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51. Supplementary Figure 3 from Effects of HER Family–targeting Tyrosine Kinase Inhibitors on Antibody-dependent Cell-mediated Cytotoxicity in HER2-expressing Breast Cancer

Author

Collins, Denis M., primary, Madden, Stephen F., primary, Gaynor, Nicola, primary, AlSultan, Dalal, primary, Le Gal, Marion, primary, Eustace, Alex J., primary, Gately, Kathy A., primary, Hughes, Clare, primary, Davies, Anthony M., primary, Mahgoub, Thamir, primary, Ballot, Jo, primary, Toomey, Sinead, primary, O'Connor, Darran P., primary, Gallagher, William M., primary, Holmes, Frankie A., primary, Espina, Virginia, primary, Liotta, Lance, primary, Hennessy, Bryan T., primary, O'Byrne, Kenneth J., primary, Hasmann, Max, primary, Bossenmaier, Birgit, primary, O'Donovan, Norma, primary, and Crown, John, primary

Published
2023
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52. Supplementary Figure 2 from Effects of HER Family–targeting Tyrosine Kinase Inhibitors on Antibody-dependent Cell-mediated Cytotoxicity in HER2-expressing Breast Cancer

Author

Collins, Denis M., primary, Madden, Stephen F., primary, Gaynor, Nicola, primary, AlSultan, Dalal, primary, Le Gal, Marion, primary, Eustace, Alex J., primary, Gately, Kathy A., primary, Hughes, Clare, primary, Davies, Anthony M., primary, Mahgoub, Thamir, primary, Ballot, Jo, primary, Toomey, Sinead, primary, O'Connor, Darran P., primary, Gallagher, William M., primary, Holmes, Frankie A., primary, Espina, Virginia, primary, Liotta, Lance, primary, Hennessy, Bryan T., primary, O'Byrne, Kenneth J., primary, Hasmann, Max, primary, Bossenmaier, Birgit, primary, O'Donovan, Norma, primary, and Crown, John, primary

Published
2023
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53. Supplementary Data Figure 1 from Effects of HER Family–targeting Tyrosine Kinase Inhibitors on Antibody-dependent Cell-mediated Cytotoxicity in HER2-expressing Breast Cancer

Author

Collins, Denis M., primary, Madden, Stephen F., primary, Gaynor, Nicola, primary, AlSultan, Dalal, primary, Le Gal, Marion, primary, Eustace, Alex J., primary, Gately, Kathy A., primary, Hughes, Clare, primary, Davies, Anthony M., primary, Mahgoub, Thamir, primary, Ballot, Jo, primary, Toomey, Sinead, primary, O'Connor, Darran P., primary, Gallagher, William M., primary, Holmes, Frankie A., primary, Espina, Virginia, primary, Liotta, Lance, primary, Hennessy, Bryan T., primary, O'Byrne, Kenneth J., primary, Hasmann, Max, primary, Bossenmaier, Birgit, primary, O'Donovan, Norma, primary, and Crown, John, primary

Published
2023
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54. Supplementary Figure 7 from Effects of HER Family–targeting Tyrosine Kinase Inhibitors on Antibody-dependent Cell-mediated Cytotoxicity in HER2-expressing Breast Cancer

Author

Collins, Denis M., primary, Madden, Stephen F., primary, Gaynor, Nicola, primary, AlSultan, Dalal, primary, Le Gal, Marion, primary, Eustace, Alex J., primary, Gately, Kathy A., primary, Hughes, Clare, primary, Davies, Anthony M., primary, Mahgoub, Thamir, primary, Ballot, Jo, primary, Toomey, Sinead, primary, O'Connor, Darran P., primary, Gallagher, William M., primary, Holmes, Frankie A., primary, Espina, Virginia, primary, Liotta, Lance, primary, Hennessy, Bryan T., primary, O'Byrne, Kenneth J., primary, Hasmann, Max, primary, Bossenmaier, Birgit, primary, O'Donovan, Norma, primary, and Crown, John, primary

Published
2023
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55. Supplementary Figure 4 from Effects of HER Family–targeting Tyrosine Kinase Inhibitors on Antibody-dependent Cell-mediated Cytotoxicity in HER2-expressing Breast Cancer

Author

Collins, Denis M., primary, Madden, Stephen F., primary, Gaynor, Nicola, primary, AlSultan, Dalal, primary, Le Gal, Marion, primary, Eustace, Alex J., primary, Gately, Kathy A., primary, Hughes, Clare, primary, Davies, Anthony M., primary, Mahgoub, Thamir, primary, Ballot, Jo, primary, Toomey, Sinead, primary, O'Connor, Darran P., primary, Gallagher, William M., primary, Holmes, Frankie A., primary, Espina, Virginia, primary, Liotta, Lance, primary, Hennessy, Bryan T., primary, O'Byrne, Kenneth J., primary, Hasmann, Max, primary, Bossenmaier, Birgit, primary, O'Donovan, Norma, primary, and Crown, John, primary

Published
2023
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56. Safety of First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC: A Pooled Analysis of CheckMate 227, CheckMate 568, and CheckMate 817

Author

Bristol Myers Squibb Foundation, Paz-Ares, Luis, Ciuleanu, Tudor-Eliade, Pluzanski, Adam, Lee, Jong-Seok, Gainor, Justin F., Otterson, Gregory A., Audigier-Valette, Clarisse, Ready, Neal, Schenker, Michael, Linardou, Helena, Caro, Reyes Bernabe, Provencio, Mariano, Zurawski, Bogdan, Lee, Ki Hyeong, Kim, Sang-We, Caserta, Claudia, Ramalingam, Suresh S., Spigel, David R., Brahmer, Julie R., Reck, Martin, O'Byrne, Kenneth J., Girard, Nicolas, Popat, Sanjay, Peters, Solange, Memaj, Arteid, Nathan, Faith Ellen, Aanur, Nivedita, Borghaei, Hossein, Bristol Myers Squibb Foundation, Paz-Ares, Luis, Ciuleanu, Tudor-Eliade, Pluzanski, Adam, Lee, Jong-Seok, Gainor, Justin F., Otterson, Gregory A., Audigier-Valette, Clarisse, Ready, Neal, Schenker, Michael, Linardou, Helena, Caro, Reyes Bernabe, Provencio, Mariano, Zurawski, Bogdan, Lee, Ki Hyeong, Kim, Sang-We, Caserta, Claudia, Ramalingam, Suresh S., Spigel, David R., Brahmer, Julie R., Reck, Martin, O'Byrne, Kenneth J., Girard, Nicolas, Popat, Sanjay, Peters, Solange, Memaj, Arteid, Nathan, Faith Ellen, Aanur, Nivedita, and Borghaei, Hossein

Abstract

[Introduction] We characterized the safety of first-line nivolumab plus ipilimumab (NIVO+IPI) in a large patient population with metastatic NSCLC and efficacy outcomes after NIVO+IPI discontinuation owing to treatment-related adverse events (TRAEs)., [Methods] We pooled data from three first-line NIVO+IPI studies (NIVO, 3 mg/kg or 240 mg every 2 wk; IPI, 1 mg/kg every 6 wk) in metastatic NSCLC (CheckMate 227 part 1, CheckMate 817 cohort A, CheckMate 568 part 1). Safety end points included TRAEs and immune-mediated adverse events (IMAEs) in the pooled population and patients aged 75 years or older., [Results] In the pooled population (N = 1255), any-grade TRAEs occurred in 78% of the patients, grade 3 or 4 TRAEs in 34%, and discontinuation of any regimen component owing to TRAEs in 21%. The most frequent TRAE and IMAE were diarrhea (20%; grade 3 or 4, 2%) and rash (17%; grade 3 or 4, 3%), respectively. The most common grade 3 or 4 IMAEs were hepatitis (5%) and diarrhea/colitis and pneumonitis (4% each). Pneumonitis was the most common cause of treatment-related death (5 of 16). Safety in patients aged 75 years or older (n = 174) was generally similar to the overall population, but discontinuation of any regimen component owing to TRAEs was more common (29%). In patients discontinuing NIVO+IPI owing to TRAEs (n = 225), 3-year overall survival was 50% (95% confidence interval: 42.6–56.0), and 42% (31.2–52.4) of 130 responders remained in response 2 years after discontinuation., [Conclusions] First-line NIVO+IPI was well tolerated in this large population with metastatic NSCLC and in patients aged 75 years or older. Discontinuation owing to TRAEs did not reduce long-term survival.

Published
2023

57. Five-Year Survival Outcomes With Nivolumab Plus Ipilimumab Versus Chemotherapy as First-Line Treatment for Metastatic Non-Small-Cell Lung Cancer in CheckMate 227

Author

Brahmer, Julie R., Lee, Jong-Seok, Ciuleanu, Tudor-Eliade, Bernabé Caro, Reyes, Nishio, Makoto, Urban, Laszlo, Audigier-Valette, Clarisse, Lupinacci, Lorena, Sangha, Randeep, Pluzanski, Adam, Burgers, Jacobus, Mahave, Mauricio, Ahmed, Samreen, Schoenfeld, Adam J., Paz-Ares, Luis, Reck, Martin, Borghaei, Hossein, O'Byrne, Kenneth J., Gupta, Ravi G., Bushong, Judith, Li, Li, Blum, Steven I., Eccles, Laura J., Ramalingam, Suresh S., Brahmer, Julie R., Lee, Jong-Seok, Ciuleanu, Tudor-Eliade, Bernabé Caro, Reyes, Nishio, Makoto, Urban, Laszlo, Audigier-Valette, Clarisse, Lupinacci, Lorena, Sangha, Randeep, Pluzanski, Adam, Burgers, Jacobus, Mahave, Mauricio, Ahmed, Samreen, Schoenfeld, Adam J., Paz-Ares, Luis, Reck, Martin, Borghaei, Hossein, O'Byrne, Kenneth J., Gupta, Ravi G., Bushong, Judith, Li, Li, Blum, Steven I., Eccles, Laura J., and Ramalingam, Suresh S.

Abstract

[Purpose] We present 5-year results from CheckMate 227 Part 1, in which nivolumab plus ipilimumab improved overall survival (OS) versus chemotherapy in patients with metastatic non–small-cell lung cancer, regardless of tumor programmed death ligand 1 (PD-L1) status., [Methods] Adults with stage IV/recurrent non–small-cell lung cancer without EGFR mutations or ALK alterations and with tumor PD-L1 ≥ 1% or < 1% (n = 1739) were randomly assigned. Patients with tumor PD-L1 ≥ 1% were randomly assigned to first-line nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. Patients with tumor PD-L1 < 1% were randomly assigned to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. End points included exploratory 5-year results for efficacy, safety, and quality of life., [Results] At a minimum follow-up of 61.3 months, 5-year OS rates were 24% versus 14% for nivolumab plus ipilimumab versus chemotherapy (PD-L1 ≥ 1%) and 19% versus 7% (PD-L1 < 1%). The median duration of response was 24.5 versus 6.7 months (PD-L1 ≥ 1%) and 19.4 versus 4.8 months (PD-L1 < 1%). Among patients surviving 5 years, 66% (PD-L1 ≥ 1%) and 64% (PD-L1 < 1%) were off nivolumab plus ipilimumab without initiating subsequent systemic anticancer treatment by the 5-year time point. Survival benefit continued after nivolumab plus ipilimumab discontinuation because of treatment-related adverse events, with a 5-year OS rate of 39% (combined PD-L1 ≥ 1% and < 1% populations). Quality of life in 5-year survivors treated with nivolumab plus ipilimumab was similar to that in the general US population through the 5-year follow-up. No new safety signals were observed., [Conclusion] With all patients off immunotherapy treatment for ≥ 3 years, nivolumab plus ipilimumab increased 5-year survivorship versus chemotherapy, including long-term, durable clinical benefit regardless of tumor PD-L1 expression. These data support nivolumab plus ipilimumab as an effective first-line treatment for patients with metastatic non–small-cell lung cancer.

Published
2023

58. Systemic and Intracranial Outcomes With First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC and Baseline Brain Metastases From CheckMate 227 Part 1

Author

Bristol Myers Squibb Foundation, Reck, Martin, Ciuleanu, Tudor-Eliade, Lee, Jong-Seok, Schenker, Michael, Zurawski, Bogdan, Kim, Sang-We, Mahave, Mauricio, Alexandru, Aurelia, Peters, Solange, Pluzanski, Adam, Bernabé Caro, Reyes, Linardou, Helena, Burgers, Jacobus A., Nishio, Makoto, Martinez-Marti, Alex, Azuma, Koichi, Axelrod, Rita, Paz-Ares, Luis, Ramalingam, Suresh S., Borghaei, Hossein, O'Byrne, Kenneth J., Li, Li, Bushong, Judith, Gupta, Ravi G., Grootendorst, Diederik J., Eccles, Laura J., Brahmer, Julie R., Bristol Myers Squibb Foundation, Reck, Martin, Ciuleanu, Tudor-Eliade, Lee, Jong-Seok, Schenker, Michael, Zurawski, Bogdan, Kim, Sang-We, Mahave, Mauricio, Alexandru, Aurelia, Peters, Solange, Pluzanski, Adam, Bernabé Caro, Reyes, Linardou, Helena, Burgers, Jacobus A., Nishio, Makoto, Martinez-Marti, Alex, Azuma, Koichi, Axelrod, Rita, Paz-Ares, Luis, Ramalingam, Suresh S., Borghaei, Hossein, O'Byrne, Kenneth J., Li, Li, Bushong, Judith, Gupta, Ravi G., Grootendorst, Diederik J., Eccles, Laura J., and Brahmer, Julie R.

Abstract

[Introduction] In CheckMate 227 Part 1, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with metastatic NSCLC, regardless of tumor programmed death-ligand 1 (PD-L1) expression. Here, we report post hoc exploratory systemic and intracranial efficacy outcomes and safety by baseline brain metastasis status at 5 years’ minimum follow-up., [Methods] Treatment-naive adults with stage IV or recurrent NSCLC without EGFR or ALK alterations, including asymptomatic patients with treated brain metastases, were enrolled. Patients with tumor PD-L1 greater than or equal to 1% were randomized to nivolumab plus ipilimumab, nivolumab, or chemotherapy; patients with tumor PD-L1 less than 1% were randomized to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy groups. Assessments included OS, systemic and intracranial progression-free survival per blinded independent central review, new brain lesion development, and safety. Brain imaging was performed at baseline (all randomized patients) and approximately every 12 weeks thereafter (patients with baseline brain metastases only)., [Results] Overall, 202 of 1739 randomized patients had baseline brain metastases (nivolumab plus ipilimumab: 68; chemotherapy: 66). At 61.3 months’ minimum follow-up, nivolumab plus ipilimumab prolonged OS versus chemotherapy in patients with baseline brain metastases (hazard ratio = 0.63; 95% confidence interval: 0.43–0.92) and in those without (hazard ratio = 0.76; 95% confidence interval: 0.66–0.87). In patients with baseline brain metastases, 5-year systemic and intracranial progression-free survival rates were higher with nivolumab plus ipilimumab (12% and 16%, respectively) than chemotherapy (0% and 6%). Fewer patients with baseline brain metastases developed new brain lesions with nivolumab plus ipilimumab (4%) versus chemotherapy (20%). No new safety signals were observed., [Conclusions] With all patients off immunotherapy for more than or equal to 3 years, nivolumab plus ipilimumab continued to provide a long-term, durable survival benefit in patients with or without brain metastases. Intracranial efficacy outcomes favored nivolumab plus ipilimumab versus chemotherapy. These results further support nivolumab plus ipilimumab as an efficacious first-line treatment for patients with metastatic NSCLC, regardless of baseline brain metastasis status.

Published
2023

59. Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis

Author

Bristol Myers Squibb Foundation, Ono Pharmaceutical, Borghaei, Hossein, Ciuleanu, Tudor-Eliade, Lee, Jong-Seok, Pluzanski, Adam, Bernabé Caro, Reyes, Gutierrez, Martin E., Ohe, Yuichiro, Nishio, Makoto, Goldman, Jacki P., Ready, Neal, Spigel, David R., Ramalingam, Suresh S., Paz-Ares, Luis, Gainor, Justin F., Ahmed, Samreen, Reck, Martin, Maio, Michele, O'Byrne, Kenneth J., Memaj, Arteid, Nathan, Faith Ellen, Tran, Phuong, Hellmann, Matthew D., Brahmer, Julie R., Bristol Myers Squibb Foundation, Ono Pharmaceutical, Borghaei, Hossein, Ciuleanu, Tudor-Eliade, Lee, Jong-Seok, Pluzanski, Adam, Bernabé Caro, Reyes, Gutierrez, Martin E., Ohe, Yuichiro, Nishio, Makoto, Goldman, Jacki P., Ready, Neal, Spigel, David R., Ramalingam, Suresh S., Paz-Ares, Luis, Gainor, Justin F., Ahmed, Samreen, Reck, Martin, Maio, Michele, O'Byrne, Kenneth J., Memaj, Arteid, Nathan, Faith Ellen, Tran, Phuong, Hellmann, Matthew D., and Brahmer, Julie R.

Abstract

[Background] First-line nivolumab plus ipilimumab prolongs survival versus chemotherapy in advanced non-small-cell lung cancer (NSCLC). We further characterized clinical benefit with this regimen in a large pooled patient population and assessed the effect of response on survival., [Patients and methods] Data were pooled from four studies of first-line nivolumab plus ipilimumab in advanced NSCLC (CheckMate 227 Part 1, 817 cohort A, 568 Part 1, and 012). Overall survival (OS), progression-free survival (PFS), objective response rate, duration of response, and safety were assessed. Landmark analyses of OS by response status at 6 months and by tumor burden reduction in responders to nivolumab plus ipilimumab were also assessed., [Results] In the pooled population (N = 1332) with a minimum follow-up of 29.1-58.9 months, median OS was 18.6 months, with a 3-year OS rate of 35%; median PFS was 5.4 months (3-year PFS rate, 17%). Objective response rate was 36%; median duration of response was 23.7 months, with 38% of responders having an ongoing response at 3 years. In patients with tumor programmed death-ligand 1 (PD-L1) <1%, ≥1%, 1%-49%, or ≥50%, 3-year OS rates were 30%, 38%, 30%, and 48%. Three-year OS rates were 30% and 38% in patients with squamous or non-squamous histology. Efficacy outcomes in patients aged ≥75 years were similar to the overall pooled population (median OS, 20.1 months; 3-year OS rate, 34%). In the pooled population, responders to nivolumab plus ipilimumab at 6 months had longer post-landmark OS than those with stable or progressive disease; 3-year OS rates were 66%, 22%, and 14%, respectively. Greater depth of response was associated with prolonged survival; in patients with tumor burden reduction ≥80%, 50% to <80%, or 30% to <50%, 3-year OS rates were 85%, 72%, and 44%, respectively. No new safety signals were identified in the pooled population., [Conclusion] Long-term survival benefit and durable response with nivolumab plus ipilimumab in this large patient population further support this first-line treatment option for advanced NSCLC.

Published
2023

63. Contributors

Author

Adjei, Alex A., primary, Ahn, Mjung-Ju, additional, Amos, Chris I., additional, Antonicelli, Alberto, additional, Asamura, Hisao, additional, Atwood, Todd, additional, Baas, Paul, additional, Bailey-Wilson, Joan E., additional, Ball, David, additional, Barlesi, Fabrice, additional, Bazan, Jose G., additional, Belderbos, José, additional, Bezjak, Andrea, additional, Billingham, Lucinda J., additional, Boffetta, Paolo, additional, Bonifazi, Martina, additional, Brahmer, Julie R., additional, Brambilla, Elisabeth, additional, Brims, Fraser, additional, Brunelli, Alessandro, additional, Bryant, Ayesha, additional, Campbell, Nicholas, additional, Carter, Brett W., additional, Cerfolio, Robert, additional, Cho, Byoung Chul, additional, Cho, William C.S., additional, Choy, Hak, additional, Chu, Chia-Yu, additional, Colburn, Glenda, additional, Colt, Henri, additional, Rosell Costa, Rafael, additional, Darling, Gail E., additional, Davis, Mellar, additional, de Groot, Patricia M., additional, de Koning, Harry J., additional, De Leyn, Paul, additional, De Ruysscher, Dirk, additional, Demiral, Ayşe Nur, additional, Derks, Jules, additional, Detterbeck, Frank C., additional, Devarakonda, Siddhartha, additional, Dingemans, Anne-Marie C., additional, Donington, Jessica S., additional, Dresler, Carolyn M., additional, Dubinett, Steven M., additional, Dy, Grace K., additional, Erasmus, Jeremy J., additional, Fairchild, Alysa, additional, Fennell, Dean A., additional, Fernando, Hiran C., additional, Filosso, Pier Luigi, additional, Flores, Raja, additional, Fong, Kwun, additional, Fox, Jesme, additional, Gandara, David R., additional, Gandhi, Leena, additional, Gaspar, Laurie, additional, Gasparini, Stefano, additional, Gazdar, Adi F., additional, Giaccone, Giuseppe, additional, Girard, Nicolas, additional, Goldstraw, Peter, additional, Gore, Elizabeth M., additional, Goss, Glenwood, additional, Govindan, Ramaswamy, additional, Greenberg, Alissa K., additional, Grunenwald, Dominique, additional, Guckenberger, Matthias, additional, Gulati, Swati, additional, Hassan, Raffit, additional, Hazzard, Christopher, additional, Hegi, Fiona, additional, Hensing, Thomas, additional, Herbst, Roy, additional, Hirsch, Fred R., additional, Horeweg, Nanda, additional, Jablons, David M., additional, Jett, James R., additional, Kaufman, Andrew, additional, Keall, Paul, additional, Kelly, Karen, additional, Kong, Feng-Ming (Spring), additional, Kubota, Kaoru, additional, Laird-Offringa, Ite A., additional, Lara, Primo N., additional, Laskin, Janessa, additional, Le, Quynh-Thu, additional, Le Péchoux, Cécile, additional, Liclican, Elvira L., additional, Lievens, Yolande, additional, Lin, Chia-Chi (Josh), additional, Loo, Billy W., additional, Manus, Michael Mac, additional, Macapinlac, Homer A., additional, Macbeth, Fergus, additional, Mackillop, William J., additional, Maher, Christopher, additional, Mambetsariev, Isa, additional, Mandrekar, Sumithra J., additional, Mansfield, Aaron S., additional, Marks, Lawrence B., additional, Mascaux, Céline, additional, Massion, Pierre P., additional, Mazieres, Julien, additional, McWilliams, Annette, additional, Mitsudomi, Tetsuya, additional, Mok, Tony, additional, Morgensztern, Daniel, additional, Mornex, Francoise, additional, Mulshine, James L., additional, Munden, Reginald F., additional, Nackaerts, Kristiaan, additional, Nakamichi, Shinji, additional, Noguchi, Masayuki, additional, Noonan, Krista, additional, Novello, Silvia, additional, Nowak, Anna K., additional, O’Byrne, Kenneth J., additional, Ohri, Nisha, additional, Okada, Morihito, additional, Ostroff, Jamie S., additional, Parikh, Mamta, additional, Park, Elyse R., additional, Park, Keunchil, additional, Pass, Harvey I., additional, Pastis, Nicholas, additional, Paz-Ares, Luis, additional, Pennell, Nathan, additional, Perol, Maurice, additional, Pillai, Rathi N., additional, Postmus, Pieter E., additional, Ramalingham, Suresh S., additional, Ramella, Sara, additional, Rami-Porta, Ramón, additional, Reck, Martin, additional, Redman, Mary W., additional, Reinmuth, Niels, additional, Ricardi, Umberto, additional, Rice, David, additional, Ridge, Carole A., additional, Rom, William N., additional, Rosenzweig, Kenneth E., additional, Ruffini, Enrico, additional, Rusch, Valerie W., additional, Salgia, Ravi, additional, Sanchez-Cespedes, Montse, additional, Saqi, Anjali, additional, Scagliotti, Giorgio V., additional, Schimmel, Selma, additional, Schwartz, Ann G., additional, Senan, Suresh, additional, Shepherd, Francis A., additional, Siegfried, Jill M., additional, Silvestri, Gerard A., additional, Simon, George R., additional, Smit, Egbert F., additional, Solomon, Stephen B., additional, Stabile, Laura P., additional, Steliga, Matthew A., additional, Stinchcombe, Thomas E., additional, Stollenwerk, Nicholas S., additional, Sun, Jong-Mu, additional, Thomas, Anish, additional, Tsao, Ming-Sound, additional, Tsay, Jun-Chieh J., additional, Van Houtte, Paul, additional, Van Schil, Paul E., additional, van Zandwijk, Nico, additional, Vansteenkiste, J.F., additional, Varella-Garcia, Marileila, additional, Veronesi, Giulia, additional, Vinod, Shalini K., additional, Vokes, Everett E., additional, Wakelee, Heather, additional, Walser, Tonya C., additional, Watanabe, Shun-ichi, additional, Weder, Walter, additional, Wei, Benjamin, additional, Wistuba, Ignacio I., additional, Yang, James Chih-Hsin, additional, Yankelevitz, David F., additional, Yasufuku, Kazuhiro, additional, Yoneda, Ken Y., additional, Zalcman, Gérard, additional, Zhou, Caicun, additional, Zhou, Yang, additional, and Zips, Daniel, additional

Published
2018
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64. Microenvironment and Lung Cancer

Author

Walser, Tonya C., primary, Liclican, Elvira L., additional, O’Byrne, Kenneth J., additional, Cho, William C.S., additional, and Dubinett, Steven M., additional

Published
2018
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65. Mono-phosphorylation at Ser4 of barrier-to-autointegration factor (Banf1) significantly reduces its DNA binding capability by inducing critical changes in its local conformation and DNA binding surface.

Author

Tang, Ming, Suraweera, Amila, Nie, Xuqiang, Li, Zilin, Lai, Pinglin, Wells, James W., O'Byrne, Kenneth J., Woods, Robert J, Bolderson, Emma, and Richard, Derek J

Abstract

Barrier-to-autointegration factor (Banf1) is a small DNA-bridging protein. The binding status of Banf1 to DNA is regulated by its N-terminal phosphorylation and dephosphorylation, which plays a critical role in cell proliferation. Banf1 can be phosphorylated at Ser4 into mono-phosphorylated Banf1, which is further phosphorylated at Thr3 to form di-phosphorylated Banf1. It was observed decades ago that mono-phosphorylated Banf1 cannot bind to DNA. However, the underlying molecular- and atomic-level mechanisms remain unclear. A clear understanding of these mechanisms will aid in interfering with the cell proliferation process for better global health. Herein, we explored the detailed atomic bases of unphosphorylated Banf1–DNA binding and how mono- and di-phosphorylation of Banf1 impair these atomic bases to eliminate its DNA-binding capability, followed by exploring the DNA-binding capability of mono- and di-phosphorylation Banf1, using comprehensive and systematic molecular modelling and molecular dynamics simulations. This work presented in detail the residue-level binding energies, hydrogen bonds and water bridges between Banf1 and DNA, some of which have not been reported. Moreover, we revealed that mono-phosphorylation of Banf1 causes its N-terminal secondary structure changes, which in turn induce significant changes in Banf1's DNA binding surface, thus eliminating its DNA-binding capability. At the atomic level, we also uncovered the alterations in interactions due to the induction of mono-phosphorylation that result in the N-terminal secondary structure changes of Banf1. Additionally, our modelling showed that phosphorylated Banf1 with their dominant N-terminal secondary structures bind to DNA with a significantly lower affinity and the docked binding pose are not stable in MD simulations. These findings help future studies in predicting effect of mutations in Banf1 on its DNA-binding capability and open a novel avenue for the development of therapeutics such as cancer drugs, targeting cell proliferation by inducing conformational changes in Banf1's N-terminal domain. [ABSTRACT FROM AUTHOR]

Published
2023
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66. The Q-IMPROvE (Queensland-IMplementation of PRecision Oncology in brEast cancer) pilot study

Author

McCart Reed, Amy E, primary, McCurry, Therese, additional, Hollway, Georgina, additional, Al-Saig, Haidar, additional, Andelkovic, Vladimir, additional, Cuff, Katharine, additional, Cummings, Margaret, additional, Fairbairn, David, additional, Inglis, Po-ling, additional, Jagger, Gillian, additional, Johanson, Helene, additional, Kalinowski, Lauren, additional, Kondrashova, Olga, additional, Koufariotis, Lambros T., additional, Kuchel, Anna, additional, Ladwa, Rahul, additional, Lau, Chiyan, additional, Lundie, Ben, additional, Fan, Helen Mar, additional, McCarthy, Nicole, additional, Middleton, Kathryn, additional, Murugappan, Kowsalya, additional, Nalder, Mark, additional, Niland, Colleen, additional, Nottage, Michelle K, additional, O’Byrne, Kenneth J, additional, Pearson, John V, additional, Roberts, Kate, additional, Hormaechea, Gorane Santamaria, additional, Snell, Cameron, additional, Steinke, Karin, additional, Suder, Aneta, additional, Tam, Diana, additional, Walpole, Euan, additional, Woodward, Natasha, additional, Wong, Clement, additional, Wong, Ho Yi, additional, Xu, Wen, additional, Simpson, Peter T, additional, Waddell, Nicola, additional, and Lakhani, Sunil R, additional

Published
2023
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67. hSSB1 (NABP2/OBFC2B) modulates the DNA damage and androgen‐induced transcriptional response in prostate cancer

Author

Adams, Mark N., primary, Croft, Laura V., additional, Urquhart, Aaron, additional, Saleem, Mohamed Ashick Mohamed, additional, Rockstroh, Anja, additional, Duijf, Pascal H. G., additional, Thomas, Patrick B., additional, Ferguson, Genevieve P., additional, Najib, Idris Mohd, additional, Shah, Esha T., additional, Bolderson, Emma, additional, Nagaraj, Shivashankar, additional, Williams, Elizabeth D., additional, Nelson, Colleen C., additional, O'Byrne, Kenneth J., additional, and Richard, Derek J., additional

Published
2023
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68. Five-Year Survival Outcomes With Nivolumab Plus Ipilimumab Versus Chemotherapy as First-Line Treatment for Metastatic Non–Small-Cell Lung Cancer in CheckMate 227

Author

Brahmer, Julie R., primary, Lee, Jong-Seok, additional, Ciuleanu, Tudor-Eliade, additional, Bernabe Caro, Reyes, additional, Nishio, Makoto, additional, Urban, Laszlo, additional, Audigier-Valette, Clarisse, additional, Lupinacci, Lorena, additional, Sangha, Randeep, additional, Pluzanski, Adam, additional, Burgers, Jacobus, additional, Mahave, Mauricio, additional, Ahmed, Samreen, additional, Schoenfeld, Adam J., additional, Paz-Ares, Luis G., additional, Reck, Martin, additional, Borghaei, Hossein, additional, O'Byrne, Kenneth J., additional, Gupta, Ravi G., additional, Bushong, Judith, additional, Li, Li, additional, Blum, Steven I., additional, Eccles, Laura J., additional, and Ramalingam, Suresh S., additional

Published
2023
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70. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials

Author

Yang, James Chih-Hsin, Wu, Yi-Long, Schuler, Martin, Sebastian, Martin, Popat, Sanjay, Yamamoto, Nobuyuki, Zhou, Caicun, Hu, Cheng-Ping, O'Byrne, Kenneth, Feng, Jifeng, Lu, Shun, Huang, Yunchao, Geater, Sarayut L, Lee, Kye Young, Tsai, Chun-Ming, Gorbunova, Vera, Hirsh, Vera, Bennouna, Jaafar, Orlov, Sergey, Mok, Tony, Boyer, Michael, Su, Wu-Chou, Lee, Ki Hyeong, Kato, Terufumi, Massey, Dan, Shahidi, Mehdi, Zazulina, Victoria, and Sequist, Lecia V

Published
2015
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71. Does EGFR Mutation Type Influence Patient-Reported Outcomes in Patients with Advanced EGFR Mutation-Positive Non-Small-Cell Lung Cancer? Analysis of Two Large, Phase III Studies Comparing Afatinib with Chemotherapy (LUX-Lung 3 and LUX-Lung 6)

Author

Wu, Yi-Long, Hirsh, Vera, Sequist, Lecia V., Hu, Cheng-Ping, Feng, Jifeng, Lu, Shun, Huang, Yunchao, Schuler, Martin, Mok, Tony, Yamamoto, Nobuyuki, O’Byrne, Kenneth, Geater, Sarayut L., Zhou, Caicun, Massey, Dan, Märten, Angela, Lungershausen, Juliane, and Yang, James Chih-Hsin

Published
2017
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72. 118 Delineation of spatial tissue signatures of immunotherapy response groups in non-small cell lung cancer (NSCLC)

Author

Kulasinghe, Arutha, primary, Monkman, James, additional, Kim, Honesty, additional, Mayer, Aaron, additional, Mehdi, Ahmed, additional, Cumberbatch, Marie, additional, Bhagat, Milan, additional, Schneider, Fabian, additional, Thaagard, Jeppe, additional, Mansfield, James, additional, Ladwa, Rahul, additional, Mueller, Scott, additional, Adams, Mark, additional, and O’byrne, Kenneth, additional

Published
2022
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73. 117 High-plex spatial proteomic profiling of immunotherapy response groups in head and neck cancer identifies tissue signatures associated with therapy response

Author

Kulasinghe, Arutha, primary, Sadeghirad, Habib, additional, Liu, Ning, additional, Monkman, James, additional, Tan, Chin Wee, additional, Cooper, Caroline, additional, Church, Sarah, additional, Schneider, Fabian, additional, Thaagard, Jeppe, additional, Mansfield, James, additional, O’byrne, Kenneth, additional, Davis, Melissa, additional, and Hughes, Brett, additional

Published
2022
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76. Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, double-blind, phase 3 trial

Author

Ramalingam, Suresh S, Jänne, Pasi A, Mok, Tony, O'Byrne, Kenneth, Boyer, Michael J, Von Pawel, Joachim, Pluzanski, Adam, Shtivelband, Mikhail, Docampo, Lara Iglesias, Bennouna, Jaafar, Zhang, Hui, Liang, Jane Q, Doherty, Jim P, Taylor, Ian, Mather, Cecile B, Goldberg, Zelanna, O'Connell, Joseph, and Paz-Ares, Luis

Published
2014
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79. Protein Tyrosine Phosphatase Non-Receptor 11 (PTPN11 /Shp2) as a Driver Oncogene and a Novel Therapeutic Target in Non-Small Cell Lung Cancer (NSCLC).

Author

Richards, Cathy E., Elamin, Yasir Y., Carr, Aoife, Gately, Kathy, Rafee, Shereen, Cremona, Mattia, Hanrahan, Emer, Smyth, Robert, Ryan, Daniel, Morgan, Ross K., Kennedy, Susan, Hudson, Lance, Fay, Joanna, O'Byrne, Kenneth, Hennessy, Bryan T., and Toomey, Sinead

Subjects
NON-small-cell lung carcinoma, PHOSPHOPROTEIN phosphatases, SOMATIC mutation, MITOGEN-activated protein kinases, SQUAMOUS cell carcinoma, PROTEIN-tyrosine phosphatase
Abstract

PTPN11 encodes the SHP2 protein tyrosine phosphatase that activates the mitogen-activated protein kinase (MAPK) pathway upstream of KRAS and MEK. PTPN11/Shp2 somatic mutations occur frequently in Juvenile myelomonocytic leukaemia (JMML); however, the role of mutated PTPN11 in lung cancer tumourigenesis and its utility as a therapeutic target has not been fully addressed. We applied mass-spectrometry-based genotyping to DNA extracted from the tumour and matched the normal tissue of 356 NSCLC patients (98 adenocarcinomas (LUAD) and 258 squamous cell carcinomas (LUSC)). Further, PTPN11 mutation cases were identified in additional cohorts, including TCGA, Broad, and MD Anderson datasets and the COSMIC database. PTPN11 constructs harbouring PTPN11 E76A, A72D and C459S mutations were stably expressed in IL-3 dependent BaF3 cells and NSCLC cell lines (NCI-H1703, NCI-H157, NCI-H1299). The MAPK and PI3K pathway activation was evaluated using Western blotting. PTPN11/Shp2 phosphatase activity was measured in whole-cell protein lysates using an Shp2 assay kit. The Shp2 inhibitor (SHPi) was assessed both in vitro and in vivo in a PTPN11-mutated cell line for improved responses to MAPK and PI3K targeting therapies. Somatic PTPN11 hotspot mutations occurred in 4/98 (4.1%) adenocarcinomas and 7/258 (2.7%) squamous cells of 356 NSCLC patients. Additional 26 PTPN11 hotspot mutations occurred in 23 and 3 adenocarcinomas and squamous cell carcinoma, respectively, across the additional cohorts. Mutant PTPN11 significantly increased the IL-3 independent survival of Ba/F3 cells compared to wildtype PTPN11 (p < 0.0001). Ba/F3, NCI-H1703, and NCI-H157 cells expressing mutant PTPN11 exhibited increased PTPN11/Shp2 phosphatase activity and phospho-ERK1/2 levels compared to cells expressing wildtype PTPN11. The transduction of the PTPN11 inactivating mutation C459S into NSCLC cell lines led to decreased phospho-ERK, as well as decreased phospho-AKT in the PTPN11-mutated NCI-H661 cell line. NCI-H661 cells (PTPN11-mutated, KRAS-wild type) were significantly more sensitive to growth inhibition by the PI3K inhibitor copanlisib (IC50: 13.9 ± 4.7 nM) compared to NCI-H1703 (PTPN11/KRAS-wild type) cells (IC50: >10,000 nM). The SHP2 inhibitor, in combination with the PI3K targeting therapy copanlisib, showed no significant difference in tumour development in vivo; however, this significantly prevented MAPK pathway induction in vitro (p < 0.0001). PTPN11/Shp2 demonstrated the in vitro features of a driver oncogene and could potentially sensitize NSCLC cells to PI3K inhibition and inhibit MAPK pathway activation following PI3K pathway targeting. [ABSTRACT FROM AUTHOR]

Published
2023
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81. Medical and Surgical Care of Patients With Mesothelioma and Their Relatives Carrying Germline BAP1 Mutations

Author

Carbone, Michele, primary, Pass, Harvey I., additional, Ak, Guntulu, additional, Alexander, H. Richard, additional, Baas, Paul, additional, Baumann, Francine, additional, Blakely, Andrew M., additional, Bueno, Raphael, additional, Bzura, Aleksandra, additional, Cardillo, Giuseppe, additional, Churpek, Jane E., additional, Dianzani, Irma, additional, De Rienzo, Assunta, additional, Emi, Mitsuru, additional, Emri, Salih, additional, Felley-Bosco, Emanuela, additional, Fennell, Dean A., additional, Flores, Raja M., additional, Grosso, Federica, additional, Hayward, Nicholas K., additional, Hesdorffer, Mary, additional, Hoang, Chuong D., additional, Johansson, Peter A., additional, Kindler, Hedy L., additional, Kittaneh, Muaiad, additional, Krausz, Thomas, additional, Mansfield, Aaron, additional, Metintas, Muzaffer, additional, Minaai, Michael, additional, Mutti, Luciano, additional, Nielsen, Maartje, additional, O’Byrne, Kenneth, additional, Opitz, Isabelle, additional, Pastorino, Sandra, additional, Pentimalli, Francesca, additional, de Perrot, Marc, additional, Pritchard, Antonia, additional, Ripley, Robert Taylor, additional, Robinson, Bruce, additional, Rusch, Valerie, additional, Taioli, Emanuela, additional, Takinishi, Yasutaka, additional, Tanji, Mika, additional, Tsao, Anne S., additional, Tuncer, A. Murat, additional, Walpole, Sebastian, additional, Wolf, Andrea, additional, Yang, Haining, additional, Yoshikawa, Yoshie, additional, Zolondick, Alicia, additional, Schrump, David S., additional, and Hassan, Raffit, additional

Published
2022
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82. Five-year survival outcomes with nivolumab (NIVO) plus ipilimumab (IPI) versus chemotherapy (chemo) as first-line (1L) treatment for metastatic non–small cell lung cancer (NSCLC): Results from CheckMate 227.

Author

Brahmer, Julie R., primary, Lee, Jong-Seok, additional, Ciuleanu, Tudor-Eliade, additional, Bernabe Caro, Reyes, additional, Nishio, Makoto, additional, Urban, Lazlo, additional, Audigier-Valette, Clarisse, additional, Lupinacci, Lorena, additional, Sangha, Randeep S., additional, Paz-Ares, Luis G., additional, Reck, Martin, additional, Borghaei, Hossein, additional, O'Byrne, Kenneth John, additional, Gupta, Ravi, additional, Bushong, Judith, additional, Li, Li, additional, Blum, Steven I., additional, Eccles, Laura, additional, and Ramalingam, Suresh S., additional

Published
2022
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84. Newly updated activity results of alrizomadlin (APG-115), a novel MDM2/p53 inhibitor, plus pembrolizumab: Phase 2 study in adults and children with various solid tumors.

Author

McKean, Meredith, primary, Tolcher, Anthony W., additional, Reeves, James Andrew, additional, Chmielowski, Bartosz, additional, Shaheen, Montaser F., additional, Beck, Joseph Thaddeus, additional, Orloff, Marlana M., additional, Somaiah, Neeta, additional, Van Tine, Brian Andrew, additional, Drabick, Joseph J., additional, Spira, Alexander I., additional, O'byrne, Kenneth, additional, Karapetis, Christos Stelios, additional, Foresto, Steven A., additional, Movva, Sujana, additional, Martinez, Jose, additional, Li, Mingyu, additional, Winkler, Robert, additional, Yang, Dajun, additional, and Zhai, Yifan, additional

Published
2022
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86. DREAM3R: Durvalumab with chemotherapy as first-line treatment in advanced pleural mesothelioma—A phase 3 randomized trial.

Author

Forde, Patrick M., primary, Nowak, Anna K., additional, Kok, Peey-Sei, additional, Brown, Chris, additional, Sun, Zhuoxin, additional, Anagnostou, Valsamo, additional, O'Byrne, Kenneth John, additional, Yip, Sonia, additional, Cook, Alistair, additional, Lesterhuis, Willem Joost, additional, Hughes, Brett Gordon Maxwell, additional, Pavlakis, Nick, additional, Brahmer, Julie R., additional, Kindler, Hedy L., additional, Tsao, Anne S., additional, Zauderer, Marjorie Glass, additional, Ramalingam, Suresh S., additional, and Stockler, Martin R., additional

Published
2022
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88. Barrier-to-autointegration-factor (Banf1) modulates DNA double-strand break repair pathway choice via regulation of DNA-dependent kinase (DNA-PK) activity

Author

Burgess, Joshua T, Cheong, Chee Man, Suraweera, Amila, Sobanski, Thais, Beard, Sam, Dave, Keyur, Rose, Maddison, Boucher, Didier, Croft, Laura V, Adams, Mark N, O’Byrne, Kenneth, Richard, Derek J, and Bolderson, Emma

Subjects
DNA-Binding Proteins, HEK293 Cells, DNA Repair, AcademicSubjects/SCI00010, Humans, DNA Breaks, Double-Stranded, DNA-Activated Protein Kinase, Genome Integrity, Repair and Replication, Homologous Recombination, Cell Line
Abstract

DNA repair pathways are essential to maintain the integrity of the genome and prevent cell death and tumourigenesis. Here, we show that the Barrier-to-Autointegration Factor (Banf1) protein has a role in the repair of DNA double-strand breaks. Banf1 is characterized as a nuclear envelope protein and mutations in Banf1 are associated with the severe premature aging syndrome, Néstor–Guillermo Progeria Syndrome. We have previously shown that Banf1 directly regulates the activity of PARP1 in the repair of oxidative DNA lesions. Here, we show that Banf1 also has a role in modulating DNA double-strand break repair through regulation of the DNA-dependent Protein Kinase catalytic subunit, DNA-PKcs. Specifically, we demonstrate that Banf1 relocalizes from the nuclear envelope to sites of DNA double-strand breaks. We also show that Banf1 can bind to and directly inhibit the activity of DNA-PKcs. Supporting this, cellular depletion of Banf1 leads to an increase in non-homologous end-joining and a decrease in homologous recombination, which our data suggest is likely due to unrestrained DNA-PKcs activity. Overall, this study identifies how Banf1 regulates double-strand break repair pathway choice by modulating DNA-PKcs activity to control genome stability within the cell.

Published
2021

89. Clinical Applications of Circulating Tumour Cells and Circulating Tumour DNA in Non-Small Cell Lung Cancer-An Update

Author

Kapeleris, Joanna, Ebrahimi Warkiani, Majid, Kulasinghe, Arutha, Vela, Ian, Kenny, Liz, Ladwa, Rahul, O’Byrne, Kenneth, Punyadeera, Chamindie, Kapeleris, Joanna, Ebrahimi Warkiani, Majid, Kulasinghe, Arutha, Vela, Ian, Kenny, Liz, Ladwa, Rahul, O’Byrne, Kenneth, and Punyadeera, Chamindie

Abstract

Despite efforts to improve earlier diagnosis of non-small cell lung cancer (NSCLC), most patients present with advanced stage disease, which is often associated with poor survival outcomes with only 15% surviving for 5 years from their diagnosis. Tumour tissue biopsy is the current mainstream for cancer diagnosis and prognosis in many parts of the world. However, due to tumour heterogeneity and accessibility issues, liquid biopsy is emerging as a game changer for both cancer diagnosis and prognosis. Liquid biopsy is the analysis of tumour-derived biomarkers in body fluids, which has remarkable advantages over the use of traditional tumour biopsy. Circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA) are two main derivatives of liquid biopsy. CTC enumeration and molecular analysis enable monitoring of cancer progression, recurrence, and treatment response earlier than traditional biopsy through a minimally invasive liquid biopsy approach. CTC-derived ex-vivo cultures are essential to understanding CTC biology and their role in metastasis, provide a means for personalized drug testing, and guide treatment selection. Just like CTCs, ctDNA provides opportunity for screening, monitoring, treatment evaluation, and disease surveillance. We present an updated review highlighting the prognostic and therapeutic significance of CTCs and ctDNA in NSCLC.

Published
2022

90. Beyond PARP1: The Potential of Other Members of the Poly (ADP-Ribose) Polymerase Family in DNA Repair and Cancer Therapeutics

Author

Richard, Iain A., Burgess, Joshua T., O’Byrne, Kenneth J., Bolderson, Emma, Richard, Iain A., Burgess, Joshua T., O’Byrne, Kenneth J., and Bolderson, Emma

Abstract

The proteins within the Poly-ADP Ribose Polymerase (PARP) family encompass a diverse and integral set of cellular functions. PARP1 and PARP2 have been extensively studied for their roles in DNA repair and as targets for cancer therapeutics. Several PARP inhibitors (PARPi) have been approved for clinical use, however, while their efficacy is promising, tumours readily develop PARPi resistance. Many other members of the PARP protein family share catalytic domain homology with PARP1/2, however, these proteins are comparatively understudied, particularly in the context of DNA damage repair and tumourigenesis. This review explores the functions of PARP4,6-16 and discusses the current knowledge of the potential roles these proteins may play in DNA damage repair and as targets for cancer therapeutics.

Published
2022

91. Medical and Surgical Care of Patients With Mesothelioma and Their Relatives Carrying Germline BAP1 Mutations

Author

Carbone, Michele, Pass, Harvey I., Ak, Guntulu, Alexander, H. Richard, Baas, Paul, Baumann, Francine, Blakely, Andrew M., Bueno, Raphael, Bzura, Aleksandra, Cardillo, Giuseppe, Churpek, Jane E., Dianzani, Irma, De Rienzo, Assunta, Emi, Mitsuru, Emri, Salih, Felley-Bosco, Emanuela, Fennell, Dean A., Flores, Raja M., Grosso, Federica, Hayward, Nicholas K., Hesdorffer, Mary, Hoang, Chuong D., Johansson, Peter A., Kindler, Hedy L., Kittaneh, Muaiad, Krausz, Thomas, Mansfield, Aaron, Metintas, Muzaffer, Minaai, Michael, Mutti, Luciano, Nielsen, Maartje, O'Byrne, Kenneth, Opitz, Isabelle, Pastorino, Sandra, Pentimalli, Francesca, de Perrot, Marc, Pritchard, Antonia, Ripley, Robert Taylor, Robinson, Bruce, Rusch, Valerie, Taioli, Emanuela, Takinishi, Yasutaka, Tanji, Mika, Tsao, Anne S., Tuncer, A. Murat, Walpole, Sebastian, Wolf, Andrea, Yang, Haining, Yoshikawa, Yoshie, Zolondick, Alicia, Schrump, David S., Hassan, Raffit, Carbone, Michele, Pass, Harvey I., Ak, Guntulu, Alexander, H. Richard, Baas, Paul, Baumann, Francine, Blakely, Andrew M., Bueno, Raphael, Bzura, Aleksandra, Cardillo, Giuseppe, Churpek, Jane E., Dianzani, Irma, De Rienzo, Assunta, Emi, Mitsuru, Emri, Salih, Felley-Bosco, Emanuela, Fennell, Dean A., Flores, Raja M., Grosso, Federica, Hayward, Nicholas K., Hesdorffer, Mary, Hoang, Chuong D., Johansson, Peter A., Kindler, Hedy L., Kittaneh, Muaiad, Krausz, Thomas, Mansfield, Aaron, Metintas, Muzaffer, Minaai, Michael, Mutti, Luciano, Nielsen, Maartje, O'Byrne, Kenneth, Opitz, Isabelle, Pastorino, Sandra, Pentimalli, Francesca, de Perrot, Marc, Pritchard, Antonia, Ripley, Robert Taylor, Robinson, Bruce, Rusch, Valerie, Taioli, Emanuela, Takinishi, Yasutaka, Tanji, Mika, Tsao, Anne S., Tuncer, A. Murat, Walpole, Sebastian, Wolf, Andrea, Yang, Haining, Yoshikawa, Yoshie, Zolondick, Alicia, Schrump, David S., and Hassan, Raffit

Abstract

The most common malignancies that develop in carriers of BAP1 germline mutations include diffuse malignant mesothelioma, uveal and cutaneous melanoma, renal cell carcinoma, and less frequently, breast cancer, several types of skin carcinomas, and other tumor types. Mesotheliomas in these patients are significantly less aggressive, and patients require a multidisciplinary approach that involves genetic counseling, medical genetics, pathology, surgical, medical, and radiation oncology expertise. Some BAP1 carriers have asymptomatic mesothelioma that can be followed by close clinical observation without apparent adverse outcomes: they may survive many years without therapy. Others may grow aggressively but very often respond to therapy. Detecting BAP1 germline mutations has, therefore, substantial medical, social, and economic impact. Close monitoring of these patients and their relatives is expected to result in prolonged life expectancy, improved quality of life, and being cost-effective. The co-authors of this paper are those who have published the vast majority of cases of mesothelioma occurring in patients carrying inactivating germline BAP1 mutations and who have studied the families affected by the BAP1 cancer syndrome for many years. This paper reports our experience. It is intended to be a source of information for all physicians who care for patients carrying germline BAP1 mutations. We discuss the clinical presentation, diagnostic and treatment challenges, and our recommendations of how to best care for these patients and their family members, including the potential economic and psychosocial impact.

Published
2022

92. Pembrolizumab-induced toxic epidermal necrolysis : Case report

Author

Chow, Kar Ven Cavan, O'Leary, Connor, Paxton-Hall, Fiona, Lambie, Duncan, O'Byrne, Kenneth, Chow, Kar Ven Cavan, O'Leary, Connor, Paxton-Hall, Fiona, Lambie, Duncan, and O'Byrne, Kenneth

Abstract

A 63-year-old man with metastatic lung adenocarcinoma presented with biopsy confirmed toxic epidermal necrolysis (TEN). Symptoms commenced following 3 cycles of carboplatin, pemetrexed and pembrolizumab, with the first cycle given ~9.5 weeks prior to presentation. The patient was managed with immunosuppressive therapy including high dose methylprednisolone, cyclosporine, intravenous immunoglobulin, antibiotics and optimal skin care, and achieved excellent recovery of the skin lesions with minimal sequelae. This rare occurrence of pembrolizumab-induced TEN has only been reported previously in a few cases with limited evidence on management. Given the increasing use of immune checkpoint inhibitors and the long half-life of these agents, our case highlights the importance of recognizing this complication and of a multidisciplinary approach to management.

Published
2022

93. First-Line Nivolumab Plus Ipilimumab in Advanced NSCLC: 4-Year Outcomes From the Randomized, Open-Label, Phase 3 CheckMate 227 Part 1 Trial

Author

Bristol-Myers Squibb, Ono Pharmaceutical, Paz-Ares, Luis, Ramalingam, Suresh S., Ciuleanu, Tudor-Eliade, Lee, Jong-Seok, Urban, Laszlo, Bernabé Caro, Reyes, Park, Keunchil, Sakai, Hiroshi, Ohe, Yuichiro, Nishio, Makoto, Audigier-Valette, Clarisse, Burgers, Jacobus A., Pluzanski, Adam, Sangha, Randeep, Gallardo, Carlos, Takeda, Masayuki, Linardou, Helena, Lupinacci, Lorena, Lee, Ki Hyeong, Caserta, Claudia, Provencio, Mariano, Carcereny, Enric, Otterson, Gregory A., Schenker, Michael, Zurawski, Bogdan, Alexandru, Aurelia, Vergnenegre, Alain, Raimbourg, Judith, Feeney, Kynan, Kim, Sang-We, Borghaei, Hossein, O'Byrne, Kenneth J., Hellmann, Matthew D., Memaj, Arteid, Nathan, Faith Ellen, Bushong, Judith, Tran, Phuong, Brahmer, Julie R., Reck, Martin, Bristol-Myers Squibb, Ono Pharmaceutical, Paz-Ares, Luis, Ramalingam, Suresh S., Ciuleanu, Tudor-Eliade, Lee, Jong-Seok, Urban, Laszlo, Bernabé Caro, Reyes, Park, Keunchil, Sakai, Hiroshi, Ohe, Yuichiro, Nishio, Makoto, Audigier-Valette, Clarisse, Burgers, Jacobus A., Pluzanski, Adam, Sangha, Randeep, Gallardo, Carlos, Takeda, Masayuki, Linardou, Helena, Lupinacci, Lorena, Lee, Ki Hyeong, Caserta, Claudia, Provencio, Mariano, Carcereny, Enric, Otterson, Gregory A., Schenker, Michael, Zurawski, Bogdan, Alexandru, Aurelia, Vergnenegre, Alain, Raimbourg, Judith, Feeney, Kynan, Kim, Sang-We, Borghaei, Hossein, O'Byrne, Kenneth J., Hellmann, Matthew D., Memaj, Arteid, Nathan, Faith Ellen, Bushong, Judith, Tran, Phuong, Brahmer, Julie R., and Reck, Martin

Abstract

[Introduction] In CheckMate 227, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with tumor programmed death-ligand 1 (PD-L1) greater than or equal to 1% (primary end point) or less than 1% (prespecified descriptive analysis). We report results with minimum 4 years' follow-up., [Methods] Adults with previously untreated stage IV or recurrent NSCLC were randomized (1:1:1) to nivolumab plus ipilimumab, nivolumab, or chemotherapy (PD-L1 ≥1%); or to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (PD-L1 <1%). Efficacy included OS and other measures. Safety included timing and management of immune-mediated adverse events (AEs). A post hoc analysis evaluated efficacy in patients who discontinued nivolumab plus ipilimumab due to treatment-related AEs (TRAEs)., [Results] After 54.8 months' median follow-up, OS remained longer with nivolumab plus ipilimumab versus chemotherapy in patients with PD-L1 greater than or equal to 1% (hazard ratio = 0.76; 95% confidence interval: 0.65–0.90) and PD-L1 less than 1% (0.64; 0.51–0.81); 4-year OS rate with nivolumab plus ipilimumab versus chemotherapy was 29% versus 18% (PD-L1 ≥1%); and 24% versus 10% (PD-L1 <1%). Benefits were observed in both squamous and nonsquamous histologies. In a descriptive analysis, efficacy was improved with nivolumab plus ipilimumab relative to nivolumab (PD-L1 ≥1%) and nivolumab plus chemotherapy (PD-L1 <1%). Safety was consistent with previous reports. The most common immune-mediated AE with nivolumab plus ipilimumab, nivolumab, and nivolumab plus chemotherapy was rash; most immune-mediated AEs (except endocrine events) occurred within 6 months from start of treatment and resolved within 3 months after, mainly with systemic corticosteroids. Patients who discontinued nivolumab plus ipilimumab due to TRAEs had long-term OS benefits, as seen in the all randomized population., [Conclusions] At more than 4 years' minimum follow-up, with all patients off immunotherapy treatment for at least 2 years, first-line nivolumab plus ipilimumab continued to demonstrate durable long-term efficacy in patients with advanced NSCLC. No new safety signals were identified. Immune-mediated AEs occurred early and resolved quickly with guideline-based management. Discontinuation of nivolumab plus ipilimumab due to TRAEs did not have a negative impact on the long-term benefits seen in all randomized patients.

Published
2022

94. Response to chemotherapy is predictive in relation to longer overall survival in an individual patient combined-analysis with pleural mesothelioma

Author

Blayney, Jaine K., Ceresoli, Giovanni L., Castagneto, Bruno, O’Brien, Mary E.R., Hasan, Baktiar, Sylvester, Richard, Rudd, Robin, Steele, Jeremy, Busacca, Sara, Porta, Camillo, Mutti, Luciano, O’Byrne, Kenneth J, Scullin, Paula, Gaafar, Rabab, Baas, Paul, Van Meerbeeck, Jan, and Fennell, Dean A.

Published
2012
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96. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study

Author

Pirker, Robert, Pereira, Jose R, von Pawel, Joachim, Krzakowski, Maciej, Ramlau, Rodryg, Park, Keunchil, de Marinis, Filippo, Eberhardt, Wilfried EE, Paz-Ares, Luis, Störkel, Stephan, Schumacher, Karl-Maria, von Heydebreck, Anja, Celik, Ilhan, and O'Byrne, Kenneth J

Published
2012
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