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Teresa M. Petrella

Bio: Teresa M. Petrella is an academic researcher from Sunnybrook Health Sciences Centre. The author has contributed to research in topics: Pembrolizumab & Ipilimumab. The author has an hindex of 24, co-authored 76 publications receiving 2941 citations.


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TL;DR: Pembrolizumab improved progression-free survival and overall survival versus ipilimumab in patients with advanced melanoma and is now a standard of care in the first-line setting, however, the optimal duration of anti-PD-1 administration is unknown.
Abstract: Summary Background Pembrolizumab improved progression-free survival and overall survival versus ipilimumab in patients with advanced melanoma and is now a standard of care in the first-line setting. However, the optimal duration of anti-PD-1 administration is unknown. We present results from 5 years of follow-up of patients in KEYNOTE-006. Methods KEYNOTE-006 was an open-label, multicentre, randomised, controlled, phase 3 study done at 87 academic institutions, hospitals, and cancer centres in 16 countries. Patients aged at least 18 years with Eastern Cooperative Oncology Group performance status of 0 or 1, ipilimumab-naive histologically confirmed advanced melanoma with known BRAFV600 status and up to one previous systemic therapy were randomly assigned (1:1:1) to intravenous pembrolizumab 10 mg/kg every 2 weeks or every 3 weeks or four doses of intravenous ipilimumab 3 mg/kg every 3 weeks. Treatments were assigned using a centralised, computer-generated allocation schedule with blocked randomisation within strata. Exploratory combination of data from the two pembrolizumab dosing regimen groups was not protocol-specified. Pembrolizumab treatment continued for up to 24 months. Eligible patients who discontinued pembrolizumab with stable disease or better after receiving at least 24 months of pembrolizumab or discontinued with complete response after at least 6 months of pembrolizumab and then progressed could receive an additional 17 cycles of pembrolizumab. Co-primary endpoints were overall survival and progression-free survival. Efficacy was analysed in all randomly assigned patients, and safety was analysed in all randomly assigned patients who received at least one dose of study treatment. Exploratory assessment of efficacy and safety at 5 years' follow-up was not specified in the protocol. Data cutoff for this analysis was Dec 3, 2018. Recruitment is closed; the study is ongoing. This study is registered with ClinicalTrials.gov, number NCT01866319. Findings Between Sept 18, 2013, and March 3, 2014, 834 patients were enrolled and randomly assigned to receive pembrolizumab (every 2 weeks, n=279; every 3 weeks, n=277), or ipilimumab (n=278). After a median follow-up of 57·7 months (IQR 56·7–59·2) in surviving patients, median overall survival was 32·7 months (95% CI 24·5–41·6) in the combined pembrolizumab groups and 15·9 months (13·3–22·0) in the ipilimumab group (hazard ratio [HR] 0·73, 95% CI 0·61–0·88, p=0·00049). Median progression-free survival was 8·4 months (95% CI 6·6–11·3) in the combined pembrolizumab groups versus 3·4 months (2·9–4·2) in the ipilimumab group (HR 0·57, 95% CI 0·48–0·67, p Interpretation Pembrolizumab continued to show superiority over ipilimumab after almost 5 years of follow-up. These results provide further support for use of pembrolizumab in patients with advanced melanoma. Funding Merck Sharp & Dohme.

709 citations

Journal ArticleDOI
TL;DR: There is sufficient evidence to show that exercise provides benefits in quality of life and muscular and aerobic fitness for people with cancer both during and after treatment, and that it does not cause harm.
Abstract: Background Development of this guideline was undertaken by the Exercise for People with Cancer Guideline Development Group, a group organized by Cancer Care Ontario’s Program in Evidence-Based Care (pebc). The purpose of the guideline was to provide guidance for clinicians with respect to exercise for patients living with cancer, focusing on the benefits of specific types of exercise, recommendations about screening requirements for new referrals, and safety concerns. Methods Consistent with the pebc’s standardized approach, a systematic search was conducted for existing guidelines, and systematic literature searches were performed in medline and embase for both systematic reviews and primary literature. Content and methodology experts performed an internal review, which was followed by an external review by targeted experts and intended users. Results The search identified three guidelines, eighteen systematic reviews, and twenty-nine randomized controlled trials with relevance to the topic. The present guideline provides recommendations for the duration, frequency, and intensity of exercise appropriate for people living with cancer. It also provides recommendations for pre-exercise assessment, safety concerns, and delivery models. Conclusions There is sufficient evidence to show that exercise provides benefits in quality of life and muscular and aerobic fitness for people with cancer both during and after treatment, and that it does not cause harm. The present guideline is intended to support the Canadian Society for Exercise Physiology’s Canadian physical activity guidelines. The recommendations are intended for clinicians and institutions treating cancer patients in Ontario, and for policymakers and program planners involved in the delivery of exercise programs for cancer patients.

178 citations

Journal ArticleDOI
Michele Maio, Karl D. Lewis1, Lev V. Demidov, Mario Mandalà, Igor Bondarenko2, Paolo A. Ascierto, Christopher Herbert, Andrzej Mackiewicz3, Piotr Rutkowski4, Alexander Guminski, Grant R. Goodman5, B. Simmons5, Chenglin Ye5, Yibing Yan5, Dirk Schadendorf, Gabriela Cinat, Luis Fein, Michael C. Brown, Andrew Haydon, Adnan Khattak, Catriona M. McNeil, Phillip Parente, Jeremy Power, Rachel Roberts-Thomson, Shahneen Sandhu, Craig Underhill, Suresh Varma, Thomas Berger, Ahmad Awada, Nathalie Blockx, Veronique Buyse, Jeroen Mebis, Fabio Franke, Sergio J Azevedo, Nicolas Silva Lazaretti, Rahima Jamal, Catalin Mihalcioiu, Teresa M. Petrella, Kerry J. Savage, Xinni Song, Ralph Wong, Nina Dabelic, Stjepko Plestina, Zeljko Vojnovic, Petr Arenberger, Ivo Kocak, Ivana Krajsová, Eugen Kubala, Bohuslav Melichar, Yvetta Vantuchova, Kadri Putnik, Brigitte Dréno, Caroline Dutriaux, Jean-Jacques Grob, Pascal Joly, Jean-Philippe Lacour, Nicolas Meyer, Laurent Mortier, Luc Thomas, Michael Fluck, Thilo Gambichler, Jessica C. Hassel, Axel Hauschild, Paul Donnellan, John McCaffrey, Derek G. Power, Samuel Ariad, Gil Bar-Sela, Daniel Hendler, Ilan G. Ron, Jacob Schachter, Paolo A. Ascierto, Alfredo Berruti, Luca Bianchi, Vanna Chiarion Sileni, Francesco Cognetti, Riccardo Danielli, Anna Maria Di Giacomo, Luca Gianni, Aron Goldhirsch, Michele Guida, Paolo Marchetti, Paola Queirolo, Armando Santoro, Ellen Kapiteijn, Paula Ferreira, Georgy Gafton, Yulia Makarova, Zoran Andric, Nada Babovic, Darjana Jovanovic, Lidija Sekulovic, Graham Lawrence Cohen, Lydia Dreosti, Daniel A. Vorobiof, Maria Teresa Curiel Garcia, Roberto Diaz Beveridge, Margarita Majem Tarruella, Ivan Marquez Rodas, Jose-M Puliats Rodriguez, Antonio Rueda Dominguez, Marianne Maroti, Karin Papworth, Olivier Michielin, Ewan Brown, Pippa Corrie, Mark Harries, Satish Kumar, Agustin Martin-Clavijo, Mark R. Middleton, Poulam M. Patel, Toby Talbot, Sanjiv S. Agarwala, Paul B. Chapman, Robert M. Conry, Gary Doolittle, Tara C. Gangadhar, Sigrun Hallmeyer, Omid Hamid, Leonel Hernandez-Aya, Douglas B. Johnson, Frederic Kass, Tatjana Kolevska, Scott Lunin, April K.S. Salama, Branimir I. Sikic, Bradley Somer, David R. Spigel, Eric D. Whitman 
TL;DR: The BRIM8 study evaluated adjuvant vemurafenib monotherapy in patients with resected, BRAFV600 mutation-positive melanoma and the result was not significant because of the prespecified hierarchical prerequisite for the primary disease-free survival analysis of cohort 2 to show a significant health benefit.
Abstract: Summary Background Systemic adjuvant treatment might mitigate the high risk of disease recurrence in patients with resected stage IIC–III melanoma. The BRIM8 study evaluated adjuvant vemurafenib monotherapy in patients with resected, BRAF V600 mutation-positive melanoma. Methods BRIM8 was a phase 3, international, double-blind, randomised, placebo-controlled study that enrolled 498 adults (aged ≥18 years) with histologically confirmed stage IIC–IIIA–IIIB (cohort 1) or stage IIIC (cohort 2) BRAF V600 mutation-positive melanoma that was fully resected. Patients were randomly assigned (1:1) by an interactive voice or web response system to receive twice-daily adjuvant oral vemurafenib 960 mg tablets or matching placebo for 52 weeks (13 × 28-day cycles). Randomisation was done by permuted blocks (block size 6) and was stratified by pathological stage and region in cohort 1 and by region in cohort 2. The investigators, patients, and sponsor were masked to treatment assignment. The primary endpoint was disease-free survival in the intention-to-treat population, evaluated separately in each cohort. Hierarchical analysis of cohort 2 before cohort 1 was prespecified. This trial is registered with ClinicalTrials.gov, number NCT01667419. Findings The study enrolled 184 patients in cohort 2 (93 were assigned to vemurafenib and 91 to placebo) and 314 patients in cohort 1 (157 were assigned to vemurafenib and 157 to placebo). At the time of data cutoff (April 17, 2017), median study follow-up was 33·5 months (IQR 25·9–41·6) in cohort 2 and 30·8 months (25·5–40·7) in cohort 1. In cohort 2 (patients with stage IIIC disease), median disease-free survival was 23·1 months (95% CI 18·6–26·5) in the vemurafenib group versus 15·4 months (11·1–35·9) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·54–1·18; log-rank p=0·026). In cohort 1 (patients with stage IIC–IIIA–IIIB disease) median disease-free survival was not reached (95% CI not estimable) in the vemurafenib group versus 36·9 months (21·4–not estimable) in the placebo group (HR 0·54 [95% CI 0·37–0·78]; log-rank p=0·0010); however, the result was not significant because of the prespecified hierarchical prerequisite for the primary disease-free survival analysis of cohort 2 to show a significant disease-free survival benefit. Grade 3–4 adverse events occurred in 141 (57%) of 247 patients in the vemurafenib group and 37 (15%) of 247 patients in the placebo group. The most common grade 3–4 adverse events in the vemurafenib group were keratoacanthoma (24 [10%] of 247 patients), arthralgia (17 [7%]), squamous cell carcinoma (17 [7%]), rash (14 [6%]), and elevated alanine aminotransferase (14 [6%]), although all keratoacanthoma events and most squamous cell carcinoma events were by default graded as grade 3. In the placebo group, grade 3–4 adverse events did not exceed 2% for any of the reported terms. Serious adverse events were reported in 40 (16%) of 247 patients in the vemurafenib group and 25 (10%) of 247 patients in the placebo group. The most common serious adverse event was basal cell carcinoma, which was reported in eight (3%) patients in each group. One patient in the vemurafenib group of cohort 2 died 2 months after admission to hospital for grade 3 hypertension; however, this death was not considered to be related to the study drug. Interpretation The primary endpoint of disease-free survival was not met in cohort 2, and therefore the analysis of cohort 1 showing a numerical benefit in disease-free survival with vemurafenib versus placebo in patients with resected stage IIC–IIIA–IIIB BRAF V600 mutation-positive melanoma must be considered exploratory only. 1 year of adjuvant vemurafenib was well tolerated, but might not be an optimal treatment regimen in this patient population. Funding F Hoffman–La Roche Ltd.

151 citations

Journal ArticleDOI
Rodabe N. Amaria1, Alexander M. Menzies2, Alexander M. Menzies3, Alexander M. Menzies4, Elizabeth M. Burton1, Richard A. Scolyer4, Richard A. Scolyer5, Michael T. Tetzlaff1, Robert Antdbacka, Charlotte E. Ariyan6, Roland L. Bassett1, Brett W. Carter1, Adil Daud7, Mark B. Faries8, Leslie A. Fecher9, Keith T. Flaherty10, Jeffrey E. Gershenwald1, Omid Hamid8, Angela Hong4, Angela Hong5, John M. Kirkwood11, Serigne Lo4, Kim Margolin12, Jane L. Messina13, Michael A. Postow6, Michael A. Postow14, Helen Rizos4, Helen Rizos15, Merrick I. Ross1, Elisa A. Rozeman16, Robyn P. M. Saw4, Robyn P. M. Saw2, Robyn P. M. Saw5, Vernon K. Sondak13, Ryan J. Sullivan10, Janis M. Taube17, John F. Thompson4, John F. Thompson2, John F. Thompson5, Bart A. van de Wiel16, Alexander M.M. Eggermont16, Michael A. Davies1, Miles C. Andrews, Donald A. Berry, Matthew S. Block, Genevieve M. Boland16, Kathryn Bollin1, Matteo S. Carlino16, Richard D. Carvajal1, Jonathan Cohen3, Diwakar Davar, Keith A. Delman, Reinhard Dummer, Michael D. Farwell, David E. Fisher, Alberto Fusi, Isabella C. Glitza, Tanja D. de Gruijl18, David E. Gyorki, Axel Hauschild, Tina J. Hieken, James Larkin, David H. Lawson, Céleste Lebbé, Jeffrey E. Lee, Michael C. Lowe, Jason J. Luke, Grant A. McArthur, David F. McDermott, Jennifer L. McQuade, Tara C. Mitchell, Teresa M. Petrella, Peter A. Prieto, Igor Puzanov, Caroline Robert, April K.S. Salama, Shaneen Sandhu, Dirk Schadendorf, Alexander N. Shoushtari, Jeffrey A. Sosman, Susan M. Swetter, Ken K. Tanabe, Samra Turajlic, Douglas S. Tyler, Scott E. Woodman, Frances C. Wright, Jonathan S. Zager, Paolo A. Ascierto, Andrew J. Spillane2, Andrew J. Spillane3, Andrew J. Spillane4, Alexander C.J. van Akkooi16, Jennifer A. Wargo1, Christian U. Blank16, Hussein Abdul-Hassan Tawbi1, Georgina V. Long4, Georgina V. Long2, Georgina V. Long3 
TL;DR: The International Neoadjuvant Melanoma Consortium is established with experts in medical oncology, surgical oncologist, pathology, radiation oncologists, radiology, and translational research to develop recommendations for investigating neoadjuant therapy in melanoma to align future trial designs and correlative analyses.
Abstract: Advances in the treatment of metastatic melanoma have improved responses and survival. However, many patients continue to experience resistance or toxicity to treatment, highlighting a crucial need to identify biomarkers and understand mechanisms of response and toxicity. Neoadjuvant therapy for regional metastases might improve operability and clinical outcomes over upfront surgery and adjuvant therapy, and has become an established role for drug development and biomarker discovery in other cancers (including locally advanced breast cancer, head and neck squamous cell carcinomas, gastroesophageal cancer, and anal cancer). Patients with clinically detectable stage III melanoma are ideal candidates for neoadjuvant therapy, because they represent a high-risk patient population with poor outcomes when treated with upfront surgery alone. Neoadjuvant therapy is now an active area of research for melanoma with numerous completed and ongoing trials (since 2014) with disparate designs, endpoints, and analyses under investigation. We have, therefore, established the International Neoadjuvant Melanoma Consortium with experts in medical oncology, surgical oncology, pathology, radiation oncology, radiology, and translational research to develop recommendations for investigating neoadjuvant therapy in melanoma to align future trial designs and correlative analyses. Alignment and consistency of neoadjuvant trials will facilitate optimal data organisation for future regulatory review and strengthen translational research across the melanoma disease continuum.

140 citations


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TL;DR: Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma.
Abstract: Background An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab — which blocks cytotoxic T-lymphocyte–associated antigen 4 to potentiate an antitumor T-cell response — administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. Methods A total of 676 HLA-A*0201–positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. Results The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P = 0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P = 0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. Conclusions Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)

13,081 citations

Journal ArticleDOI
TL;DR: Among patients with advanced melanoma, significantly longer overall survival occurred with combination therapy with nivolumab plus ipilimumab or with n ivolumAB alone than with ipil optimumab alone.
Abstract: BackgroundNivolumab combined with ipilimumab resulted in longer progression-free survival and a higher objective response rate than ipilimumab alone in a phase 3 trial involving patients with advanced melanoma. We now report 3-year overall survival outcomes in this trial. MethodsWe randomly assigned, in a 1:1:1 ratio, patients with previously untreated advanced melanoma to receive nivolumab at a dose of 1 mg per kilogram of body weight plus ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses, followed by nivolumab at a dose of 3 mg per kilogram every 2 weeks; nivolumab at a dose of 3 mg per kilogram every 2 weeks plus placebo; or ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses plus placebo, until progression, the occurrence of unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to programmed death ligand 1 (PD-L1) status, BRAF mutation status, and metastasis stage. The two primary end points were progression-free survival a...

3,794 citations

Journal ArticleDOI
09 Feb 2017-Cell
TL;DR: As the molecular mechanisms of resistance to immunotherapy are elucidated, actionable strategies to prevent or treat them may be derived to improve clinical outcomes for patients.

3,131 citations

Journal ArticleDOI
TL;DR: Two broad categories of tumor escape based on cellular and molecular characteristics of the tumor microenvironment are suggested, which appear to resist immune attack through immune system exclusion or ignorance and may require distinct immunotherapeutic interventions for maximal therapeutic effect.
Abstract: Most tumor cells express antigens that can mediate recognition by host CD8(+) T cells. Cancers that are detected clinically must have evaded antitumor immune responses to grow progressively. Recent work has suggested two broad categories of tumor escape based on cellular and molecular characteristics of the tumor microenvironment. One major subset shows a T cell-inflamed phenotype consisting of infiltrating T cells, a broad chemokine profile and a type I interferon signature indicative of innate immune activation. These tumors appear to resist immune attack through the dominant inhibitory effects of immune system-suppressive pathways. The other major phenotype lacks this T cell-inflamed phenotype and appears to resist immune attack through immune system exclusion or ignorance. These two major phenotypes of tumor microenvironment may require distinct immunotherapeutic interventions for maximal therapeutic effect.

2,939 citations