Neoadjuvant dabrafenib combined with trametinib for resectable, stage IIIB–C, BRAFV600 mutation-positive melanoma (NeoCombi): a single-arm, open-label, single-centre, phase 2 trial

Georgina V. Long, Robyn P. M. Saw, Serigne Lo, Omgo E. Nieweg, Kerwin F. Shannon, Maria Gonzalez, Alexander Guminski, Jenny H. Lee, Hansol Lee, Peter M. Ferguson, Robert V. Rawson, James S. Wilmott, John F. Thompson, Richard F. Kefford, Sydney Ch'ng, Jonathan R. Stretch, Louise Emmett, Rony Kapoor, Helen Rizos, Andrew J. Spillane & 2 others Richard A. Scolyer, Alexander M. Menzies

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background: Adjuvant dabrafenib plus trametinib therapy improves relapse-free survival in patients with resected stage III melanoma. We aimed to ascertain the proportion of patients who would have a pathological response and a response according to Response Evaluation Criteria in Solid Tumors (RECIST) after neoadjuvant dabrafenib plus trametinib therapy for resectable clinical stage III melanoma. Methods: NeoCombi was a single-arm, open-label, single-centre, phase 2 study done at Melanoma Institute Australia (Sydney, NSW, Australia). Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, clinical stage IIIB–C (American Joint Committee on Cancer [AJCC] 7th edition), BRAFV600-mutant melanoma, and had an Eastern Cooperative Oncology Group performance status of 1 or lower. Patients received 150 mg dabrafenib orally, twice daily, plus 2 mg trametinib orally, once daily, for 52 weeks (12 weeks of neoadjuvant therapy before complete resection of the pre-therapy tumour bed, and 40 weeks of adjuvant therapy thereafter). CT and PET scans were done at baseline and before resection. The primary outcomes were the proportion of patients achieving a complete pathological response and the proportion of patients achieving a response according to RECIST at week 12, analysed as per protocol. This trial is registered with ClinicalTrials.gov, NCT01972347, and follow-up of patients is ongoing. Findings: Between Aug 20, 2014, and April 19, 2017, 40 patients were screened, of whom 35 eligible patients were enrolled, received neoadjuvant dabrafenib plus trametinib, and underwent resection. At the data cutoff (Sept 24, 2018), median follow-up was 27 months (IQR 21–36). At resection, 30 (86%) patients achieved a RECIST response; 16 (46%; 95% CI 29–63) had a complete response and 14 (40%; 24–58) had a partial response. Five patients (14%; 95% CI 5–30) had stable disease, and no patients progressed. After resection and pathological evaluation, all 35 patients achieved a pathological response, of whom 17 (49%; 95% CI 31–66) patients had a complete pathological response and 18 (51%; 95% CI 34–69) had a non-complete pathological response. Treatment-related serious adverse events occurred in six (17%) of 35 patients and grade 3–4 adverse events occurred in ten (29%) patients. No treatment-related deaths were reported. Interpretation: Neoadjuvant dabrafenib plus trametinib therapy could be considered in the management of RECIST-measurable resectable stage III melanoma as it led to a high proportion of patients achieving a complete response according to RECIST and a high proportion of patients achieving a complete pathological response, with no progression during neoadjuvant therapy. Funding: GlaxoSmithKline; Novartis; National Health and Medical Research Council, Australia; and Melanoma Institute Australia.

LanguageEnglish
Pages961-971
Number of pages11
JournalThe Lancet Oncology
Volume20
Issue number7
Early online date3 Jun 2019
DOIs
Publication statusPublished - 1 Jul 2019

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Melanoma
Mutation
dabrafenib
trametinib
Neoadjuvant Therapy
Therapeutics
Response Evaluation Criteria in Solid Tumors
Biomedical Research
Neoplasms

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Long, Georgina V. ; Saw, Robyn P. M. ; Lo, Serigne ; Nieweg, Omgo E. ; Shannon, Kerwin F. ; Gonzalez, Maria ; Guminski, Alexander ; Lee, Jenny H. ; Lee, Hansol ; Ferguson, Peter M. ; Rawson, Robert V. ; Wilmott, James S. ; Thompson, John F. ; Kefford, Richard F. ; Ch'ng, Sydney ; Stretch, Jonathan R. ; Emmett, Louise ; Kapoor, Rony ; Rizos, Helen ; Spillane, Andrew J. ; Scolyer, Richard A. ; Menzies, Alexander M. / Neoadjuvant dabrafenib combined with trametinib for resectable, stage IIIB–C, BRAFV600 mutation-positive melanoma (NeoCombi) : a single-arm, open-label, single-centre, phase 2 trial. In: The Lancet Oncology. 2019 ; Vol. 20, No. 7. pp. 961-971.
@article{a3b290776dc8472c80c1b091e8a2ed52,
title = "Neoadjuvant dabrafenib combined with trametinib for resectable, stage IIIB–C, BRAFV600 mutation-positive melanoma (NeoCombi): a single-arm, open-label, single-centre, phase 2 trial",
abstract = "Background: Adjuvant dabrafenib plus trametinib therapy improves relapse-free survival in patients with resected stage III melanoma. We aimed to ascertain the proportion of patients who would have a pathological response and a response according to Response Evaluation Criteria in Solid Tumors (RECIST) after neoadjuvant dabrafenib plus trametinib therapy for resectable clinical stage III melanoma. Methods: NeoCombi was a single-arm, open-label, single-centre, phase 2 study done at Melanoma Institute Australia (Sydney, NSW, Australia). Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, clinical stage IIIB–C (American Joint Committee on Cancer [AJCC] 7th edition), BRAFV600-mutant melanoma, and had an Eastern Cooperative Oncology Group performance status of 1 or lower. Patients received 150 mg dabrafenib orally, twice daily, plus 2 mg trametinib orally, once daily, for 52 weeks (12 weeks of neoadjuvant therapy before complete resection of the pre-therapy tumour bed, and 40 weeks of adjuvant therapy thereafter). CT and PET scans were done at baseline and before resection. The primary outcomes were the proportion of patients achieving a complete pathological response and the proportion of patients achieving a response according to RECIST at week 12, analysed as per protocol. This trial is registered with ClinicalTrials.gov, NCT01972347, and follow-up of patients is ongoing. Findings: Between Aug 20, 2014, and April 19, 2017, 40 patients were screened, of whom 35 eligible patients were enrolled, received neoadjuvant dabrafenib plus trametinib, and underwent resection. At the data cutoff (Sept 24, 2018), median follow-up was 27 months (IQR 21–36). At resection, 30 (86{\%}) patients achieved a RECIST response; 16 (46{\%}; 95{\%} CI 29–63) had a complete response and 14 (40{\%}; 24–58) had a partial response. Five patients (14{\%}; 95{\%} CI 5–30) had stable disease, and no patients progressed. After resection and pathological evaluation, all 35 patients achieved a pathological response, of whom 17 (49{\%}; 95{\%} CI 31–66) patients had a complete pathological response and 18 (51{\%}; 95{\%} CI 34–69) had a non-complete pathological response. Treatment-related serious adverse events occurred in six (17{\%}) of 35 patients and grade 3–4 adverse events occurred in ten (29{\%}) patients. No treatment-related deaths were reported. Interpretation: Neoadjuvant dabrafenib plus trametinib therapy could be considered in the management of RECIST-measurable resectable stage III melanoma as it led to a high proportion of patients achieving a complete response according to RECIST and a high proportion of patients achieving a complete pathological response, with no progression during neoadjuvant therapy. Funding: GlaxoSmithKline; Novartis; National Health and Medical Research Council, Australia; and Melanoma Institute Australia.",
author = "Long, {Georgina V.} and Saw, {Robyn P. M.} and Serigne Lo and Nieweg, {Omgo E.} and Shannon, {Kerwin F.} and Maria Gonzalez and Alexander Guminski and Lee, {Jenny H.} and Hansol Lee and Ferguson, {Peter M.} and Rawson, {Robert V.} and Wilmott, {James S.} and Thompson, {John F.} and Kefford, {Richard F.} and Sydney Ch'ng and Stretch, {Jonathan R.} and Louise Emmett and Rony Kapoor and Helen Rizos and Spillane, {Andrew J.} and Scolyer, {Richard A.} and Menzies, {Alexander M.}",
year = "2019",
month = "7",
day = "1",
doi = "10.1016/S1470-2045(19)30331-6",
language = "English",
volume = "20",
pages = "961--971",
journal = "Lancet Oncology",
issn = "1470-2045",
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Long, GV, Saw, RPM, Lo, S, Nieweg, OE, Shannon, KF, Gonzalez, M, Guminski, A, Lee, JH, Lee, H, Ferguson, PM, Rawson, RV, Wilmott, JS, Thompson, JF, Kefford, RF, Ch'ng, S, Stretch, JR, Emmett, L, Kapoor, R, Rizos, H, Spillane, AJ, Scolyer, RA & Menzies, AM 2019, 'Neoadjuvant dabrafenib combined with trametinib for resectable, stage IIIB–C, BRAFV600 mutation-positive melanoma (NeoCombi): a single-arm, open-label, single-centre, phase 2 trial' The Lancet Oncology, vol. 20, no. 7, pp. 961-971. https://doi.org/10.1016/S1470-2045(19)30331-6

Neoadjuvant dabrafenib combined with trametinib for resectable, stage IIIB–C, BRAFV600 mutation-positive melanoma (NeoCombi) : a single-arm, open-label, single-centre, phase 2 trial. / Long, Georgina V.; Saw, Robyn P. M.; Lo, Serigne; Nieweg, Omgo E.; Shannon, Kerwin F.; Gonzalez, Maria; Guminski, Alexander; Lee, Jenny H.; Lee, Hansol; Ferguson, Peter M.; Rawson, Robert V.; Wilmott, James S.; Thompson, John F.; Kefford, Richard F.; Ch'ng, Sydney; Stretch, Jonathan R.; Emmett, Louise; Kapoor, Rony; Rizos, Helen; Spillane, Andrew J.; Scolyer, Richard A.; Menzies, Alexander M.

In: The Lancet Oncology, Vol. 20, No. 7, 01.07.2019, p. 961-971.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Neoadjuvant dabrafenib combined with trametinib for resectable, stage IIIB–C, BRAFV600 mutation-positive melanoma (NeoCombi)

T2 - Lancet Oncology

AU - Long,Georgina V.

AU - Saw,Robyn P. M.

AU - Lo,Serigne

AU - Nieweg,Omgo E.

AU - Shannon,Kerwin F.

AU - Gonzalez,Maria

AU - Guminski,Alexander

AU - Lee,Jenny H.

AU - Lee,Hansol

AU - Ferguson,Peter M.

AU - Rawson,Robert V.

AU - Wilmott,James S.

AU - Thompson,John F.

AU - Kefford,Richard F.

AU - Ch'ng,Sydney

AU - Stretch,Jonathan R.

AU - Emmett,Louise

AU - Kapoor,Rony

AU - Rizos,Helen

AU - Spillane,Andrew J.

AU - Scolyer,Richard A.

AU - Menzies,Alexander M.

PY - 2019/7/1

Y1 - 2019/7/1

N2 - Background: Adjuvant dabrafenib plus trametinib therapy improves relapse-free survival in patients with resected stage III melanoma. We aimed to ascertain the proportion of patients who would have a pathological response and a response according to Response Evaluation Criteria in Solid Tumors (RECIST) after neoadjuvant dabrafenib plus trametinib therapy for resectable clinical stage III melanoma. Methods: NeoCombi was a single-arm, open-label, single-centre, phase 2 study done at Melanoma Institute Australia (Sydney, NSW, Australia). Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, clinical stage IIIB–C (American Joint Committee on Cancer [AJCC] 7th edition), BRAFV600-mutant melanoma, and had an Eastern Cooperative Oncology Group performance status of 1 or lower. Patients received 150 mg dabrafenib orally, twice daily, plus 2 mg trametinib orally, once daily, for 52 weeks (12 weeks of neoadjuvant therapy before complete resection of the pre-therapy tumour bed, and 40 weeks of adjuvant therapy thereafter). CT and PET scans were done at baseline and before resection. The primary outcomes were the proportion of patients achieving a complete pathological response and the proportion of patients achieving a response according to RECIST at week 12, analysed as per protocol. This trial is registered with ClinicalTrials.gov, NCT01972347, and follow-up of patients is ongoing. Findings: Between Aug 20, 2014, and April 19, 2017, 40 patients were screened, of whom 35 eligible patients were enrolled, received neoadjuvant dabrafenib plus trametinib, and underwent resection. At the data cutoff (Sept 24, 2018), median follow-up was 27 months (IQR 21–36). At resection, 30 (86%) patients achieved a RECIST response; 16 (46%; 95% CI 29–63) had a complete response and 14 (40%; 24–58) had a partial response. Five patients (14%; 95% CI 5–30) had stable disease, and no patients progressed. After resection and pathological evaluation, all 35 patients achieved a pathological response, of whom 17 (49%; 95% CI 31–66) patients had a complete pathological response and 18 (51%; 95% CI 34–69) had a non-complete pathological response. Treatment-related serious adverse events occurred in six (17%) of 35 patients and grade 3–4 adverse events occurred in ten (29%) patients. No treatment-related deaths were reported. Interpretation: Neoadjuvant dabrafenib plus trametinib therapy could be considered in the management of RECIST-measurable resectable stage III melanoma as it led to a high proportion of patients achieving a complete response according to RECIST and a high proportion of patients achieving a complete pathological response, with no progression during neoadjuvant therapy. Funding: GlaxoSmithKline; Novartis; National Health and Medical Research Council, Australia; and Melanoma Institute Australia.

AB - Background: Adjuvant dabrafenib plus trametinib therapy improves relapse-free survival in patients with resected stage III melanoma. We aimed to ascertain the proportion of patients who would have a pathological response and a response according to Response Evaluation Criteria in Solid Tumors (RECIST) after neoadjuvant dabrafenib plus trametinib therapy for resectable clinical stage III melanoma. Methods: NeoCombi was a single-arm, open-label, single-centre, phase 2 study done at Melanoma Institute Australia (Sydney, NSW, Australia). Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, clinical stage IIIB–C (American Joint Committee on Cancer [AJCC] 7th edition), BRAFV600-mutant melanoma, and had an Eastern Cooperative Oncology Group performance status of 1 or lower. Patients received 150 mg dabrafenib orally, twice daily, plus 2 mg trametinib orally, once daily, for 52 weeks (12 weeks of neoadjuvant therapy before complete resection of the pre-therapy tumour bed, and 40 weeks of adjuvant therapy thereafter). CT and PET scans were done at baseline and before resection. The primary outcomes were the proportion of patients achieving a complete pathological response and the proportion of patients achieving a response according to RECIST at week 12, analysed as per protocol. This trial is registered with ClinicalTrials.gov, NCT01972347, and follow-up of patients is ongoing. Findings: Between Aug 20, 2014, and April 19, 2017, 40 patients were screened, of whom 35 eligible patients were enrolled, received neoadjuvant dabrafenib plus trametinib, and underwent resection. At the data cutoff (Sept 24, 2018), median follow-up was 27 months (IQR 21–36). At resection, 30 (86%) patients achieved a RECIST response; 16 (46%; 95% CI 29–63) had a complete response and 14 (40%; 24–58) had a partial response. Five patients (14%; 95% CI 5–30) had stable disease, and no patients progressed. After resection and pathological evaluation, all 35 patients achieved a pathological response, of whom 17 (49%; 95% CI 31–66) patients had a complete pathological response and 18 (51%; 95% CI 34–69) had a non-complete pathological response. Treatment-related serious adverse events occurred in six (17%) of 35 patients and grade 3–4 adverse events occurred in ten (29%) patients. No treatment-related deaths were reported. Interpretation: Neoadjuvant dabrafenib plus trametinib therapy could be considered in the management of RECIST-measurable resectable stage III melanoma as it led to a high proportion of patients achieving a complete response according to RECIST and a high proportion of patients achieving a complete pathological response, with no progression during neoadjuvant therapy. Funding: GlaxoSmithKline; Novartis; National Health and Medical Research Council, Australia; and Melanoma Institute Australia.

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UR - http://purl.org/au-research/grants/nhmrc/1093017

U2 - 10.1016/S1470-2045(19)30331-6

DO - 10.1016/S1470-2045(19)30331-6

M3 - Article

VL - 20

SP - 961

EP - 971

JO - Lancet Oncology

JF - Lancet Oncology

SN - 1470-2045

IS - 7

ER -