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The grammar in this abstract is generally correct, but there's a minor issue with sentence structure in one part. Here's a slightly revised version with improved grammar and flow:ROS1 tyrosine kinase inhibitors (TKIs) are highly effective in ROS1-positive non-small cell lung cancer, but resistance remains a challenge. We investigated the activity of various TKIs against wildtype and mutant ROS1, focusing on the emerging L2086F resistance mutation. Using Ba/F3 and NIH3T3 cell models, CRISPR/Cas9-edited isogenic wildtype and mutant patient-derived cell lines, and in vivo tumor growth studies, we compared type I TKIs (crizotinib, entrectinib, taletrectinib, lorlatinib, and repotrectinib) to type II TKIs (cabozantinib and merestinib) and the type I FLT3 inhibitor gilteritinib. The ROS1 L2086F mutant kinase showed resistance to type I TKIs, while type II TKIs retained activity. Gilteritinib inhibited both wildtype and L2086F mutant ROS1 but was ineffective against the G2032R mutation. Structural analyses revealed distinct binding poses for cabozantinib and gilteritinib, explaining their efficacy against L2086F. Clinical cases demonstrated cabozantinib's effectiveness in patients with TKI-resistant, ROS1 L2086F mutant NSCLCs. This study provides the first comprehensive report of ROS1 L2086F in the context of later-generation TKIs, including macrocyclic inhibitors. While cabozantinib effectively inhibits ROS1 L2086F, its multi-kinase inhibitor nature highlights the need for more selective and better-tolerated TKIs to overcome kinase-intrinsic resistance. Gilteritinib may offer an alternative for targeting ROS1 L2086F with distinct off-target toxicities, but further studies are required to fully evaluate its potential in this setting.
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BACKGROUND: While NTRK fusion-positive cancers can be exquisitely sensitive to first-generation TRK inhibitors, resistance inevitably occurs, mediated in many cases by acquired NTRK mutations. Next-generation inhibitors (e.g., selitrectinib, repotrectinib) maintain activity against these TRK mutant tumors; however, there are no next-generation TRK inhibitors approved by the FDA and select trials have stopped treating patients. Thus, the identification of novel, potent and specific next-generation TRK inhibitors is a high priority. METHODS: In silico modeling and in vitro kinase assays were performed on TRK wild type (WT) and TRK mutant kinases. Cell viability and clonogenic assays as well as western blots were performed on human primary and murine engineered NTRK fusion-positive TRK WT and mutant cell models. Finally, zurletrectinib was tested in vivo in human xenografts and murine orthotopic glioma models harboring TRK-resistant mutations. RESULTS: In vitro kinase and in cell-based assays showed that zurletrectinib, while displaying similar potency against TRKA, TRKB, and TRKC WT kinases, was more active than other FDA approved or clinically tested 1st- (larotrectinib) and next-generation (selitrectinib and repotrectinib) TRK inhibitors against most TRK inhibitor resistance mutations (13 out of 18). Similarly, zurletrectinib inhibited tumor growth in vivo in sub-cute xenograft models derived from NTRK fusion-positive cells at a dose 30 times lower when compared to selitrectinib. Computational modeling suggests this stronger activity to be the consequence of augmented binding affinity of zurletrectinib for TRK kinases. When compared to selitrectinib and repotrectinib, zurletrectinib showed increased brain penetration in rats 0.5 and 2 h following a single oral administration. Consistently, zurletrectinib significantly improved the survival of mice harboring orthotopic NTRK fusion-positive, TRK-mutant gliomas (median survival = 41.5, 66.5, and 104 days for selitrectinib, repotrectinib, and zurletrectinib respectively; P < 0.05). CONCLUSION: Our data identifies zurletrectinib as a novel, highly potent next-generation TRK inhibitor with stronger in vivo brain penetration and intracranial activity than other next-generation agents.
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Resistencia a Medicamentos Antineoplásicos , Inibidores de Proteínas Quinases , Receptor trkA , Receptor trkB , Receptor trkC , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Animais , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Receptor trkA/genética , Receptor trkA/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptor trkB/antagonistas & inibidores , Receptor trkB/genética , Receptor trkC/genética , Receptor trkC/antagonistas & inibidores , Linhagem Celular Tumoral , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Ratos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Pirazóis/farmacologia , Glioma/tratamento farmacológico , Glioma/genética , Glioma/patologia , Pirimidinas/farmacologia , Mutação , Feminino , Glicoproteínas de MembranaRESUMO
Large-scale tumor molecular profiling has revealed that diverse cancer histologies are driven by common pathways with unifying biomarkers that can be exploited therapeutically. Disease-agnostic basket trials have been increasingly utilized to test biomarker-driven therapies across cancer types. These trials have led to drug approvals and improved the lives of patients while simultaneously advancing our understanding of cancer biology. This review focuses on the practicalities of implementing basket trials, with an emphasis on molecularly targeted trials. We examine the biologic subtleties of genomic biomarker and patient selection, discuss previous successes in drug development facilitated by basket trials, describe certain novel targets and drugs, and emphasize practical considerations for participant recruitment and study design. This review also highlights strategies for aiding patient access to basket trials. As basket trials become more common, steps to ensure equitable implementation of these studies will be critical for molecularly targeted drug development.
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Activating point mutations in the MET tyrosine kinase domain (TKD) are oncogenic in a subset of papillary renal cell carcinomas. Here, using comprehensive genomic profiling among >600,000 patients, we identify activating MET TKD point mutations as putative oncogenic driver across diverse cancers, with a frequency of â¼0.5%. The most common mutations in the MET TKD defined as oncogenic or likely oncogenic according to OncoKB resulted in amino acid substitutions at positions H1094, L1195, F1200, D1228, Y1230, M1250, and others. Preclinical modeling of these alterations confirmed their oncogenic potential and also demonstrated differential patterns of sensitivity to type I and type II MET inhibitors. Two patients with metastatic lung adenocarcinoma harboring MET TKD mutations (H1094Y, F1200I) and no other known oncogenic drivers achieved confirmed partial responses to a type I MET inhibitor. Activating MET TKD mutations occur in multiple malignancies and may confer clinical sensitivity to currently available MET inhibitors. Significance: The identification of targetable genomic subsets of cancer has revolutionized precision oncology and offers patients treatments with more selective and effective agents. Here, we demonstrate that activating, oncogenic MET tyrosine kinase domain mutations are found across a diversity of cancer types and are responsive to MET tyrosine kinase inhibitors.
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Neoplasias Pulmonares , Mutação Puntual , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-met , Humanos , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Animais , Camundongos , Linhagem Celular TumoralRESUMO
While tyrosine kinase inhibitors (TKI) have shown remarkable efficacy in anaplastic lymphoma kinase (ALK) fusion-positive advanced non-small cell lung cancer (NSCLC), clinical outcomes vary and acquired resistance remains a significant challenge. We conducted a retrospective study of patients with ALK-positive NSCLC who had clinico-genomic data independently collected from two academic institutions (n = 309). This was paired with a large-scale genomic cohort of patients with ALK-positive NSCLC who underwent liquid biopsies (n = 1,118). Somatic co-mutations in TP53 and loss-of-function alterations in CDKN2A/B were most commonly identified (24.1% and 22.5%, respectively in the clinical cohort), each of which was independently associated with inferior overall survival (HR: 2.58; 95% confidence interval, CI: 1.62-4.09 and HR: 1.93; 95% CI: 1.17-3.17, respectively). Tumors harboring EML4-ALK variant 3 (v3) were not associated with specific co-alterations but were more likely to develop ALK resistance mutations, particularly G1202R and I1171N (OR: 4.11; P < 0.001 and OR: 2.94; P = 0.026, respectively), and had inferior progression-free survival on first-line TKI (HR: 1.52; 95% CI: 1.03-2.25). Non-v3 tumors were associated with L1196M resistance mutation (OR: 4.63; P < 0.001). EML4-ALK v3 and somatic co-alterations in TP53 and CDKN2A/B are associated with inferior clinical outcomes. v3 status is also associated with specific patterns of clinically important ALK resistance mutations. These tumor-intrinsic features may inform rational selection and optimization of first-line and consolidative therapy. SIGNIFICANCE: In a large-scale, contemporary cohort of patients with advanced ALK-positive NSCLC, we evaluated molecular characteristics and their impact on acquired resistance mutations and clinical outcomes. Our findings that certain ALK variants and co-mutations are associated with differential survival and specific TKI-relevant resistance patterns highlight potential molecular underpinnings of the heterogenous response to ALK TKIs and nominate biomarkers that may inform patient selection for first-line and consolidative therapies.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Estudos Retrospectivos , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/genéticaRESUMO
Purpose: Despite the robust efficacy of ROS1 tyrosine kinase inhibitors (TKIs) in ROS1-positive non-small cell lung cancer, TKI resistance continues to hamper durability of the therapeutic response. The resistance liabilities of next-generation ROS1 TKI are sparsely characterized. Design: We compared the activity of type I TKIs (crizotinib, entrectinib, taletrectinib, lorlatinib, and repotrectinib) to the type II TKIs (cabozantinib and merestinib), and to the type I FLT3 inhibitor, gilteritinib, in CD74-ROS1 wildtype and F2004C, L2026M, G2032R, or L2086 mutant Ba/F3 cells. The findings from the Ba/F3 cell model were confirmed using NIH3T3 colony formation assays and in vivo tumor growth. CRISPR/Cas9 gene editing was used to generate isogenic wildtype and L2086F mutant TPM3-ROS1 expressing patient-derived cell lines. These lines were used to further evaluate TKI activity using cell viability and immunoblotting methods. Molecular modeling studies enabled the characterization of structural determinants of TKI sensitivity in wildtype and mutant ROS1 kinase domains. We also report clinical cases of ROS1 TKI resistance that were treated with cabozantinib. Results: ROS1 L2086F mutant kinase is resistant to type I TKI including crizotinib, entrectinib, lorlatinib, repotrectinib, taletrectinib, while the type II TKI cabozantinib and merestinib retain activity. Additionally, we found that gilteritinib, a type I FLT3 inhibitor, inhibited wildtype and L2086F mutant ROS1, however ROS1 G2032R solvent front mutation imposed resistance. The specific binding poses adopted by cabozantinib in the DFG-out kinase conformation and gilteritinib in the DFG-in kinase, provide rationale for their activity in the ROS1 mutants. Clinical cases demonstrated response to cabozantinib in tumors developing TKI resistance due to the ROS1 L2086F mutation. Conclusion: Cabozantinib and gilteritinib effectively inhibit ROS1 L2086F. Clinical activity of cabozantinib is confirmed in patients with TKI-resistant, ROS1 L2086F mutant NSCLC. Gilteritinib may offer an alternative with distinct off-target toxicities, however further studies are required. Since cabozantinib and gilteritinib are multi-kinase inhibitors, there is a persistent unmet need for more selective and better-tolerated TKI to overcome ROS1 L2086F kinase-intrinsic resistance. Translational relevance: ROS1 L2086F is an emerging recurrent resistance mutation to type I ROS1 TKIs, including later generation TKIs. Here, we show corroborating preclinical and clinical evidence for the activity of the quinolone-based type II TKI, cabozantinib, in ROS1 L2086F resistance setting. In addition, we show activity of the pyrazine carboxamide-based type I TKI, gilteritinib, in ROS1 L2086F resistance, suggesting that gilteritinib could be another option for ROS1 L2086F TKI-resistant patients. This study represents the first comprehensive report of ROS1 L2086F in the context of later-generation TKIs, including the macrocyclic inhibitors.
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INTRODUCTION: Select tyrosine kinase inhibitors (TKIs) used to treat oncogene-driven lung cancers also inhibit MATE-1. When MATE-1 is blocked, creatinine is retained in the serum. Elevated creatinine levels raise the specter of drug-induced intrarenal insufficiency despite the lack of true renal injury. We conducted a systematic analysis of MATE-1 inhibitor (MATEi)-treated patients to comprehensively characterize this phenomenon. METHODS: Patients with oncogene-driven lung cancer treated with a wide variety of MATEi TKIs (brigatinib, cabozantinib, capmatinib, crizotinib, entrectinib, lorlatinib, pralsetinib, selpercatinib, and tepotinib) were eligible for an analysis of renal dysfunction. Acute kidney injury was classified on the basis of creatinine levels (Kidney Disease: Improving Global Outcomes criteria) as stage 1 (≥1.5× but <2× baseline), stage 2 (≥2× but <3× baseline), or stage 3 (>3× baseline). When available, cystatin C, a marker of kidney function unaffected by MATE-1, was used to evaluate the glomerular filtration rate (GFR). RESULTS: We identified 863 patients receiving MATEi TKIs including crizotinib (39%, n = 333), lorlatinib (17%, n = 144), cabozantinib (10%, n = 87), selpercatinib (10%, n = 82), capmatinib (9%, n = 77), brigatinib (6%, n = 53), entrectinib (5%, n = 45), tepotinib (5%, n = 41), and pralsetinib (0.1%, n = 1). Of the 90 patients (10%) with acute kidney injury, Kidney Disease: Improving Global Outcomes stages 1, 2, and 3 were observed in 72% (n = 65), 21% (n = 19), and 7% (n = 6) of patients, respectively. Concurrently drawn creatinine and cystatin C levels on TKI therapy were available for 17 patients. In most cases (n = 15 of 17), the calculated GFR was higher using cystatin C versus creatinine. The percentage of patients whose GFR was higher using cystatin C versus creatinine by less than 10 mL/min, 10 to 19 mL/min, 20 to 29 mL/min, and more than or equal to 30 mL/min was 27% (n = four of 15), 20% (n = three of 15), 20% (n = three of 15), and 33% (n = five of 15), respectively. Long-term data in three patients that spanned 3 years revealed that GFR was higher using cystatin C versus creatinine in 96% (n = 49 of 51) of all time points. Using a virtual clinical trial GFR cutoff of 40 mL/min, the percentage of eligible patients rose from 41% (n = seven of 17) using creatinine calculations to 71% (n = 12 of 17) using cystatin C calculations. CONCLUSIONS: The calculated GFR in patients with cancer receiving MATEi TKIs was higher in almost all cases when using cystatin C. When serum creatinine level seems elevated in patients receiving MATE-1 inhibitors, we recommend recalculating GFR using cystatin C before searching for other etiologies of kidney injury and reducing or stopping TKI therapy.
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Injúria Renal Aguda , Neoplasias Pulmonares , Humanos , Cistatina C , Creatinina , Neoplasias Pulmonares/tratamento farmacológico , Crizotinibe , Taxa de Filtração Glomerular , Rim , BiomarcadoresRESUMO
PURPOSE: RET rearrangements and RET activating point mutations represent targetable genomic alterations in advanced solid tumors. However, the frequency and clinicopathologic characteristics of wild-type RET amplification in cancer and its potential role as a targetable oncogenic driver are not well-characterized. METHODS: In two institutional cohorts of patients with solid cancers from the Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering Cancer Center (MSKCC) whose tumors underwent next-generation sequencing (NGS), the frequency and clinicopathologic features of wild-type RET amplification in the absence of RET rearrangements or activating mutations was assessed. The findings were validated using merged data from The Cancer Genome Atlas (TCGA), Genomics Evidence Neoplasia Information Exchange (GENIE), and China Pan-Cancer data sets. RESULTS: The frequency of wild-type RET amplification across all solid cancers was 0.08% (26 of 32,505) in the DFCI cohort, 0.05% (26 of 53,152) in the MSKCC cohort, and 0.25% (71 of 28,623) in the cohort from TCGA, GENIE, and China Pan-Cancer. Cancer types with RET amplification included non-small-cell lung cancer (NSCLC), hepatobiliary cancer, prostate cancer, breast cancer, and others. The median RET copy number in RET-amplified cases was 7.5 (range, 6-36) in the DFCI cohort and 5.7 (range, 4-27.7) in the MSKCC cohort. Among 11 RET-amplified NSCLCs, eight had no other concurrent driver mutations. Finally, we report on a 69-year-old man with recurrent NSCLC harboring high-level wild-type RET amplification (22-28 copies) as the only identified putative genomic driver who experienced both a systemic and intracranial confirmed response to the RET inhibitor selpercatinib. CONCLUSION: Amplification of wild-type RET represents a novel, targetable molecular subset of cancer.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Masculino , Humanos , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/genética , Mutação , Recidiva Local de Neoplasia , Proteínas Proto-Oncogênicas c-ret/genéticaRESUMO
PURPOSE: Acquired RET fusions have been reported at resistance to treatment with EGFR inhibitors in EGFR-mutant non-small cell lung cancer (NSCLC); however, a multicenter cohort of patients with EGFR-mutant lung cancers treated with osimertinib and selpercatinib for RET fusion-mediated osimertinib resistance has not previously been published. PATIENTS AND METHODS: Patients who received selpercatinib in combination with osimertinib on a prospective expanded access clinical trial (NCT03906331) and single-patient compassionate use programs across five countries were centrally analyzed. All patients had advanced EGFR-mutant NSCLC with a RET fusion detected from tissue or plasma following osimertinib therapy. Clinicopathologic and outcomes data were collected. RESULTS: Fourteen patients with EGFR-mutant and RET fusion-positive lung cancers who experienced prior progression on osimertinib received osimertinib and selpercatinib. EGFR exon 19 deletions (±T790M, 86%) and non-KIF5B fusions (CCDC6-RET 50%, NCOA4-RET 36%) predominated. Osimertinib 80 mg daily and selpercatinib 80 mg twice daily were the most commonly administered dosages. The response rate, disease control rate, and median treatment duration were 50% [95% confidence interval (CI), 25%-75%, n = 12], 83% (95% CI, 55%-95%), and 7.9 months (range, 0.8-25+), respectively. Resistance was complex, involving EGFR on-target (EGFR C797S), RET on-target (RET G810S), and off-target (EML4-ALK/STRN-ALK, KRAS G12S, BRAF V600E) mechanisms; RET fusion loss; or polyclonal mechanisms. CONCLUSIONS: For patients with EGFR-mutant NSCLC with an acquired RET fusion as a mechanism of EGFR inhibitor resistance, the addition of selpercatinib to osimertinib was feasible and safe and offered clinical benefit, supporting the prospective evaluation of this combination. See related commentary by Krebs and Popat, p. 2951.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Mutação/efeitos dos fármacos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Compostos de Anilina/farmacologia , Proteínas Proto-Oncogênicas c-ret/genéticaRESUMO
Oncogenes that occur in ≤5% of non-small-cell lung cancers have been defined as 'rare'; nonetheless, this frequency can correspond to a substantial number of patients diagnosed annually. Within rare oncogenes, less commonly identified alterations (such as HRAS, NRAS, RIT1, ARAF, RAF1 and MAP2K1 mutations, or ERBB family, LTK and RASGRF1 fusions) can share certain structural or oncogenic features with more commonly recognized alterations (such as KRAS, BRAF, MET and ERBB family mutations, or ALK, RET and ROS1 fusions). Over the past 5 years, a surge in the identification of rare-oncogene-driven lung cancers has challenged the boundaries of traditional clinical grade diagnostic assays and profiling algorithms. In tandem, the number of approved targeted therapies for patients with rare molecular subtypes of lung cancer has risen dramatically. Rational drug design has iteratively improved the quality of small-molecule therapeutic agents and introduced a wave of antibody-based therapeutics, expanding the list of actionable de novo and resistance alterations in lung cancer. Getting additional molecularly tailored therapeutics approved for rare-oncogene-driven lung cancers in a larger range of countries will require ongoing stakeholder cooperation. Patient advocates, health-care agencies, investigators and companies with an interest in diagnostics, therapeutics and real-world evidence have already taken steps to surmount the challenges associated with research into low-frequency drivers.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Receptores ErbB/genética , Mutação , Terapia de Alvo MolecularRESUMO
Lurbinectedin and paclitaxel showed synergism in preclinical studies and have non-completely overlapping toxicity profiles. This phase I trial evaluated a combination of paclitaxel and lurbinectedin with/without bevacizumab in advanced tumors. This trial was divided into Group A, which evaluated weekly paclitaxel (60 or 80 mg) plus lurbinectedin (3.0-5.0 mg flat dose [FD] or 2.2 mg/m2) every 3 weeks in advanced solid tumors; and Group B, which evaluated bevacizumab (BEV, 15 mg/kg) added to the recommended dose (RD) defined in Group A in advanced epithelial ovarian or non-small cell lung cancer (NSCLC). 67 patients (A, n = 55; B, n = 12) were treated. The RD was paclitaxel 80 mg/m2 on Day (D)1,D8 plus lurbinectedin 2.2 mg/m2 on D1. At this RD, myelotoxicity was reversible and manageable, and most non-hematological toxicities were mild/moderate. Adding BEV did not notably change tolerability. Twenty-five confirmed responses were observed: 20/51 evaluable patients in Group A (overall response rate [ORR] = 39% at all dose levels and at the RD), and 5/10 evaluable patients in Group B (ORR = 50%). Most responders had breast (n = 7/12 patients), small cell lung (SCLC) (n = 5/7), epithelial ovarian (n = 3/9) and endometrial cancer (n = 3/11) in Group A, and epithelial ovarian (n = 3/4) and NSCLC (n = 2/6) in Group B. Clinical benefit rate was 61% in Group A (58% at the RD), and 90% in Group B. No major pharmacokinetic drug-drug interactions were observed. Paclitaxel/lurbinectedin and paclitaxel/lurbinectedin/BEV are feasible combinations. Further development is warranted of paclitaxel/lurbinectedin in SCLC, breast, and endometrial cancer, and of paclitaxel/lurbinectedin/BEV in epithelial ovarian cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Neoplasias do Endométrio , Neoplasias Pulmonares , Feminino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Paclitaxel/uso terapêuticoRESUMO
INTRODUCTION: Spontaneous chylous effusions are rare; however, they have been observed by independent investigators in patients treated with RET tyrosine kinase inhibitors (TKIs). METHODS: This multicenter, retrospective study evaluated the frequency of chylous effusions in patients treated with RET TKIs. Clinicopathologic features and management of patients with chylous effusions were evaluated. RESULTS: A pan-cancer cohort of 7517 patients treated with one or more multikinase inhibitor or selective RET TKI and a selective TKI cohort of 96 patients treated with selpercatinib or pralsetinib were analyzed. Chylous effusions were most common with selpercatinib (7%), followed by agerafenib (4%), cabozantinib (0.3%), and lenvatinib (0.02%); none were observed with pralsetinib. Overall, 12 patients had chylothorax, five had chylous ascites, and five had both. Time from TKI initiation to diagnosis ranged from 0.5 to 50 months. Median fluid triglyceride level was lower in chylothoraces than in chylous ascites (397 mg/dL [interquartile range: 304-4000] versus 3786 mg/dL [interquartile range: 842-6596], p = 0.035). Malignant cells were present in 13% (3 of 22) of effusions. Chyle leak was not identified by lymphangiography. After initial drainage, 76% of patients with chylothorax and 80% with chylous ascites required additional interventions. Selpercatinib dose reduction and discontinuation rates in those with chylous effusions were 47% and 0%, respectively. Median time from diagnosis to disease progression was not reached (95% confidence interval: 14.5-undefined); median time from diagnosis to TKI discontinuation was 11.4 months (95% confidence interval: 8.2-14.9). CONCLUSIONS: Chylous effusions can emerge during treatment with selected RET TKIs. Recognition of this side effect is key to prevent potential misattribution of worsening effusions to progressive malignancy.
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Quilotórax , Ascite Quilosa , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Humanos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Estudos RetrospectivosRESUMO
Werner's syndrome is caused by the inactivation of both WRN alleles and is characterized by premature aging and increased risk of neoplasms, especially those of mesenchymal origins, such as sarcomas. Given the characteristic genomic instability, patients with this syndrome are more susceptible to develop toxicities when exposed to cytotoxic agents, such as alkylators and anthracyclines. The impact of the monoallelic WRN mutation on treatment-associated toxicities is poorly understood. Here, we report a patient with locally advanced dedifferentiated liposarcoma of the retroperitoneum harboring a heterozygous germline inactivation mutation in the WRN gene, who was treated with a classic regimen of ifosfamide and doxorubicin and developed exacerbated and prolonged hematological and renal toxicities.
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Central nervous system (CNS) metastases constitute a challenge for the design of anaplastic lymphoma kinase (ALK) fusion-positive lung cancer trials. The ASCEND-7 study of ceritinib demonstrates the feasibility of broadening CNS eligibility criteria to include symptomatic brain and leptomeningeal disease and highlights design features that contemporary trials will need to incorporate. See related article by Chow et al., p. 2506.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias do Sistema Nervoso Central , Neoplasias Pulmonares , Quinase do Linfoma Anaplásico , Encéfalo/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Sistema Nervoso Central , Neoplasias do Sistema Nervoso Central/diagnóstico , Humanos , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas , Receptores Proteína Tirosina Quinases , SulfonasRESUMO
PURPOSE: In GI cancers, anaplastic lymphoma kinase (ALK) rearrangements are extremely less frequent than in non-small-cell lung cancer but may be important to offer personalized strategies of treatment in selected patients. Data about the activity and efficacy of ALK inhibitors (ALKi) in GI cancers are scarce. MATERIALS AND METHODS: We assembled a clinical and molecular international data set of pretreated patients with metastatic or nonresectable cancers of GI primary tumor origin with documented ALK rearrangement treated with at least one line of ALKi. Measurable disease as per RECIST 1.1 was required for response analysis. RESULTS: Primary tumor sites were distributed as follows: 5 (38%) pancreas, 3 (23%) right colon, and 1 (8%) for each one of gastric, duodenal, rectal, left colon, and biliary tract sites. Seven patients (54%) were treated with alectinib, 5 (38%) with crizotinib, and 1 (8%) with entrectinib. After disease progression, five patients (38%) received a subsequent ALKi treatment line, and at the time of data cutoff date, treatment was still ongoing in two patients. Five of 12 evaluable patients (41%) achieved a partial response to first-line ALKi, five patients (41%) had stable disease, and 2 (17%) had progressive disease. No complete responses were registered. At a median follow-up of 39.6 months (interquartile range: 19.8-59.5), the median progression-free survival was 5.0 months (95% CI, 3.68 to no response) and the median overall survival was 9.3 months (95% CI, 5.46 to no response). CONCLUSION: Treatment with ALKi provides remarkable responses and clinical benefit in pretreated patients with ALK fusion-positive GI malignancies. Despite the rarity, ALK rearrangements represent an important therapeutic target in individual pretreated patients with GI solid tumors. Further work providing prospective clinical validation of this target is needed.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Gastrointestinais , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Crizotinibe/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Estudos Prospectivos , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
NTRK fusions drive oncogenesis in a variety of adult cancers. The approval of the first-generation TRK inhibitors, larotrectinib and entrectinib, for any cancer with an NTRK fusion represented a focal point in tumor-agnostic drug development. These agents achieve high response rates and durable disease control, and display intracranial activity. The use of these agents has resulted in a deeper understanding of the clinical consequences of TRK inhibition. These on-target side effects include dizziness, weight gain, and withdrawal pain. The study of TRK inhibitor resistance led to the development of next generation drugs, such as selitrectinib, repotrectinib, taletrectinib, and other agents that maintain disease control against selected acquired kinase domain mutations. This review discusses the clinical efficacy of TRK inhibitors, their safety profiles, and resistance mechanisms with a focus on data in adult cancers.
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Neoplasias , Proteínas de Fusão Oncogênica , Adulto , Humanos , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Proteínas de Fusão Oncogênica/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
BACKGROUND: Immune checkpoint inhibitors may be associated with multiple immune-related toxicities. Cardiovascular adverse effects are underreported in clinical trials. METHODS: We conducted a systematic review and meta-analysis to evaluate cardiovascular adverse effects incidence among patients with solid tumors receiving immune checkpoint inhibitors in randomized clinical trials and the relative risk of presenting these effects compared to placebo or best supportive care. The search was conducted through MEDLINE, Embase, and Scopus databases from January 1st, 2010 until July 1st, 2020. Outcomes were reported following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. RESULTS: 57 randomized clinical trials including 12,118 patients were included. All grade CV AEs incidence rate was 8.32% (95% CI = 6.35%-10.53%). When only grade 3-5 CV AEs were considered, ICIs were significantly associated with increased risk than placebo or BSC (RR = 1.36; 95% CI = 1.06-1.73; p = 0.01). CONCLUSION: This meta-analysis corroborates the hypothesis of increased CV risk related to immune checkpoint inhibitors.
RESUMO
SUMMARY We report a rare case of Cushing's syndrome in a 37-year-old female who initially presented with localized acinic cell carcinoma of the parotid gland. In January 2014, she underwent a right parotidectomy with facial nerve preservation and adjuvant radiotherapy. In August 2018, she presented a histologically-proven local regional relapse. The patient was considered for salvage surgery with facial nerve sacrifice and remained with no evidence of disease. One year later the patient developed pulmonary dissemination and started to gain weight and developed facial plethora and acne on the face and upper trunk. In a physical examination, the patient presented moon face, buffalo hump, acne and stage 2 hypertension. Biochemical evaluation confirmed ACTH-dependent Cushing's syndrome. IHC for ACTH in the lung biopsy revealed strong positive staining for ACTH confirming a diagnosis of ectopic ACTH secretion by a metastatic parotid acinic cell carcinoma. Ketoconazole (600 mg/d) was started to treat the CS. In addition, as chemotherapy was initiated to treat the metastatic disease. After the fifth cycle of chemotherapy, ketoconazole was suspended and the patient remained in remission of CS for four months, when CS recurred. A unique feature of this case is related to the clinical CS relapse associated with disease progression, which needed prompt treatment with ketoconazole, resulting in a significant improvement in the patient's condition. Although rare, should be attentive for possible CS features in patients with high-grade salivary gland carcinomas, since the diagnosis of ectopic secretion of ACTH may significantly impact their management and outcomes.
Assuntos
Humanos , Feminino , Adulto , Síndrome de ACTH Ectópico/complicações , Síndrome de ACTH Ectópico/diagnóstico , Neoplasias Parotídeas/complicações , Carcinoma/complicações , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/etiologia , Hormônio Adrenocorticotrópico , Recidiva Local de NeoplasiaRESUMO
We report a rare case of Cushing's syndrome in a 37-year-old female who initially presented with localized acinic cell carcinoma of the parotid gland. In January 2014, she underwent a right parotidectomy with facial nerve preservation and adjuvant radiotherapy. In August 2018, she presented a histologically-proven local regional relapse. The patient was considered for salvage surgery with facial nerve sacrifice and remained with no evidence of disease. One year later the patient developed pulmonary dissemination and started to gain weight and developed facial plethora and acne on the face and upper trunk. In a physical examination, the patient presented moon face, buffalo hump, acne and stage 2 hypertension. Biochemical evaluation confirmed ACTH-dependent Cushing's syndrome. IHC for ACTH in the lung biopsy revealed strong positive staining for ACTH confirming a diagnosis of ectopic ACTH secretion by a metastatic parotid acinic cell carcinoma. Ketoconazole (600 mg/d) was started to treat the CS. In addition, as chemotherapy was initiated to treat the metastatic disease. After the fifth cycle of chemotherapy, ketoconazole was suspended and the patient remained in remission of CS for four months, when CS recurred. A unique feature of this case is related to the clinical CS relapse associated with disease progression, which needed prompt treatment with ketoconazole, resulting in a significant improvement in the patient's condition. Although rare, should be attentive for possible CS features in patients with high-grade salivary gland carcinomas, since the diagnosis of ectopic secretion of ACTH may significantly impact their management and outcomes.
Assuntos
Síndrome de ACTH Ectópico , Carcinoma , Síndrome de Cushing , Neoplasias Parotídeas/complicações , Síndrome de ACTH Ectópico/complicações , Síndrome de ACTH Ectópico/diagnóstico , Hormônio Adrenocorticotrópico , Adulto , Carcinoma/complicações , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/etiologia , Feminino , Humanos , Recidiva Local de NeoplasiaRESUMO
Fusions involving TRK protein tyrosine kinases are oncogenic drivers in a variety of tumors in children and adults, with a prevalence of â¼0.2% in non-small cell lung cancer. Diagnosis can be challenging due to structural features such as NTRK intron length, but next-generation sequencing (NGS), including RNA-based NGS, increases detection. The first-generation TRK inhibitors, larotrectinib and entrectinib, have demonstrated clinically meaningful antitumor activity in TRK fusion-positive cancers in a tumor-agnostic fashion and should be considered first-line therapeutic options for TRK fusion-positive lung cancers. Furthermore, the first-generation TRK inhibitors are well tolerated. Care should be taken, however, to monitor on-target adverse events, such as dizziness, weight gain, paresthesias, and withdrawal pain. On-target and off-target mechanisms mediating TRK inhibitor resistance may occur. Next-generation TRK inhibitors, such as selitrectinib, repotrectinib, and taletrectinib, are available on ongoing clinical trials and address on-target resistance. This review will focus on NTRK fusions and TRK-directed targeted therapy specifically in the context of lung cancer.