Bilateral facial neuritis associated with dabrafenib and trametinib after failure of neoadjuvant immunotherapy for stage III melanoma

9503 Background: Pathological complete response (pCR) to neoadjuvant systemic therapy (NST) correlates with survival, and is recognized as a path to regulatory approval in several cancers. Recent trials have reported that neoadjuvant immunotherapy (IT) and targeted therapy (TT) regimens achieve high pCR rates and impressive recurrence-free survival in stage III melanoma, however, the relationship between pCR, relapse-free (RFS) and overall survival (OS) in larger datasets of melanoma patients (pts) remains unknown. Methods: We pooled data from 6 modern NST clinical trials of anti-PD-1 based immunotherapy or BRAF/MEK targeted therapy conducted across institutions participating in the INMC. Pts with RECIST measurable, surgically resectable clinical stage III melanoma who underwent surgery were included. NST regimens included nivolumab (as monotherapy or in combination with ipilimumab), pembrolizumab or dabrafenib+trametinib. Baseline disease characteristics, treatment regimen, pCR and RFS were examined. Results: 184 pts with clinical stage III melanoma (AJCCv7: 100 IIIB, 84 IIIC) completed NST (133 IT, 51 TT) and underwent surgery. Median age was 57y (range 18-87). A pCR was observed in 41% of patients; 51 (38%) with IT and 24 (47%) with TT. Median follow-up post-surgery is 13 mo (95% CI 12-16); 10 mo with IT and 22 mo with TT. 44 (24%) pts have recurred (17 loco-regional, 21 distant, 6 both sites at first recurrence), 18 (14%) after IT and 26 (51%) after TT. 12-month RFS was improved with IT vs TT (83% vs 65%, p < 0.001). For those with pCR, 7% have recurred, 0/51 (0%) after IT, 7/17 (41%) after TT. For those without pCR, 34% have recurred, 18/82 (22%) after IT and 19/27 (70%) after TT. 12-month RFS was improved in those with pCR vs without pCR (95% vs 62%, p < 0.001), including in those with IT (100% vs 72%, p < 0.001) and TT (88% vs 43%, p < 0.001). 16 (9%) patients have died including two who had a pCR, both from TT. Conclusions: Neoadjuvant IT and TT are active regimens in resectable clinical stage III melanoma patients and are associated with high pCR rate. The ability to achieve pCR correlates with improved RFS and remarkably no patient with pCR from immunotherapy has recurred to date.

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Surgical removal of the index node marked using magnetic seed localization to assess response to neoadjuvant immunotherapy in patients with stage III melanoma

British Journal of Surgery ◽

10.1002/bjs.11168 ◽

2019 ◽

Vol 106 (5) ◽

pp. 519-522 ◽

Cited By ~ 10

Author(s):

B. Schermers ◽

V. Franke ◽

E. A. Rozeman ◽

B. A. van de Wiel ◽

A. Bruining ◽

...

Keyword(s):

Stage Iii ◽

Surgical Removal ◽

Neoadjuvant Immunotherapy ◽

Seed Localization ◽

Stage Iii Melanoma

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Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma

Nature Medicine ◽

10.1038/s41591-020-01211-7 ◽

2021 ◽

Vol 27 (2) ◽

pp. 256-263

Author(s):

E. A. Rozeman ◽

E. P. Hoefsmit ◽

I. L. M. Reijers ◽

R. P. M. Saw ◽

J. M. Versluis ◽

...

Keyword(s):

Stage Iii ◽

Neoadjuvant Immunotherapy ◽

Stage Iii Melanoma

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Preliminary results from the international neoadjuvant melanoma consortium (INMC).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.9581 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 9581-9581 ◽

Cited By ~ 11

Author(s):

Alexander M. Menzies ◽

Elisa A. Rozeman ◽

Rodabe Navroze Amaria ◽

Richard A. Scolyer ◽

Michael T. Tetzlaff ◽

...

Keyword(s):

Clinical Stage ◽

Single Agent ◽

Complete Response ◽

Stage Iii ◽

Resected Specimen ◽

Neoadjuvant Immunotherapy ◽

Immune Therapies ◽

Hematoxylin And Eosin ◽

Stage Iii Melanoma

9581 Background: For several cancers, response to neoadjuvant therapy (NAT) correlates with survival. Targeted and immune therapies achieve high response rates and durable survival in many patients with metastatic melanoma. Their role as NAT for stage III disease is not clear, and whether pathological response following NAT correlates with relapse-free (RFS) or overall survival (OS) in melanoma is unknown. Methods: Pooled clinical data from four ongoing NAT clinical trials (NCT02437279, NCT02231775, NCT02519322, NCT01972347) at three large melanoma centers participating in the INMC were examined. All trials included only patients with surgically resectable clinical stage III melanoma. NAT regimens included dabrafenib/trametinib (DT) and nivolumab (nivo) [single agent or in combination with ipilimumab (ipi/nivo)]. Patients who had undergone surgery prior to 27th January 2017 are included in this preliminary analysis. A pathological complete response (pCR) was defined as no viable melanoma cells in the resected specimen by hematoxylin and eosin evaluations by dedicated dermatopathologists. Results: 58 patients with clinical stage III melanoma (AJCCv7: 18 IIIB, 40 IIIC) have completed NAT and undergone surgery. 18 received neoadjuvant immunotherapy (IT): ipi/nivo x2 doses (N = 10), ipi/nivo x3 doses (N = 4) or nivo x4 doses (N = 4). 40 received neoadjuvant DT, either for two (N = 10) or three months (N = 30). Median age is 55 years (range 22-84). A pCR was observed in 50% of patients, 7 (39%) with IT and 22 (55%) with DT. Median follow-up is 10.2 months (95% CI 8.7-12.5). 14 (24%) patients have recurred (5 local, 8 distant, 1 both), 2 (11%) after IT, 12 (30%) after DT. For those with pCR, 14% have recurred, 0/7 (0%) after IT, 4/22 (18%) after DT. In contrast, for those without pCR, 34% have recurred, 2/11 (18%) after IT and 8/18 (44%) after DT. Two deaths have occurred, both after neoadjuvant TT. Early data suggests improved RFS in those with pCR. Conclusions: Neoadjuvant targeted and immunotherapy are active regimens in clinical stage III melanoma patients and are associated with high pCR rate. Preliminary data suggest pCR correlates with improved RFS. Updated data will be presented. Clinical trial information: NCT02437279, NCT02231775, NCT02519322, NCT01972347.

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FDG-PET/CT response and outcome of neoadjuvant immunotherapy for clinical stage III melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e21569 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e21569-e21569

Author(s):

Milton Jose De Barros E. Silva ◽

Caio Dabbous Liz ◽

Marcos Rezende Teixeira ◽

José Augusto Rinck ◽

Monique Celeste Tavares ◽

...

Keyword(s):

Fdg Pet ◽

Clinical Stage ◽

Complete Response ◽

The Other ◽

Stage Iii ◽

Mixed Response ◽

Neoadjuvant Immunotherapy ◽

Pet Ct ◽

Stage Iii Melanoma ◽

Fdg Pet Ct

e21569 Background: Neoadjuvant immunotherapy with nivolumab 3mg/kg and ipilimumab 1mg/kg for two cycles(N3+I1) or anti-PD1 for 3-8 weeks for clinical stage III melanoma have shown rates of pCR/near-pCR about 60% or 30%, respectively. The prognosis of this group seems to be excellent so far. On the other hand, patients classified as pathological non-response have a worse outcome and early identification of this group may allow us to tailor treatment before surgery. Methods: We conducted a retrospective analysis of patients with clinical stage III melanoma treated with neoadjuvant immune checkpoint blockade who did baseline and pre-operative FDG-PET/CT. The total number of FGD avid lesions and the percentual difference between the maximum SUV per lesion was calculated. The pathological results were correlated to FGD-PET/CT findings. Results: Between January 2019 and January 2021, nine patients with clinical stage III melanoma were identified. Six patients received Nivolumab 3m/kg and Ipilimumab 1mg/kg for two cycles and 3 received anti-PD1 for 60 days. Baseline FDG-PET/CT showed just one avid lesion in 7 patients, 2 avid lesions in one patient and 3 avid lesions in one patient. All known lesions identified by CT scan were also captured by FGD-PET/CT. After the neoadjuvant treatment, 4 patients achieved pCR/near-pCR. All of them were treated with N3+I1. Two of them had metabolic complete response (including the one with 3 PET- avid lesions) and 2 had reduction on FDG concentration (-31% and – 76%). Three patients had absence of response: 100% of viable tumor cells (VTC), all of them with increase in FDG concentration (+12% to + 307%) and appearance of a new lesion in one case. Two out of them were treated with anti-PD1. One patient had partial response (40% of VTC). Interestingly, this patient developed sarcoidosis-like reaction with increase of SUV in the index lesion (+68%) and appearance of mediastinal lymph-nodes. One patient, who had two lesions, presented a mixed response: complete response in one and 90% of VTC in the other. FDG-PET/CT was able to detect both responses (metabolic complete response and increase of FGD concentration of 17%, respectively). Conclusions: Reduction in FGD-PET/CT concentration with no appearance of new lesion(s) is associated with significant pathological response. An increase of SUV or appearance of new lesion(s) should be carefully interpreted.

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