Efficacy and safety of anti-PD1 monotherapy or in combination with ipilimumab after BRAF/MEK inhibitors in patients with BRAF mutant metastatic melanoma
Background Patients with V600BRAF mutant metastatic melanoma have higher rates of progression-free survival (PFS) and overall survival (OS) with first-line anti-PD1 (PD1]+anti-CTLA-4 (IPI) versus PD1. Whether this is also true after BRAF/MEKi therapy is unknown. We aimed to determine the efficacy an...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2022-07-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/7/e004610.full |
| _version_ | 1818536118224683008 |
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| author | Lisa Zimmer Serigne Lo Celeste Lebbe Olivier Michielin Ines Pires da Silva Paolo Antonio Ascierto Matteo Carlino Alexander Menzies Douglas B Johnson Claudia Trojanello Georgina Long Tasnia Ahmed Clara Allayous Johanna Mangana Florentia Dimitriou Danny Zakria Camille Gerard |
| author_facet | Lisa Zimmer Serigne Lo Celeste Lebbe Olivier Michielin Ines Pires da Silva Paolo Antonio Ascierto Matteo Carlino Alexander Menzies Douglas B Johnson Claudia Trojanello Georgina Long Tasnia Ahmed Clara Allayous Johanna Mangana Florentia Dimitriou Danny Zakria Camille Gerard |
| author_sort | Lisa Zimmer |
| collection | DOAJ |
| description | Background Patients with V600BRAF mutant metastatic melanoma have higher rates of progression-free survival (PFS) and overall survival (OS) with first-line anti-PD1 (PD1]+anti-CTLA-4 (IPI) versus PD1. Whether this is also true after BRAF/MEKi therapy is unknown. We aimed to determine the efficacy and safety of PD1 versus IPI +PD1 after BRAF/MEK inhibitors (BRAF/MEKi).Methods Patients with V600BRAF mutant metastatic melanoma treated with BRAF/MEKi who had subsequent PD1 versus IPI+PD1 at eight centers were included. The endpoints were objective response rate (ORR), PFS, OS and safety in each group.Results Of 200 patients with V600E (75%) or non-V600E (25%) mutant metastatic melanoma treated with BRAF/MEKi (median time of treatment 7.6 months; treatment cessation due to progressive disease in 77%), 115 (57.5%) had subsequent PD1 and 85 (42.5%) had IPI+PD1. Differences in patient characteristics between PD1 and IPI+PD1 groups included, age (med. 63 vs 54 years), time between BRAF/MEKi and PD1±IPI (16 vs 4 days), Eastern Cooperative Oncology Group Performance Status (ECOG PS) of ≥1 (62% vs 44%), AJCC M1C/M1D stage (72% vs 94%) and progressing brain metastases at the start of PD1±IPI (34% vs 57%). Median follow-up from PD1±IPI start was 37.8 months (95% CI, 33.9 to 52.9). ORR was 36%; 34% with PD1 vs 39% with IPI+PD1 (p=0.5713). Median PFS was 3.4 months; 3.4 with PD1 vs 3.6 months with IPI+PD1 (p=0.6951). Median OS was 15.4 months; 14.4 for PD1 vs 20.5 months with IPI+PD1 (p=0.2603). The rate of grade 3 or 4 toxicities was higher with IPI+PD1 (31%) vs PD1 (7%). ORR, PFS and OS were numerically higher with IPI+PD1 vs PD1 across most subgroups except for females, those with <10 days between BRAF/MEKi and PD1±IPI, and those with stage III/M1A/M1B melanoma. The combination of ECOG PS=0 and absence of liver metastases identified patients with >3 years OS (area under the curve, AUC=0.74), while ECOG PS ≥1, progressing brain metastases and presence of bone metastases predicted primary progression (AUC=0.67).Conclusions IPI+PD1 and PD1 after BRAF/MEKi have similar outcomes despite worse baseline prognostic features in the IPI+PD1 group, however, IPI+PD1 is more toxic. A combination of clinical factors can identify long-term survivors, but less accurately those with primary resistance to immunotherapy after targeted therapy. |
| first_indexed | 2024-12-11T18:33:50Z |
| format | Article |
| id | doaj.art-21c29e95030742fcaad36b5414ae6fcf |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-12-11T18:33:50Z |
| publishDate | 2022-07-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-21c29e95030742fcaad36b5414ae6fcf2022-12-22T00:54:50ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-07-0110710.1136/jitc-2022-004610Efficacy and safety of anti-PD1 monotherapy or in combination with ipilimumab after BRAF/MEK inhibitors in patients with BRAF mutant metastatic melanomaLisa Zimmer0Serigne Lo1Celeste Lebbe2Olivier Michielin3Ines Pires da Silva4Paolo Antonio Ascierto5Matteo Carlino6Alexander Menzies7Douglas B Johnson8Claudia Trojanello9Georgina Long10Tasnia Ahmed11Clara Allayous12Johanna Mangana13Florentia Dimitriou14Danny Zakria15Camille Gerard16Department of Dermatology, University Hospital of Essen, Essen, GermanyMelanoma Institute Australia and University of Sydney, Sydney, New South Wales, AustraliaAP-HP Dermatology and CIC, INSERM U976, Saint Louis Hospital, Université de Paris, Paris, FranceDepartment of Oncology, Lausanne University Hospital, Lausanne, SwitzerlandMelanoma Institute Australia and University of Sydney, Sydney, New South Wales, AustraliaIstituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, ItalyBlacktown Hospital and the University of Sydney, Sydney, New South Wales, AustraliaMelanoma Institute Australia, North Sydney, New South Wales, AustraliaDepartment of Medicine, Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USAUnit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Campania, ItalyMelanoma Institute Australia, North Sydney, New South Wales, AustraliaMelanoma Institute Australia, North Sydney, New South Wales, AustraliaDepartment of Dermatology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, Île-de-France, FranceDepartment of Dermatology, University Hospital Zurich, Zurich, SwitzerlandMelanoma Institute Australia, North Sydney, New South Wales, AustraliaVanderbilt University Medical Center, Nashville, Tennessee, USAPrecision Oncology Centre, CHUV, Lausanne, SwitzerlandBackground Patients with V600BRAF mutant metastatic melanoma have higher rates of progression-free survival (PFS) and overall survival (OS) with first-line anti-PD1 (PD1]+anti-CTLA-4 (IPI) versus PD1. Whether this is also true after BRAF/MEKi therapy is unknown. We aimed to determine the efficacy and safety of PD1 versus IPI +PD1 after BRAF/MEK inhibitors (BRAF/MEKi).Methods Patients with V600BRAF mutant metastatic melanoma treated with BRAF/MEKi who had subsequent PD1 versus IPI+PD1 at eight centers were included. The endpoints were objective response rate (ORR), PFS, OS and safety in each group.Results Of 200 patients with V600E (75%) or non-V600E (25%) mutant metastatic melanoma treated with BRAF/MEKi (median time of treatment 7.6 months; treatment cessation due to progressive disease in 77%), 115 (57.5%) had subsequent PD1 and 85 (42.5%) had IPI+PD1. Differences in patient characteristics between PD1 and IPI+PD1 groups included, age (med. 63 vs 54 years), time between BRAF/MEKi and PD1±IPI (16 vs 4 days), Eastern Cooperative Oncology Group Performance Status (ECOG PS) of ≥1 (62% vs 44%), AJCC M1C/M1D stage (72% vs 94%) and progressing brain metastases at the start of PD1±IPI (34% vs 57%). Median follow-up from PD1±IPI start was 37.8 months (95% CI, 33.9 to 52.9). ORR was 36%; 34% with PD1 vs 39% with IPI+PD1 (p=0.5713). Median PFS was 3.4 months; 3.4 with PD1 vs 3.6 months with IPI+PD1 (p=0.6951). Median OS was 15.4 months; 14.4 for PD1 vs 20.5 months with IPI+PD1 (p=0.2603). The rate of grade 3 or 4 toxicities was higher with IPI+PD1 (31%) vs PD1 (7%). ORR, PFS and OS were numerically higher with IPI+PD1 vs PD1 across most subgroups except for females, those with <10 days between BRAF/MEKi and PD1±IPI, and those with stage III/M1A/M1B melanoma. The combination of ECOG PS=0 and absence of liver metastases identified patients with >3 years OS (area under the curve, AUC=0.74), while ECOG PS ≥1, progressing brain metastases and presence of bone metastases predicted primary progression (AUC=0.67).Conclusions IPI+PD1 and PD1 after BRAF/MEKi have similar outcomes despite worse baseline prognostic features in the IPI+PD1 group, however, IPI+PD1 is more toxic. A combination of clinical factors can identify long-term survivors, but less accurately those with primary resistance to immunotherapy after targeted therapy.https://jitc.bmj.com/content/10/7/e004610.full |
| spellingShingle | Lisa Zimmer Serigne Lo Celeste Lebbe Olivier Michielin Ines Pires da Silva Paolo Antonio Ascierto Matteo Carlino Alexander Menzies Douglas B Johnson Claudia Trojanello Georgina Long Tasnia Ahmed Clara Allayous Johanna Mangana Florentia Dimitriou Danny Zakria Camille Gerard Efficacy and safety of anti-PD1 monotherapy or in combination with ipilimumab after BRAF/MEK inhibitors in patients with BRAF mutant metastatic melanoma Journal for ImmunoTherapy of Cancer |
| title | Efficacy and safety of anti-PD1 monotherapy or in combination with ipilimumab after BRAF/MEK inhibitors in patients with BRAF mutant metastatic melanoma |
| title_full | Efficacy and safety of anti-PD1 monotherapy or in combination with ipilimumab after BRAF/MEK inhibitors in patients with BRAF mutant metastatic melanoma |
| title_fullStr | Efficacy and safety of anti-PD1 monotherapy or in combination with ipilimumab after BRAF/MEK inhibitors in patients with BRAF mutant metastatic melanoma |
| title_full_unstemmed | Efficacy and safety of anti-PD1 monotherapy or in combination with ipilimumab after BRAF/MEK inhibitors in patients with BRAF mutant metastatic melanoma |
| title_short | Efficacy and safety of anti-PD1 monotherapy or in combination with ipilimumab after BRAF/MEK inhibitors in patients with BRAF mutant metastatic melanoma |
| title_sort | efficacy and safety of anti pd1 monotherapy or in combination with ipilimumab after braf mek inhibitors in patients with braf mutant metastatic melanoma |
| url | https://jitc.bmj.com/content/10/7/e004610.full |
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