who received at least one dose of the study drugs. This study is registered with Center for Drug Evaluation of China National Medical Products Administration (CTR20191231) and Clinicaltrials.gov (NCT04632758).
RESULTS
From September 4, 2019, to December 2, 2020, a total of 292 patients were randomized and treated; 143 with iruplinalkib and 149 with crizotinib. At this interim analysis (145 events), the median follow-up time was 26.7 months (range: 3.7-37.7) in the iruplinalkib group and 25.9 months (range: 0.5-35.9) in the crizotinib group. The PFS assessed by IRC was significantly longer among patients in the iruplinalkib group (median PFS, 27.7 mo [95% confidence interval (CI): 26.3-not estimable] versus 14.6 mo [95% CI: 11.1-16.5] in the crizotinib group; hazard ratio, 0.34 [98.02% CI: 0.23-0.52], p < 0.0001). The ORR assessed by IRC was 93.0% (95% CI: 87.5-96.6) in the iruplinalkib group and 89.3% (95% CI: 83.1-93.7) in the crizotinib group. The intracranial ORR was 90.9% (10 of 11, 95% CI: 58.7-99.8) in the iruplinalkib group and 60.0% (nine of 15, 95% CI: 32.3-83.7) in the crizotinib group for patients with measurable baseline CNS metastases. Incidence of grade 3 or 4 treatment-related adverse events was 51.7% in the iruplinalkib group and 49.7% in the crizotinib group.
CONCLUSIONS
Iruplinalkib was found to have significantly improved PFS and improved intracranial antitumor activity versus crizotinib. Iruplinalkib may be a new treatment option for patients with advanced ALK-positive and ALK TKI-naive NSCLC.
FUNDING
This study was funded by Qilu Pharmaceutical Co., Ltd., Jinan, People's Republic of China, and partly supported by the National Science and Technology Major Project for Key New Drug Development (2017ZX09304015).
Topics: Humans; Male; Female; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Middle Aged; Crizotinib; Adult; Aged; Protein Kinase Inhibitors; Anaplastic Lymphoma Kinase
PubMed: 38280448
DOI: 10.1016/j.jtho.2024.01.013 -
International Journal of Molecular... Apr 2024Numerous studies suggest the involvement of adenosine-5'-triphosphate (ATP) and similar nucleotides in the pathophysiology of asthma. Androgens, such as testosterone...
Numerous studies suggest the involvement of adenosine-5'-triphosphate (ATP) and similar nucleotides in the pathophysiology of asthma. Androgens, such as testosterone (TES), are proposed to alleviate asthma symptoms in young men. ATP and uridine-5'-triphosphate (UTP) relax the airway smooth muscle (ASM) via purinergic P2Y and P2Y receptors and K channel opening. We previously demonstrated that TES increased the expression of voltage-dependent K (K) channels in ASM. This study investigates how TES may potentiate ASM relaxation induced by ATP and UTP. Tracheal tissues treated with or without TES (control group) from young male guinea pigs were used. In organ baths, tracheas exposed to TES (40 nM for 48 h) showed enhanced ATP- and UTP-evoked relaxation. Tetraethylammonium, a K channel blocker, annulled this effect. Patch-clamp experiments in tracheal myocytes showed that TES also increased ATP- and UTP-induced K currents, and this effect was abolished with flutamide (an androgen receptor antagonist). K channels were involved in this phenomenon, which was demonstrated by inhibition with 4-aminopyridine. RB2 (an antagonist of almost all P2Y receptors except for P2Y), as well as N-ethylmaleimide and SQ 22,536 (inhibitors of G proteins and adenylyl cyclase, respectively), attenuated the enhancement of the K currents induced by TES. Immunofluorescence and immunohistochemistry studies revealed that TES did not modify the expression of P2Y receptors or COX-1 and COX-2, while we have demonstrated that this androgen augmented the expression of K1.2 and K1.5 channels in ASM. Thus, TES leads to the upregulation of P2Y signaling and K channels in guinea pig ASM, enhancing ATP and UTP relaxation responses, which likely limits the severity of bronchospasm in young males.
Topics: Animals; Uridine Triphosphate; Guinea Pigs; Muscle Relaxation; Male; Adenosine Triphosphate; Trachea; Testosterone; Adenylyl Cyclases; Muscle, Smooth; Potassium Channels, Voltage-Gated; Signal Transduction; Receptors, Purinergic P2
PubMed: 38731872
DOI: 10.3390/ijms25094652 -
International Journal of Molecular... Aug 2023Amplification of the () gene is a mechanism of acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine-kinase-inhibitors (TKIs) in over 20% of patients...
Amplification of the () gene is a mechanism of acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine-kinase-inhibitors (TKIs) in over 20% of patients with advanced -mutated (m+) non-small lung cancer (NSCLC). However, it may also occur de novo in 2-8% of m+ NSCLC cases as a potential mechanism of intrinsic resistance. These patients represent a group with unmet needs, since there is no standard therapy currently approved. Several new MET inhibitors are being investigated in clinical trials, but the results are awaited. Meanwhile, as an alternative strategy, combinations of EGFR-TKIs with the MET/ALK/ROS1-TKI Crizotinib may be used in this setting, despite this use is principally off-label. Thus, we studied five of these amplified cases receiving EGFR-TKI and Crizotinib doublet after progression on EGFR-TKI treatment to assess the benefits and challenges related to this combination and the possible occurrence of genomic and phenotypic co-alterations. Furthermore, we compared our cases with other real-world reports on Crizotinib/EGFR-TKI combinations, which appeared effective, especially in patients with high-level amplification. Yet, we observed that the co-occurrence of other genomic and phenotypical alterations may affect the response to combined EGFR-TKI and Crizotinib. Finally, given the heterogeneity of amplification, the diagnostic methods for assessing it may be discrepant. In this respect, we observed that for optimal detection, immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing should be used together, as these methods possess different sensitivities and complement each other in characterizing amplification. Additionally, we addressed the issue of managing -mutated NSCLC patients with de novo amplification causing primary EGFR-TKI resistance. We conclude that, while data from clinical trials with new MET inhibitors are still pending, adding Crizotinib to EGFR-TKI in NSCLC patients acquiring amplification at progression on EGFR-TKI monotherapy is a reasonable approach, with a progression-free survival of 3-19 months.
Topics: Humans; Crizotinib; ErbB Receptors; In Situ Hybridization, Fluorescence; Lung Neoplasms; Proto-Oncogene Proteins c-met; Tyrosine Kinase Inhibitors
PubMed: 37685884
DOI: 10.3390/ijms241713077