Kerry S Courneya, Janette L Vardy, Christopher J O'Callaghan, Sharlene Gill, Christine M Friedenreich, Rebecca K S Wong, Haryana M Dhillon, Victoria Coyle, Neil S Chua, Derek J Jonker, Philip J Beale, Kamal Haider, Patricia A Tang, Tony Bonaventura, Ralph Wong, Howard J Lim, Matthew E Burge, Stacey Hubay, Michael Sanatani, Kristin L Campbell, Fernanda Z Arthuso, Jane Turner, Ralph M Meyer, Michael Brundage, Patti O'Brien, Dongsheng Tu, Christopher M Booth
{"title":"Structured Exercise after Adjuvant Chemotherapy for Colon Cancer.","authors":"Kerry S Courneya, Janette L Vardy, Christopher J O'Callaghan, Sharlene Gill, Christine M Friedenreich, Rebecca K S Wong, Haryana M Dhillon, Victoria Coyle, Neil S Chua, Derek J Jonker, Philip J Beale, Kamal Haider, Patricia A Tang, Tony Bonaventura, Ralph Wong, Howard J Lim, Matthew E Burge, Stacey Hubay, Michael Sanatani, Kristin L Campbell, Fernanda Z Arthuso, Jane Turner, Ralph M Meyer, Michael Brundage, Patti O'Brien, Dongsheng Tu, Christopher M Booth","doi":"10.1056/NEJMoa2502760","DOIUrl":"https://doi.org/10.1056/NEJMoa2502760","url":null,"abstract":"<p><strong>Background: </strong>Preclinical and observational studies suggest that exercise may improve cancer outcomes. However, definitive level 1 evidence is lacking.</p><p><strong>Methods: </strong>In this phase 3, randomized trial conducted at 55 centers, we assigned patients with resected colon cancer who had completed adjuvant chemotherapy to participate in a structured exercise program (exercise group) or to receive health-education materials alone (health-education group) over a 3-year period. The primary end point was disease-free survival.</p><p><strong>Results: </strong>From 2009 through 2024, a total of 889 patients underwent randomization to the exercise group (445 patients) or the health-education group (444 patients). At a median follow-up of 7.9 years, disease-free survival was significantly longer in the exercise group than in the health-education group (hazard ratio for disease recurrence, new primary cancer, or death, 0.72; 95% confidence interval [CI], 0.55 to 0.94; P = 0.02). The 5-year disease-free survival was 80.3% in the exercise group and 73.9% in the health-education group (difference, 6.4 percentage points; 95% CI, 0.6 to 12.2). Results support longer overall survival in the exercise group than in the health-education group (hazard ratio for death, 0.63; 95% CI, 0.43 to 0.94). The 8-year overall survival was 90.3% in the exercise group and 83.2% in the health-education group (difference, 7.1 percentage points; 95% CI, 1.8 to 12.3). Musculoskeletal adverse events occurred more often in the exercise group than in the health-education group (in 18.5% vs. 11.5% of patients).</p><p><strong>Conclusions: </strong>A 3-year structured exercise program initiated soon after adjuvant chemotherapy for colon cancer resulted in significantly longer disease-free survival and findings consistent with longer overall survival. (Funded by the Canadian Cancer Society and others; CHALLENGE ClinicalTrials.gov number, NCT00819208.).</p>","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":" ","pages":""},"PeriodicalIF":96.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144200790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Danny Rischin, Sandro Porceddu, Fiona Day, Daniel P Brungs, Hayden Christie, James E Jackson, Brian N Stein, Yungpo Bernard Su, Rahul Ladwa, Gerard Adams, Samantha E Bowyer, Zulfiquer Otty, Naoya Yamazaki, Paolo Bossi, Amarnath Challapalli, Axel Hauschild, Annette M Lim, Vishal A Patel, Joanna L Walker, Maite De Liz Vassen Schurmann, Paola Queirolo, Javier Cañueto, Flavio Augusto Ferreira da Silva, Alexander Stratigos, Alexander Guminski, Charles Lin, Fernanda Damian, Lukas Flatz, Anne E Taylor, David R Carr, Samuel Harris, Dmitry Kirtbaya, Gaëlle Quereux, Piotr Rutkowski, Nicole Basset-Seguin, Nikhil I Khushalani, Caroline Robert, Haisong Ju, Camryn Joseph, Shikha Bansal, Chieh-I Chen, Frank Seebach, Suk-Young Yoo, Israel Lowy, Priscila Goncalves, Matthew G Fury
{"title":"Adjuvant Cemiplimab or Placebo in High-Risk Cutaneous Squamous-Cell Carcinoma.","authors":"Danny Rischin, Sandro Porceddu, Fiona Day, Daniel P Brungs, Hayden Christie, James E Jackson, Brian N Stein, Yungpo Bernard Su, Rahul Ladwa, Gerard Adams, Samantha E Bowyer, Zulfiquer Otty, Naoya Yamazaki, Paolo Bossi, Amarnath Challapalli, Axel Hauschild, Annette M Lim, Vishal A Patel, Joanna L Walker, Maite De Liz Vassen Schurmann, Paola Queirolo, Javier Cañueto, Flavio Augusto Ferreira da Silva, Alexander Stratigos, Alexander Guminski, Charles Lin, Fernanda Damian, Lukas Flatz, Anne E Taylor, David R Carr, Samuel Harris, Dmitry Kirtbaya, Gaëlle Quereux, Piotr Rutkowski, Nicole Basset-Seguin, Nikhil I Khushalani, Caroline Robert, Haisong Ju, Camryn Joseph, Shikha Bansal, Chieh-I Chen, Frank Seebach, Suk-Young Yoo, Israel Lowy, Priscila Goncalves, Matthew G Fury","doi":"10.1056/NEJMoa2502449","DOIUrl":"https://doi.org/10.1056/NEJMoa2502449","url":null,"abstract":"<p><strong>Background: </strong>Patients who have cutaneous squamous-cell carcinoma with high-risk features are at risk for recurrence after definitive local therapy. The benefit of systemic adjuvant therapy options has not been well established in clinical trials.</p><p><strong>Methods: </strong>In a phase 3, randomized trial, we enrolled patients with local or regional cutaneous squamous-cell carcinoma, after surgical resection and postoperative radiotherapy, at high risk for recurrence owing to nodal features (extracapsular extension with largest node ≥20 mm in diameter or at least three involved nodes) or nonnodal features (in-transit metastases, T4 lesion [with bone invasion], perineural invasion, or locally recurrent tumor with ≥1 additional risk feature). Patients were assigned in a 1:1 ratio to receive adjuvant cemiplimab (350 mg) or placebo, administered intravenously every 3 weeks for 12 weeks, followed by a dose increase to 700 mg administered every 6 weeks for up to 36 weeks (≤48 weeks total). The primary end point was disease-free survival. Secondary end points included freedom from locoregional recurrence, freedom from distant recurrence, and safety.</p><p><strong>Results: </strong>A total of 415 patients were assigned to cemiplimab (209) or placebo (206). The median follow-up was 24 months. Cemiplimab was superior to placebo with respect to disease-free survival (24 vs. 65 events; hazard ratio for disease recurrence or death, 0.32; 95% confidence interval [CI], 0.20 to 0.51; P<0.001). The estimated 24-month disease-free survival was 87.1% (95% CI, 80.3 to 91.6) with cemiplimab and 64.1% (95% CI, 55.9 to 71.1) with placebo. Cemiplimab led to lower risks of locoregional recurrence (9 events, vs. 40 with placebo; hazard ratio, 0.20; 9% CI, 0.09 to 0.40) and distant recurrence (10 vs. 26 events; hazard ratio, 0.35; 95% CI, 0.17 to 0.72). Adverse events of grade 3 or higher occurred in 23.9% of the patients who received cemiplimab and in 14.2% of those who received placebo; discontinuation due to adverse events occurred in 9.8% and 1.5%, respectively.</p><p><strong>Conclusions: </strong>Adjuvant cemiplimab therapy led to longer disease-free survival than placebo among patients at high risk for recurrence of cutaneous squamous-cell carcinoma. (Funded by Regeneron Pharmaceuticals and Sanofi; C-POST ClinicalTrials.gov number, NCT03969004.).</p>","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":" ","pages":""},"PeriodicalIF":96.2,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144200782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kohei Shitara, Eric Van Cutsem, Mahmut Gümüş, Sara Lonardi, Christelle de la Fouchardière, Clélia Coutzac, Jeroen Dekervel, Daniel Hochhauser, Lin Shen, Wasat Mansoor, Bo Liu, Lorenzo Fornaro, Min-Hee Ryu, Jeeyun Lee, Cátia Faustino, Jean-Philippe Metges, Josep Tabernero, Fábio Franke, Yelena Y Janjigian, Fabricio Souza, Lori Jukofsky, Yumin Zhao, Takahiro Kamio, Aziz Zaanan, Filippo Pietrantonio
{"title":"Trastuzumab Deruxtecan or Ramucirumab plus Paclitaxel in Gastric Cancer.","authors":"Kohei Shitara, Eric Van Cutsem, Mahmut Gümüş, Sara Lonardi, Christelle de la Fouchardière, Clélia Coutzac, Jeroen Dekervel, Daniel Hochhauser, Lin Shen, Wasat Mansoor, Bo Liu, Lorenzo Fornaro, Min-Hee Ryu, Jeeyun Lee, Cátia Faustino, Jean-Philippe Metges, Josep Tabernero, Fábio Franke, Yelena Y Janjigian, Fabricio Souza, Lori Jukofsky, Yumin Zhao, Takahiro Kamio, Aziz Zaanan, Filippo Pietrantonio","doi":"10.1056/NEJMoa2503119","DOIUrl":"https://doi.org/10.1056/NEJMoa2503119","url":null,"abstract":"<p><strong>Background: </strong>On the basis of phase 2 studies, trastuzumab deruxtecan was approved for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric cancer or gastroesophageal junction adenocarcinoma who had previously received trastuzumab-based therapy. Ramucirumab plus paclitaxel is also a standard second-line treatment option regardless of HER2 status.</p><p><strong>Methods: </strong>We conducted an international, randomized, phase 3 trial comparing second-line trastuzumab deruxtecan at a dose of 6.4 mg per kilogram of body weight with ramucirumab plus paclitaxel in patients with HER2-positive metastatic gastric cancer or gastroesophageal junction adenocarcinoma confirmed on tumor biopsy conducted after the patient had progression while receiving trastuzumab-based therapy. The primary end point was overall survival. Secondary end points included progression-free survival, confirmed objective response (complete or partial response lasting ≥4 weeks), disease control, duration of response, and safety.</p><p><strong>Results: </strong>Among 494 patients who had undergone randomization, overall survival was significantly longer with trastuzumab deruxtecan than with ramucirumab plus paclitaxel (median, 14.7 vs. 11.4 months; hazard ratio for death, 0.70; 95% confidence interval, 0.55 to 0.90; P = 0.004). Significant results were also seen with regard to progression-free survival (hazard ratio for disease progression or death, 0.74; 95% CI, 0.59 to 0.92) and confirmed objective response (in 44.3% of the patients in the trastuzumab deruxtecan group vs. 29.1% of those in the ramucirumab-paclitaxel group). The incidence of drug-related adverse events of any grade was 93.0% with trastuzumab deruxtecan and 91.4% with ramucirumab plus paclitaxel; the incidence of drug-related adverse events of grade 3 or higher was 50.0% and 54.1%, respectively. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 13.9% of the patients who received trastuzumab deruxtecan (grade 1 or 2 in 33 patients and grade 3 in 1) and in 1.3% of those who received ramucirumab plus paclitaxel (grade 3 in 2 patients and grade 5 in 1).</p><p><strong>Conclusions: </strong>Trastuzumab deruxtecan led to significantly longer overall survival than ramucirumab plus paclitaxel among patients with HER2-positive metastatic gastric cancer or gastroesophageal junction adenocarcinoma. Adverse events were common in both groups. Events of interstitial lung disease or pneumonitis with trastuzumab deruxtecan, a known risk, were mainly low-grade. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Gastric04 ClinicalTrials.gov number, NCT04704934.).</p>","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":" ","pages":""},"PeriodicalIF":96.2,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144200803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mario Campone, Michelino De Laurentiis, Komal Jhaveri, Xichun Hu, Sylvain Ladoire, Anne Patsouris, Claudio Zamagni, Jiuwei Cui, Marina Cazzaniga, Timucin Cil, Katarzyna J Jerzak, Christian Fuentes, Tetsuhiro Yoshinami, Alvaro Rodriguez-Lescure, Ahmet Sezer, Andrea Fontana, Valentina Guarneri, Andrea Molckovsky, Marie-Ange Mouret-Reynier, Umut Demirci, Yongqiang Zhang, Olga Valota, Dongrui R Lu, Marcella Martignoni, Janaki Parameswaran, Xin Zhi, Erika P Hamilton
{"title":"Vepdegestrant, a PROTAC Estrogen Receptor Degrader, in Advanced Breast Cancer.","authors":"Mario Campone, Michelino De Laurentiis, Komal Jhaveri, Xichun Hu, Sylvain Ladoire, Anne Patsouris, Claudio Zamagni, Jiuwei Cui, Marina Cazzaniga, Timucin Cil, Katarzyna J Jerzak, Christian Fuentes, Tetsuhiro Yoshinami, Alvaro Rodriguez-Lescure, Ahmet Sezer, Andrea Fontana, Valentina Guarneri, Andrea Molckovsky, Marie-Ange Mouret-Reynier, Umut Demirci, Yongqiang Zhang, Olga Valota, Dongrui R Lu, Marcella Martignoni, Janaki Parameswaran, Xin Zhi, Erika P Hamilton","doi":"10.1056/NEJMoa2505725","DOIUrl":"https://doi.org/10.1056/NEJMoa2505725","url":null,"abstract":"<p><strong>Background: </strong>Vepdegestrant is an oral proteolysis-targeting chimera (PROTAC) estrogen receptor (ER) degrader that directly harnesses the ubiquitin-proteasome system.</p><p><strong>Methods: </strong>In this phase 3, open-label, randomized trial, we enrolled patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer who had received one previous line of cyclin-dependent kinase 4 and 6 inhibitor therapy plus one line of endocrine therapy (and up to one additional line of endocrine therapy). Patients were randomly assigned in a 1:1 ratio to receive vepdegestrant at a dose of 200 mg orally once every day of each 28-day cycle or fulvestrant at a dose of 500 mg, administered intramuscularly, on day 1 and day 15 of cycle 1 and on day 1 of subsequent cycles, with randomization stratified according to <i>ESR1</i>-mutation status and presence or absence of visceral disease. The primary end point was progression-free survival as assessed by blinded independent central review among the patients with <i>ESR1</i> mutations and among all the patients who underwent randomization. Progression-free survival was estimated with Kaplan-Meier methods and hazard ratios with a stratified Cox proportional-hazards model.</p><p><strong>Results: </strong>A total of 624 patients underwent randomization; 313 were assigned to receive vepdegestrant, and 311 to receive fulvestrant. Among the 270 patients with <i>ESR1</i> mutations, the median progression-free survival was 5.0 months (95% confidence interval [CI], 3.7 to 7.4) with vepdegestrant and 2.1 months (95% CI, 1.9 to 3.5) with fulvestrant (hazard ratio, 0.58 [95% CI, 0.43 to 0.78]; P<0.001). Among all the patients, the median progression-free survival was 3.8 months (95% CI, 3.7 to 5.3) with vepdegestrant and 3.6 months (95% CI, 2.6 to 4.0) with fulvestrant (hazard ratio, 0.83 [95% CI, 0.69 to 1.01]; P = 0.07). Adverse events of grade 3 or higher occurred in 23.4% of the patients in the vepdegestrant group and in 17.6% of the patients in the fulvestrant group. Adverse events led to treatment discontinuation in 2.9% and 0.7% of the patients, respectively.</p><p><strong>Conclusions: </strong>Among patients with ER-positive, HER2-negative advanced breast cancer, vepdegestrant was associated with significantly longer progression-free survival than fulvestrant in the subgroup with <i>ESR1</i> mutations but not in the full patient population. (Funded by Pfizer and Arvinas Estrogen Receptor; VERITAC-2 ClinicalTrials.gov number, NCT05654623.).</p>","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":" ","pages":""},"PeriodicalIF":96.2,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144200804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Komal L Jhaveri, Seock-Ah Im, Cristina Saura, Sibylle Loibl, Kevin Kalinsky, Peter Schmid, Sherene Loi, Eirini Thanopoulou, Noopur Shankar, Yanling Jin, Thomas J Stout, Tiffany D Clark, Chunyan Song, Dejan Juric, Nicholas C Turner
{"title":"Overall Survival with Inavolisib in <i>PIK3CA</i>-Mutated Advanced Breast Cancer.","authors":"Komal L Jhaveri, Seock-Ah Im, Cristina Saura, Sibylle Loibl, Kevin Kalinsky, Peter Schmid, Sherene Loi, Eirini Thanopoulou, Noopur Shankar, Yanling Jin, Thomas J Stout, Tiffany D Clark, Chunyan Song, Dejan Juric, Nicholas C Turner","doi":"10.1056/NEJMoa2501796","DOIUrl":"https://doi.org/10.1056/NEJMoa2501796","url":null,"abstract":"<p><strong>Background: </strong>In the phase 3, double-blind, randomized INAVO120 trial, treatment with inavolisib plus palbociclib-fulvestrant led to a significant progression-free survival benefit, as compared with placebo plus palbociclib-fulvestrant, among patients with <i>PIK3CA</i>-mutated, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer who had had relapse during or within 12 months after completion of adjuvant endocrine therapy.</p><p><strong>Methods: </strong>We randomly assigned patients with <i>PIK3CA</i>-mutated, hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer who had had disease recurrence or progression during or within 12 months after completion of adjuvant endocrine therapy to receive inavolisib plus palbociclib-fulvestrant (inavolisib group) or placebo plus palbociclib-fulvestrant (placebo group). In the current report, we provide the results of the final analysis of overall survival, including updated data on efficacy and safety.</p><p><strong>Results: </strong>A total of 161 patients were assigned to the inavolisib group, and 164 to the placebo group. After a median follow-up of 34.2 months in the inavolisib group and 32.3 months in the placebo group, the median overall survival was 34.0 months (95% confidence interval [CI], 28.4 to 44.8) with inavolisib and 27.0 months (95% CI, 22.8 to 38.7) with placebo (hazard ratio for death, 0.67; 95% CI, 0.48 to 0.94; P = 0.02 [prespecified boundary for statistical significance, P<0.0469]). An objective response occurred in 62.7% (95% CI, 54.8 to 70.2) of patients in the inavolisib group and 28.0% (95% CI, 21.3 to 35.6) of those in the placebo group (P<0.001). The updated hazard ratio for disease progression or death was 0.42 (95% CI, 0.32 to 0.55). Adverse events led to discontinuation of inavolisib in 6.8% of patients and discontinuation of placebo in 0.6%. The incidence of hyperglycemia, stomatitis or mucosal inflammation, gastrointestinal toxic effects (e.g., diarrhea), and ocular toxic effects (e.g., dry eye and blurred vision) was higher with inavolisib than with placebo.</p><p><strong>Conclusions: </strong>Treatment with inavolisib plus palbociclib-fulvestrant led to a significant overall survival benefit, as compared with placebo plus palbociclib-fulvestrant. Hyperglycemia, stomatitis or mucosal inflammation, gastrointestinal toxic effects, and ocular toxic effects were reported more frequently with inavolisib than with placebo. (Funded by F. Hoffmann-La Roche; INAVO120 ClinicalTrials.gov number, NCT04191499.).</p>","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":" ","pages":""},"PeriodicalIF":96.2,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144200787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Elena Elez, Takayuki Yoshino, Lin Shen, Sara Lonardi, Eric Van Cutsem, Cathy Eng, Tae Won Kim, Harpreet Singh Wasan, Jayesh Desai, Fortunato Ciardiello, Rona Yaeger, Timothy S Maughan, Van K Morris, Christina Wu, Tiziana Usari, Robert Laliberte, Samuel S Dychter, Xiaosong Zhang, Josep Tabernero, Scott Kopetz
{"title":"Encorafenib, Cetuximab, and mFOLFOX6 in <i>BRAF</i>-Mutated Colorectal Cancer.","authors":"Elena Elez, Takayuki Yoshino, Lin Shen, Sara Lonardi, Eric Van Cutsem, Cathy Eng, Tae Won Kim, Harpreet Singh Wasan, Jayesh Desai, Fortunato Ciardiello, Rona Yaeger, Timothy S Maughan, Van K Morris, Christina Wu, Tiziana Usari, Robert Laliberte, Samuel S Dychter, Xiaosong Zhang, Josep Tabernero, Scott Kopetz","doi":"10.1056/NEJMoa2501912","DOIUrl":"https://doi.org/10.1056/NEJMoa2501912","url":null,"abstract":"<p><strong>Background: </strong>First-line treatment with encorafenib plus cetuximab (EC) with or without chemotherapy (oxaliplatin, leucovorin, and fluorouracil [mFOLFOX6]) for <i>BRAF</i> V600E-mutated metastatic colorectal cancer, an aggressive subtype with a poor prognosis, was compared with standard care (chemotherapy with or without bevacizumab) in an open-label, phase 3 trial, which showed significance regarding one of the two primary end points, objective response according to blinded independent central review (odds ratio for EC+mFOLFOX6 vs. standard care, 2.44; one-sided P<0.001). This result led to accelerated Food and Drug Administration approval of this investigational combination therapy for <i>BRAF</i> V600E-mutated metastatic colorectal cancer, including as first-line therapy. Data on progression-free survival (the second primary end point) and an updated interim analysis of overall survival are now available.</p><p><strong>Methods: </strong>We randomly assigned patients with untreated <i>BRAF</i> V600E-mutated metastatic colorectal cancer to receive EC, EC+mFOLFOX6, or standard care. The two primary end points were objective response (reported previously) and progression-free survival according to blinded independent central review in the EC+mFOLFOX6 group and the standard-care group. The key secondary end point was overall survival.</p><p><strong>Results: </strong>Significantly longer progression-free survival was seen with EC+mFOLFOX6 than with standard care (median, 12.8 vs. 7.1 months; hazard ratio for progression or death, 0.53; 95% confidence interval [CI], 0.41 to 0.68; P<0.001). In an interim analysis, overall survival was significantly longer with EC+mFOLFOX6 than with standard care (median, 30.3 vs. 15.1 months; hazard ratio for death, 0.49; 95% CI, 0.38 to 0.63; P<0.001). The incidence of serious adverse events during treatment was 46.1% with EC+mFOLFOX6 and 38.9% with standard care. Safety profiles were consistent with those known for each agent.</p><p><strong>Conclusions: </strong>This trial showed significantly longer progression-free survival and overall survival with first-line treatment with EC+mFOLFOX6 than with standard care among patients with <i>BRAF</i> V600E-mutated metastatic colorectal cancer. (Funded by Pfizer and others; BREAKWATER ClinicalTrials.gov number, NCT04607421.).</p>","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":" ","pages":""},"PeriodicalIF":96.2,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144188555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Identification and Treatment of Alcohol Use Disorder.","authors":"Hanna Blaney, Elliot Tapper","doi":"10.1056/NEJMc2502755","DOIUrl":"https://doi.org/10.1056/NEJMc2502755","url":null,"abstract":"","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"392 20","pages":"2078"},"PeriodicalIF":96.2,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144175612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Daratumumab in Relapsed or Refractory Pediatric Immune Thrombocytopenia.","authors":"Ting Sun, Yunfei Chen, Lei Zhang","doi":"10.1056/NEJMc2501527","DOIUrl":"https://doi.org/10.1056/NEJMc2501527","url":null,"abstract":"","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"392 20","pages":"2069-2071"},"PeriodicalIF":96.2,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144175659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Identification and Treatment of Alcohol Use Disorder.","authors":"Alain Braillon, Florian Naudet","doi":"10.1056/NEJMc2502755","DOIUrl":"https://doi.org/10.1056/NEJMc2502755","url":null,"abstract":"","PeriodicalId":54725,"journal":{"name":"New England Journal of Medicine","volume":"392 20","pages":"2078-2079"},"PeriodicalIF":96.2,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144175669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}