ROBERTO HEGG
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Obstetrícia e Ginecologia, Faculdade de Medicina - Docente
LIM/58 - Laboratório de Ginecologia Estrutural e Molecular, Hospital das Clínicas, Faculdade de Medicina
LIM/58 - Laboratório de Ginecologia Estrutural e Molecular, Hospital das Clínicas, Faculdade de Medicina
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- Efficacy and Safety of Bevacizumab-Containing Therapy in Newly Diagnosed Ovarian Cancer ROSiA Single-Arm Phase 3B Study(2017) OZA, Amit M.; SELLE, Frederic; DAVIDENKO, Irina; KORACH, Jacob; MENDIOLA, Cesar; PAUTIER, Patricia; CHMIELOWSKA, Ewa; BAMIAS, Aristotelis; DECENSI, Andrea; ZVIRBULE, Zanete; GONZALEZ-MARTIN, Antonio; HEGG, Roberto; JOLY, Florence; ZAMAGNI, Claudio; GADDUCCI, Angiolo; MARTIN, Nicolas; ROBB, Stephen; COLOMBO, NicolettaObjective: The aim of this study was to assess the safety and efficacy of extending bevacizumab therapy beyond 15 months in nonprogressive ovarian cancer. Patients and Methods: In this multinational prospective single-armstudy (ClinicalTrials.gov NCT01239732), eligible patients had International Federation of Gynecology and Obstetrics stage IIB to IVor grade 3 stage I to IIA ovarian cancer without clinical signs or symptoms of gastrointestinal obstruction or history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the preceding 6 months. Prior neoadjuvant chemotherapy was permitted. After debulking surgery, patients received bevacizumab 15 (or 7.5) mg/kg every 3 weeks (q3w) with 4 to 8 cycles of paclitaxel (investigator's choice of 175 mg/m(2) q3w or 80 mg/m(2) weekly) plus carboplatin AUC 5 to 6 q3w. Single-agent bevacizumab was continued until progression or for up to 24 months. The primary end point was safety. Results: Between December 2010 and May 2012, 1021 patients from 35 countries began study treatment. Bevacizumab was administered at 15 mg/kg in 89% of patients and for more than 15 months in 53%. Median follow-up duration was 32 months (range, 1-50 months). The most common all-grade adverse events were hypertension (55% of patients), neutropenia (49%), and alopecia (43%). The most common grade 3 or higher-grade adverse events were neutropenia (27%) and hypertension (25%). Bevacizumab was discontinued because of proteinuria in 5% of patients and hypertension in 3%. Median progression-free survival (PFS) was 25.5 months (95% confidence interval, 23.7-27.6 months). Conclusion: Extended bevacizumab demonstrated increased incidences of proteinuria and hypertension compared with 12 or 15 months of bevacizumab in previous trials, but these rarely led to bevacizumab discontinuation. Median PFS is the longest reported for front line bevacizumab-containing therapy. The longer bevacizumab duration beyond 15 months in this study may improve PFS without substantially compromising safety.
- IMpassion031: Results from a phase III study of neoadjuvant (neoadj) atezolizumab plus chemotherapy in early triple-negative breast cancer (TNBC)(2020) HARBECK, N.; ZHANG, H.; BARRIOS, C. H.; SAJI, S.; JUNG, K. H.; HEGG, R.; KOEHLER, A.; SOHN, J.; IWATA, H.; TELLI, M. L.; FERRARIO, C.; PUNIE, K.; PENAULT-LLORCA, F.; PATEL, S.; DUC, A. Nguyen; LISTE-HERMOSO, M.; MAIYA, V.; MOLINERO, L.; CHUI, S. Y.; MITTENDORF, E.
- Genomic markers of response to monotherapy abemaciclib in the nextMONARCH 1 study(2020) HAMILTON, Erika P.; CORTES, Javier; JERUSALEM, Guy; KAUFMAN, Peter A.; OZYILKAN, Ozgur; HEGG, Roberto; LITCHFIELD, Lacey M.; WANG, Hong; GRAHAM, Hillary T.; WIJAYAWARDANA, Sameera R.; JANSEN, Valerie M.; MARTIN, Miguel
- Everolimus Plus Endocrine Therapy for Postmenopausal Women With Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer A Clinical Trial(2018) ROYCE, Melanie; BACHELOT, Thomas; VILLANUEVA, Cristian; OZGUROGLU, Mustafa; AZEVEDO, Sergio J.; CRUZ, Felipe Melo; DEBLED, Marc; HEGG, Roberto; TOYAMA, Tatsuya; FALKSON, Carla; JEONG, Joon; SRIMUNINNIMIT, Vichien; GRADISHAR, William J.; ARCE, Christina; RIDOLFI, Antonia; LIN, Chinjune; CARDOSO, FatimaIMPORTANCE Cotargeting the mammalian target of rapamycin pathway and estrogen receptor may prevent or delay endocrine resistance in patients receiving first-line treatment for advanced breast cancer. OBJECTIVE To investigate the combination of everolimus plus endocrine therapy in first-line and second-line treatment settings for postmenopausal women with estrogen receptor-positive, human epidermal growth receptor 2-negative advanced breast cancer. DESIGN, SETTING, AND PARTICIPANTS In the multicenter, open-label, single-arm, phase 2 BOLERO-4 (Breast Cancer Trials of Oral Everolimus) clinical trial, 245 patients were screened for eligibility; 202 were enrolled between March 7, 2013, and December 17, 2014. A median follow-up of 29.5 months had been achieved by the data cutoff date (December 17, 2016). INTERVENTIONS Patients received first-line treatment with everolimus, 10mg/d, plus letrozole, 2.5mg/d. Second-line treatment with everolimus, 10mg/d, plus exemestane, 25 mg/d, was offered at the investigator's discretion upon initial disease progression. MAIN OUTCOMES AND MEASURES The primary end pointwas investigator-assessed progression-free survival in the first-line setting per Response Evaluation Criteria in Solid Tumors, version 1.0. Safety was assessed in patients who received at least 1 dose of study medication and at least 1 postbaseline safety assessment. RESULTS A total of 202 women treated in the first-line setting had a median age of 64.0 years (interquartile range, 58.0-70.0 years) with metastatic (194 [96.0%]) or locally advanced (8 [4.0%]) breast cancer. Median progression-free survival was 22.0 months (95% CI, 18.1-25.1 months) with everolimus and letrozole. Median overall survival was not reached; 24-month estimated overall survival rate was 78.7%(95% CI, 72.1%-83.9%). Fifty patients started second-line treatment; median progression-free survival was 3.7 months (95% CI, 1.9-7.4 months). No new safety signals were observed. In the first-line setting, the most common all-grade adverse event was stomatitis (139 [68.8%]); the most common grade 3 to 4 adverse event was anemia (21 [10.4%]). In the second-line setting, the most common adverse events were stomatitis and decreased weight (10 [20.0%] each); the most common grade 3 to 4 adverse event was hypertension (5 [10.0%]). There were 50 (24.8%) deaths overall during the study; 40 were due to study indication (breast cancer). CONCLUSIONS AND RELEVANCE The results of this trial add to the existing body of evidence suggesting that everolimus plus endocrine therapy is a good first-line treatment option for postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer.
- Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial(2012) ISMAEL, Gustavo; HEGG, Roberto; MUEHLBAUER, Susanne; HEINZMANN, Dominik; LUM, Bert; KIM, Sung-Bae; PIENKOWSKI, Tadeusz; LICHINITSER, Mikhail; SEMIGLAZOV, Vladimir; MELICHAR, Bohuslav; JACKISCH, ChristianBackground A subcutaneous formulation of trastuzumab has been developed, offering potential improvements in patient convenience and resource use compared with the standard intravenous infusion of the drug. We compared the pharmacokinetic profile, efficacy, and safety of the subcutaneous and intravenous formulations in patients with HER2-positive early breast cancer. Methods The HannaH study was a phase 3, randomised, international, open-label, trial in the (neo)adjuvant setting. Patients with HER2-positive, operable, locally advanced or inflammatory breast cancer were randomly assigned to eight cycles of neoadjuvant chemotherapy administered concurrently with trastuzumab every 3 weeks either intravenously (8 mg/kg loading dose, 6 mg/kg maintenance dose) or subcutaneously (fixed dose of 600 mg); 1: 1 ratio. Chemotherapy consisted of four cycles of docetaxel (75 mg/m(2)) followed by four cycles of fluorouracil (500 mg/m(2)), epirubicin (75 mg/m(2)), and cyclophosphamide (500 mg/m(2)), every 3 weeks. After surgery, patients continued trastuzumab to complete 1 year of treatment. Coprimary endpoints were serum trough concentration (C-trough) at pre-dose cycle 8 before surgery (non-inferiority margin for the ratio between groups of 0.80) and pathological complete response (pCR; non-inferiority margin for the difference between groups of -12.5%), analysed in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT00950300. Findings 299 patients were randomly assigned to receive intravenous trastuzumab and 297 to receive subcutaneous trastuzumab. The geometric mean presurgery C-trough was 51.8 mu g/mL (coefficient of variation 52.5%) in the intravenous group and 69.0 mu g/mL (55.8%) in the subcutaneous group. The geometric mean ratio of C-trough subcutaneous to C-trough intravenous was 1.33 (90% CI 1.24-1.44). 107 (40.7%) of 263 patients in the intravenous group and 118 (45.4%) of 260 in the subcutaneous group achieved a pCR. The difference between groups in pCR was 4.7% (95% CI -4.0 to 13.4). Thus subcutaneous trastuzumab was non-inferior to intravenous trastuzumab for both coprimary endpoints. The incidence of grade 3-5 adverse events was similar between groups. The most common of these adverse events were neutropenia (99 [33.2%] of 298 patients in the intravenous group vs 86 [29.0%] of 297 in the subcutaneous group), leucopenia (17 [5.7%] vs 12 [4.0%]), and febrile neutropenia (10 [3.4%] vs 17 [5.7%]). However, more patients had serious adverse events in the subcutaneous group (62 [21%] of 297 patients) than in the intravenous group (37 [12%] of 298); the difference was mainly attributable to infections and infestations (24 [8.1%] in the subcutaneous group vs 13 [4.4%] in the intravenous group). Four adverse events led to death (one in the intravenous group and three in the subcutaneous group), all of which occurred during the neoadjuvant phase. Of these, two-both in the subcutaneous group-were deemed to be treatment related. Interpretation Subcutaneous trastuzumab, administered over about 5 min, has a pharmacokinetic profile and efficacy non-inferior to standard intravenous administration, with a similar safety profile to intravenous trastuzumab, and therefore offers a valid treatment alternative.
- Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer(2012) BASELGA, Jose; CORTES, Javier; KIM, Sung-Bae; IM, Seock-Ah; HEGG, Roberto; IM, Young-Hyuck; ROMAN, Laslo; PEDRINI, Jose Luiz; PIENKOWSKI, Tadeusz; KNOTT, Adam; CLARK, Emma; BENYUNES, Mark C.; ROSS, Graham; SWAIN, Sandra M.BACKGROUND The anti-human epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody trastuzumab improves the outcome in patients with HER2-positive metastatic breast cancer. However, most cases of advanced disease eventually progress. Pertuzumab, an anti-HER2 humanized monoclonal antibody that inhibits receptor dimerization, has a mechanism of action that is complementary to that of trastuzumab, and combination therapy with the two antibodies has shown promising activity and an acceptable safety profile in phase 2 studies involving patients with HER2-positive breast cancer. METHODS We randomly assigned 808 patients with HER2-positive metastatic breast cancer to receive placebo plus trastuzumab plus docetaxel (control group) or pertuzumab plus trastuzumab plus docetaxel (pertuzumab group) as first-line treatment until the time of disease progression or the development of toxic effects that could not be effectively managed. The primary end point was independently assessed progression-free survival. Secondary end points included overall survival, progression-free survival as assessed by the investigator, the objective response rate, and safety. RESULTS The median progression-free survival was 12.4 months in the control group, as compared with 18.5 months in the pertuzumab group (hazard ratio for progression or death, 0.62; 95% confidence interval, 0.51 to 0.75; P<0.001). The interim analysis of overall survival showed a strong trend in favor of pertuzumab plus trastuzumab plus docetaxel. The safety profile was generally similar in the two groups, with no increase in left ventricular systolic dysfunction; the rates of febrile neutropenia and diarrhea of grade 3 or above were higher in the pertuzumab group than in the control group. CONCLUSIONS The combination of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged progression-free survival, with no increase in cardiac toxic effects. (Funded by F. Hoffmann-La Roche/Genentech; ClinicalTrials.gov number, NCT00567190.)
- Phase III study of lapatinib (L) plus trastuzumab (T) and aromatase inhibitor (AI) vs T plus AI vs L plus AI in postmenopausal women (PMW) with HER2+, HR+ metastatic breast cancer (MBC): ALTERNATIVE.(2017) GRADISHAR, William John; HEGG, Roberto; IM, Seock-Ah; PARK, In Hae; TJULANDIN, Sergei; KENNY, Sarah; SARP, Severine; WILLIAMS, Lisa; IZQUIERDO, Miguel A.; JOHNSTON, Stephen R. D.
- First-Line Trastuzumab Plus an Aromatase Inhibitor, With or Without Pertuzumab, in Human Epidermal Growth Factor Receptor 2-Positive and Hormone Receptor-Positive Metastatic or Locally Advanced Breast Cancer (PERTAIN): A Randomized, Open-Label Phase II Trial(2018) RIMAWI, Mothaffar; FERRERO, Jean-Marc; HABA-RODRIGUEZ, Juan de la; POOLE, Christopher; PLACIDO, Sabino De; OSBORNE, C. Kent; HEGG, Roberto; EASTON, Valerie; WOHLFARTH, Christine; ARPINO, GraziaPurposeTo assess pertuzumab plus trastuzumab and an aromatase inhibitor (AI) in patients with human epidermal growth factor receptor 2 (HER2)-positive and hormone receptor-positive metastatic/locally advanced breast cancer (MBC/LABC).Patients and MethodsThe PERTAIN trial (NCT01491737) is an ongoing randomized, open-label, multicenter80 sites and eight countriesphase II trial. Patients have HER2-positive, hormone receptor-positive MBC/LABC and no prior systemic therapy with the exception of endocrine. Random assignment was 1:1 to intravenous pertuzumab (840 mg loading dose followed by 420 mg every 3 weeks) plus trastuzumab (8 mg/kg followed by 6 mg/kg every 3 weeks), and oral anastrozole (1 mg every day) or letrozole (2.5 mg every day), or trastuzumab and an AI. Induction intravenous docetaxel every 3 weeks or paclitaxel every week could be administered for 18 to 24 weeks at the investigator's discretion (decided before but given after random assignment). Primary end point was progression-free survival (PFS). Patients were stratified by whether they received induction chemotherapy and their time since adjuvant hormone therapy.ResultsOne hundred twenty-nine patients were randomly assigned per arm (February 2012 to October 2014; intent-to-treat populations); 75 in one arm and 71 in the other were chosen to receive induction chemotherapy. Stratified median PFS was 18.89 months (95% CI, 14.09 to 27.66 months) in the pertuzumab plus trastuzumab arm and 15.80 months (95% CI, 11.04 to 18.56 months) in the trastuzumab arm (stratified hazard ratio, 0.65; 95% CI, 0.48 to 0.89; P = .0070). Serious adverse events (AEs) were reported for 42 (33.1%) of 127 and 24 (19.4%) of 124 patients in the safety populations of the pertuzumab plus trastuzumab and trastuzumab arms, respectively. Rates of grade 3 AEs were 64 (50.4%) of 127 and 48 (38.7%) of 124, respectively. There were no deaths as a result of AEs.ConclusionPERTAIN met its primary PFS end point. Pertuzumab plus trastuzumab and an AI is effective for the treatment of HER2-positive MBC/LABC. The safety profile was consistent with previous trials of pertuzumab plus trastuzumab.
conferenceObject Abemaciclib combined with adjuvant endocrine therapy in patients with high risk early breast cancer who received neoadjuvant chemotherapy (NAC).(2021) MARTIN, Miguel; HEGG, Roberto; KIM, Sung-Bae; SCHENKER, Michael; GRECEA, Daniela; GARCIA-SAENZ, Jose A.; PAPAZISIS, Konstantinos; OUYANG, Quchang; LACKO, Aleksandra; OKSUZOGLU, Berna; REEVES, James Andrew; OKERA, Meena; TESTA, Laura; SHIMIZU, Chikako; WEI, Ran; FORRESTER, Tammy D.; MUNOZ, Maria; ZIMMERMANN, Annamaria H.; HEADLEY, Desiree; JOHNSTON, Stephen R. D.- Effect of neoadjuvant chemotherapy on low-density lipoprotein (LDL) receptor and LDL receptor-related protein 1 (LRP-1) receptor in locally advanced breast cancer(2012) PIRES, L. A.; HEGG, R.; FREITAS, F. R.; TAVARES, E. R.; ALMEIDA, C. P.; BARACAT, E. C.; MARANHAO, R. C.Low-density lipoprotein (LDL) receptors are overexpressed in most neoplastic cell lines and provide a mechanism for the internalization and concentration of drug-laden nanoemulsions that bind to these receptors. The aim of the present study was to determine whether the administration of standard chemotherapeutic schemes can alter the expression of LDL and LDL receptor-related protein 1 (LRP-1) receptors in breast carcinoma. Fragments of tumoral and normal breast tissue from 16 consecutive volunteer women with breast cancer in stage II or III were obtained from biopsies before the beginning of neoadjuvant chemotherapy and after chemotherapy, from fragments excised during mastectomy. Tissues were analyzed by immunohistochemistry for both receptors. Because complete response to treatment was achieved in 4 patients, only the tumors from 12 were analyzed. Before chemotherapy, there was overexpression of LDL receptor in the tumoral tissue compared to normal breast tissue in 8 of these patients. LRP-1 receptor overexpression was observed in tumors of 4 patients. After chemotherapy, expression of both receptors decreased in the tumors of 6 patients, increased in 4 and was unchanged in 2. Nonetheless, even when chemotherapy reduced receptors expression, the expression was still above normal. The fact that chemotherapy does not impair LDL receptors expression supports the use of drug carrier systems that target neoplastic cells by the LDL receptor endocytic pathway in patients on conventional chemotherapy.