Citations 3
Tumor Treating Fields With Gemcitabine and Nab-Paclitaxel for Locally Advanced Pancreatic Adenocarcinoma: Randomized, Open-Label, Pivotal Phase III PANOVA-3 Study
Babiker, Hani M. , Picozzi, Vincent J. , Chandana, Sreenivasa R , Melichar, Bohuslav, Kasi, Anup , Gang, Jin, Gállego, Javier , Bullock, Andrea J. , Chunyi, Hao, Hitre, Erika, Osipov, Arsen , Alés, Inmaculada, Dragovich, Tomislav, Lee, Woo Jin , Feeney, Kynan, Ueno, Makoto , Seufferlein, Thomas , Investigators, on behalf of the PANOVA-3 Study, Osipov, Arsen, Matrana, Marc , Blondin, Nicholas, Shroff, Rachna T. , Orr, Douglas, Anderson, Michael J. , Shields, Anthony F. , Hamm, John , Bullock, Andrea, Nagireddy, Sumana, Kolodney, Joanna, Dragovich, Tomislav, Maniam, Ajit, Sears, Judith D., Stilwill, Joseph, Cusnir, Mike , Niewiaroska, Anna, Small, William, Kasi, Anup, Tache, Jason, Ross, Sharona, Shihabi, Samer, Gandhi, Sunil, Reeves, J. N. , Green, Garrett , Feinstein, Trevor, Huyck, Timothy K., Ramdin, Nadia, Marsh, Robert , Jiang, Yixing , Hatoum, Hassan , Manda, Sudhir, Kochenderfer, Mark D., Illum, Henrik, Richards, Donald , Valilis, P., Wong, Lucas, Newton, Herbert B. , Abdelrahim, Maen, Einspahr, David, Siegel, Richard, McKenney, Scott, Narang, Mohit , Cárdenes, Higinia R. , Thanikachalam, Kannan , Raff, Joshua P. , Ye, Joseph , Behl, Deepti , Kam, Audrey E., DeRose, Paul, Tasneem, A. , Brenner, Warren, Santos, Jennifer De Los , Rausch, D C, Trikha, Gaurav, Gabrail, Nashat , Mowat, Rex B., Jahangir, Khawaja, Schumaker, Robert P. , Soffen, Edward , Bravin, Eric, Gupta, Mukul Kumar , Bedoya-Apraez, Ivan Dario, Kang, Tyler Y., Lemay, Frédéric , Vincent, Mark , Létourneau, Richard, Doehring, Christine, Haberkorn, Mike, Rußwurm, Karen, Chater, Jack, Küng, Marc , Schacher, Sabine, Passhak, Maria , Geva, Ravit , Hubert, Ayala, Golan, Talia , Senellart, Hélène, Trouilloud, Isabelle , Blan, Jean-Frederic, Dourthe, Luis-Marie, Roy, Florence Le, Martin-Babau, J., Greil, Richard , Schreil, Georg, Gerger, Armin , Eisterer, Wolfgang , Mercadé, T. Macarulla, Cubillo, Antonio , Pons, Francesc Valladares, Díaz, Inmaculada Alés, Rivera, Fernando , Sarvise, Mariano Ponz, Airoldi, Mario , Bellotti, Giovanna, Corsi, Domenico , Antonuzzo, Lorenzo , Melichar, Bohuslav, Holečková, Petra , Kotasek, Rostislav, Němeček, Radim , Cutsem, Eric van, Laethem, Jean‐Luc Van , Sym, Sun Jin , Kim, Jin Young , Oh, Sang Cheul , Park, Joon Oh, Kim, Jin Won , Lee, Myung Ah , Choi, Hye Jin, Kang, Seok Yun , Mruk, Andrzej, Freier, Beata, Kosakowska, Ewa Anna, Kocsis, Judit, Csőszi, Tibor , Hitre, Erika, Al-Farhat, Yousuf, Cang, Shundong , Jin, Gang , Zuo, Changzeng, Song, Lijie, Wu, Zheng , Gao, Jie , Zhang, Tao� , Wang, Yusheng , Yuan, Xin , Li, Zhi-Hua , Chen, Rufu , Cai, Xiujun , Zhu, Zhizhen, Bai, Yuxian , Bai, Chunmei, Yau, Thomas, Joubert, Warren , Wong, Ka Yeung Mark, Harris, Marion , Mišir, Ana, Faccio, Adilson , Cruz, Felipe Melo , Azevedo, Srergio De, Victorino, Ana Paula , Paiva, Tadeu Ferreira, Franke, Fábio , Tiscoski, Katsuki Arima , Parolla, Gabriel, Lilno, Flora, Siqueira, Mariana Bruno , Lyra, Marcos, Lira, Jose Luis Martinez, Oliva, Dolores Mendoza, Vazquez, Arturo, Luviano, Jesus Elvis Cabrera, Gutiérrez, Erika Castillo , Camargo, Vanessa Rosas, Guerra, Cristian Chavez, Flores, Osvaldo Hernandez, Contreras, Jessica Reyes, Villanueva, Ángel Gómez, Villanueva, Omar Zayas, Bullock, Andrea , Wyrwicz, Lucjan , Osipov, Arsen , De La Fouchardiere, Christelle , Lee, Woojin , Ueno, Makoto , Van Cutsem, Eric , Macarulla, Teresa , Babiker, Hani , Antonuzzo, Lorenzo , Melichar, Bohuslav, Kasi, Anup , Gang, Jin, Gallego, Javier , Hitre, Erika, Fouchardière, Christelle de la , Dragovich, Tomislav, Philip, Philip A. , Cutsem, Eric Van , Macarulla, Teresa , Investigators, on behalf of the PANOVA-3 Study, Spigel, David R. , Osipov, Arsen, Lou, Emil , Bullock, Andrea, Dragovich, Tomislav, Coveler, Andrew L. , Arena, Francis P. , Kasi, Anup, Ross, Sharona , Reeves, James, Green, Garrett, Uemura, Marc Isamu , Ye, Joseph, Wang, James Z. , Rausch, Daniel, Park, Jae‐Hyun , Schumaker, Robert, Gupta, Mukul, Letourneau, Richard, Fuchs, Martin , Vogel, Arndt , Chater, Jack, Schacher, Sabine, Stemmer, Salomon M. , Dourthe, Luis-Marie, Abdelghani, Méher Ben , Pons, Francesc Valladares, Guillén‐Ponce, Carmen , Yayá, Ricardo , Ponz‐Sarvisé, Mariano , Vincenzi, Bruno , Melichar, Bohuslav, Petruzelka, Lubos B. , Cutsem, Eric van, Borbath, Ivan , Hwang, Jun‐Eul , Oh, Sung Yong , Lee, Moon Hee , Choi, Hye Jin , Chon, Hong Jae , Ramlau, Rodryg , Mruk, Andrzej, Hitre, Erika, Bassam, Ali, Hao, Chunyi , Liang, Bo , Li, Wei , Bai, Chunmei , Joubert, Warren, Marx, Gavin M. , Azevedo, Srergio De, Hoff, Paulo M. , Vazquez, Arturo, Guerra, Cristian Chavez, Cortez, David Orta, Campos-Gómez, Saúl , Espinoza, Iván Romarico González
Journal of Clinical Oncology | May 31, 2025 | Volume: 43 | Issue: 21 | Pages: 2350-2360
PURPOSE Tumor treating fields (TTFields) use alternating electric fields to disrupt cancer cell proliferation. Feasibility of TTFields therapy with gemcitabine/nab-paclitaxel was previously demonstrated in patients with advanced pancreatic adenocarcinoma. PANOVA-3 was designed to confirm safety and efficacy of TTFields in patients with unresectable locally advanced pancreatic adenocarcinoma (LA-PAC). METHODS In this global phase III trial, 571 patients with newly diagnosed LA-PAC were randomly assigned to receive gemcitabine 1,000 mg/m 2 and nab-paclitaxel 125 mg/m 2 by intravenous infusion once a day on days 1, 8, and 15 of a 28-day cycle with or without TTFields. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), local PFS, pain-free survival, and overall response rate (ORR). Distant PFS was analyzed post hoc. RESULTS OS was significantly prolonged using TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel (median, 16.2 months [95% CI, 15.0 to 18.0] v 14.2 months [95% CI, 12.8 to 15.4]; hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.99]; P = .039). PFS, local PFS, and ORR were not improved. Pain-free survival was significantly prolonged with TTFields with gemcitabine/nab-paclitaxel (median, 15.2 months [95% CI, 10.3 to 22.8] v 9.1 months [95% CI, 7.4 to 12.7]; HR, 0.74 [95% CI, 0.56 to 0.97]; P = .027), as was distant PFS (median, 13.9 months [95% CI, 12.2 to 16.8] v 11.5 months [95% CI, 10.4 to 12.9]; HR, 0.74 [95% CI, 0.57 to 0.96]; P = .022). Device-related skin adverse events (AEs) were experienced by 76.3% of patients. Most device-related skin AEs were mild to moderate, with 7.7% of patients reporting a grade 3 AE. CONCLUSION This study demonstrated significant OS, pain-free survival, and distant PFS benefits for TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in patients with unresectable LA-PAC, with no additive systemic toxicity.
DNA Mismatch Repair Gene Variant Classification: Evaluating the Utility of Somatic Mutations and Mismatch Repair Deficient Colonic Crypts and Endometrial Glands
Walker, Romy , Mahmood, Khalid , Como, Julia , Joo, Jihoon E. , Georgeson, Peter , Joseland, Sharelle , Preston, Susan , Pope, Bernard J. , Chan, James , Austin, Rachel , Bojadzieva, Jasmina , Campbell, Ainsley , Edwards, Emma, Goodwin, Annabel , Harris, Marion , Ip, Emilia , Kirk, Judy , Mansour, Julia, Fan, Helen Mar , Nichols, Cassandra , Pachter, Nicholas , Ragunathan, Abiramy, Spigelman, Allan D. , Susman, Rachel , Pai, Rish K. , Rosty, Christophe , Winship, Ingrid , Buchanan, Daniel D. , Pope, Bernard J , Chan, James M , Winship, Ingrid M , Buchanan, Daniel D , Rosty, Christophe , Georgeson, Peter , Clendenning, Mark , Gleeson, Margaret A. , Christie, Michael , Jenkins, Mark A. , Macrae, Finlay
Cancers | October 10, 2023 | Volume: 15 | Issue: 20 | Pages: 4925
Germline pathogenic variants in the DNA mismatch repair (MMR) genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. Lynch syndrome specific tumor features were evaluated for their ability to support the ACMG/InSiGHT framework in classifying variants of uncertain clinical significance (VUS) in the MMR genes. Twenty-eight CRC or EC tumors from 25 VUS carriers (6xMLH1, 9xMSH2, 6xMSH6, 4xPMS2), underwent targeted tumor sequencing for the presence of microsatellite instability/MMR-deficiency (MSI-H/dMMR) status and identification of a somatic MMR mutation (second hit). Immunohistochemical testing for the presence of dMMR crypts/glands in normal tissue was also performed. The ACMG/InSiGHT framework reclassified 7/25 (28%) VUS to likely pathogenic (LP), three (12%) to benign/likely benign, and 15 (60%) VUS remained unchanged. For the seven re-classified LP variants comprising nine tumors, tumor sequencing confirmed MSI-H/dMMR (8/9, 88.9%) and a second hit (7/9, 77.8%). Of these LP reclassified variants where normal tissue was available, the presence of a dMMR crypt/gland was found in 2/4 (50%). Furthermore, a dMMR endometrial gland in a carrier of an MSH2 exon 1-6 duplication provides further support for an upgrade of this VUS to LP. Our study confirmed that identifying these Lynch syndrome features can improve MMR variant classification, enabling optimal clinical care.
Adjuvant nab -Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial
Tempero, Margaret A. , Pelzer, Uwe , Oh, Do‐Youn , Li, Chung‐Pin , Tortora, Giampaolo , Chang, Heung-Moon, Lopez, Charles D. , Bekaii‐Saab, Tanios , Ko, Andrew H. , Santoro, Armando , Noel, Marcus Smith , Dean, Andrew , Riess, Hanno, Philip, Philip, Moore, Malcolm J. , Goldstein, David , Ferrara, Stefano, Bruchec, Yvan Le, Lu, Brian , Epstein, Richard A. , Vasey, Paul L., Shapiro, Jeremy, Burge, Matthew , Chua, Yu Jo , Harris, Marion , Prager, Gerald W. , Dittrich, Christian , Längle, Friedrich, Philipp‐Abbrederis, Kathrin, Greil, Richard , Stöger, Herbert, Girschikofsky, Michael , Kuehr, Thomas, Laethem, Jean–Luc Van, Laurent, Stéphanie , Ko, Yoo Joung, Dowden, Scot, Kavan, Petr , Tehfe, Mustapha Édouard, Kubala, Eugen, Kohoutek, Milan, Yilmaz, Mette, Parner, Vibeke K., Salminen, Tapio , Soveri, Leena‐Maija , Korkeila, Eija, Taı̈eb, Julien , Artru, Pascal , Guimbaud, Rosine , Turpin, Antony, Kunzmann, Volker , Kreth, Florian, Oettle, Helmut, Karthaus, Meinolf , Folprecht, Gunnar , Kullmann, Frank , Reiser, Marcel , Heinemann, Volker , Wörns, Marcus‐Alexander , Schulz, H. , Garlipp, Benjamin , Chan, Lam Stephen, Juhász, Balázs , Landherr, László, Pintér, Tamás , Kahán, Zsuzsanna , McDermott, Raymond, Power, Derek G. , Siena, Salvatore, Milella, Michèle , Bagalá, Cinzia, Roila, Fausto, Fanello, Silvia, Wilmink, Johanna W. , Groot, Jan Willem de, Creemers, G.J., Rodrigues, Tânia , Tai, David , Mercadé, T. Macarulla, Medina, Manuel Hidalgo, Mena, Alfredo Carrato, Santasusana, Joan Maurel, Oncala, Maria Jose Flor, Martín, Carlos Gómez , Muñoz, Andrés, García, Ruth Vera, Alés, Inmaculada, Rivera, Fernando , Sastre, Javier , Wu, Cheng‐Chung, Tien, Yu‐Wen , Chan, De-Chuan , Hwang, Tsann‐Long , Evans, Jeffry, Wadsley, Jonathan , Chiorean, E. Gabriela , Bendell, Johanna C. , Kindler, Hedy L. , Fernando, Nishan H., Beg, Muhammad Shaalan , LoConte, Noelle K. , Posey, James , Malhotra, Rajat, Sohal, Davendra , Brenner, Warren, Womack, Mark, Seth, Rahul , lyer, Renuka, Bahary, Nathan , Marsh, Robert , Chua, Cynthia C., Reeves, J. N. , Manji, Gulam A. , Sahai, Vaibhav , Messersmith, Wells A. , Zakari, Ahmed, Bullock, Andrea J. , Musher, Benjamin , Kim, Edward , Bajor, David J., Huyck, Tim, Hatoum, Hassan , Xiong, Henry, Pasche, Boris , Lacy, Jill , Olowokure, Olugbenga, Cohn, Allen Lee, Richards, Donald , Martin, Robert C.G. , Paulson, Andrew Scott , Fanta, Paul T. , Krishnamurthi, Smitha , Fuloria, Jyotsna, McDermott, Ray , Turpin, Anthony , O'Reilly, Eileen M , Winter, Jordan Michael , Oh, Do-Youn , Li, Chung-Pin , Tortora, Giampaolo , Bekaii-Saab, Tanios S , Santoro, Armando , Park, Joon Oh , Dean, Andrew , Van Cutsem, Eric , Berlin, Jordan D. , Tabernero, Josep , Biankin, Andrew V , LoConte, Noelle , Taieb, Julien , McDermott, Ray , Prager, Gerald W , Sahai, Vaibhav , O’Reilly, Eileen M. , Frassineti, Giovanni Luca , Shan, Yan‐Shen , Cutsem, Eric Van , Tabernero, Josep , Li, Mingyu , Zhang, George , Biankin, Andrew V. , Reni, Michele , Vasey, Paul, Pavlakis, Nick , Tebbutt, Niall C. , Längle, Friedrich, Dhani, Neesha C. , Tehfe, Mustapha , Pfeiffer, Per , Osterlund, Pia J. , Tougeron, David , Caroli‐Bosc, François‐Xavier , Walter, Thomas , Bachet, Jean‐Baptiste , Block, Andreas, Venerito, Marino , Trojan, Jörg , Lerch, Markus M. , Schulz, Holger, Yau, Thomas , Juhasz, Balazs, Bodoky, Gyorgy , Gianni, Luca , Siena, Salvatore , Falcone, Alfredo , Berardi, Rossana , Costanzo, Francesco Di , Ardizzoni, Andrea , Maiello, Evaristo , Barroso, Eduardo , Sarmento, Cristina, Chee, Cheng Ean , López López, Rafael , Sáez, Berta Laquente, Chan, De‐Chuan , Evans, Jeffry, Corrie, Pippa G. , Cardin, Dana B. , Noonan, Anne M. , George, Thomas J. , Arena, Francis P. , McWilliams, Robert R. , Seth, Rahul, Ramirez, Robert A. , Reeves, James, El-Khoueiry, Anthony B. , Weaver, Robert, Dreicer, Robert , Borad, Mitesh J. , Huyck, Timothy K., Xiong, Henry Q., Oberstein, Paul E.
Journal of Clinical Oncology | December 15, 2022 | Volume: 41 | Issue: 11 | Pages: 2007-2019
PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m 2 ) + gemcitabine (1,000 mg/m 2 ) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.