Search

BACKGROUND Historically leptomeningeal metastases (LM) from melanoma have a poor prognosis, with a median survival of only 2 months despite treatment. Targeted therapy and immune checkpoint inhibitors are promising new treatment options in advanced melanoma. We sought to determine the impact of targeted therapy and immunotherapy on the outcome of melanoma patients with LM and to evaluate the influence of prognostic factors. PATIENTS AND METHODS We analyzed a series of 39 consecutive patients diagnosed with LM from melanoma between May 2010 and March 2015 treated at the Netherlands Cancer Institute. Thirty-four of these patients also had brain metastases (BM). Statistical analyses assessed the influence of clinical and biological characteristics on survival. RESULTS Median overall survival of the entire cohort was 6.9 weeks (95% confidence interval 0.9-12.8). Due to a poor performance status or rapidly progressive disease, 14 patients received no treatment. Median overall survival of untreated patients after the diagnosis of LM was 2.9 versus 16.9 weeks for treated patients (P < 0.001). The median survival of 21 patients treated with systemic targeted therapy and/or immunotherapy, with or without RT was 21.7 weeks (range 2-235 weeks). Five patients had LM without BM. Three of these patients died within 3 weeks before any treatment was given, whereas 2 patients are in ongoing remission for 26 weeks (following dabrafenib) and 235 weeks (following WBRT and ipilimumab). Elevated serum lactate dehydrogenase and S100B at diagnosis of LM were associated with shorter survival. CONCLUSION LM from melanoma still has an extremely poor prognosis. As observed in extracranial metastatic disease, new treatment modalities such as systemic targeted therapy and immune checkpoint inhibitors seem to increase overall survival in LM, and may result in long-term remission. These new treatment options should be considered in patients with LM.

Background Adoptive cell therapy (ACT) with T cell receptor (TCR) gene modified peripheral blood T cells creates large pools of tumor reactive T cells. Based on preclinical validation we have selected a high affinity MART-1-specific TCR for TCR gene therapy in metastatic melanoma (MM). Utilizing a novel GMP production protocol we performed a phase I trial to asses feasibility, safety and efficacy of TCR gene therapy in pts with MM. Methods HLA-A2*0201+ pts with irresectable stage IIIc/IV melanoma, expressing MART-1 and MHC class I, with no standard treatment options were included. Autologous T cells were isolated via apheresis and transduced with a MP-71 retroviral vector encoding the 1D3HMCys MART-1 TCR and expanded ex vivo in presence of IL-7 and IL-15. Non-myeloablative chemotherapy was given prior to one i.v. infusion of MART-1 TCR transduced T cells in a dose escalating manner after evaluation of adverse events (AEs). Feasibility, safety (CTCAE 4.0) and ORR (RECIST 1.1) were assessed. Results Twelve heavily pretreated metastatic cutaneous (n = 7) and uveal (n = 5) melanoma (mUM) pts were treated with MART-1 TCR transduced T cells across 4 dose cohorts. Transduction efficiency was 42-76%. Viability of the cell product was 92.9-98.5%. Pt 1 received 4.56 x 109 MART-1 TCR transduced T cells but died 9 days post infusion due to multiple organ failure. Subsequent pts received 5 x 107 (n = 3; cohort (c) 2), 25 x 107 (n = 2; c3) and 10 x 107 (n = 6; c4) cells. On-target AEs were dose-dependent and included dermatitis (10/11) max grade 3, uveitis (3/11) max grade 2 and ototoxicity (4/11) max grade 3, highest in cohort 3. Four pts (n = 2 c3; n = 2 c4) showed signs of cytokine release syndrome and 3 pts required tocilizumab. Objective PR by RECIST 1.1 was seen in 2 pts (17%), with a DOR of 4.2 (mUM, c4) and 8.4 (c3) months. Persistence of transduced T cells in peripheral blood was correlated with infused cell dose. Conclusions Treatment with MART-1 TCR transduced peripheral blood T cells expanded in presence of IL-7 and IL-15 led to severe dose-dependent toxicity with a maximum tolerated dose of 10 x 107 transduced cells. Despite observed responses, toxicity limited further development and use of this MART-1 TCR cellular therapy in MM patients. NCT02654821. Clinical trial identification NCT02654821. Legal entity responsible for the study Netherlands Cancer Institute/Antoni van Leeuwenhoek hospital (NKI-AVL). Funding KWF Kankerbestrijding. Disclosure J.H. Beijnen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Modra Pharmaceuticals BV . J.V. van Thienen: Honoraria (institution), Advisory / Consultancy: Pfizer ; Honoraria (institution), Advisory / Consultancy: Novartis. C.U. Blank: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: GSK; Honoraria (self), Advisory / Consultancy: GenMab; Honoraria (self), Advisory / Consultancy: Pierre Fabre ; Research grant / Funding (institution): NanoString. T.N. Schumacher: Advisory / Consultancy: Adaptive Biotechnologies; Advisory / Consultancy, Shareholder / Stockholder / Stock options: AIMM Therapeutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Allogene Therapeutics; Advisory / Consultancy: Amgen; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Merus; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Neon Therapeutics; Advisory / Consultancy: Scenic Biotech; Advisory / Consultancy: Third Rock Ventures; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Merck KGaA; Shareholder / Stockholder / Stock options: Neogene Therapeutics; Shareholder / Stockholder / Stock options: Scenic Biotech. J.B.A.G. Haanen: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): BMS; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (institution), Advisory / Consultancy: Pfizer; Honoraria (institution), Advisory / Consultancy: AZ/MedImmune; Honoraria (institution), Advisory / Consultancy: Roche/Genentech; Honoraria (institution), Advisory / Consultancy: Ipsen; Honoraria (institution), Advisory / Consultancy: Bayer; Honoraria (institution), Advisory / Consultancy: Immunocore; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (institution), Advisory / Consultancy: Seattle Genetics; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Neon Therapeutics; Honoraria (institution), Advisory / Consultancy: Celsius Therapeutics; Honoraria (institution), Advisory / Consultancy: Gadet ; Honoraria (institution), Advisory / Consultancy: GSK. All other authors have declared no conflicts of interest.

Background Outcome of high-risk stage III melanoma patients (pts) was poor with a 5-year OS rate of Methods Between Augustus 2015 and October 2016, 20 stage IIIB/IIIC melanoma pts with palpable nodal disease were included in the phase Ib feasibility OpACIN trial. Pts were randomized to receive IPI 3 mg/kg + NIVO 1 mg/kg, either adj 4 courses or split 2 courses neoadj and 2 adj. Path response, as reviewed by a blinded pathologist, was defined as Results After a median FU of 36.7 months (minimum 28.3 months FU of pts alive) none of the 7 pts with a path response in the neoadj arm have relapsed. Both non-responding pts in the neoadj have relapsed versus 4 pts in the adj arm. One pt has died in the neoadj arm and 3 in the adj arm. The estimated 3-year RFS rate was 80% for the neoadj arm and 60% for the adj arm. The 3-year OS rates were 90% and 67%, respectively. Of the 18 (90%) pts that had developed 1 or more grade 3-4 adverse events all have recovered to ≤ grade 1, except for grade 2 endocrine toxicities needing hormonal supplementation therapy that are ongoing in 8 (50%) of 16 pts alive. Conclusions OpACIN was the first trial investigating neoadj IPI + NIVO in pts with macroscopic stage III melanoma, thus having the longest FU. At 3 years FU, no new safety events occurred and none of the pts with a path response have relapsed, suggesting that path response could be considered as surrogate marker for RFS and OS in neoadjuvant checkpoint inhibitor trials. Clinical trial identification NCT02437279. Legal entity responsible for the study Netherlands Cancer Institute. Funding BMS. Disclosure C.U. Blank: Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: Roche; Advisory / Consultancy: GSK; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: GenMab; Advisory / Consultancy: Lilly; Research grant / Funding (institution): NanoString; Advisory / Consultancy: Pierre Fabre. J.V. van Thienen: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis. J.B.A.G. Haanen: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Pfizer; Advisory / Consultancy: AZ/MedImmune; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Immunocore; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy, Research grant / Funding (institution): Neon Therapeutics; Advisory / Consultancy: Celsius Therapautics; Advisory / Consultancy: Gadet; Advisory / Consultancy: GSK. A.C.J. van Akkooi: Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: MSD Merck; Advisory / Consultancy: Merck-Pfizer; Advisory / Consultancy: 4SC. T.N. Schumacher: Advisory / Consultancy: Adaptive Biotechnologies; Advisory / Consultancy, Shareholder / Stockholder / Stock options: AIMM Therapeutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Allogene Therapeutics; Advisory / Consultancy: Amgen; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Merus; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Neon Therapeutics; Advisory / Consultancy: Scenic Biotech; Research grant / Funding (institution): MSD; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Merck KGaA; Shareholder / Stockholder / Stock options: Neogene Therapeutics; Shareholder / Stockholder / Stock options, Venture partner: Third Rock Venture. E.A. Rozeman: Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: NanoString. All other authors have declared no conflicts of interest.

Background Immune-checkpoint inhibitors have revolutionized advanced melanoma care. Despite major improvements in survival, many patients do not derive long-term benefit and treatment could cause severe side-effects. Since several new (combination) therapies are or will become available, early prediction of non-responsiveness (NR) to anti-PD-1 monotherapy becomes relevant in order to enable early switch to next line (combination) treatment and avoid nonsensical care. Methods Advanced melanoma patients treated with pembrolizumab (PEM) who started PEM between June 2014 and August 2016 were included in this retrospective analysis. S100 and lactate dehydrogenase (LDH) levels were routinely determined prior to initiation of PEM and every 3-weeks during treatment. NR to treatment was defined as progressive disease or death at 6 months after start of PEM. Biomarker response characteristic (BReC) plots were obtained and LDH and S100 response cut-offs were determined based on two criteria: specificity for NR > 95% and feasibility to use in clinical practice. Next, sensitivity, specificity and predictive values were generated per follow-up time point (week 3, 6, 9, 12 and 15). Results 166 advanced melanoma patients were included. The BReC analyses showed clear relations between an early (week 3 to 15) increase in tumor biomarker and NR. An increase of > 50% in LDH or a > 100% increase in S100 above the upper limit of normal compared to baseline at any follow-up interval was determined as criterion to positively test for NR. Obtained specificity ranged from 0.97-0.98 and the positive predictive value ranged from 0.92-0.96 for the studied follow-up intervals. Obtained sensitivity for detecting non-responsiveness ranged from 0.25 (95% CI; 0.16-0.35) at 3 weeks of follow-up to 0.35 (95% CI; 0.24-0.47) at 12 weeks of follow-up. Conclusions An early increase in S100 and/or LDH are strong parameters for non-responsiveness to PD-1 blockade in advanced melanoma. Prospective confirmation is needed before clinical implementation. Legal entity responsible for the study Netherlands Cancer Institute. Funding Netherlands Cancer Institute. Disclosure E.A. Rozeman: Travel / Accommodation / Expenses: NanoString; Travel / Accommodation / Expenses: MSD. J.V. van Thienen: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis. J.B.A.G. Haanen: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Pfizer; Advisory / Consultancy: AZ/MedImmune; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Immunocore; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Neon Therapeutics; Advisory / Consultancy: Celsius; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Gadet. C.U. Blank: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Lilly ; Advisory / Consultancy: GSK; Advisory / Consultancy: GenMab; Research grant / Funding (institution): NanoString; Advisory / Consultancy: Roche; Advisory / Consultancy: Pierre Fabre. All other authors have declared no conflicts of interest.