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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The MyPathway multiple-basket study (ClinicalTrials.gov identifier: NCT02091141) is evaluating targeted therapies in nonindicated tumors with relevant molecular alterations. We assessed pertuzumab + trastuzumab in a tissue-agnostic cohort of adult patients with human epidermal growth factor receptor 2 (HER2)-amplified and/or -overexpressed and/or -mutated solid tumors. The primary end point was objective response rate (ORR); secondary end points included survival and safety. At data cutoff (March 2022), 346 patients with HER2 amplification and/or overexpression with/without HER2 mutations (n = 263), or HER2 mutations alone (n = 83) had been treated. Patients with HER2 amplification and/or overexpression had an ORR of 25.9% (68/263, 95% CI, 20.7 to 31.6), including five complete responses (urothelial [n = 2], salivary gland [n = 2], and colon [n = 1] cancers). Activity was higher in those with wild-type (ORR, 28.1%) versus mutated KRAS (ORR, 7.1%). Among patients with HER2 amplification, ORR was numerically higher in patients with immunohistochemistry (IHC) 3+ (41.0%; 32/78) or 2+ (21.9%; 7/32), versus 1+ (8.3%; 1/12) or no expression (0%; 0/20). In patients with HER2 mutations alone, ORR was 6.0% (5/83, 95% CI, 2.0 to 13.5). Pertuzumab + trastuzumab showed activity in various HER2-amplified and/or -overexpressed tumors with wild-type KRAS, with the range of activity dependent on tumor type, but had limited activity in the context of KRAS mutations, HER2 mutations alone, or 0-1+ HER2 expression.
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Anticuerpos Monoclonales Humanizados , Neoplasias , Proteínas Proto-Oncogénicas p21(ras) , Adulto , Humanos , Trastuzumab/efectos adversos , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Receptor ErbB-2/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGROUND: Sapanisertib, a dual mTORC1/2 inhibitor, may offer more complete inhibition of the PI3K/AKT/mTOR pathway than mTORC1 inhibitors, such as everolimus. This phase II study evaluated the efficacy and safety of single-agent sapanisertib and sapanisertib plus the PI3Kα inhibitor TAK-117, vs. everolimus in patients with advanced clear cell renal cell carcinoma (ccRCC) that had progressed on or after VEGF-targeted therapy. MATERIALS AND METHODS: Patients with histologically confirmed, advanced ccRCC were randomized 1:1:1 to receive single-agent everolimus 10 mg once daily, single-agent sapanisertib 30 mg once weekly, or sapanisertib 4 mg plus TAK-117 200 mg, both once daily for 3 days/week, in 28-day cycles. The primary endpoint was progression-free survival (PFS). RESULTS: Ninety-five patients were treated with everolimus or sapanisertib (n = 32 each), or sapanisertib plus TAK-117 (n = 31). There were no significant differences in PFS among the 3 groups or across any subgroups. Median PFS was 3.8 months with everolimus vs. 3.6 months with sapanisertib (HR, 1.33; 95% CI, 0.75-2.36), and 3.1 months with sapanisertib plus TAK-117 (HR, 1.37; 95% CI, 0.75-2.52). No significant differences in overall survival were seen among groups. Overall response rate was 16.7%, 0%, and 7.1%, respectively. Discontinuations due to treatment-emergent adverse events were 15.6%, 28.1%, and 29.0%. CONCLUSION: Sapanisertib with or without TAK-117 was less tolerable and did not improve efficacy vs. everolimus in patients with advanced ccRCC who had relapsed after or were refractory to VEGF-targeted therapies. Dual mTORC1/2 inhibition may not be an effective therapeutic approach for these patients.
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Carcinoma de Células Renales , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Everolimus/efectos adversos , Factor A de Crecimiento Endotelial Vascular , Fosfatidilinositol 3-QuinasasRESUMEN
High tumor mutational burden (TMB-H) correlates with improved immunotherapy response. We assessed atezolizumab 1,200 mg every 3 weeks for TMB-H tumors from MyPathway (NCT02091141), a phase IIa multibasket study. One hundred twenty-one patients had advanced solid tumors with TMB ≥10 mut/Mb by any Clinical Laboratory Improvement Amendments (CLIA)-certified assay. The preplanned primary endpoint was objective response rate (ORR) in patients with TMB ≥16 mut/Mb tumors by FoundationOne TMB testing [F1(CDx)]. Patients with F1(CDx) TMB ≥10 and <16 mut/Mb were also evaluated. Ninety patients with 19 tumor types and F1(CDx) TMB ≥10 mut/Mb were efficacy evaluable. In 42 patients with F1(CDx) TMB ≥16 mut/Mb, confirmed ORR was 38.1% [16/42; 95% confidence interval (CI), 23.6-54.4], and disease control rate was 61.9% (26/42; 95% CI, 45.6-76.4) versus 2.1% (1/48; 95% CI, 0.1-11.1) and 22.9% (11/48; 95% CI, 12.0-37.3) for 48 patients with TMB ≥10 and <16 mut/Mb. Responses were observed in nine different tumor types (47%; 9/19). SIGNIFICANCE: Atezolizumab monotherapy had promising, durable clinical activity across a variety of advanced solid tumor types in patients with TMB ≥16 mut/Mb tumors lacking other suitable treatment options and who were immunotherapy-naïve at enrollment, regardless of microsatellite instability status. Limited activity was observed in tumors with TMB ≥10 and <16 mut/Mb. See related commentary by Maron and Klempner, p. 602. This article is highlighted in the In This Issue feature, p. 587.
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Anticuerpos Monoclonales Humanizados , Neoplasias , Anticuerpos Monoclonales Humanizados/uso terapéutico , Biomarcadores de Tumor , Humanos , Inestabilidad de Microsatélites , Mutación , Neoplasias/tratamiento farmacológico , Neoplasias/genéticaRESUMEN
BACKGROUND: AR is a targetable pathway with AR modulation inhibiting estrogen- and androgen-mediated cell proliferation. Orteronel is an oral, selective, nonsteroidal inhibitor of 17, 20-lyase, a key enzyme in androgen biosynthesis. This study evaluated single-agent orteronel in AR+ metastatic breast cancer (MBC). METHODS: Male/female patients with AR+ MBC were grouped in Cohort 1: AR+ TNBC with l-3 prior chemotherapy regimens or Cohort 2: AR+ HR+ (estrogen [ER+]/ progesterone receptor [PR+] positive) HER2+/- with 1 to 3 prior hormonal and at least 1 prior chemotherapy regimen. Patients with HER2+ MBC must have received at least 2 lines of HER2-targeted therapy. Orteronel was administered at 300 mg BID; response rate was the primary endpoint. RESULTS: Seventy patients were enrolled (Cohort 1, n = 26 and Cohort 2, n = 44). Median treatment duration was 7.1 weeks. Seven patients were on treatment for ≥6 months. One of the 21 evaluated patients in Cohort 1 (4.8%) had an objective response. In Cohort 2, none of the first 23 patients to be evaluated had a response and accrual was stopped. Median progression-free and overall survival were 1.8 and 8.3 months, respectively. Toxicities were predominantly Grade 1 or 2 nausea/vomiting (36%) and fatigue (31%). Grade 3 or 4 events in ≥5% of patients included increased amylase/lipase (10%) and hypertension (6%). CONCLUSIONS: Orteronel demonstrated limited clinical activity in heavily pre-treated AR+ MBC. Further development of orteronel in MBC is not recommended. Further efforts to validate the AR as a therapeutic target should focus on identifying new markers predictive of sensitivity to AR-targeted agents.
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Neoplasias de la Mama , Receptores Androgénicos , Andrógenos/uso terapéutico , Neoplasias de la Mama/patología , Estrógenos/uso terapéutico , Femenino , Humanos , Imidazoles , Masculino , Naftalenos , Receptores Androgénicos/metabolismoRESUMEN
Biomarkers are needed in patients with non-clear cell renal cell carcinomas (NC-RCC), particularly papillary renal cell carcinoma, in order to inform on initial treatment selection and identify potentially novel targets for therapy. We enrolled 108 patients in ASPEN, an international randomized open-label phase 2 trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC treated with the mTOR inhibitor everolimus (n=57) or the vascular endothelial growth factor (VEGF) receptor inhibitor sunitinib (n=51), stratified by MSKCC risk and histology. The primary endpoint was overall survival (OS) and secondary efficacy endpoints for this exploratory biomarker analysis were radiographic progression-free survival (rPFS) defined by intention-to-treat using the RECIST 1.1 criteria and radiographic response rates. Tissue biomarkers (n=78) of mTOR pathway activation (phospho-S6 and -Akt, c-kit) and VEGF pathway activation (HIF-1α, c-MET) were prospectively explored in tumor tissue by immunohistochemistry prior to treatment and associated with clinical outcomes. We found that S6 activation was more common in poor risk NC-RCC tumors and S6/Akt activation was associated with worse PFS and OS outcomes with both everolimus and sunitinib, while c-kit was commonly expressed in chromophobe tumors and associated with improved outcomes with both agents. C-MET was commonly expressed in papillary tumors and was associated with lower rates of radiographic response but did not predict PFS for either agent. In multivariable analysis, both pAkt and c-kit were statistically significant prognostic biomarkers of OS. No predictive biomarkers of treatment response were identified for clinical outcomes. Most biomarker subgroups had improved outcomes with sunitinib as compared to everolimus.
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BACKGROUND: Systemic therapies for metastatic biliary tract cancers are few, and patients have a median overall survival of less than 1 year. MyPathway evaluates the activity of US Food and Drug Administration-approved therapies in non-indicated tumours with potentially actionable molecular alterations. In this study, we present an analysis of patients with metastatic biliary tract cancers with HER2 amplification, overexpression, or both treated with a dual anti-HER2 regimen, pertuzumab plus trastuzumab, from MyPathway. METHODS: MyPathway is a non-randomised, multicentre, open-label, phase 2a, multiple basket study. Patients aged 18 years and older with previously treated metastatic biliary tract cancers with HER2 amplification, HER2 overexpression, or both and an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled from 23 study sites in the USA and received intravenous pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) plus trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). The primary endpoint was investigator-assessed objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The primary outcome and adverse events were analysed in all patients who received at least one dose of pertuzumab and trastuzumab. This trial is registered with ClinicalTrials.gov, NCT02091141, and is ongoing. FINDINGS: 39 patients enrolled in the MyPathway HER2 biliary tract cancer cohort between Oct 28, 2014, and May 29, 2019, were evaluable for anti-tumour activity by the March 10, 2020, data cutoff date. Median follow-up was 8·1 months (IQR 2·7-15·7). Nine of 39 patients achieved a partial response (objective response rate 23% [95% CI 11-39]). Grade 3-4 treatment-emergent adverse events were reported in 18 (46%) of 39 patients, most commonly increased alanine aminotransferase and increased aspartate aminotransferase (each five [13%] of 39). Treatment-related grade 3 adverse events were reported in three (8%) of 39 patients, including increased alanine aminotransferase, aspartate aminotransferase, blood alkaline phosphatase, and blood bilirubin. Serious treatment-emergent adverse events were observed in ten (26%) of 39 patients, of which only abdominal pain occurred in more than one patient (two [5%] of 39). There were no treatment-related serious adverse events, treatment-related grade 4 events, or deaths. INTERPRETATION: Treatment was well tolerated in patients with previously treated HER2-positive metastatic biliary tract cancer. The response rate is promising for the initiation of randomised, controlled trials of pertuzumab plus trastuzumab in this patient population. FUNDING: F Hoffmann-La Roche-Genentech.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapéutico , Anciano , Neoplasias del Sistema Biliar/metabolismo , Neoplasias del Sistema Biliar/patología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Supervivencia sin Progresión , Receptor ErbB-2/antagonistas & inhibidores , Criterios de Evaluación de Respuesta en Tumores Sólidos , Tasa de Supervivencia , Estados UnidosRESUMEN
BACKGROUND: The use of immune checkpoint inhibitors combined with vascular endothelial growth factor (VEGF)-targeted therapy as second-line treatment for metastatic clear cell renal cancer (mRCC) has not been evaluated prospectively. OBJECTIVE: To evaluate the efficacy and safety of atezolizumab + bevacizumab following disease progression on atezolizumab or sunitinib monotherapy in patients with mRCC. DESIGN, SETTING, AND PARTICIPANTS: IMmotion150 was a multicenter, randomized, open-label, phase 2 study of patients with untreated mRCC. Patients randomized to the atezolizumab or sunitinib arm who had investigator-assessed progression as per RECIST 1.1 could be treated with second-line atezolizumab + bevacizumab. INTERVENTION: Patients received atezolizumab 1200 mg intravenously (IV) plus bevacizumab 15 mg/kg IV every 3 wk following disease progression on either atezolizumab or sunitinib monotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The secondary endpoints analyzed during the second-line part of IMmotion150 included objective response rate (ORR), progression-free survival (PFS), and safety. PFS was examined using Kaplan-Meier methods. RESULTS AND LIMITATIONS: Fifty-nine patients in the atezolizumab arm and 78 in the sunitinib arm were eligible, and 103 initiated second-line atezolizumab + bevacizumab (atezolizumab arm, n = 44; sunitinib arm, n = 59). ORR (95% confidence interval [CI]) was 27% (19-37%). The median PFS (95% CI) from the start of second line was 8.7 (5.6-13.7) mo. The median event follow-up duration was 19.4 (12.9-21.9) mo among the 25 patients without a PFS event. Eighty-six (83%) patients had treatment-related adverse events; 31 of 103 (30%) had grade 3/4 events. Limitations were the small sample size and selection for progressors. CONCLUSIONS: The atezolizumab + bevacizumab combination had activity and was tolerable in patients with progression on atezolizumab or sunitinib. Further studies are needed to investigate sequencing strategies in mRCC. PATIENT SUMMARY: Patients with advanced kidney cancer whose disease had worsened during treatment with atezolizumab or sunitinib began second-line treatment with atezolizumab + bevacizumab. Tumors shrank in more than one-quarter of patients treated with this combination, and side effects were manageable.
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Carcinoma de Células Renales , Neoplasias Renales , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab/efectos adversos , Carcinoma de Células Renales/tratamiento farmacológico , Progresión de la Enfermedad , Humanos , Neoplasias Renales/tratamiento farmacológico , Sunitinib/uso terapéutico , Factor A de Crecimiento Endotelial VascularRESUMEN
PURPOSE: Biomarkers are needed in patients with non-clear cell renal cell carcinomas (NC-RCC) to inform treatment selection but also to identify novel therapeutic targets. We thus sought to profile circulating angiokines in the context of a randomized treatment trial of everolimus versus sunitinib. PATIENTS AND METHODS: ASPEN (NCT01108445) was an international, randomized, open-label phase II trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC with no prior systemic therapy. Patients were randomized to everolimus or sunitinib and treated until disease progression or unacceptable toxicity. The primary endpoint was radiographic progression-free survival (PFS) defined by RECIST 1.1. Plasma angiokines were collected at baseline, cycle 3, and progression and associated with PFS and overall survival (OS). RESULTS: We enrolled 108 patients, 51 received sunitinib and 57 everolimus; of these, 99 patients had evaluable plasma for 23 angiokines. At the final data cutoff, 94 PFS and 64 mortality events had occurred. Angiokines that were independently adversely prognostic for OS were osteopontin (OPN), TIMP-1, thrombospondin-2 (TSP-2), hepatocyte growth factor (HGF), and VCAM-1, and these were also associated with poor-risk disease. Stromal derived factor 1 (SDF-1) was associated with improved survival. OPN was also significantly associated with worse PFS. No statistically significant angiokine-treatment outcome interactions were observed for sunitinib or everolimus. Angiopoeitin-2 (Ang-2), CD-73, HER-3, HGF, IL6, OPN, PIGF, PDGF-AA, PDGF-BB, SDF-1, TGF-b1-b2, TGFb-R3, TIMP-1, TSP-2, VCAM-1, VEGF, and VEGF-R1 levels increased with progression on everolimus, while CD-73, ICAM-1, IL6, OPN, PlGF, SDF-1, TGF-b2, TGFb-R3, TIMP-1, TSP-2, VEGF, VEGF-D, and VCAM-1 increased with progression on sunitinib. CONCLUSIONS: In patients with metastatic NC-RCC, we identified several poor prognosis angiokines and immunomodulatory chemokines during treatment with sunitinib or everolimus, particularly OPN.
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Antineoplásicos , Carcinoma de Células Renales , Neoplasias Renales , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Renales/patología , Linfocinas/uso terapéutico , Factor de Crecimiento Placentario , Pirroles/efectos adversos , Resultado del TratamientoRESUMEN
Cancer of unknown primary (CUP) is a rare malignancy that presents with metastatic disease and no identifiable site of origin. Most patients have unfavorable features and attempts to treat based on tissue-of-origin identification have not yielded a survival advantage compared with empiric chemotherapy. Next-generation sequencing has revealed genomic alterations that can be targeted in selected cases, suggesting that CUP represents a unique malignancy in which the genomic aberrations may be integral to the diagnosis. Recent trials focusing on tailored combination therapy matched to the genomic alterations in each cancer are providing new avenues of clinical investigation. Here, we discuss recent findings on molecular aberrations in CUP and how the genomic and immune landscape can be leveraged to optimize therapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Biomarcadores de Tumor/antagonistas & inhibidores , Neoplasias Primarias Desconocidas/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Toma de Decisiones Clínicas/métodos , Ensayos Clínicos como Asunto , Análisis Mutacional de ADN , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Terapia Molecular Dirigida/métodos , Neoplasias Primarias Desconocidas/diagnóstico , Neoplasias Primarias Desconocidas/genética , Neoplasias Primarias Desconocidas/mortalidad , Selección de Paciente , Medicina de Precisión/métodos , Supervivencia sin ProgresiónRESUMEN
PURPOSE: Women with residual invasive breast cancer at the primary site or axillary lymph nodes following neoadjuvant chemotherapy have a high risk of recurrence. Eribulin improves survival in patients with metastatic breast cancer who progress after anthracycline and taxane therapy. This phase 2 trial assessed the efficacy of postoperative eribulin in breast cancer patients who did not achieve a pCR following standard neoadjuvant chemotherapy. METHODS: Women with localized breast cancer who had residual invasive cancer following ≥ 4 cycles of standard anthracycline and/or taxane-containing neoadjuvant chemotherapy received adjuvant eribulin treatment. HER2-positive patients also received trastuzumab for 1 year. Adjuvant hormonal therapy and locoregional radiotherapy were administered as per institutional guidelines. Primary endpoint was the 2-year DFS rate. Three patient cohorts were analyzed: TNBC (Cohort A), HR+/HER2- (Cohort B), and HER2+ (Cohort C). RESULTS: One hundred twenty-six patients (Cohort A-53, Cohort B-42, and Cohort C-31) were enrolled. Neoadjuvant chemotherapy included a taxane and an anthracycline in 70%. Eribulin was well tolerated; 84% of patients received the planned 6 cycles. After a median follow-up of 28 months, the 24-month DFS rates were 56% (95% CI 42, 69), 83% (95% CI 67, 91), and 73% (95% CI 53, 86) for Cohorts A, B, and C, respectively. The most common grade 3/4 treatment-related adverse events were neutropenia (26%), leukopenia (13%), and neuropathy (7%). CONCLUSION: Administration of adjuvant eribulin after neoadjuvant chemotherapy was feasible and well tolerated. The 24-month DFS rate did not reach the study target levels in any of the cohorts and was similar to DFS previously described in these cohorts following neoadjuvant chemotherapy alone.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Quimioterapia Adyuvante/mortalidad , Resistencia a Antineoplásicos/efectos de los fármacos , Terapia Neoadyuvante/mortalidad , Adulto , Anciano , Antraciclinas/administración & dosificación , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/patología , Hidrocarburos Aromáticos con Puentes/administración & dosificación , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Furanos/administración & dosificación , Humanos , Cetonas/administración & dosificación , Persona de Mediana Edad , Ensayos Clínicos Controlados no Aleatorios como Asunto , Pronóstico , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Tasa de Supervivencia , Taxoides/administración & dosificación , Trastuzumab/administración & dosificaciónRESUMEN
BACKGROUND: Therapies targeting estrogen receptor signaling are standard for patients with hormone receptor (HR)-positive (HR+) metastatic breast cancer (MBC). Dysregulation of the phosphoinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is associated with treatment resistance. Addition of the mTOR inhibitor, everolimus, to exemestane doubled progression-free survival (PFS) in HR+/HER2- MBC patients whose disease had previously progressed during endocrine therapy. In this phase II study, we used everolimus in addition to the most recent endocrine therapy during which a patient's disease progressed, in an attempt to restore and extend the benefit of the antiestrogen therapy in patients with HR+/HER2- MBC. PATIENTS AND METHODS: Patients with HR+ MBC who progressed on antiestrogen therapy received everolimus (10 mg orally daily) in combination with the antiestrogen therapy most recently administered. Treatment was administered in 4-week cycles and continued until disease progression or unacceptable toxicity. Blood and archival tumor specimens were collected for VeriStrat (Biodesix, Inc) and Foundation One (Foundation Medicine) assays, respectively. Accrual of 42 evaluable patients allowed detection of improvement in median PFS from 2.8 months (expected with hormonal treatment alone) to 5 months (power 80%, α = 5%). RESULTS: Forty-seven patients were enrolled and treated. After a median follow-up of 22.2 months, median PFS was 6.6 months. Secondary efficacy end points included: overall response rate, 6%; clinical benefit rate, 40%; and median overall survival, 21.1 months. No unexpected toxicity was observed. Efficacy could not be correlated with PI3K/AKT/mTOR alterations or VeriStrat (Biodesix, Inc) prognostic signatures. CONCLUSION: After progression during antiestrogen therapy, the addition of everolimus, without changing the hormonal therapy, resulted in a median PFS of 6.6 months, suggesting efficacy in patients with HR+/HER2- MBC.
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Antineoplásicos Hormonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Everolimus/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Hormonales/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Biopsia , Mama/patología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Progresión de la Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Everolimus/farmacología , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Pronóstico , Supervivencia sin Progresión , Receptor ErbB-2/análisis , Receptores de Estrógenos/antagonistas & inhibidores , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
BACKGROUND: Current bevacizumab-based regimens have failed to improve survival in patients with recurrent glioblastoma. To improve treatment efficacy, we evaluated bevacizumab + BKM120, an oral pan-class I PI3K inhibitor, in this patient population. METHODS: A brief phase I study established the optimal BKM120 dose to administer with standard-dose bevacizumab. BKM120 60 mg PO daily + bevacizumab 10 mg/kg IV every 2 weeks in 28-day cycles was then administered to patients with relapsed/refractory glioblastoma in the phase II portion. RESULTS: Eighty-eight patients enrolled (phase I, 12; phase II, 76). In phase I, BKM120 80 mg PO daily produced dose limiting toxicity in 3 of 6 patients; a BKM120 dose of 60 mg PO daily was established as the maximum tolerated dose. In phase II, the median progression-free survival (PFS) was 4.0 months (95% CI 3.4, 5.4), PFS at 6 months was 36.5%, and the overall response rate was 26%. Forty-two patients (57%) experienced one or more serious treatment related toxicities. The most common CNS toxicities included mood alteration (17%) and confusion (12%); however, these were often difficult to classify as treatment- versus tumor-related. CONCLUSIONS: The efficacy seen in this study is similar to the efficacy previously reported with single-agent bevacizumab. This regimen was poorly tolerated, despite the low daily dose of BKM120. Further development of this combination for the treatment of glioblastoma is not recommended.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/química , Terapia Recuperativa , Adulto , Anciano , Anciano de 80 o más Años , Aminopiridinas/administración & dosificación , Bevacizumab/administración & dosificación , Femenino , Estudios de Seguimiento , Glioblastoma/patología , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Morfolinas/administración & dosificación , Recurrencia Local de Neoplasia/patología , Neoplasias/patología , Pronóstico , Tasa de SupervivenciaRESUMEN
BACKGROUND: This randomized, double-blinded, phase II trial evaluated the efficacy of carboplatin and pemetrexed plus either apatorsen, an antisense oligonucleotide targeting heat shock protein (Hsp) 27 mRNA, or placebo in patients with previously untreated metastatic nonsquamous non-small cell lung cancer (NSCLC). METHODS: Patients were randomized 1:1 to Arm A (carboplatin/pemetrexed plus apatorsen) or Arm B (carboplatin/pemetrexed plus placebo). Treatment was administered in 21-day cycles, with restaging every two cycles, until progression or intolerable toxicity. Serum Hsp27 levels were analyzed at baseline and during treatment. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate, and toxicity. RESULTS: The trial enrolled 155 patients (median age 66 years; 44% Eastern Cooperative Oncology Group performance status 0). Toxicities were similar in the 2 treatment arms; cytopenias, nausea, vomiting, and fatigue were the most frequent treatment-related adverse events. Median PFS and OS were 6.0 and 10.8 months, respectively, for Arm A, and 4.9 and 11.8 months for Arm B (differences not statistically significant). Overall response rates were 27% for Arm A and 32% for Arm B. Sixteen patients (12%) had high serum levels of Hsp27 at baseline. In this small group, patients who received apatorsen had median PFS of 10.8 months, and those who received placebo had median PFS 4.8 months. CONCLUSION: The addition of apatorsen to carboplatin and pemetrexed was well tolerated but did not improve outcomes in patients with metastatic nonsquamous NSCLC cancer in the first-line setting. IMPLICATIONS FOR PRACTICE: This randomized, double-blinded, phase II trial evaluated the efficacy of carboplatin and pemetrexed plus either apatorsen, an antisense oligonucleotide targeting heat shock protein 27 mRNA, or placebo in patients with previously untreated metastatic nonsquamous non-small cell lung cancer (NSCLC). The addition of apatorsen to carboplatin and pemetrexed was well tolerated but did not improve outcomes in patients with metastatic nonsquamous NSCLC cancer in the first-line setting.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Oligonucleótidos/uso terapéutico , Pemetrexed/uso terapéutico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carboplatino/farmacología , Carcinoma de Pulmón de Células no Pequeñas/patología , Método Doble Ciego , Femenino , Humanos , Masculino , Estadificación de Neoplasias , Oligonucleótidos/farmacología , Pemetrexed/farmacologíaRESUMEN
BACKGROUND: Therapies targeting HER2 have improved clinical outcomes in HER2-positive breast and gastric cancers, and are emerging as potential treatments for HER2-positive metastatic colorectal cancer. MyPathway evaluates the activity of targeted therapies in non-indicated tumour types with potentially predictive molecular alterations. We aimed to assess the activity of pertuzumab and trastuzumab in patients with HER2-amplified metastatic colorectal cancer. METHODS: MyPathway is an ongoing, phase 2a, multiple basket study. Patients in this subset analysis were aged 18 years or older and had treatment-refractory, histologically confirmed HER2-amplified metastatic colorectal cancer with measurable or evaluable disease and an Eastern Cooperative Oncology Group performance status score of 2 or less, enrolled from 25 hospitals or clinics in 16 states of the USA. Patients received pertuzumab (840 mg loading dose, then 420 mg every 3 weeks, intravenously) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks, intravenously). The primary endpoint was the proportion of patients who achieved an objective response based on investigator-reported tumour responses. Analyses were done per protocol. This ongoing trial is registered with ClinicalTrials.gov, number NCT02091141. FINDINGS: Between Oct 20, 2014, and June 22, 2017, 57 patients with HER2-amplified metastatic colorectal cancer were enrolled in the MyPathway study and deemed eligible for inclusionin this cohort analysis. Among these 57 evaluable patients, as of Aug 1, 2017, one (2%) patient had a complete response and 17 (30%) had partial responses; thus overall 18 of 57 patients achieved an objective response (32%, 95% CI 20-45). The most common treatment-emergent adverse events were diarrhoea (19 [33%] of 57 patients), fatigue (18 [32%] patients), and nausea (17 [30%] patients). Grade 3-4 treatment-emergent adverse events were recorded in 21 (37%) of 57 patients, most commonly hypokalaemia and abdominal pain (each three [5%] patients). Serious treatment-emergent adverse events were reported in ten (18%) patients and two (4%) of these adverse events (ie, chills and infusion-related reaction) were considered treatment related. There were no treatment-related deaths. INTERPRETATION: Dual HER2-targeted therapy with pertuzumab plus trastuzumab is well tolerated and could represent a therapeutic opportunity for patients with heavily pretreated, HER2-amplified metastatic colorectal cancer. FUNDING: F Hoffmann-La Roche/Genentech.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Receptor ErbB-2/genética , Trastuzumab/uso terapéutico , Anciano , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Resistencia a Antineoplásicos , Femenino , Amplificación de Genes , Humanos , Masculino , Persona de Mediana Edad , Receptor ErbB-2/antagonistas & inhibidores , Resultado del TratamientoRESUMEN
BACKGROUND: Eribulin mesylate is a non-taxane microtubule inhibitor effective in the treatment of metastatic breast cancer refractory to anthracyclines and taxanes. In preclinical studies, additional mechanisms of eribulin included reversal of epithelial mesenchymal transition and tumor vascular remodeling. The present study compared the safety and efficacy of eribulin plus cyclophosphamide (ErC) to docetaxel plus cyclophosphamide (TC) as neoadjuvant therapy for operable HER2- breast cancer. PATIENTS AND METHODS: Women with invasive HER2- breast adenocarcinoma with no distant metastases were eligible. After a 10-patient safety lead-in, the patients were randomized 2:1 to receive either ErC (eribulin 1.4 mg/m2 on days 1 and 8 plus cyclophosphamide 600 mg/m2 on day 1) or TC (docetaxel 75 mg/m2 plus cyclophosphamide 600 mg/m2 on day 1) administered every 21 days for 6 cycles, followed by surgery. The pathologic complete response (pCR) rate was the primary endpoint. Tumor samples collected at baseline and at surgery were assayed for select epithelial mesenchymal transition and vascular density markers: E-cadherin, vimentin, and CD31 expression. RESULTS: A total of 76 patients were enrolled. Of the 76 patients, 10 received ErC in the lead-in phase and 66 were randomized to ErC (n = 44) or TC (n = 22). The pCR rates with ErC and TC were 13% and 9%, respectively. Both regimens produced frequent neutropenia and peripheral neuropathy. Both regimens increased vascular density as measured by CD31 staining. CONCLUSION: The neoadjuvant regimens of ErC and TC resulted in relatively low pCR rates in this patient population. No unexpected toxicities were observed. Our results also provided no suggestion that ErC is a neoadjuvant treatment with greater efficacy than that of standard regimens.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Lobular/tratamiento farmacológico , Terapia Neoadyuvante/mortalidad , Adulto , Anciano , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/secundario , Carcinoma Lobular/secundario , Ciclofosfamida/administración & dosificación , Docetaxel/administración & dosificación , Femenino , Estudios de Seguimiento , Furanos/administración & dosificación , Humanos , Cetonas/administración & dosificación , Metástasis Linfática , Persona de Mediana Edad , Pronóstico , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Tasa de SupervivenciaRESUMEN
In the version of this article originally published, there was an error in Fig. 2n. The top line of the HR comparison chart originally was Atezo + bev vs sun. It should have been Atezo + bev vs atezo. The error has been corrected in the HTML and PDF versions of this article.
RESUMEN
We describe results from IMmotion150, a randomized phase 2 study of atezolizumab (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in 305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+ populations. Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively. Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with PFS. Angiogenesis, T-effector/IFN-γ response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments. These molecular profiles suggest that prediction of outcomes with anti-VEGF and immunotherapy may be possible and offer mechanistic insights into how blocking VEGF may overcome resistance to immune checkpoint blockade.