TY - JOUR
T1 - Melanoma brain metastases that progress on BRAF-MEK inhibitors demonstrate resistance to ipilimumab-nivolumab that is associated with the Innate PD-1 Resistance Signature (IPRES)
AU - Lau, Peter Kar Han
AU - Feran, Breon
AU - Smith, Lorey
AU - Lasocki, Arian
AU - Molania, Ramyar
AU - Smith, Kortnye
AU - Weppler, Alison
AU - Angel, Christopher
AU - Kee, Damien
AU - Bhave, Prachi
AU - Lee, Belinda
AU - Young, Richard J.
AU - Iravani, Amir
AU - Yeang, Hanxian Aw
AU - Vergara, Ismael A.
AU - Kok, David
AU - Drummond, Kate
AU - Neeson, Paul Joseph
AU - Sheppard, Karen E.
AU - Papenfuss, Tony
AU - Solomon, Benjamin J.
AU - Sandhu, Shahneen
AU - McArthur, Grant A.
N1 - Funding Information:
Professor Grant A McArthur; [email protected]
Funding Information:
Twitter Peter Kar Han Lau @drpeterlau, Lorey Smith @Smith_Lorey, Ramyar Molania @RamyarMolania, Kortnye Smith @kortnye_s, Damien Kee @ DrDamienKee, Benjamin J Solomon @bensolomon1 and Grant A McArthur @ McArthurGrant Acknowledgements We would like to thank the patients and families who participated and donated tissue used in this work. We are indebted to Peter and Bernice Moritz, who kindly provided funds that enabled the sequencing for this project. We would also like to thank Sonia Mailer (sample acquisition), Gisela Mir Arnau (RNA sequencing) and Melanie Watson (statistical assistance). PKHL was supported by the Australian Government post graduate award. AL was supported by a Peter MacCallum Cancer Foundation Discovery Partner Fellowship.
Publisher Copyright:
©
PY - 2021/10/8
Y1 - 2021/10/8
N2 - Background Melanoma brain metastases (MBMs) are a challenging clinical problem with high morbidity and mortality. Although first-line dabrafenib-trametinib and ipilimumab-nivolumab have similar intracranial response rates (50%-55%), central nervous system (CNS) resistance to BRAF-MEK inhibitors (BRAF-MEKi) usually occurs around 6 months, and durable responses are only seen with combination immunotherapy. We sought to investigate the utility of ipilimumab-nivolumab after MBM progression on BRAF-MEKi and identify mechanisms of resistance. Methods Patients who received first-line ipilimumab-nivolumab for MBMs or second/third line ipilimumab-nivolumab for intracranial metastases with BRAF V600 mutations with prior progression on BRAF-MEKi and MRI brain staging from March 1, 2015 to June 30, 2018 were included. Modified intracranial RECIST was used to assess response. Formalin-fixed paraffin-embedded samples of BRAF V600 mutant MBMs that were naïve to systemic treatment (n=18) or excised after progression on BRAF-MEKi (n=14) underwent whole transcriptome sequencing. Comparative analyses of MBMs naïve to systemic treatment versus BRAF-MEKi progression were performed. Results Twenty-five and 30 patients who received first and second/third line ipilimumab-nivolumab, were included respectively. Median sum of MBM diameters was 13 and 20.5 mm for the first and second/third line ipilimumab-nivolumab groups, respectively. Intracranial response rate was 75.0% (12/16), and median progression-free survival (PFS) was 41.6 months for first-line ipilimumab-nivolumab. Efficacy of second/third line ipilimumab-nivolumab after BRAF-MEKi progression was poor with an intracranial response rate of 4.8% (1/21) and median PFS of 1.3 months. Given the poor activity of ipilimumab-nivolumab after BRAF-MEKi MBM progression, we performed whole transcriptome sequencing to identify mechanisms of drug resistance. We identified a set of 178 differentially expressed genes (DEGs) between naïve and MBMs with progression on BRAF-MEKi treatment (p value
AB - Background Melanoma brain metastases (MBMs) are a challenging clinical problem with high morbidity and mortality. Although first-line dabrafenib-trametinib and ipilimumab-nivolumab have similar intracranial response rates (50%-55%), central nervous system (CNS) resistance to BRAF-MEK inhibitors (BRAF-MEKi) usually occurs around 6 months, and durable responses are only seen with combination immunotherapy. We sought to investigate the utility of ipilimumab-nivolumab after MBM progression on BRAF-MEKi and identify mechanisms of resistance. Methods Patients who received first-line ipilimumab-nivolumab for MBMs or second/third line ipilimumab-nivolumab for intracranial metastases with BRAF V600 mutations with prior progression on BRAF-MEKi and MRI brain staging from March 1, 2015 to June 30, 2018 were included. Modified intracranial RECIST was used to assess response. Formalin-fixed paraffin-embedded samples of BRAF V600 mutant MBMs that were naïve to systemic treatment (n=18) or excised after progression on BRAF-MEKi (n=14) underwent whole transcriptome sequencing. Comparative analyses of MBMs naïve to systemic treatment versus BRAF-MEKi progression were performed. Results Twenty-five and 30 patients who received first and second/third line ipilimumab-nivolumab, were included respectively. Median sum of MBM diameters was 13 and 20.5 mm for the first and second/third line ipilimumab-nivolumab groups, respectively. Intracranial response rate was 75.0% (12/16), and median progression-free survival (PFS) was 41.6 months for first-line ipilimumab-nivolumab. Efficacy of second/third line ipilimumab-nivolumab after BRAF-MEKi progression was poor with an intracranial response rate of 4.8% (1/21) and median PFS of 1.3 months. Given the poor activity of ipilimumab-nivolumab after BRAF-MEKi MBM progression, we performed whole transcriptome sequencing to identify mechanisms of drug resistance. We identified a set of 178 differentially expressed genes (DEGs) between naïve and MBMs with progression on BRAF-MEKi treatment (p value
KW - central nervous system neoplasms
KW - immunotherapy
KW - melanoma
KW - tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85117128026&partnerID=8YFLogxK
U2 - 10.1136/jitc-2021-002995
DO - 10.1136/jitc-2021-002995
M3 - Article
C2 - 34625515
SN - 2051-1426
VL - 9
JO - Journal for ImmunoTherapy of Cancer
JF - Journal for ImmunoTherapy of Cancer
IS - 10
M1 - e002995
ER -