On this episode of the SO files, Brad and Linda cover the recently published trials on adjuvant options for melanoma, including the COMBI-AD trial and the CHECKMATE-238 trial. As a very special guest, they’ll be interviewing Dr. Robert Andtbacka, Associate Professor of Surgery at the University of Utah, co-author of the recently published MSLT II trial, panel member of the NCCN guidelines on Melanoma, and lead investigator in the use of viral oncolytic therapy “T-VEC”. Given these new results, how will our approach to completion lymph node dissection and adjuvant therapy change in patients with advanced melanoma?
Melanoma Staging and Treatment 1:46
Overview of checkpoint blockade/BRAF/MEK targeted therapies 11:58
Overview of papers: CHECKMATE 238/COMBI-AD trials 17:30
Interview with Dr. Andtbacka 23:59
HIGH YIELD: Dr. Andtbacka summarizes how he will synthesize MSLTII/new adjuvant options into his practice for advanced melanoma 51:05
Updated overview of the current guidelines for the workup and treatment of patients with melanoma.
Phase III MSLT1 trial which definitively established the utility of SLN biopsy for intermediate thickness melanomas. Improved recurrence free and melanoma specific survival for patients with SLN metastases identified.
Great discussion of MSLTII trial results, with guest Dr. Faries (lead author of MSLTII trial).
Faries MB, Thompson JF, Cochran AJ, Andtbacka RH, Mozzillo N, Zager JS, Jahkola T, Bowles TL, Testori A, Beitsch PD, Hoekstra HJ, Moncrieff M, Ingvar C, Wouters MWJM, Sabel MS, Levine EA, Agnese D, Henderson M, Dummer R, Rossi CR, Neves RI, Trocha SD, Wright F, Byrd DR, Matter M, Hsueh E, MacKenzie-Ross A, Johnson DB, Terheyden P, Berger AC, Huston TL, Wayne JD, Smithers BM, Neuman HB, Schneebaum S, Gershenwald JE, Ariyan CE, Desai DC, Jacobs L, McMasters KM, Gesierich A, Hersey P, Bines SD, Kane JM, Barth RJ, McKinnon G, Farma JM, Schultz E, Vidal-Sicart S, Hoefer RA, Lewis JM, Scheri R, Kelley MC, Nieweg OE, Noyes RD, Hoon DSB, Wang HJ1, Elashoff DA, Elashoff RM.
Recently published paper that established among patients with intermediate thickness melanoma (1.2-3.5mm) and a positive SLN biopsy there is equivalent melanoma specific survival at 3 years in the immediate completion lymphadenectomy group and the observation group (DSS 86% in both groups at 3 yrs).
Major papers establishing efficacy of checkpoint blockade (PD-1/ CTLA-4) in metastatic melanoma
Two landmark Phase III Trials published in 2010 and 2011, respectively, that established survival benefit for patients with advanced melanoma treated with CTLA-4 blockade (ipilimumab).
Pair of practice changing articles, appearing in the June 2012 edition of NEJM, establishing efficacy of PD-1 /PD-L1 blockade in a variety of cancers, including melanoma.
Phase I Trials appearing in NEJM in 2013 and 2015, respectively, established clinical efficacy of combination CTLA-4 + PD-1 blockade in melanoma.
Keynote-006 trial, appearing in NEJM in 2015, either Q2 or Q4 wk PD-1 pembrolizumab (PD-1 inhibitor) vs. ipilimumab (10mg/kg), with a 12 mo OS of 74.1% (HR for death 0.63) and 68.4%, respectively, in advanced melanoma, versus ipilimumab group 58.2% 1 yr OS.
CheckMate-067 trial, NEJM 2015, unresectable stage III/IV melanoma PFS 11.3mo combined group vs. 6.9months nivolumab alone group (3mg/kg) vs. 2.9mo ipilimumab alone group. In tumors PD-L1 + (5%+ tumor cells PD-L1 staining) 14mo median PFS combined and PD-1 alone group (vs. 3.9 months ipilimumab alone group). PD-L1 low tumors combined group 11.2mo median PFS, 5.3mo nivolumab alone group, and 2.9 months ipilimumab alone group. Grade 3/4 toxicity 43% nivolumab alone, 56% ipilimumab alone, 69% combined. Treatment related event leading to d/c therapy <15% both alone groups, and 36% in combined group. Most common tx related adverse events: diarrhea, fatigue, rash, pruritus, nausea, vomiting, colitis, headache.
NEJM Sept 2017, 3 year OS outcomes of above discussed CheckMate-067 trial, OS 58% combined group, 52% nivolumab group (3mg/kg), 34% ipilimumab group. Combined therapy with trend to improved OS and PFS at all PD-L1 expression levels, although CI crossed 1 at all levels with PD-L1 expression 1%+, suggesting predominance of benefit from PD-1 therapy at these higher PD-L1 tumor levels. Discussion of risks/benefits to be had at these levels of PD-L1 expression, as clearly combined therapy comes at the cost of increased side effects.
Major papers establishing efficacy of targeting the MAPK signal transduction pathway in advanced melanoma
BRIM-3 study group, Phase III RCT NEJM 2011, established efficacy of BRAF inhibition in advanced BRAF V600E melanoma, with OS at 6 months 84% BRAF inhibition group (Vemurafenib) vs. 64% chemo group.
Keith T. Flaherty, M.D., Caroline Robert, M.D., Ph.D., Peter Hersey, M.D., Ph.D., Paul Nathan, M.D., Ph.D., Claus Garbe, M.D., Mohammed Milhem, M.B., Lev V. Demidov, M.D., Jessica C. Hassel, M.D., Piotr Rutkowski, M.D., Ph.D., Peter Mohr, M.D., Reinhard Dummer, M.D., Uwe Trefzer, M.D., James M.G. Larkin, M.D., Jochen Utikal, M.D., Brigitte Dreno, M.D., Marta Nyakas, M.D., Mark R. Middleton, Ph.D., Jürgen C. Becker, M.D., Ph.D., Michelle Casey, Ph.D., Laurie J. Sherman, R.N., Frank S. Wu, M.D., Ph.D., Daniele Ouellet, Ph.D., Anne-Marie Martin, Ph.D., Kiran Patel, M.D., and Dirk Schadendorf, M.D., for the METRIC Study Group
METRIC Study Group, phase III RCT, NEJM 2012, established survival benefit MEK inhibition with Trametinib (OS @ 6mo 81%) vs. chemo (OS @ 6mo 67%) in BRAF V600E or V600K unresectable stage IIIc or stage IV melanoma.
Above papers, NEJM 2014 and 2015, respectively, established combined BRAF/MEK inhibition in advanced BRAF V600 mutant melanoma as being superior to BRAF inhibition alone. Median PFS 11.4mo Dabrafenib + Trametinib vs. 7.3mo Vemurafenib alone (Robert et. al.), and 9.3mo Dabrafenib + Trametinib vs. 8.8mo Debrafenib alone (Long et. al.). OS also increased in both combined groups.
EORTC 18071 Phase III RCT, NEJM 2016, adjuvant Ipilimumab (10mg/kg) vs. placebo in resected stage III melanoma. OS at 5 years 65% Ipilimumab group vs. 54% placebo group (p=0.001). Grade 3/4 adverse events 54% tx group vs. 26% placebo group, with 5 patients (1%) dying due to adverse immune related events in the tx group.
Karl D. Lewis, Michele Maio, Mario Mandalà, Betty J Nelson, Grant R. Goodman, Dirk Schadendorf
Vemurafenib alone as an adjuvant agent showed benefit in resected Stage IIC-IIIA patients, but did not show a statistically significant benefit in DFS in Stage IIIC patients. Results recently presented at ESMO 2017.
Papers We Discussed
New Adjuvant Therapy Data
Jeffrey Weber, M.D., Ph.D., Mario Mandala, M.D., Michele Del Vecchio, M.D., Helen J. Gogas, M.D., Ph.D., Ana M. Arance, M.D., Ph.D., C. Lance Cowey, M.D., Stéphane Dalle, M.D., Ph.D., Michael Schenker, M.D., Vanna Chiarion-Sileni, M.D., Ivan Marquez-Rodas, M.D., Ph.D., Jean-Jacques Grob, M.D., Marcus O. Butler, M.D., Mark R. Middleton, Ph.D., Michele Maio, M.D., Ph.D., Victoria Atkinson, M.B., B.S., Paola Queirolo, M.D., Rene Gonzalez, M.D., Ragini R. Kudchadkar, M.D., Michael Smylie, M.D., Nicolas Meyer, M.D., Laurent Mortier, M.D., Ph.D., Michael B. Atkins, M.D., Georgina V. Long, Ph.D., M.B., B.S., Shailender Bhatia, M.D., Celeste Lebbé, M.D., Ph.D., Piotr Rutkowski, M.D., Ph.D., Kenji Yokota, M.D., Naoya Yamazaki, M.D., Ph.D., Tae M. Kim, M.D., Ph.D., Veerle de Pril, M.Sc., Javier Sabater, Pharm.D., M.Sc., Anila Qureshi, M.D., M.P.H., James Larkin, F.R.C.P., Ph.D., and Paolo A. Ascierto, M.D., for the CheckMate 238 Collaborators
The CHECKMATE 238 trial: adjuvant nivolumab provided significant improvements in RFS at 18 month compared to ipilimumab (10mg/kg) in Stage IIIB-IV patients after complete resection, and was significantly better tolerated than ipilimumab. 12mo RFS 70% Nivolumab group vs. 61% Ipilimumab group (p<0.0001). Relationship held true for most subgroups as well, including both PD-L1 low and high tumors. Grade 3/4 treatment events 14% Nivulumab group vs. 46% Ipilimumab group. (Ipilimumab dose 10mg/kg)
Georgina V. Long, M.B., B.S., Ph.D., Axel Hauschild, M.D., Ph.D., Mario Santinami, M.D., Victoria Atkinson, M.D., Mario Mandalà, M.D., Vanna Chiarion-Sileni, M.D., James Larkin, Ph.D., Marta Nyakas, M.D., Caroline Dutriaux, M.D., Andrew Haydon, M.B., B.S., Ph.D., Caroline Robert, M.D., Laurent Mortier, M.D., Ph.D., Jacob Schachter, M.D., Dirk Schadendorf, M.D., Ph.D., Thierry Lesimple, M.D., Ruth Plummer, M.D., Ran Ji, Ph.D., Pingkuan Zhang, M.D., Bijoyesh Mookerjee, M.D., Jeff Legos, Ph.D., Richard Kefford, M.B., B.S., Ph.D., Reinhard Dummer, M.D., and John M. Kirkwood, M.D.
The ‘COMBI-AD’ trial: in patients with BRAF V600E or V600K mutated tumors, combination of dabrafenib and trametinib significantly improved the primary end point of relapse free survival over placebo (3yr RFS 58% vs 39%) in patients who had undergone complete resection and lymphadenectomy for Stage III disease.
Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, Delman KA, Spitler LE, Puzanov I, Agarwala SS, Milhem M, Cranmer L, Curti B, Lewis K, Ross M, Guthrie T, Linette GP, Daniels GA, Harrington K, Middleton MR, Miller WH Jr, Zager JS, Ye Y, Yao B, Li A, Doleman S, VanderWalde A, Gansert J, Coffin RS.
Phase III Optim trial comparing T-VEC intralesional therapy vs. subcutaneous GMCSF in patients with non-resectable stage IIIB-IV melanoma. Median survival nearly 2 years with T-VEC vs. ~1.5 years with GMCSF (HR T-VEC 0.79). Favorable side effect profile for T-VEC.
Igor Puzanov, Mohammed M. Milhem, David Minor, Omid Hamid, Ai Li, Lisa Chen, Michael Chastain, Kevin S. Gorski, Abraham Anderson, Jeffrey Chou, Howard L. Kaufman, and Robert H.I. Andtbacka
Phase Ib trial demonstrating that oncolytic immuntherapy with T-VEC can be combined with anti-CTLA4 therapy, with a 50% objective response rate in advanced melanoma, with 44% of responses lasting >6months. Combination therapy appears to have > efficacy than either therapy alone.
Antoni Ribas, Reinhard Dummer, Igor Puzanov, Ari VanderWalde, Robert H.I. Andtbacka, Olivier Michielin, Anthony J. Olszanski, Josep Malvehy, Jonathan Cebon, Eugenio Fernandez, John M. Kirkwood, Thomas F. Gajewski, Lisa Chen, Kevin S. Gorski, Abraham A. Anderson, Scott J. Diede, Michael E. Lassman, Jennifer Gansert, F. Stephen Hodi, and Georgina V. Long
In combination with anti-PD-1 therapy, intratumoral injection of an oncolytic virus
engineered to enhance immune recognition of cancer resulted in a high response rate (33% complete response rate!!) in patients with advanced melanoma.
This episode was produced by Linda Jin and Brad Krasnick.
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