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Neoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN ( NCT02437279 ) and phase 2 OpACIN-neo ( NCT02977052 ) studies 1 , 2 . While the results are promising, data on the durability of these pathologic responses and baseline biomarkers for response and survival were lacking. After a median follow-up of 4 years, none of the patients with a pathologic response ( n  = 7/9 patients) in the OpACIN study had relapsed. In OpACIN-neo ( n  = 86), the 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders ( P  < 0.001). High tumor mutational burden (TMB) and high interferon-gamma-related gene expression signature score (IFN-γ score) were associated with pathologic response and low risk of relapse; pRR was 100% in patients with high IFN-γ score/high TMB; patients with high IFN-γ score/low TMB or low IFN-γ score/high TMB had pRRs of 91% and 88%; while patients with low IFN-γ score/low TMB had a pRR of only 39%. These data demonstrate long-term benefit in patients with a pathologic response and show the predictive potential of TMB and IFN-γ score. Our findings provide a strong rationale for a randomized phase 3 study comparing neoadjuvant ipilimumab plus nivolumab versus standard adjuvant therapy with antibodies against the programmed cell death protein-1 (anti-PD-1) in macroscopic stage III melanoma. Long-term outcomes and biomarker analyses of two neoadjuvant immunotherapy clinical trials in melanoma patients support the clinical benefit of this treatment approach and uncover prognostic correlates of response.

The altered iron concentration in many neurodegenerative diseases such as Alzheimer's disease (AD) has led to the development of MRI sequences that are sensitive to the accompanying changes in the transverse relaxation rate. Heavily T2*-weighted imaging sequences at high magnetic field strength (7T and above), in particular, show potential for detecting small changes in iron concentration. However, these sequences require a long echo time in combination with a long scanning time for high resolution and are therefore prone to image artifacts caused by physiological fluctuations, patient motion or system instabilities. Many groups have found that the high image quality that was obtained using high resolution T2*-weighted sequences at 7T in healthy volunteers, could not be obtained in AD patients. In this study the source of the image artifacts was investigated in phantom and in healthy volunteer experiments by incorporating movement parameters and resonance frequency (f0) variations which were measured in AD patients. It was found that image degradation caused by typical f0 variations was a factor-of-four times larger than artifacts caused by movement characteristic of AD patients in the scanner. In addition to respiratory induced f0 variations, large jumps in the f0 were observed in AD patients. By implementing a navigator echo technique to correct for f0 variations, the image quality of high resolution T2*-weighted images increased considerably. This technique was successfully applied in five AD patients and in five subjective memory complainers. Visual scoring showed improvements in image quality in 9 out of 10 subjects. Ghosting levels were reduced by 24±13%.

IntroductionImmune checkpoint inhibition (ICI) has improved patients’ outcomes in advanced melanoma, often resulting in durable response. However, not all patients have durable responses and the patients with dissociated response are a valuable subgroup to identify mechanisms of ICI resistance.MethodsStage IV melanoma patients treated with ICI and dissociated response were retrospectively screened for available samples containing sufficient tumor at least at two time-points. Included were one patient with metachronous regressive and progressive lesions at the same site, two patients with regressive and novel lesion at different sites, and three patients with regressive and progressive lesions at different sites. In addition, four patients with acquired resistant tumor samples without a matched second sample were included.ResultsIn the majority of patients, the progressive tumor lesion contained higher CD8+ T cell counts/mm2 and interferon-gamma (IFNγ) signature level, but similar tumor PD-L1 expression. The tumor mutational burden levels were in 2 out 3 lesions higher compared to the corresponding regressive tumors lesion.In the acquired tumor lesions, high CD8+/mm2 and relatively high IFNγ signature levels were observed. In one patient in both the B2M and PTEN gene a stop gaining mutation and in another patient a pathogenic POLE mutation were found.ConclusionIntrapatient comparison of progressive versus regressive lesions indicates no defect in tumor T cell infiltration, and in general no tumor immune exclusion were observed.

BackgroundImmune checkpoint inhibitors (ICI) substantially improve outcome for patients with cancer. However, the majority of patients develops immune-related adverse events (irAEs), which can be persistent and significantly reduce quality of life. Neurological irAEs occur in 1–5% of patients and can induce severe, permanent sequelae or even be fatal. In order to improve the diagnosis and treatment of neurological irAEs and to better understand their pathogenesis, we assessed whether previous neurotropic infections are associated with neurological irAEs.MethodsNeurotropic infections that might predispose to ICI-induced neurological irAEs were analyzed in 61 melanoma patients from 3 countries, the Netherlands, Australia and Germany, including 24 patients with neurotoxicity and 37 control patients. In total, 14 viral, 6 bacterial, and 1 protozoal infections previously reported to trigger neurological pathologies were assessed using routine serology testing. The Dutch and Australian cohorts (NL) included pre-treatment plasma samples of patients treated with neoadjuvant ICI therapy (OpACIN-neo and PRADO trials; NCT02977052). In the Dutch/Australian cohort a total of 11 patients with neurological irAEs were compared to 27 control patients (patients without neurological irAEs). The German cohort (LMU) consisted of serum samples of 13 patients with neurological irAE and 10 control patients without any documented irAE under ICI therapy.ResultsThe association of neurological irAEs with 21 possible preceding infections was assessed by measuring specific antibodies against investigated agents. The seroprevalence of all the tested viral (cytomegalovirus, Epstein-Barr-Virus, varicella-zoster virus, measles, rubella, influenza A and B, human herpes virus 6 and 7, herpes simplex virus 1 and 2, parvovirus B19, hepatitis A and E and human T-lymphotropic virus type 1 and 2), bacterial (Borrelia burgdorferi sensu lato, Campylobacter jejuni, Mycoplasma pneumoniae, Coxiella burnetti, Helicobacter pylori, Yersinia enterocolitica and Y. pseudotuberculosis) and protozoal (Toxoplasma gondii) infections was similar for patients who developed neurological irAEs as compared to control patients. Thus, the analysis provided no evidence for an association of described agents tested for seroprevalence with ICI induced neurotoxicity.ConclusionPrevious viral, bacterial and protozoal neurotropic infections appear not to be associated with the development of neurological irAEs in melanoma patients who underwent therapy with ICI across 3 countries. Further efforts are needed to unravel the factors underlying neurological irAEs in order to identify risk factors for these toxicities, especially with the increasing use of ICI in earlier stage disease.

A 73-year-old man, without any medical history, had presented with dark urine and pale stool without pain. Diagnostic imaging revealed a tumour in the pancreas with liver metastases. Histopathological examination showed a well-differentiated pancreatic neuroendocrine tumour. After a stable 2.5 years on everolimus, progression of the liver metastases was seen and a switch was made to chemotherapy. Three months later, he developed progressive spinal neurological symptoms. MRI of the spine and brain revealed leptomeningeal contrast-enhancing lesions. Cytopathological examination of the cerebrospinal fluid showed malignant epithelial cells compatible with well-differentiated neuroendocrine tumour. Epithelial cell-adhesion molecule-based flow cytometry of the cerebrospinal fluid confirmed the presence of epithelial tumour cells. Based on these results, the diagnosis of leptomeningeal metastases of an originally well-differentiated neuroendocrine tumour of the pancreas was made.

Purpose To examine socioeconomic disparities in health-related quality of life (HRQoL) and healthcare use during the last year of life of patients with advanced cancer. Methods Data was used from a prospective, longitudinal, multicenter, observational study of patients with advanced cancer in forty Dutch hospitals (eQuiPe). Adult patients with stage IV cancer completed 3-monthly questionnaires until death. Socioeconomic position (SEP) was defined as estimated income on street-level. Mixed-effects regression analysis was used to identify associated factors. Results A total of 639 patients were included, 14% with a lower SEP, 59% medium SEP and 28% higher SEP. Patients with a lower SEP were more often lower educated (40% vs. 18%, p  < 0.001) and less often reported to have a partner (61% vs. 90%, p  < 0.001) than those with a higher SEP. In the last year of life, patients with lower SEP were more likely to experience disease-related financial difficulties than those with higher SEP (28% vs. 12%, p = 0.001; β 8.2, 95%CI 2.9–13.3). No significant associations were found between SEP and HRQoL, hospital admissions or emergency department admissions. Although, patients with lower SEP had more frequent (≥ 5 per month) interactions with healthcare professionals than patients with higher SEP in the last year of life (OR 1.9, 95%CI 1.0–3.5). Conclusion Some socioeconomic disparities are present during the last year of life of patients with advanced cancer. It is important for clinicians to be aware of the greater financial impact and higher healthcare utilization in patients with a lower SEP to ensure equitable end-of-life care.

BackgroundBefore adjuvant checkpoint inhibition the 5-year overall survival (OS) rate was poor (<50%) in high-risk stage III melanoma patients. Adjuvant CTLA-4 (ipilimumab, IPI) and PD-1 (nivolumab, NIVO, or pembrolizumab) blockade have been shown to improve relapse-free survival (RFS) and OS (latter only for IPI so far). Due to a broader immune activation neoadjuvant therapy with checkpoint inhibitors might be more effective than adjuvant, as suggested in preclinical experiments. The OpACIN trial compared neoadjuvant versus adjuvant IPI plus NIVO, while the subsequent OpACIN-neo trial tested three different dosing schedules of neoadjuvant IPI plus NIVO without adjuvant therapy. High pathologic response rates of 74–78% were induced by neoadjuvant IPI plus NIVO. Here, we present the 36- and 24-months RFS of the OpACIN and OpACIN-neo trial, respectively.Materials and MethodsThe phase 1b OpACIN trial included 20 stage IIIB/IIIC melanoma patients, which were randomized to receive IPI 3 mg/kg plus NIVO 1 mg/kg either adjuvant 4 cycles or split 2 cycles neoadjuvant and 2 adjuvant. In the phase 2 OpACIN-neo trial, 86 patients were randomized to 2 cycles neoadjuvant treatment, either in arm A: 2x IPI 3 mg/kg plus NIVO 1 mg/kg q3w (n=30), arm B: 2x IPI 1 mg/kg plus NIVO 3 mg/kg q3w (n=30), or arm C: 2x IPI 3 mg/kg q3w followed immediately by 2x NIVO 3 mg/kg q3w (n=26). Pathologic response was defined as <50% viable tumor cells and in both trials centrally reviewed by a blinded pathologist. RFS rates were estimated using the Kaplan-Meier method.ResultsOnly 1 of 71 (1.4%) patients with a pathologic response on neoadjuvant therapy had relapsed, versus 16 of 23 patients (69.6%) without a pathologic response, after a median follow-up of 36 months for the OpACIN and 24 months for the OpACIN-neo trial. In the OpACIN trial, the estimated 3-year RFS rate for the neoadjuvant arm was 80% (95% CI: 59%-100%) versus 60% (95% CI: 36%-100%) for the adjuvant arm. Median RFS was not reached for any of the arms within the OpACIN-neo trial. Estimated 24-months RFS rate was 84% for all patients (95% CI: 76%-92%); 90% for arm A (95% CI: 80%-100%), 78% for arm B (95% CI: 63%-96%) and 83% for arm C (95% CI: 70%-100%). Baseline interferon-γ gene expression score and tumor mutational burden predict response.ConclusionsOpACIN for the first time showed a potential benefit of neoadjuvant IPI plus NIVO versus adjuvant immunotherapy, whereas the OpACIN-neo trial confirmed the high pathologic response rates that can be achieved by neoadjuvant IPI plus NIVO. Both trials show that pathologic response can function as a surrogate markers for RFS.Clinical trial informationNCT02437279, NCT02977052Disclosure InformationJ.M. Versluis: None. E.A. Rozeman: None. A.M. Menzies: F. Consultant/Advisory Board; Modest; BMS, MSD, Novartis, Roche, Pierre-Fabre. I.L.M. Reijers: None. O. Krijgsman: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; BMS. E.P. Hoefsmit: None. B.A. van de Wiel: None. K. Sikorska: None. C. Bierman: None. P. Dimitriadis: None. M. Gonzalez: None. A. Broeks: None. R.M. Kerkhoven: None. A.J. Spillane: None. J.B.A.G. Haanen: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; BMS, MSD, Neon Therapeutics, Novartis. F. Consultant/Advisory Board; Modest; BMS, MSD, Novartis, Pfizer, AZ/MedImmune, Rocher/Genentech, Ipsen, Bayer, Immunocore, SeattleGenetics, Neon Therapeutics, Celsius Therapeutics, Gadet, GSK. W.J. van Houdt: None. R.P.M. Saw: None. H. Eriksson: None. A.C.J. van Akkooi: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; Amgen, BMS, Novartis. F. Consultant/Advisory Board; Modest; Amgen, BMS, Novartis, MSD Merck, Merck-Pfizer, 4SC. R.A. Scolyer: F. Consultant/Advisory Board; Modest; MSD, Neracare, Myriad, Novartis. T.N. Schumacher: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; MSD, BMS, Merck. E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; AIMM Therapeutics, Allogene Therapeutics, Amgen, Merus, Neogene Therapeutics, Neon Therapeutics. F. Consultant/Advisory Board; Modest; Adaptive Biotechnologies, AIMM Therapeutics, Allogene Therapeutics, Amgen, Merus, Neon Therapeutics, Scenic Biotech. Other; Modest; Third Rock Ventures. G.V. Long: F. Consultant/Advisory Board; Modest; Aduro, Amgen, BMS, Mass-Array, Pierre-Fabre, Novartis, Merck MSD, Roche. C.U. Blank: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; BMS, Novartis, NanoString. E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; Uniti Cars, Neon Therapeutics, Forty Seven. F. Consultant/Advisory Board; Modest; BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre-Fabre.

BackgroundThe previous OpACIN and OpACIN-neo studies investigating neoadjuvant IPI plus NIVO have demonstrated high pathologic response rates (74–78%) and favorable long-term outcomes for patients (pts) with a pathological response; at 36 and 18 months follow up only 1/71 (1.4%) responders has relapsed. In contrast, pathological non-responders have a poor prognosis; 15/23 (65.2%) have relapsed so far. This emphasizes the need for baseline biomarkers predictive of non-response and new neoadjuvant treatment combinations for these pts. In our previous studies, baseline IFN-γ signature high pts were more likely to respond to IPI plus NIVO. The DONIMI study tests the combination of NIVO ± IPI combined with a class 1 histone deacetylase inhibitor, domatinostat (DOM), according to the pts IFN-γ signature. We have developed a neoadjuvant IFN-γ signature, based on the signature previously described by Ayers et al., that will be used for the first time to classify pts in this prospective trial.Trial designThis two-center investigator-initiated phase 1b study aims to assess the safety and feasibility of neoadjuvant NIVO ± DOM ± IPI in 45 stage III melanoma pts with macroscopic de-novo or recurrent disease. IFN-γ signature high pts (n=20) will be randomized (stratified by center) to Arm A (2 cycles NIVO 240 mg q3wk) or Arm B (2 cycles NIVO 240 mg q3wk + DOM 200 mg twice daily (BID), d1-14, q3wk). IFN-γ signature low pts (n=25) will be randomized to Arm C (2 cycles NIVO 240 mg q3wk + DOM 200 mg BID, d1-14, q3wk) or Arm D (2 cycles NIVO 240 mg q3wk + IPI 80 mg q3wk + DOM 200 mg once daily (OD), d1-14, q3wk). Based on safety data of the first 5 pts in arm D, the remaining pts will be treated with either a higher dosing scheme (200 mg BID, d1-14, q3wks), a lower dosing scheme (100 mg OD, d1-14, q3wks) or the same dosing scheme (200 mg OD, d1-14, q3wks). The primary endpoint is safety and feasibility. A treatment arm will be declared as not feasible if 2/5 or 3/10 patients cannot adhere to the planned time of surgery (week 6 ± 1week) due to treatment-related adverse events. Biopsies (week 0, 3), blood samples (week 0, 3, 6, 12) and feces (week 0, 3, 6) will be collected for translational research. To date, 7 patients have been enrolled.Clinical trial informationNCT04133948Disclosure InformationI.L.M. Reijers: None. E.A. Rozeman: None. P. Dimitriadis: None. O. Krijgsman: C. Other Research Support (supplies, equipment, receipt of drugs or other in-kind support); Modest; BMS. L.J.W. Bosch: None. S. Cornelissen: None. J. Bouwman: None. J.M. Versluis: None. D. Rao: None. B. van de Wiel: None. A.J. Spillane: None. R.A. Scolyer: F. Consultant/Advisory Board; Modest; MSD, Neracare, Myriad, Novartis. A.M. Menzies: F. Consultant/Advisory Board; Modest; BMS, MSD Oncology, Novartis, Pierre Fabre, Roche. A.C.J. van Akkooi: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; Amgen, BMS, Novartis. F. Consultant/Advisory Board; Modest; Amgen, BMS, Novartis, MSD, Merck, Merck-Pfizer, 4SC. G.V. Long: F. Consultant/Advisory Board; Modest; Aduro, Amgen, BMS, Mass-Array, Pierre-Fabre, Novartis, Merck MSD, Roche. C.U. Blank: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; BMS, Novartis, Nanostring. F. Consultant/Advisory Board; Modest; BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, Genmab, Pierre Fabre.

The altered iron concentration in many neurodegenerative diseases such as Alzheimer's disease (AD) has led to the development of MRI sequences that are sensitive to the accompanying changes in the transverse relaxation rate. Heavily T sub(2)*-weighted imaging sequences at high magnetic field strength (7 T and above), in particular, show potential for detecting small changes in iron concentration. However, these sequences require a long echo time in combination with a long scanning time for high resolution and are therefore prone to image artifacts caused by physiological fluctuations, patient motion or system instabilities. Many groups have found that the high image quality that was obtained using high resolution T sub(2)*-weighted sequences at 7 T in healthy volunteers, could not be obtained in AD patients. In this study the source of the image artifacts was investigated in phantom and in healthy volunteer experiments by incorporating movement parameters and resonance frequency (f0) variations which were measured in AD patients. It was found that image degradation caused by typical f0 variations was a factor-of-four times larger than artifacts caused by movement characteristic of AD patients in the scanner. In addition to respiratory induced f0 variations, large jumps in the f0 were observed in AD patients. By implementing a navigator echo technique to correct for f0 variations, the image quality of high resolution T sub(2)*-weighted images increased considerably. This technique was successfully applied in five AD patients and in five subjective memory complainers. Visual scoring showed improvements in image quality in 9 out of 10 subjects. Ghosting levels were reduced by 24 +/- 13%.