Pathological response and tumour bed histopathological features correlate with survival following neoadjuvant immunotherapy in 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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Personalized response-driven adjuvant therapy after combination ipilimumab and nivolumab in high-risk resectable stage III melanoma: PRADO trial.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.tps9605 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. TPS9605-TPS9605 ◽

Cited By ~ 3

Author(s):

Irene Reijers ◽

Elisa A. Rozeman ◽

Alexander M. Menzies ◽

Bart A. Van De Wiel ◽

Hanna Eriksson ◽

...

Keyword(s):

Lymph Node ◽

Stage Iv ◽

Pathologic Response ◽

Pathological Response ◽

Stage Iii ◽

Phase 2 ◽

Primary Endpoints ◽

Phase 1B ◽

Stage Iii Melanoma

TPS9605 Background: Adjuvant (adj) immune checkpoint inhibition (ICI) improves relapse free survival (RFS) in stage III melanoma patients (pts). However, preclinical and translational data suggest that neo-adjuvant (neoadj) treatment might be favorable due to broader immune activation. The phase 1b OpACIN study comparing neoadj to adj IPI plus NIVO demonstrated a high pathological response rate (pRR) of 78% complicated by 90% gr 3-4 immune-related adverse events (irAEs). The phase 2 OpACIN-neo trial tested safety and efficacy of three different schemes of neoadj IPI+NIVO and identified two cycles of IPI 1mg/kg + NIVO 3mg/kg as well tolerated (20% gr 3-4 irAEs), with a high pRR of 77%. In both trials, none of the pts with a pathologic response have relapsed after a median follow-up of 30 and 8.3 months. In stage IV melanoma, long-term benefit is observed in patients achieving CR with ICI, even after cessation of therapy. This raises the question of whether a therapeutic lymph node dissection (TLND) can be omitted when a deep pathologic response with neoadj IPI+NIVO is achieved. Methods: The aim of this international multi-center investigator-initiated phase 2 PRADO extension study is to confirm the pRR and toxicity of 2 cycles of neoadjuvant IPI 1mg/kg + NIVO 3mg/kg (the preferred OPACIN-neo regimen) and to test response-driven subsequent therapy i.e. omitting surgery and adjuvant ICI based on the pathological response. 100-110 pts with stage IIIB/C melanoma and a measurable lymph node (≥15mm according to RECIST 1.1) will receive two cycles of IPI 1mg/kg + NIVO 3mg/kg after marker placement into the largest lymph node metastasis. After six weeks, pts will undergo resection of the index lymph node. For pCR/near pCR, pts will not undergo TLND; For pPR, pts will undergo TLND; and for pNR, pts will undergo TLND and start adjuvant NIVO or targeted therapy +/- radiotherapy for 52 weeks. Primary endpoints are pRR of marked lymph node and RFS at 24 months. Baseline biopsies, blood samples (week 0, 6, 12) and faeces (week 0, 6) will be collected for translational research analyses. The first patient in this trial was included in October 2018; 22 patients have been enrolled. Clinical trial information: NCT02977052.

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A phase II study of neoadjuvant pembrolizumab and lenvatinib for resectable stage III melanoma: The neopele study.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.tps10088 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. TPS10088-TPS10088

Author(s):

Maria Gonzalez ◽

Alexander M. Menzies ◽

Thomas Pennington ◽

Robyn PM Saw ◽

Andrew J. Spillane ◽

...

Keyword(s):

Clinical Trials ◽

Phase Ii ◽

Response Rate ◽

Metabolic Response ◽

Pathological Response ◽

High Rate ◽

Stage Iii ◽

Histopathological Analysis ◽

Surgical Specimen ◽

Stage Iii Melanoma

TPS10088 Background: Recent clinical trials of neoadjuvant (neo-adj) ipilimumab combined with nivolumab (OpACIN & OpACIN-neo) in resectable stage III melanoma show that a pathological response ( < 50% viable tumour at the tumour bed as determined by histopathological analysis) is associated with a prolonged relapse-free survival compared to no pathological response. Furthermore, recurrences seldom occur in those who have a pathological response following neo-adj immunotherapy with only 1/71 pts (1.4%) having recurred. In contrast, 15/23 (65.2%) pts with no pathological response have relapsed to date. The NeoPeLe trial will test the hypothesis that the synergistic combination of PD-1 blockade (pembrolizumab) with anti-angiogenic/multiple RTK inhibitor (lenvatinib) will result in a high rate of pathological response in the resected surgical specimen with a low rate of toxicity. Tissue and blood biomarkers are drawn at several timepoints and correlated to clinical and pathological endpoints to explore mechanisms of response and resistance. We will compare pathological response rate, and other clinical outcomes in this study, with previously published neo-adj clinical trials to select the best schedules for larger-scale clinical testing. Across neo-adj studies, we will also analyse the tissue collected to explore determinants of the optimal therapy for individual pts, whilst minimising toxicity. Methods: Eligible pts with stage IIIB/C/D, resectable and measurable (RECIST 1.1) nodal metastatic melanoma will be enrolled to this phase II single-centre trial (n = 20). All pts undergo complete nodal resection (RES) at wk 6 following neo-adj therapy with pembrolizumab (200mg, IV, 3 wkly) and lenvatinib (20mg, oral, daily). Adjuvant therapy with pembrolizumab is given for 46 wks after RES. After 52 wks of the study treatment, pts will be followed for relapse and survival for 5 years. CT and FDG PET/CT are used to measure response and exclude progression in the neo-adj phase, and to monitor for recurrence during adj and post treatment phases. Blood and tumour samples are collected at baseline, day 8, RES and at relapse if feasible. Faecal samples are collected at baseline and before RES. The primary endpoint is the complete pathological response rate at RES following 6 wks of neo-adj therapy. Secondary endpoints include RECIST response, metabolic response, OS, RFS, safety/tolerability, surgical outcomes, quality of life, and biomarker analyses. Clinical trial information: NCTNCT04207086.

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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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