Oligometastatic Melanoma Research Articles

Approaches to the treatment of oligometastatic melanoma in the era of immunotargeted therapy

Approaches to the treatment of oligometastatic melanoma in the era of immunotargeted therapy

Stereotactic body radiotherapy as a viable treatment on extracranial oligometastases in melanoma patients: a retrospective multicentric study.

Stereotactic radiotherapy (SBRT) potentially has a role in the management of oligometastatic melanoma. However, literature with data specific to this management is very limited. The objectives of this study were to evaluate the time to local control (LC) of extra-cranial melanoma metastases after SBRT treatment and to help establish if SBRT is a useful therapy for oligometastatic melanoma. A retrospective study was conducted with data collected from two referral centers in France between 2007 and 2020. The oligometastatic status of patients was reported based on the latest recommendations with a maximum of three lesions prior to treatment. A total of 69 patients receiving SBRT for 88 oligometastatic melanoma metastases were included. The median follow-up time was 42.6 months. Most patients were treated for metachronous oligometastatic lesions. Occurrence of oligoprogression, oligorecurrence, and oligopersistence was reported in 42.0%, 39.1%, and 17.4% of cases, respectively. Treated lesions were mostly pulmonary (40.6%), followed by lymph node (34.8%) and hepatic sites (24.6%). Progression-free survival at 1, 2, and 3 years were 47.0% (35-59), 27.0% (16-39), and 25.0% (15.0-37.0), respectively. Time to LC rates at 1, 2, and 3 years were 94.2% (87.0-98.1), 90.3% (81.3-96.1), and 90.3% (81.3-96.1), respectively. Overall survival at 1, 2, and 3 years were 87% (76.0-93.0), 74.0% (76.0-93.0), and 61.0% (47.0-73.0), respectively. Only 17.4% of patients experienced acute, grade 1 or grade 2 toxicities with no reports of grade 3 or higher toxicities. SBRT demonstrated efficacy in managing melanoma patients with extracranial oligometastases and showed an overall low toxicity profile. Future randomized studies are needed to establish the role of SBRT in therapeutic approaches for patients with oligometastatic melanoma.

Oligometastatic melanoma to the pancreas: a guide to management from a surgical perspective

Oligometastatic melanoma to the pancreas: a guide to management from a surgical perspective

Abstract CT167: Neoadjuvant ipilimumab/nivolumab in locally advanced or oligometastatic melanoma: An open label, single arm, multi-institutional clinical study with molecular and immunological biomarker’s analysis

Abstract Efficacy, safety, together with molecular and immunological biomarkers were studied in a sequential clinical trial of neoadjuvant immunotherapy, surgery and adjuvant immunotherapy in locally advanced or oligometastatic melanoma patients (pts), within an open label, single arm and two sites study. Treatment schedule consisted in four primary cycles of inverted dose ipilimumab 1 mg/kg and nivolumab 3 mg/kg every 3 weeks, followed by radical surgery and adjuvant nivolumab 480 mg every 4 weeks for 6 cycles. Primary objective was pathological complete remission (pCR) rate, according to International Neoadjuvant Melanoma Consortium (INMC) criteria, while secondary objectives were: safety, feasibility and efficacy; QoL; identification of biomarkers of response and resistance; degree of immune activation; longitudinal evaluation of the gut microbiome. From March 2019 to April 2021, 43 pts were enrolled in the trial and, with an intent to treat of 35 pts, 34 completed the primary phase, 31 received surgery and 28 completed the adjuvant phase. Four pts were withdrawn during primary phase for progression (2), toxicity (1) and consent withdrawal (1). Study primary endpoint has been met since 20/31 pts undergoing surgery reached a pCR/near pCR (65%), 4/31 (13%) a pathological partial remission (pPR) and 7/31 (22%) pts a pathological no response. With a median follow-up of 17 months, 33/35 pts are alive. Treatment failure occurred in 9 pts: 2 pts progressed during primary phase and did not undergo surgery; 7 pts progressed during adjuvant (3 pts) or follow-up phase (4 pts). Six out of these 7 pts were classified as pNR at surgery, while the other, classified as pCR, did not receive adjuvant therapy. Both pts in stage IV relapsed. Unfortunately, one pt died for ischemic stroke after 5 months from adjuvant therapy while on CR. Treatment related toxicities were mainly G1-2 and only 6 pts (17%) developed G3-4 adverse events (AE): 3 transaminitis, 1 pneumonitis, 1 myocarditis, 1 CPK increase and 1 dermatomyositis. Translational studies on samples collected before, during therapy and at progression have been performed: whole exome sequencing and gut microbiota dynamics on longitudinal samples showed some relationships with responses and developing resistances. These data, never presented elsewhere previously, are in part new and in part confirmatory of immunological or molecular signatures described by other groups. In conclusion, primary immunotherapy with Ipilimumab/Nivolumab in pts affected by locally advanced/oligometastatic melanoma is able to achieve an elevated pCR/near pCR rate which appears to be predictive of long term relapse free survival. Translational data analyzed longitudinally on each patient can allow for a better selection of pts, giving new insight on the mechanisms of melanoma progression and resistance. Citation Format: Pier Francesco Ferrucci, Bruno Achutti Duso, Luigi Nezi, Luca Mazzarella, Fiorenza Lotti, Sara Gandini, Gianmarco Orsolini, Elisabetta Pennacchioli, Patrizia Gnagnarella, Teresa Manzo, Simone Ribero, Maria Teresa Fierro, Rebecca Senetta, Concetta Riviello, Virginia Caliendo, Pietro Quaglino, Massino Barberis, Giuseppina Bonizzi, Emilia Cocorocchio. Neoadjuvant ipilimumab/nivolumab in locally advanced or oligometastatic melanoma: An open label, single arm, multi-institutional clinical study with molecular and immunological biomarker’s analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT167.

Primary ipilimumab/nivolumab followed by adjuvant nivolumab in patients with locally advanced or oligometastatic melanoma: Update on outcome.

9574 Background: The aim of neo-adjuvant therapy in locally advanced or oligometastatic melanoma is to facilitate radical resection, improve outcomes and undertake research to identify biomarkers of response and resistance. The optimal schedule to balance efficacy vs toxicity in dual PD1/CTLA4 blockade regimens remains a matter of debate. We initiated an open- label, single arm study to investigate the Nivo 3/ Ipi 1 schedule as primary treatment of locally advanced or oligometastatic melanoma patients (pts). Methods: Treatment schedule consists in 4 neoadjuvant cycles of Ipilimumab 1 mg/kg and Nivolumab 3 mg/kg every 3 weeks, followed by surgery and adjuvant Nivolumab 480 mg every 4 weeks for 6 cycles. Primary objective is pathological complete remission (pCR) rate, according to Neoadjuvant Melanoma Consortium criteria. Secondary objectives are: safety, feasibility and efficacy; QoL; identification of molecular and immunological biomarkers of response and resistance (somatic genetic drivers, tumor mutational burden, mutational signatures, predicted neoantigens, germline HLA typing, somatic HLA mutations and liquid biopsy); degree of immune activation; evaluation of microbioma Results: From March 2019 to April 2021, 35 pts were included within the trial. All pts completed the treatment program. 6 pts (17%) developed immune-related (IR) G3-4 adverse events (AE): 3 transaminitis, 1 pneumonitis, 1 myocarditis and 1 CPK increase; all of them but one underwent surgery after toxicity resolution. 4 pts (11%) experienced G3-4 non-IR AE. 31 pts underwent surgery after neoadjuvant phase: pCR, near pCR, pathological partial remission (pPR) and pathological no response (pNR) were achieved in 18 (58%), 2 (7%), 4 (13%) and 7 (22%) cases, respectively. 2 pts progressed before surgery and 8 pts progressed during/after adjuvant phase (6/8 in NR at surgery). 4 pts died, 3 after disease progression and 1 for ischemic stroke 5 months after the end of therapy. At 18 months, progression free survival (PFS) and overall survival (OS) were 80 and 85%, respectively (median follow-up: 23 months); non responders (pNR) have a higher risk of relapse or death vs responders (pCR+near pCR+pPR) [HR= 4.11, 95%CI (0.96 -17) adjusted for age, p=0.06]. Conclusions: Our study lends further support to the adoption of the Nivo 3/ Ipi 1 schedule as primary treatment for locally advanced/oligometastatic melanoma, as this regimen achieved a pCR/near pCR rate of 65% with a rate of severe IR-AEs (17%) lower than previously reported in CheckMate 511 trial (34%) using Nivo3/Ipi1 schedule. Available translational data on potential genomic biomarkers of response, gut microbiome and systemic inflammatory landscape evaluated longitudinally during therapy on each patient will be presented. Clinical trial information: 2018-002172-40.

1072P Primary ipilimumab/nivolumab immunotherapy followed by adjuvant nivolumab in patients with locally advanced or oligometastatic melanoma: Update on outcome

The aim of neo-adjuvant therapy in locally advanced or oligometastatic melanoma is to facilitate radical resection, improve outcomes and undertake research to identify biomarkers of response and resistance. We investigate the efficacy of Ipilimumab/Nivolumab combination as primary treatment of locally advanced or oligometastatic melanoma patients (pts), within an open label, single arm study.

1147P Primary ipilimumab/nivolumab immunotherapy followed by adjuvant nivolumab in locally advanced or oligometastatic melanoma: Preliminary results

1147P Primary ipilimumab/nivolumab immunotherapy followed by adjuvant nivolumab in locally advanced or oligometastatic melanoma: Preliminary results

Deep abscopal response to radiotherapy and anti-PD-1 in an oligometastatic melanoma patient with unfavorable pretreatment immune signature

Radiotherapy can elicit abscopal effects in non-irradiated metastases, particularly under immune checkpoint blockade (ICB). We report on two elderly patients with oligometastatic melanoma treated with anti-PD-1 and stereotactic body radiation therapy (SBRT). Before treatment, patient 1 showed strong tumor infiltration with exhausted CD8+ T cells and high expression of T cell-attracting chemokines. This patient rapidly mounted a complete response, now ongoing for more than 4.5 years. Patient 2 exhibited low CD8+ T cell infiltration and high expression of immunosuppressive arginase. After the first SBRT, his non-irradiated metastases did not regress and new metastases occurred although neoepitope-specific and differentiation antigen-specific CD8+ T cells were detected in the blood. A second SBRT after 10 months on anti-PD-1 induced a radiologic complete response correlating with an increase in activated PD-1-expressing CD8 T cells. Apart from a new lung lesion, which was also irradiated, this deep abscopal response lasted for more than 2.5 years. However, thereafter, his disease progressed and the activated PD-1-expressing CD8 T cells dropped. Our data suggest that oligometastatic patients, where a large proportion of the tumor mass can be irradiated, are good candidates to improve ICB responses by RT, even in the case of an unfavorable pretreatment immune signature, after progression on anti-PD-1, and despite advanced age. Besides repeated irradiation, T cell epitope-based immunotherapies (e.g., vaccination) may prolong antitumor responses even in patients with unfavorable pretreatment immune signature.

Neoadjuvant BRAF-targeted therapy in regionally advanced and oligometastatic melanoma.

Current management of locoregional and oligometastatic melanoma is typically with surgery; however, some patients are unable to undergo resection due to location/size of their tumors and/or the anticipated morbidity of the surgery. While there are currently no established guidelines for neoadjuvant therapy in melanoma, neoadjuvant BRAF-targeted therapy may make resection more feasible. A retrospective analysis was conducted of 23 patients with BRAFV600-mutant, stage III/IV melanoma treated with BRAF-targeted therapy prior to surgery, with no adjuvant treatment. Surgical specimens, preoperative imaging, and clinical outcomes were evaluated. Results: Ten of 23 patients (44%) attained a pathologic complete response (pCR), with no correlation between RECIST response based on preoperative imaging and pathologic response. After a median of 43-month follow-up, only 1 patient (10%) with a pCR recurred, while 8 of 13 (62%) patients without a pCR recurred. Patients with a pCR had significantly improved relapse-free (RFS) and overall survival (OS) compared to patients with residual tumor. Neoadjuvant BRAF-targeted therapy is associated with a high pCR rate in patients with stage III-IV melanoma, which may correlate with improved RFS and OS.

Abstract 526: Tumor-draining lymph node irradiation reduces tumor-infiltrating stem-like CD8+T-cells and abrogates the abscopal effect

Abstract Purpose: PD-1 and PD-L1 antagonists are efficacious because cancer induces T-cell exhaustion via upregulation of PD-L1 and persistent antigen exposure. Our lab, has shown that the proliferative burst following αPD-L1 therapy of exhausted CD8+PD-1+T-cells is restricted to a “stem-like” CD8+T-cell subset in a murine chronic viral infection model. The role of these stem-like CD8+T-cells in malignancies and whether these cells respond to other immuno-stimulation including radiotherapy (RT) is unknown. RT’s immuno-stimulation includes acting as an in-situ vaccine by liberating cryptic tumor neo-antigens, generating a potent anti-tumor CD8+T-cell response, synergizing with αPD-1/L1 and leading to control at distant sites of disease outside the radiation field (abscopal effect). In initial studies, we found these stem-like CD8+T-cells in B16F10 tumors and at high frequencies in the tumor-draining lymph nodes (TDLN) of immunocompetent mice. Here, we investigated: (1) the impact of tumor-directed RT on this stem-like CD8+T-cell population in the tumor and TDLN in the context of an abscopal response, and (2) due to the high frequency of stem-like CD8+T-cells in the TDLN, whether depletion of lymphocytes from the TDLN via RT influenced the abscopal effect. Experimental Design: We developed a preclinical model of oligo-metastatic melanoma to evaluate the role of stem-like CD8+ T-cells and the TDLN in the abscopal effect. This was done with unilateral tumor-directed RT with or without TDLN-directed RT. This was also done in the presence and absence of αPD-L1. Results: Tumor-directed RT improved local tumor control and induced an abscopal response with a concomitant increase in tumor infiltrating tumor-specific stem-like CD8+T-cells. Tumor-specific stem-like CD8+T-cells were also observed in the TDLN of tumors on both sides. Importantly, the tumor-directed RT increased tumor-specific T-cell proliferation in the TDLNs bilaterally despite only being targeted at one tumor. Given this robust proliferative response and the high frequency of stem-like CD8+T-cells in the TDLN, we next evaluated the role of the TDLN in mediating the abscopal effect. We found that the abscopal effect is impaired if the TDLN is lymphocyte depleted with TDLN-directed RT in the presence or absence of αPD-L1. Additionally, the tumor-directed RT mediated increase in stem-like T-cells in the irradiated and unirradiated tumor was abrogated with TDLN-directed RT. Conclusion: Our results demonstrate slowed distant tumor growth following irradiation of a local site and that this correlates with an increase in tumor-infiltrating stem-like CD8+T-cells which is reduced with TDLN-directed RT. These data suggest a critical role for both the stem-like CD8+T-cells and the TDLN in mediating the abscopal effect. Citation Format: Zachary S. Buchwald, Tahseen H. Nasti, Christiane S. Eberhardt, Andreas Wieland, David Lawson, Walter Curran, Rafi Ahmed, Mohammad K. Khan. Tumor-draining lymph node irradiation reduces tumor-infiltrating stem-like CD8+T-cells and abrogates the abscopal effect [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 526.

Dosimetric Characterization of an Abscopal Response in a Patient With Oligometastatic Melanoma Undergoing Concurrent Treatment With Pembrolizumab and Stereotactic Body Radiotherapy (SBRT)

Dosimetric Characterization of an Abscopal Response in a Patient With Oligometastatic Melanoma Undergoing Concurrent Treatment With Pembrolizumab and Stereotactic Body Radiotherapy (SBRT)

Clinical Outcomes After Pulmonary Metastasectomy for Melanoma: A Population-Based Study

Resection of pulmonary metastases is an important treatment option for patients with oligometastatic melanoma. There are currently no published data available on population-level outcomes. Here, we report outcomes of a registry-based study of patients who underwent lung resection for cutaneous melanoma metastases. The study population was all cases of cutaneous melanoma in Ontario, Canada, with resection of pulmonary metastases from 2004 to 2012. Melanoma cases were identified using the population-based Ontario Cancer Registry and were linked with hospital records to identify thoracic surgery. Pathology reports from the Ontario Cancer Registry were used to confirm the histology of resected lesions and determine tumor-related prognostic factors. Overall survival was described, and multivariable Cox regression utilized. Ninety-nine patients underwent resection of cutaneous melanoma lung metastases. Mean age was 58 years. Sixty-day postoperative mortality was 0%. Two-year and 5-year overall survival from time of resection was 44%and 21%, respectively (95% confidence intervals: 34% to 54% and 12% to 31%, respectively). Two-year overall survival was 57% for lesion size less than 1.5 cm; 43% for lesion size 1.5 to 2.2 cm; and 35% for lesion size 2.2 cm or greater (confidence intervals: 35% to 73%, 26% to 59%, and 19% to 52%, respectively). In the multivariable stepwise selected model, the only significant variable was size 2.3 cm or greater (hazard ratio 1.64, confidence interval: 1.001 to 2.68). Greater lesion size was correlated with positive margin status (p= 0.04); there were no survivors beyond 2years with positive margins. In this unselected population-based study, 21% of patients were 5-year survivors after pulmonary metastasectomy for melanoma. There was worse survival with greater lesion size. Greater lesion size was associated with positive margin status.

Role of extra cranial stereotactic body radiation therapy in the management of Stage IV melanoma.

To investigate the role of extracranial stereotactic body radiation therapy (SBRT) in the management of oligometastatic melanoma. Patients affected by Stage IV melanoma, with less than three extracranial metastatic lesions, who received SBRT were included in this analysis. Acute and late toxicity, local control (LC), overall survival (OS) and progression-free survival (PFS) were analysed. 31 patients were included in the study. 16 patients (51.6%) were treated for lung meta-stases, 8 patients for liver metastases (25.8%) and 7 (22.6%) for nodal metastases. 38 lesions were irradiated. With a median follow-up time of 13 months, 11 patients (35.4%) were still alive, in four cases (12.9%) with no evidence of disease. Median OS was 10.6 months, and OS at 6, 12 and 24 months was 77, 41 and 21% respectively. LC at 12 and 24 months was 96.6 and 82.8%. 23 patients (74.2%) developed distant metastases. Median PFS was 5.8 months, and PFS at 6, 12 and 24 months was 48.2, 18.5 and 13.9% respectively. Number of irradiated lesions showed a statistically significant correlation only with LC (p = 0.03). Response of the irradiated lesion was related to OS (p = 0.019). Local response showed also a borderline correlation with PFS (p = 0.07). SBRT for extracranial metastases from melanoma is feasible and well tolerated. Response of the irradiated lesions is predictive of OS. Advances in knowledge: SBRT for melanoma extracranial metastases is feasible and the response of the irradiated lesions is predictive of OS.

Recurrence and Survival Outcomes After Percutaneous Thermal Ablation of Oligometastatic Melanoma

ObjectivesTo evaluate focal treatment of melanoma metastases and to explore whether any potential extended survival benefit exists in a select patient population. Patients and MethodsAll patients who underwent image-guided local thermal ablation of metastatic melanoma over an 11-year period (January 1, 2002, to December 31, 2013) were retrospectively identified using an internally maintained clinical registry. Only patients with oligometastatic stage IV disease amenable to complete ablation of all clinical disease at the time of ablation were included in the analysis. Overall survival and median progression-free survival periods were calculated. ResultsThirty-three patients with primary ocular or nonocular melanoma had 66 metastases treated in the lungs, liver, bones, or soft tissues. Eleven (33%) patients were on systemic medical therapy at the time of the procedure. The median survival time was 3.8 years (range, 0.5-10.5 years), with a 4-year estimated survival of 44.1% (95% CI, 28%-68%). Local recurrence at the ablation site developed in 15.1% (5 of 33) of the patients and 13.6% of the tumors (9 of 66). The median progression-free survival time was 4.4 months (95% CI, 1.4 months to 10.5 years), with an estimated 1-year progression-free survival of 30.3% (95% CI, 18%-51%). A subgroup analysis identified 11 patients with primary ocular melanoma and 22 with nonocular melanoma, with a median survival time of 3.9 years (range, 0.9-4.7 years) and 3.8 years (range, 0.5-10.5 years), respectively (P=.58). There were no major complications and no deaths within 30 days of the procedure. ConclusionSelective use of image-guided thermal ablation of oligometastatic melanoma may provide results similar to surgical resection in terms of technical effectiveness and oncologic outcomes with minimal risk.

Definitive Management of Oligometastatic Melanoma in a Murine Model Using Combined Ablative Radiation Therapy and Viral Immunotherapy

The oligometastatic state is an intermediate state between a malignancy that can be completely eradicated with conventional modalities and one in which a palliative approach is undertaken. Clinically, high rates of local tumor control are possible with stereotactic ablative radiation therapy (SABR), using precisely targeted, high-dose, low-fraction radiation therapy. However, in oligometastatic melanoma, virtually all patients develop progression systemically at sites not initially treated with ablative radiation therapy that cannot be managed with conventional chemotherapy and immunotherapy. We have demonstrated in mice that intravenous administration of vesicular stomatitis virus (VSV) expressing defined tumor-associated antigens (TAAs) generates systemic immune responses capable of clearing established tumors. Therefore, in the present preclinical study, we tested whether the combination of systemic VSV-mediated antigen delivery and SABR would be effective against oligometastatic disease. We generated a model of oligometastatic melanoma in C57BL/6 immunocompetent mice and then used a combination of SABR and systemically administered VSV-TAA viral immunotherapy to treat both local and systemic disease. Our data showed that SABR generates excellent control or cure of local, clinically detectable, and accessible tumor through direct cell ablation. Also, the immunotherapeutic activity of systemically administered VSV-TAA generated T-cell responses that cleared subclinical metastatic tumors. We also showed that SABR induced weak T-cell-mediated tumor responses, which, particularly if boosted by VSV-TAA, might contribute to control of local and systemic disease. In addition, VSV-TAA therapy alone had significant effects on control of both local and metastatic tumors. We have shown in the present preliminary murine study using a single tumor model that this approach represents an effective, complementary combination therapy model that addresses the need for both systemic and local control in oligometastatic melanoma.

Recurrence and survival outcomes following percutaneous thermal ablation of oligometastatic melanoma.

e20040 Background: Focal treatment of melanoma metastases has been demonstrated to provide extended survival in a very select patient population. To our knowledge, percutaneous image-guided thermal ablation of metastatic lesions has not been described for patients with stage IV melanoma. Methods: All patients who underwent image-guided local thermal ablation of metastatic melanoma over an 11-year period (2002-2013) were retrospectively identified using an internally maintained clinical registry. Only patients with oligometastatic stage IV disease amenable to complete ablation of all clinical disease at the time of ablation were included in our analysis. Progression of disease was followed with contrast-enhanced CT, MRI or PET/CT for identification of local recurrence at the ablation site, recurrent organ specific and/or new metastatic disease outside the previously treated organ. Overall survival and median progression-free survival (including local recurrence at the ablation site, treated organ recurrence and new metastatic disease) were calculated. Results: Thirty-three patients with primary ocular or cutaneous melanoma had 67 metastases treated in the lungs, liver, bones or soft tissues. Thirteen (39.4%) patients were on systemic medical therapy at the time of the procedure. The median survival time was 3.8 years with 5-year estimated survival of 27.5% (95% Cl: 14.6 to 51.9%). Local recurrence at the ablation site developed in 15.1% (5/33) of patients and 13.4% of tumors (9/67). Median progression-free survival time was 4.4 months with estimated 1-year progression-free survival of 30.3% (95% Cl:18.1 to 50.8%). There were no major complications and no deaths within 30 days post procedure. Conclusions: We demonstrate that image-guided thermal ablation of metastatic melanoma amenable to complete ablation of all clinical disease confers a potential survival benefit with minimal risk.

Definitive Management of Oligometastatic Melanoma in a Murine Model Using Combined Ablative Radiation Therapy (SABR) and Viroimmunotherapy (VI)

We aimed to characterize the clinical and immunologic effects of SABR combined with VI in murine oligometastatic melanoma (OM). Although SABR leads to durable local control in OM, the majority of patients progress systemically. We have previously demonstrated that melanoma cDNA antigens expressed on the vesicular stomatitis virus (VSV) lead to robust, anti-melanoma immunity in mice. Therefore, we hypothesized that the combination of SABR and VSV may lead to improved local and metastatic disease control.