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Sahlgrenska Center for Cancer Research, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenWallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, SwedenDepartment of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
Sahlgrenska Center for Cancer Research, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenDepartment of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
Sahlgrenska Center for Cancer Research, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenDepartment of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
Sahlgrenska Center for Cancer Research, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenDepartment of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
Melanoma Institute Australia, The University of Sydney, Sydney AustraliaFaculty of Medicine and Health, The University of Sydney, Sydney, AustraliaRoyal North Shore and Mater Hospitals, Sydney, Australia
Melanoma Institute Australia, The University of Sydney, Sydney AustraliaFaculty of Medicine and Health, The University of Sydney, Sydney, AustraliaDepartment of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Camperdown, Australia
Department of Surgery, Royal Adelaide Hospital, Adelaide, AustraliaAdelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia
Department of Surgery, Royal Adelaide Hospital, Adelaide, AustraliaAdelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia
Department of Surgery, Royal Adelaide Hospital, Adelaide, AustraliaAdelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia
Melanoma Institute Australia, The University of Sydney, Sydney AustraliaDepartment of Medical Oncology, Westmead and Blacktown Hospitals, The Crown Princess Mary Cancer Centre, Sydney, Australia
Melanoma Institute Australia, The University of Sydney, Sydney AustraliaFaculty of Medicine and Health, The University of Sydney, Sydney, AustraliaRoyal North Shore and Mater Hospitals, Sydney, Australia
Department of Cutaneous Oncology Moffitt Cancer Center, Tampa, USADepartment of Oncologic Sciences, University of South Florida Morsani College of Medicine, Tampa, USA
Sahlgrenska Center for Cancer Research, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenWallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, SwedenDepartment of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
The efficacy of immunotherapy for melanoma in-transit metastases is unknown.
•
An international multicenter retrospective cohort study.
•
Systemic immunotherapy is an effective treatment for melanoma in-transit metastases.
Abstract
Purpose
Guidelines addressing melanoma in-transit metastasis (ITM) recommend immune checkpoint inhibitors (ICI) as a first-line treatment option, despite the fact that there are no efficacy data available from prospective trials for exclusively ITM disease. The study aims to analyze the outcome of patients with ITM treated with ICI based on data from a large cohort of patients treated at international referral clinics.
Methods
A multicenter retrospective cohort study of patients treated between January 2015 and December 2020 from Australia, Europe, and the USA, evaluating treatment with ICI for ITM with or without nodal involvement (AJCC8 N1c, N2c, and N3c) and without distant disease (M0). Treatment was with PD-1 inhibitor (nivolumab or pembrolizumab) and/or CTLA-4 inhibitor (ipilimumab). The response was evaluated according to the RECIST criteria modified for cutaneous lesions.
Results
A total of 287 patients from 21 institutions in eight countries were included. Immunotherapy was first-line treatment in 64 (22%) patients. PD-1 or CTLA-4 inhibitor monotherapy was given in 233 (81%) and 23 (8%) patients, respectively, while 31 (11%) received both in combination. The overall response rate was 56%, complete response (CR) rate was 36%, and progressive disease (PD) rate was 32%. Median PFS was ten months (95% CI 7.4–12.6 months) with a one-, two-, and five-year PFS rate of 48%, 33%, and 18%, respectively. Median MSS was not reached, and the one-, two-, and five-year MSS rates were 95%, 83%, and 71%, respectively.
Conclusion
Systemic immunotherapy is an effective treatment for melanoma ITM. Future studies should evaluate the role of systemic immunotherapy in the context of multimodality therapy, including locoregional treatments such as surgery, intralesional therapy, and regional therapies.
]. According to the American Joint Committee on Cancer (AJCC) staging system, patients with ITM are considered to have stage III disease with a corresponding high risk of both locoregional and systemic recurrence [
]. When there are few lesions and all can be removed with an excision, surgical resection is recommended, but for patients with unresectable ITM (e.g., multiple, bulky, or quickly recurrent), there are numerous locoregional treatment options available. These include isolated limb perfusion (ILP) [
Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III-IV melanoma.
]. These locoregional therapies offer very high overall response rates (ORR) (70–90%) and complete response (CR) rates (50–70%). The majority of the literature on locoregional treatments are retrospective series, with few prospective clinical trials, and there are no studies directly comparing these locoregional treatments with each other or to systemic immunotherapy [
There have been major advances recently in the treatment of advanced melanoma with the introduction of effective systemic treatments, including targeted therapies with BRAF-MEK inhibitors [
Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial.
]. These agents have proven to be effective in unresectable disease as well as in the adjuvant and neoadjuvant settings. Many guidelines addressing ITM recommend ICI as an option for first-line treatment, despite the fact that there are no data available from prospective trials on the efficacy of these agents for ITM. When the pivotal registration trials of PD-1 inhibitors for patients with advanced melanoma were analyzed, no patients with exclusively ITM were identified [
The aim of this study was to analyze the outcome of patients with ITM treated with immune checkpoint blockade using PD-1 inhibitors and/or a CTLA-4 inhibitor based on real-world data from a large international cohort of patients from melanoma centers in Australia, Europe, and the USA.
2. Material and Methods
2.1 Study design
A multicenter retrospective cohort study that included patients treated between January 2015 and December 2020. All participating study sites are national or regional referral clinics for the treatment of melanoma. The study was conducted in adherence to the ethical principles of the Declaration of Helsinki, Good Clinical Practice (GCP) and ICH Guidelines with the approval of the Swedish Ethical Review Authority (477–18 and 2021–02315). Sahlgrenska University Hospital served as the coordinating center and participating institutions obtained appropriate ethical approval and performed independent data extraction and provided data to the coordinating center in compliance with individual institutional requirements and negotiated data use agreements.
2.2 Study cohort
This study included cutaneous melanoma patients treated with ICIs for in-transit melanoma metastases (AJCC8 stages IIIB-D), with or without concurrent nodal involvement (AJCC8 N1c, N2c, and N3c). Patients were included if they were treated with a PD-1 inhibitor (nivolumab or pembrolizumab) and/or CTLA-4 inhibitor (ipilimumab); with or without previous treatment for in-transit metastases, e.g., surgery, locoregional, and systemic treatments. Patients having received concomitant therapies parallel to ICI treatment were excluded. All in-transit lesions were required to be evaluable by RECIST criteria, but modified so that lesions not visible by radiology were measured by calipers instead. Patients with previous or synchronous distant metastases (stage IV disease) were excluded.
2.3 Outcomes
The primary endpoint was CR rate, with best overall response, time to local progression (TTLP), time to nodal progression (TTNP), time to systemic progression (TTSP), progression-free survival (PFS), melanoma-specific survival (MSS), and overall survival (OS) as secondary endpoints. MSS and OS were calculated from the start of immunotherapy to death or end of follow-up, and PFS was calculated from the start of immunotherapy to progression or death. The response was evaluated as the best response during follow-up according to the RECIST criteria modified for cutaneous lesions (allowing for caliper measurement if lesions were not visible on radiology). To be considered a CR, all lesions had to disappear. Partial response (PR) was defined as a decrease of more than 30% of the total tumor burden, measured as a number of lesions or shrinkage in the largest tumor diameter. Progressive disease (PD) was defined as an increase of more than 25% in existing lesions or the appearance of new lesions. Stable disease (SD) was defined as when criteria for CR, PR, or PD were not met.
2.4 Statistical analysis
Survival was estimated using the Kaplan-Meier method and analyzed using the log-rank test. Adjusted analyses were performed using binary logistic regression for CR and Cox regression for TTLP, PFS, and MSS, with results reported as hazard ratios (HR) with 95% confidence intervals (CIs) and p-values. Statistical significance was set at p < 0.05. Covariates for adjustment were selected a priori (age, gender, performance status, geographic region, T-status, mutational status, having received adjuvant therapy, anatomical site of ITM, number of ITM, size of largest ITM>=30 mm, lymph node status, and having received previous treatment for ITM). Statistical analysis was performed using SPSS version 24.0 (SPSS Inc., Chicago, IL, USA).
3. Results
A total of 287 patients with melanoma ITM from 21 institutions in eight different countries treated with immunotherapy were included in the analysis (Supplementary Table 1). Overall, 161 patients (56%) were male, and the median age at the start of ICI was 69 years (IQR 59–78). The median time from melanoma diagnosis to the first in-transit recurrence was 13 months (IQR 5–30). The most common site for in-transit metastasis was the lower limb, both for females (95/124, 77%) and males (74/157, 47%), and 127 (44%) had concomitant lymph node metastasis. A BRAF mutation was present in 84 (29%) and an NRAS mutation in 57 (20%) of the tumors. The most common histological subtypes of the primary melanomas were nodular (35%) and superficial spreading (32%), while acral lentiginous was present in only 8% of the patients. Ulceration was present in 122 (42.5%) of primary tumors (Table 1). Data on disease stage at diagnosis of the primary melanoma were available for 88% (n = 253) of patients, with 1% (n = 2) stage 0, 9% (n = 25) stage I, 24% (n = 60) stage II, and 66% (n = 166) stage III.
Table 1Baseline patient characteristics at start of ICI for ITM.
Immunotherapy was first-line treatment in 22% (n = 64) of the patients, or 60% (n = 173) if excluding previous surgical excisions. The remaining 40% of patients received previous treatments, either one or a combination of multiple therapies, with ILP (12%, n = 34), TVEC (10%, n = 28), radiotherapy (9%, n = 27), or ILI (3%, n = 9) being the most common (Table 1). Regional differences in treatment regimens were found when comparing geographical location, and treatments given prior to immunotherapy were in Europe previous surgical excision 66% (n = 69), ILP 14% (n = 15), ILI 2% (n = 2), and TVEC 11% (n = 12), in North America, the treatments were previous surgical excision 60% (n = 78), ILP 14% (n = 18), ILI 4% (n = 5), and TVEC 11% (n = 14), and in Australia, the treatments were previous surgical excision 80% (n = 41), ILP 2% (n = 1), ILI 4% (n = 2), and TVEC 4% (n = 2).
Single-agent treatment with a PD-1 or CTLA-4 inhibitor was given in 81% (n = 233) and 8% (n = 23) of the patients, respectively, while 11% (n = 31) received combination therapy with both a PD-1 and a CTLA-4 inhibitor. The median treatment time was five months (IQR 2–12), and the median follow-up time was 20 months (IQR 12–37). The ORR was 56%. The best response rate was CR in 36% (n = 104), PR in 20% (n = 58), SD in 11% (n = 32), and PD in 32% (n = 93) of the patients, respectively. The CR rate was 37% (86/233) for single-agent PD-1 inhibitor, 30% (7/23) for single-agent CTLA-4 inhibitor, and 35% (11/31) for the combination treatment of PD-1 and CTLA-4 inhibitor, with ORR of 56%, 43%, and 68%, respectively (Table 2). In both univariate and multivariate analysis, no predictive factors for CR were identified (Table 3).
Table 2Response rate based on the type of treatment and subsequent disease progression.
The median time to local progression was 12 months (95% CI 6.0–18.0) and occurred in 160 patients (56%). There was a significant difference in time to local progression depending on response, where the median time was not met for CR, and for patients with a PR or SD, 23 and 21 months, respectively (p < 0.001) (Fig. 1). A total of 72 patients (25%) developed regional nodal progression after a median time of five months (95% CI 2.9–7.1). A total of 89 patients (31%) progressed with distant metastases after a median time of nine months (95% CI 6.7–11.3).
Fig. 1Local progression-free survival (in-transit metastasis) based on response of treatment from start of immunotherapy.
Out of the 104 patients that experienced an initial CR, 24 patients (23%) later progressed with further ITM after a median time of ten months, ten patients (10%) progressed with lymph node metastases after a median time of seven months, and 16 patients (15%) progressed with distant metastases after a median time of ten months (Table 2).
The median PFS from the start of ICI was ten months (95% CI 7.5–12.5 months) with a one-, two-, and five-year PFS rate of 47%, 33%, and 19%, respectively. When dividing PFS based on the type of immunotherapy received, there was no significant difference with a median PFS of ten months for single-agent PD-1 inhibitor, nine months for single-agent CTLA-4 inhibitor, and nine months for the combination treatment of PD-1 and CTLA-4 inhibitor (p = 0.77) (Fig. 2). In multivariate analysis, only ECOG performance status ≥2 (HR 2.16, 95% CI 1.04–4.50, p = 0.04) was found to be predictive for PFS (Supplementary Table 2).
Fig. 2Progression-free survival from start of immunotherapy by treatment.
One-, two-, and five-year MSS rate from the start of ICI was 95%, 83%, and 72%, respectively, with median MSS not reached (Supplementary Fig. 1). In multivariate analysis, female sex (HR 0.40, 95% CI 0.17–0.92, p = 0.03), ECOG performance status ≥2 (HR 7.52, 95% CI 2.14–26.46, p = 0.01), and positive lymph node status at the start of immunotherapy (HR 2.84, 95% CI 1.15–7.06, p = 0.02) were found to be the prognostic for MSS (Supplementary Table 3). The one-, two-, and five-year OS was 92%, 77%, and 63%, respectively, with median OS not reached at the time of analysis. Melanoma-specific survival analyzed by best response from the start of ICI showed that response was a significant factor for survival (log-rank p < 0.001) (Fig. 3).
Fig. 3Melanoma-specific survival by best response from the start of ICI.
This is the largest pooled multi-institutional analysis to date presenting real-world (outside of clinical trials) outcomes for patients with in-transit metastasis treated with systemic immunotherapy. The topic is clinically challenging and a pooled analysis is timely, particularly as patients with ITM only were not included as a subgroup for analysis in the previous registration trials for unresectable stage III or stage IV melanoma [
]. Nan Tie et al. presented a retrospective analysis of 54 patients with in-transit metastasis treated with PD-1 inhibitor (nivolumab or pembrolizumab) ± CTLA-4 inhibitor (ipilimumab) at three tertiary hospitals in Australia. Their cohort (partly included in this study) is comparable to ours in patient characteristics and treatment regimes, except that our study includes more patients with ulcerated primary tumors and more patients with concurrent nodal metastasis at the start of immunotherapy. We report a higher one- and two-year OS, while ORR and PFS are comparable.
More recently, Zaremba et al. retrospectively reported on 191 patients with unresectable stage IIIB-D in-transit and satellite metastases from 16 centers in Germany. Notably, they excluded patients who had received prior treatments followed by adjuvant immunotherapy and only included patients receiving PD-1±CTLA4-inhibitor as first-line treatment. Patient characteristics were, again, roughly comparable to this cohort, but the overall CR rate for patients receiving PD-1 inhibitor was only 13% [
Our CR rate is also higher than the response data from the registration trials investigating immunotherapy for unresectable stage III and stage IV patients. The CR rates in these registration trials range from a CR rate of 2% for CTLA4-inhibitor monotherapy, up to 22% for combination PD-1 and CTLA4-inhibitors [
Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study.
Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial.
Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial.
Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006).
Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study.
]. Though the direct comparison is difficult, we also see a significantly higher MSS in our CR patient group. We also see an unexpectedly high CR rate of 30% for single-agent CTLA4 in this study. This is significantly higher than reported from other cohorts and is possibly an overestimate due to the small sample size of only twenty-three patients in this subgroup. However, it should be noted that direct comparisons of response rates are complicated by the lack of a standardized method of judging response in cutaneous lesions. We used RECIST criteria for the definition of response, with the modification that the lesions did not have to be visible on radiology, but could be measured by calipers. This is a strength, since the response rates can be compared to other publications, and using calipers is the most common way in-transit lesions are measured. Of note, how the response was evaluated was not stated at all in the Zaremba manuscript [
] used the WHO criteria for PR (50% cut-off). In addition, any biological particularities of in-transit metastases underlying response and progression patterns are currently unknown.
Other treatment options for patients with ITM include, e.g., TVEC, ILI, or ILP, with reported CR rates of up to 62%, 38%, and 65%, respectively [
T-VEC for stage IIIB-IVM1a melanoma achieves high rates of complete and durable responses and is associated with tumor load: a clinical prediction model.
]. Owing to the heterogeneous follow-up between these different studies, any comparison of response duration is not possible. In the current cohort, there was no benefit of having received locoregional treatments prior to immunotherapy. This finding can be the result of a selection bias due to our study design, where only patients progressing after a previous locoregional treatment were included. Patients with limited and resectable in-transit metastases may undergo a resection of the metastases followed by adjuvant systemic therapy, supported by data from the CheckMate-238 study showing a benefit in four-year RFS favoring nivolumab over ipilimumab with a HR of 0.63.
Another important finding was the rate of patients with no response and primary resistance; the rate of PD as the best response in this real-world cohort was 32% compared to 30% in Nan Tie et al. [
]. We, therefore, hypothesize that for patients with multiple, bulky, or quickly recurrent ITM, a combination of locoregional with systemic treatment might be appealing. This strategy might combine the very high ORR and low PD rates of T-VEC, ILP, or ILI, together with a systemic treatment that would also treat undetected micrometastatic disease outside of the area treated with locoregional therapy.
Hypothetically, the combination of locoregional and systemic treatment might not just have effects independent of each other but might also act in synergy. It has, for example, been shown that ILP leads to an activation of tumor-specific T-cells, which potentially can be enhanced by the addition of a PD-1 inhibitor [
Melan-A specific CD8+ T lymphocytes after hyperthermic isolated limb perfusion: a pilot study in patients with in-transit metastases of malignant melanoma.
], and the following placebo-controlled Masterkey-265 phase III trial showed an increased response rate (18% vs. 12%), however, without any benefit in PFS or OS after a median of 31 months of follow-up [
1037O MASTERKEY-265: a phase III, randomized, placebo (Pbo)-controlled study of talimogene laherparepvec (T) plus pembrolizumab (P) for unresectable stage IIIB–IVM1c melanoma (MEL).
]. On the other hand, TVEC has been shown to be an effective salvage therapy with ORR of 51% and CR rates of 37% after the failure of systemic immunotherapy for ITM [
Talimogene laherparepvec (T-VEC) for the treatment of advanced locoregional melanoma after failure of immunotherapy: an international multi-institutional experience.
]. Another phase III trial (ILLUMINATE-301), examined the synergistic effect of intratumoral injections of the Toll-like receptor 9 agonist tilsotolimod together with ipilimumab, however, there was no difference in ORR compared to ipilimumab alone, 8.8% vs 8.6% (data not published). In summary, the optimal combination and sequence of these different treatment modalities for patients with ITM needs further clarification through prospective trials. Two examples of ongoing studies are the Nivo-ILP (ClinicalTrials.gov: NCT03685890) and NIVEC (ClinicalTrials.gov: NCT04330430) studies, which are examining the combination of ILP and nivolumab and T-VEC and nivolumab for patients with ITM, respectively.
We demonstrate a five-year OS of 63%, and in comparison, 44% for patients treated with ILI as shown by Kroon et al.; 26% for patients treated with ILP as shown by Olofsson Bagge et al.; and 49% for patients treated with TVEC (stage IIIB-IV M1a patients) as reported by Andtbacka et al. [
Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III-IV melanoma.
]. However, any direct comparisons are not possible as some of these studies were undertaken before effective systemic therapies were available, and the patient selection criteria/baseline characteristics, patient prognosis, methodologies, and follow-up times are also very different.
The relatively low rate of BRAF positive patients in the current cohort, 32% (84/266) when excluding missing values, can be compared to 42% (71/170) in the material by Zaremba et al., and 19% (10/52) in the material by Nan Tie et al. Hypothetically, patients developing in-transit metastasis might have a different proportion of BRAF mutations, or there may be a selection bias where patients with a BRAF-mutation to a larger extent have received targeted therapies rather than immunotherapy. Unfortunately, based on the current data, we cannot draw any conclusions concerning this, but it is indeed a question that warrants further investigation.
A strength of this study is the large, international, and multi-center cohort. This results in what we believe to be an accurate overview of current practice and outcomes internationally. There were regional differences in treatment regimens when comparing centers by geographical location, and it is very possible that these differences reflect dissimilarities in either treatment availability or management approach between countries. Further, the study is limited by the retrospective design, inherent selection bias, and relatively small sub-groups. Also, as has been noted previously, measurement of treatment response in this patient group is difficult as the disease in this stage may not be accurately evaluable by RECIST [
] criteria. Many institutions report using RECIST criteria modified for cutaneous lesions, but do not specify the modifications further. In our view, there is currently a lack of objective and standardized criteria by which to assess in-transit lesions sufficiently accurately, and future research should be focused on this aspect.
5. Conclusions
In summary, systemic immunotherapy with checkpoint inhibition is an effective treatment for melanoma in-transit metastases. Future studies should be conducted to establish not only the optimal sequencing, timing, and role of surgery and/or other locoregional therapies in combination with systemic immunotherapy but also the mechanisms of clinical immune responses making such treatments effective.
The Swedish Cancer Society (Dnr 19 0040 Pj). Knut and Alice Wallenberg Foundation, Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Sweden
Conflict of interest statement
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
R Olofsson Bagge: Advisory boards for Amgen, Bristol-Myers Squibb, Merck Sharp & Dhome, Novartis, Roche, and Sanofi Genzyme. Speaker honorarium from Roche and Pfizer. Institutional research grant from Astra Zeneca and SkylineDx.
L Ny: Consultant/advisory role for Bristol-Myers Squibb, Merck Sharp & Dhome, Novartis, Pierre Fabre, Sanofi Genzyme and Zealth. Speaker honorarium from Bristol-Myers Squibb, Leo Pharma, Merck Sharp & Dhome, Novartis, and Pfizer. Institutional research support from Merck Sharp & Dhome and Syndax Pharmaceuticals.
T Hieken: Institutional research funding from Genentech and SkylineDx.
M Block: Advisory Boards TILT Biotherapeutics, Viewpoint Molecular Targeting and Sorrento Therapeutics. Grant/Research support from: Genentech, Marker Therapeutics, Immune Design, Pharmacyclics, Merck, Bristol-Myers Squibb, Transgene, Viewpoint Molecular Targeting and Sorrento Therapeutics.
F Dimitriou: Honoraria and travel support from Merck Sharp & Dohme and Sun Pharma.
AM Menzies: Advisory boards for Bristol-Myers Squibb, Merck Sharp & Dhome, Novartis, Roche, Pierre-Fabre and Qbiotics.
RPM Saw: Honoraria for advisory board participation from Merck Sharp & Dhome, Novartis and Qbiotics, and speaking honoraria from Bristol-Myers Squibb and Novartis.
A Rogiers: Speaker fee from Merck Sharpe and Dohme.
G Karakousis: Investigator intitated research trial institutional support from Merck.
L Pallan: Speakers fees and travel support from Bristol-Myers Squibb. Conference attendance support from Eli-Lilly.
JT Vetto: Speakers fee from CastleBiosciences.
D Gyorki: Advisory board Amgen, Provectus and Bayer. Speaker fees Bristol-Myers Squibb and Merck Sharp & Dhome.
PA Ascierto: Consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen and iTeos. Research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer and Sanofi.
R Dummer: intermittent, project focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome, Bristol-Myers Squibb, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA and touchIME outside the submitted work.
N Asher: Advisory boards for Medison, Bristol-Myers Squibb, Merck Sharp & Dhome, Novartis, Roche, and Sanofi. Speaker honoraria from Medison, Bristol-Myers Squibb, Merck Sharp & Dhome, Novartis, and Sanofi. Institutional research grants from Medison and Novartis.
H Helgadottir: Advisory boards for Merck Sharp & Dhome and Novartis. Speaker honorarium from Bristol-Myers Squibb.
MS Carlino: Advisory board member for Amgen, Bristol-Myers Squibb, Eisai, Ideaya, Merck Sharp & Dhome, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche, Merck and Sanofi, and honoraria from Bristol-Myers Squibb, Merck Sharp & Dhome, and Novartis.
J Weber: Consult for Merck, Genentech, Astra Zeneca, GlaxoSmithKline, Novartis, Nektar, Celldex, Incyte, Biond, ImCheck, Sellas, Evaxion and EMD Serono. Advisory board member Bristol-Myers Squibb. Equity in Biond, Evaxion, Instil Bio and Neximmune. Scientific advisory boards for CytoMx, Incyte, ImCheck, Biond, Sellas, Instil Bio OncoC4 and Neximmune. Institutional research support from Bristol-Myers Squibb, Merck, GlaxoSmithKline, Moderna, Pfizer, Novartis and Astra Zeneca. Named on patents from Moffitt Cancer Center and Biodesix.
D Ollila: Advisory boards and/or Consulting for Philogen, Merck, Novartis and Castle Biosciences. Medical Advisory Bopard - Delcath Systems. Speaker honorarium from Sun Pharma and Pfizer. Institutional research funding from Neracare, Castle Biosciences, Delcath Systems, Philogen and Provectus, GV Long: Consultant advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma inc, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Evaxion Biotech A/S, Hexel AG, Highlight Therapeutics S.L., Merck Sharpe & Dohme, Novartis Pharma AG, OncoSec, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals Inc, SkylineDX B.V. and Specialised Therapeutics Australia Pty Ltd.
J Zager: Advisory boards and/or Consulting for Philogen, Merck, Novartis and Castle Biosciences. Medical Advisory Board Delcath Systems. Speaker honorarium from Sun Pharma and Pfizer. Institutional research funding from Neracare, Castle Biosciences, Delcath Systems, Philogen and Provectus.
A van Akkooi: Advisory Board and Consultancy Honoraria from Amgen, Bristol-Myers Squibb, Novartis, Merck Sharp & Dhome, Merck, Pfizer, Pierre Fabre, Sanofi, Sirius Medical and 4SC. Research grants from Amgen, Merck and Pfizer. All unrelated to current work and paid to institute.
The funding bodies had no part in the design of the study, the collection of data, in the analysis of data or in writing the manuscript.
Acknowledgements
This publication is dedicated to the memory of our colleague and friend Dr Dale Han.
Appendix A. Supplementary data
The following is the supplementary data to this article:
Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III-IV melanoma.
Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial.
Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study.
Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial.
Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial.
Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006).
Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study.
T-VEC for stage IIIB-IVM1a melanoma achieves high rates of complete and durable responses and is associated with tumor load: a clinical prediction model.
Melan-A specific CD8+ T lymphocytes after hyperthermic isolated limb perfusion: a pilot study in patients with in-transit metastases of malignant melanoma.
1037O MASTERKEY-265: a phase III, randomized, placebo (Pbo)-controlled study of talimogene laherparepvec (T) plus pembrolizumab (P) for unresectable stage IIIB–IVM1c melanoma (MEL).
Talimogene laherparepvec (T-VEC) for the treatment of advanced locoregional melanoma after failure of immunotherapy: an international multi-institutional experience.
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