C N Owen1, A N Shoushtari2, D Chauhan3, D J Palmieri4, B Lee5, M W Rohaan6, J Mangana7, V Atkinson8, F Zaman9, A Young10, C Hoeller11, P Hersey1, R Dummer7, M A Khattak12, M Millward13, S P Patel14, A Haydon9, D B Johnson10, S Lo1, C U Blank6, S Sandhu5, M S Carlino15, J M G Larkin3, A M Menzies16, G V Long17. 1. Melanoma Institute Australia, The University of Sydney, Sydney, Australia. 2. Memorial Sloan Kettering Cancer Center, New York, USA. 3. The Royal Marsden NHS Foundation Trust, London, UK. 4. Westmead Hospital and Blacktown Hospitals, Sydney, Australia. 5. Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Australia. 6. Netherlands Cancer Institute, Amsterdam, Netherlands. 7. University Hospital Zurich, Zürich, Switzerland. 8. Greenslopes Private Hospital, Princess Alexandra Hospital and The University of Queensland, Brisbane, Australia. 9. The Alfred Hospital, Melbourne, Australia. 10. Vanderbilt University Medical Center, Nashville, USA. 11. Medical University of Vienna, Vienna, Austria. 12. Fiona Stanley Hospital, The University of Western Australia, Perth, Australia. 13. School of Medicine and Pharmacology, Nedlands, Australia. 14. The University of Texas MD Anderson Cancer Center, Houston, USA. 15. Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Westmead Hospital and Blacktown Hospitals, Sydney, Australia. 16. Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Royal North Shore and Mater Hospitals, Sydney, Australia. 17. Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Royal North Shore and Mater Hospitals, Sydney, Australia. Electronic address: georgina.long@sydney.edu.au.
Abstract
BACKGROUND: Anti-programmed cell death protein 1 (PD-1) antibodies (PD1) prolong recurrence-free survival in high-risk resected melanoma; however, approximately 25%-30% of patients recur within 1 year. This study describes the pattern of recurrence, management and outcomes of patients who recur with adjuvant PD1 therapy. PATIENTS AND METHODS: Consecutive patients from 16 centres who recurred having received adjuvant PD1 therapy for resected stage III/IV melanoma were studied. Recurrence characteristics, management and outcomes were examined; patients with mucosal melanoma were analysed separately. RESULTS: Melanoma recurrence occurred in 147 (17%) of ∼850 patients treated with adjuvant PD1. In those with cutaneous melanoma (n = 136), median time to recurrence was 4.6 months (range 0.3-35.7); 104 (76%) recurred during (ON) adjuvant PD1 after a median 3.2 months and 32 (24%) following (OFF) treatment cessation after a median 12.5 months, including in 21 (15%) who ceased early for toxicity. Fifty-nine (43%) recurred with locoregional disease only and 77 (57%) with distant disease. Of those who recurred locally, 22/59 (37%) subsequently recurred distantly. Eighty-nine (65%) patients received systemic therapy after recurrence. Of those who recurred ON adjuvant PD1, none (0/6) responded to PD1 alone; 8/33 assessable patients (24%) responded to ipilimumab (alone or in combination with PD1) and 18/23 (78%) responded to BRAF/MEK inhibitors. Of those who recurred OFF adjuvant PD1, two out of five (40%) responded to PD1 monotherapy, two out of five (40%) responded to ipilimumab-based therapy and 9/10 (90%) responded to BRAF/MEK inhibitors. CONCLUSIONS: Most patients who recur early despite adjuvant PD1 develop distant metastases. In those who recur ON adjuvant PD1, there is minimal activity of further PD1 monotherapy, but ipilimumab (alone or in combination with PD1) and BRAF/MEK inhibitors have clinical utility. Retreatment with PD1 may have activity in select patients who recur OFF PD1.
BACKGROUND: Anti-programmed cell death protein 1 (PD-1) antibodies (PD1) prolong recurrence-free survival in high-risk resected melanoma; however, approximately 25%-30% of patients recur within 1 year. This study describes the pattern of recurrence, management and outcomes of patients who recur with adjuvant PD1 therapy. PATIENTS AND METHODS: Consecutive patients from 16 centres who recurred having received adjuvant PD1 therapy for resected stage III/IV melanoma were studied. Recurrence characteristics, management and outcomes were examined; patients with mucosal melanoma were analysed separately. RESULTS: Melanoma recurrence occurred in 147 (17%) of ∼850 patients treated with adjuvant PD1. In those with cutaneous melanoma (n = 136), median time to recurrence was 4.6 months (range 0.3-35.7); 104 (76%) recurred during (ON) adjuvant PD1 after a median 3.2 months and 32 (24%) following (OFF) treatment cessation after a median 12.5 months, including in 21 (15%) who ceased early for toxicity. Fifty-nine (43%) recurred with locoregional disease only and 77 (57%) with distant disease. Of those who recurred locally, 22/59 (37%) subsequently recurred distantly. Eighty-nine (65%) patients received systemic therapy after recurrence. Of those who recurred ON adjuvant PD1, none (0/6) responded to PD1 alone; 8/33 assessable patients (24%) responded to ipilimumab (alone or in combination with PD1) and 18/23 (78%) responded to BRAF/MEK inhibitors. Of those who recurred OFF adjuvant PD1, two out of five (40%) responded to PD1 monotherapy, two out of five (40%) responded to ipilimumab-based therapy and 9/10 (90%) responded to BRAF/MEK inhibitors. CONCLUSIONS: Most patients who recur early despite adjuvant PD1 develop distant metastases. In those who recur ON adjuvant PD1, there is minimal activity of further PD1 monotherapy, but ipilimumab (alone or in combination with PD1) and BRAF/MEK inhibitors have clinical utility. Retreatment with PD1 may have activity in select patients who recur OFF PD1.
Authors: Alexander M M Eggermont; Christian U Blank; Mario Mandala; Georgina V Long; Victoria Atkinson; Stéphane Dalle; Andrew Haydon; Mikhail Lichinitser; Adnan Khattak; Matteo S Carlino; Shahneen Sandhu; James Larkin; Susana Puig; Paolo A Ascierto; Piotr Rutkowski; Dirk Schadendorf; Rutger Koornstra; Leonel Hernandez-Aya; Michele Maio; Alfonsus J M van den Eertwegh; Jean-Jacques Grob; Ralf Gutzmer; Rahima Jamal; Paul Lorigan; Nageatte Ibrahim; Sandrine Marreaud; Alexander C J van Akkooi; Stefan Suciu; Caroline Robert Journal: N Engl J Med Date: 2018-04-15 Impact factor: 91.245
Authors: Lisa Zimmer; Susmitha Apuri; Zeynep Eroglu; Lisa A Kottschade; Andrea Forschner; Ralf Gutzmer; Max Schlaak; Lucie Heinzerling; Angela M Krackhardt; Carmen Loquai; Svetomir N Markovic; Richard W Joseph; Kelly Markey; Jochen S Utikal; Carsten Weishaupt; Simone M Goldinger; Vernon K Sondak; Jonathan S Zager; Dirk Schadendorf; Nikhil I Khushalani Journal: Eur J Cancer Date: 2017-02-17 Impact factor: 9.162
Authors: Douglas B Johnson; Eirini Pectasides; Emily Feld; Fei Ye; Shilin Zhao; Romany Johnpulle; Ryan Merritt; David F McDermott; Igor Puzanov; Donald Lawrence; Jeffrey A Sosman; Elizabeth Buchbinder; Ryan J Sullivan Journal: J Immunother Date: 2017-01 Impact factor: 4.456
Authors: Caroline Robert; Jean J Grob; Daniil Stroyakovskiy; Boguslawa Karaszewska; Axel Hauschild; Evgeny Levchenko; Vanna Chiarion Sileni; Jacob Schachter; Claus Garbe; Igor Bondarenko; Helen Gogas; Mario Mandalá; John B A G Haanen; Celeste Lebbé; Andrzej Mackiewicz; Piotr Rutkowski; Paul D Nathan; Antoni Ribas; Michael A Davies; Keith T Flaherty; Paul Burgess; Monique Tan; Eduard Gasal; Maurizio Voi; Dirk Schadendorf; Georgina V Long Journal: N Engl J Med Date: 2019-06-04 Impact factor: 91.245
Authors: James Larkin; Vanna Chiarion-Sileni; Rene Gonzalez; Jean Jacques Grob; C Lance Cowey; Christopher D Lao; Dirk Schadendorf; Reinhard Dummer; Michael Smylie; Piotr Rutkowski; Pier F Ferrucci; Andrew Hill; John Wagstaff; Matteo S Carlino; John B Haanen; Michele Maio; Ivan Marquez-Rodas; Grant A McArthur; Paolo A Ascierto; Georgina V Long; Margaret K Callahan; Michael A Postow; Kenneth Grossmann; Mario Sznol; Brigitte Dreno; Lars Bastholt; Arvin Yang; Linda M Rollin; Christine Horak; F Stephen Hodi; Jedd D Wolchok Journal: N Engl J Med Date: 2015-05-31 Impact factor: 91.245
Authors: Sandra P D'Angelo; James Larkin; Jeffrey A Sosman; Celeste Lebbé; Benjamin Brady; Bart Neyns; Henrik Schmidt; Jessica C Hassel; F Stephen Hodi; Paul Lorigan; Kerry J Savage; Wilson H Miller; Peter Mohr; Ivan Marquez-Rodas; Julie Charles; Martin Kaatz; Mario Sznol; Jeffrey S Weber; Alexander N Shoushtari; Mary Ruisi; Joel Jiang; Jedd D Wolchok Journal: J Clin Oncol Date: 2016-11-07 Impact factor: 44.544
Authors: Jeffrey Weber; Mario Mandala; Michele Del Vecchio; Helen J Gogas; Ana M Arance; C Lance Cowey; Stéphane Dalle; Michael Schenker; Vanna Chiarion-Sileni; Ivan Marquez-Rodas; Jean-Jacques Grob; Marcus O Butler; Mark R Middleton; Michele Maio; Victoria Atkinson; Paola Queirolo; Rene Gonzalez; Ragini R Kudchadkar; Michael Smylie; Nicolas Meyer; Laurent Mortier; Michael B Atkins; Georgina V Long; Shailender Bhatia; Celeste Lebbé; Piotr Rutkowski; Kenji Yokota; Naoya Yamazaki; Tae M Kim; Veerle de Pril; Javier Sabater; Anila Qureshi; James Larkin; Paolo A Ascierto Journal: N Engl J Med Date: 2017-09-10 Impact factor: 91.245
Authors: Georgina V Long; Axel Hauschild; Mario Santinami; Victoria Atkinson; Mario Mandalà; Vanna Chiarion-Sileni; James Larkin; Marta Nyakas; Caroline Dutriaux; Andrew Haydon; Caroline Robert; Laurent Mortier; Jacob Schachter; Dirk Schadendorf; Thierry Lesimple; Ruth Plummer; Ran Ji; Pingkuan Zhang; Bijoyesh Mookerjee; Jeff Legos; Richard Kefford; Reinhard Dummer; John M Kirkwood Journal: N Engl J Med Date: 2017-09-10 Impact factor: 91.245
Authors: Felicity Newell; Yan Kong; James S Wilmott; Peter A Johansson; Peter M Ferguson; Chuanliang Cui; Zhongwu Li; Stephen H Kazakoff; Hazel Burke; Tristan J Dodds; Ann-Marie Patch; Katia Nones; Varsha Tembe; Ping Shang; Louise van der Weyden; Kim Wong; Oliver Holmes; Serigne Lo; Conrad Leonard; Scott Wood; Qinying Xu; Robert V Rawson; Pamela Mukhopadhyay; Reinhard Dummer; Mitchell P Levesque; Göran Jönsson; Xuan Wang; Iwei Yeh; Hong Wu; Nancy Joseph; Boris C Bastian; Georgina V Long; Andrew J Spillane; Kerwin F Shannon; John F Thompson; Robyn P M Saw; David J Adams; Lu Si; John V Pearson; Nicholas K Hayward; Nicola Waddell; Graham J Mann; Jun Guo; Richard A Scolyer Journal: Nat Commun Date: 2019-07-18 Impact factor: 14.919
Authors: Paolo A Ascierto; Allison Betof Warner; Christian Blank; Corrado Caracò; Sandra Demaria; Jeffrey E Gershenwald; Nikhil I Khushalani; Georgina V Long; Jason J Luke; Janice M Mehnert; Caroline Robert; Piotr Rutkowski; Hussein A Tawbi; Iman Osman; Igor Puzanov Journal: J Transl Med Date: 2022-05-10 Impact factor: 8.440
Authors: Kristy K Broman; Tasha M Hughes; Lesly A Dossett; James Sun; Michael J Carr; Dennis A Kirichenko; Avinash Sharma; Edmund K Bartlett; Amanda Ag Nijhuis; John F Thompson; Tina J Hieken; Lisa Kottschade; Jennifer Downs; David E Gyorki; Emma Stahlie; Alexander van Akkooi; David W Ollila; Jill Frank; Yun Song; Giorgos Karakousis; Marc Moncrieff; Jenny Nobes; John Vetto; Dale Han; Jeffrey Farma; Jeremiah L Deneve; Martin D Fleming; Matthew Perez; Kirsten Baecher; Michael Lowe; Roger Olofsson Bagge; Jan Mattsson; Ann Y Lee; Russell S Berman; Harvey Chai; Hidde M Kroon; Roland M Teras; Juri Teras; Norma E Farrow; Georgia M Beasley; Jane Yc Hui; Lukas Been; Schelto Kruijff; David Boulware; Amod A Sarnaik; Vernon K Sondak; Jonathan S Zager Journal: J Am Coll Surg Date: 2020-12-13 Impact factor: 6.532
Authors: Zeynep Eroglu; Kristy K Broman; Jonathan Zager; Nikhil I Khushalani; John F Thompson; Amanda Nijhuis; Tina J Hieken; Lisa Kottschade; Jeffrey M Farma; Meghan Hotz; Jeremiah Deneve; Martin Fleming; Edmund K Bartlett; Avinash Sharma; Lesly Dossett; Tasha Hughes; David E Gyorki; Jennifer Downs; Giorgos Karakousis; Yun Song; Ann Lee; Russell S Berman; Alexander van Akkooi; Emma Stahlie; Dale Han; John Vetto; Georgia Beasley; Norma E Farrow; Jane Yuet Ching Hui; Marc Moncrieff; Jenny Nobes; Kirsten Baecher; Matthew Perez; Michael Lowe; David W Ollila; Frances A Collichio; Roger Olofsson Bagge; Jan Mattsson; Hidde M Kroon; Harvey Chai; Jyri Teras; James Sun; Michael J Carr; Ankita Tandon; Nalan Akgul Babacan; Younchul Kim; Mahrukh Naqvi Journal: J Immunother Cancer Date: 2022-08 Impact factor: 12.469