BACKGROUND: Patients with gastro-oesophageal adenocarcinoma with tumour-positive lymph nodes (ypN+) or positive surgical margins (R1) following neoadjuvant chemotherapy and resection are at high risk of recurrence. Adjuvant nivolumab is effective in oesophageal/oesophagogastric junction cancer and residual pathological disease following chemoradiation and surgery. Immune checkpoint inhibition has shown efficacy in advanced gastro-oesophageal cancer. We hypothesised that nivolumab/ipilimumab would be more effective than adjuvant chemotherapy in high-risk (ypN+ and/or R1) patients with gastro-oesophageal adenocarcinoma following neoadjuvant chemotherapy and resection. PATIENTS AND METHODS: VESTIGE was an academic international, multicentre, open-label, randomised phase II trial evaluating the efficacy of adjuvant nivolumab/ipilimumab versus chemotherapy in gastro-oesophageal adenocarcinoma at high risk of recurrence. Patients were randomised 1 : 1 to receive standard adjuvant chemotherapy (same regimen as neoadjuvant) or nivolumab 3 mg/kg intravenously (i.v.) every 2 weeks plus ipilimumab 1 mg/kg i.v. every 6 weeks for 1 year. Key inclusion criteria included ypN+ and/or R1 status after neoadjuvant chemotherapy plus surgery. The primary endpoint was disease-free survival in the intent-to-treat population. Secondary endpoints included overall survival, locoregional and distant failure rates, and safety according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. RESULTS: The independent Data Monitoring Committee reviewed data from 189 of the planned 240 patients in June 2022 and recommended stopping recruitment due to futility. At the time of final analysis, median follow-up was 25.3 months for 195 patients (98 nivolumab/ipilimumab and 97 chemotherapy). Median disease-free survival for the nivolumab/ipilimumab group was 11.4 months [95% confidence interval (CI) 8.4-16.8 months] versus 20.8 months (95% CI 15.0-29.9 months) for the chemotherapy group, hazard ratio 1.55 (95% CI 1.07-2.25, one-sided P = 0.99). The 12-month disease-free survival rates were 47.1% and 64.0%, respectively. There were no toxicity concerns or excess early discontinuations. CONCLUSION: Nivolumab/ipilimumab did not improve disease-free survival compared with chemotherapy in patients with ypN+ and/or R1 gastro-oesophageal adenocarcinoma following neoadjuvant chemotherapy and surgery.

• MeSH
• Adenocarcinoma * pathology   drug therapy   therapy   MeSH
• Chemotherapy, Adjuvant methods   MeSH
• Adult MeSH
• Gastrectomy MeSH
• Esophagogastric Junction * pathology   MeSH
• Immunotherapy methods   MeSH
• Ipilimumab administration & dosage   therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Recurrence, Local * pathology   prevention & control   drug therapy   epidemiology   MeSH
• Esophageal Neoplasms * pathology   drug therapy   therapy   MeSH
• Stomach Neoplasms * pathology   drug therapy   therapy   surgery   MeSH
• Neoadjuvant Therapy * methods   adverse effects   MeSH
• Nivolumab administration & dosage   therapeutic use   MeSH
• Disease-Free Survival MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase II MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH

PURPOSE: CheckMate 914 is a two-part, randomized phase III trial evaluating adjuvant nivolumab plus ipilimumab (part A) or adjuvant nivolumab monotherapy (part B) versus placebo in mutually exclusive populations of patients with localized renal cell carcinoma (RCC) at high risk of postnephrectomy recurrence. Part A showed no disease-free survival (DFS) benefit for adjuvant nivolumab plus ipilimumab versus placebo. We report results from part B. METHODS: Patients were randomly assigned (2:1:1) to nivolumab (240 mg once every 2 weeks for up to 12 doses), placebo, or nivolumab (240 mg once every 2 weeks for up to 12 doses) plus ipilimumab (1 mg/kg once every 6 weeks for up to four doses). The planned treatment duration was 24 weeks (approximately 5.5 months). The primary end point was DFS per blinded independent central review (BICR) for nivolumab versus placebo; safety was a secondary end point. RESULTS: Overall, 825 patients were randomly assigned to nivolumab (n = 411), placebo (n = 208), or nivolumab plus ipilimumab (n = 206). With a median follow-up of 27.0 months (range, 18.0-42.4), the primary end point of improved DFS per BICR with nivolumab versus placebo was not met (hazard ratio [HR], 0.87 [95% CI, 0.62 to 1.21]; P = .40); the median DFS was not reached in either arm, and 18-month DFS rates were 78.4% versus 75.4%. The HR for DFS per investigator was 0.80 (95% CI, 0.58 to 1.12; P = .19). Grade 3-4 all-cause adverse events (AEs) occurred in 17.2%, 15.0%, and 28.9% of patients with nivolumab, placebo, and nivolumab plus ipilimumab, respectively. Any-grade treatment-related AEs led to discontinuation in 9.6%, 1.0%, and 28.4%, respectively. CONCLUSION: Part B of CheckMate 914 did not meet the primary end point of improved DFS for nivolumab versus placebo in patients with localized RCC at high risk of postnephrectomy recurrence.

• MeSH
• Chemotherapy, Adjuvant MeSH
• Adult MeSH
• Double-Blind Method MeSH
• Ipilimumab * therapeutic use   administration & dosage   adverse effects   MeSH
• Carcinoma, Renal Cell * drug therapy   surgery   MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Recurrence, Local * MeSH
• Kidney Neoplasms * drug therapy   pathology   surgery   MeSH
• Nephrectomy * MeSH
• Nivolumab * therapeutic use   administration & dosage   adverse effects   MeSH
• Disease-Free Survival MeSH
• Antineoplastic Combined Chemotherapy Protocols therapeutic use   adverse effects   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Randomized Controlled Trial MeSH

Předložená kazuistika popisuje případ pacientky s metastazujícím maligním melanomem anorekta. Vzhledem k synchronní generalizaci do lymfatických uzlin a plic, a tedy nemožnosti kurativního chirurgického či radioterapeutického řešení, byla pacientka léčena několika liniemi systémové léčby. V souladu s doporučenými postupy a též pro BRAF negativitu melanomu byla v 1. linii léčby indikována kombinovaná imunoterapie ipilimumabem a nivolumabem. Následně pro opakované progrese onemocnění absolvovala pacientka ještě dvě linie konvenční chemoterapie a poté s ohledem na metastatický rozsev do mozku ještě 3 cykly léčby temozolomidem. Mozkové metastázy byly ošetřeny Leksellovým gama nožem (LGN), později byla pro další progresi využita možnost paliativního celomozkového ozáření (WBRT - whole brain radiotherapy). V závěru života pacientka podstoupila paliativní radioterapii primárního ložiska anorekta s cílem ulevit od obtěžujících symptomů. Dále využívala ambulance hojení ran a podpůrnou péči paliativní kliniky, později domácího hospicu. Pacientka zemřela 33 měsíců od stanovení diagnózy metastazujícího melanomu a 12 měsíců od zjištění mozkových metastáz.

The presented case report describes the case of a patient with mucosal primary metastasizing malignant melanoma of the anorectum. Due to the synchronous generalization to the lymph nodes and lungs and therefore the impossibility of a curative surgical or radiotherapy solution, the patient was treated with several lines of systemic treatment. In accordance with guidelines and for BRAF negativity, combined immunotherapy with ipilimumab and nivolumab was indicated in the 1st line of treatment. Subsequently, due to repeated progression of the disease, the patient completed two more lines of conventional chemotherapy and then, regarding metastatic spread to the brain, three more cycles of temozolomide treatment. Brain metastases were treated with the Leksell Gamma Knife (LGN), later for further progression the palliative whole brain radiotherapy (WBRT) was used. At the end of her life, the patient underwent palliative radiotherapy of the primary anorectal lesion with the aim of relieving the bothersome symptoms, she used a wound healing clinic and supportive care through a palliative clinic, later a home hospice. The patient died 33 months after the diagnosis of metastatic melanoma and 12 months after the diagnosis of brain metastases.

• MeSH
• Dacarbazine pharmacology   therapeutic use   MeSH
• Immunotherapy methods   MeSH
• Ipilimumab pharmacology   therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Melanoma surgery   drug therapy   radiotherapy   MeSH
• Neoplasm Metastasis MeSH
• Anus Neoplasms * surgery   drug therapy   radiotherapy   MeSH
• Brain Diseases radiotherapy   MeSH
• Nivolumab pharmacology   therapeutic use   MeSH
• Palliative Care methods   MeSH
• Antineoplastic Protocols MeSH
• Death MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Case Reports MeSH

BACKGROUND: Non-clear cell renal cell cancers (nccRCCs) are a heterogeneous group of more than 20 different entities, but are rarely included in large, randomized trials. Tyrosine kinase inhibitors with or without immune checkpoint inhibition are considered as a standard of care (SOC), but optimal treatment is not yet defined. We designed the first prospective randomized trial comparing ipilimumab/nivolumab to SOC. PATIENTS AND METHODS: We randomized adult patients with previously untreated advanced or metastatic nccRCC 1:1 to nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 doses followed by fixed dose nivolumab of 240 mg every 2 weeks or 480 mg every 4 weeks or to SOC. Patients were stratified by histology and by IMDC risk score. Central pathology review was mandatory. The primary endpoint was the overall survival (OS) rate at 12 months, secondary endpoints included median OS, response rate, progression-free survival (PFS), safety and quality of life. RESULTS: In total, 157 patients were assigned to receive ipilimumab/nivolumab, and 152 to SOC. The 12-month survival rate was 78% with ipilimumab/nivolumab [95% confidence interval (CI) 71-84%] compared to 68% with SOC (95% CI 60-75%, P = 0.026). Median OS was 33.2 months versus 25.2 months, P = 0.163 [HR 0.81 (0.61-1.099)]. PFS was similar in both arms [HR 0.99 (0.77-1.28)]. The ORR was 32.8% versus 19.3%. No major differences between papillary and non-papillary RCC subtypes were observed for any endpoint. Exploratory analysis showed a significant OS advantage [HR 0.56 (95% CI 0.37-0.86)] associated with a PD-L1 CPS score ≥1. Treatment discontinuation due to toxicity occurred in 27 patients (17%) with ipilimumab/nivolumab and 13 patients (9%) with SOC. CONCLUSIONS: Ipilimumab/nivolumab demonstrated a significantly longer OS at the 12-month milestone and an acceptable toxicity profile. Our results therefore underline a relevant clinical benefit of ipilimumab/nivolumab in previously untreated nccRCC entities compared to current SOC.

• MeSH
• Progression-Free Survival MeSH
• Adult MeSH
• Ipilimumab * administration & dosage   adverse effects   MeSH
• Carcinoma, Renal Cell * drug therapy   pathology   mortality   MeSH
• Quality of Life MeSH
• Middle Aged MeSH
• Humans MeSH
• Kidney Neoplasms * drug therapy   pathology   mortality   MeSH
• Nivolumab * administration & dosage   adverse effects   MeSH
• Prospective Studies MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   adverse effects   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Standard of Care MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase II MeSH
• Randomized Controlled Trial MeSH
• Comparative Study MeSH

PURPOSE: There are limited treatment options for advanced melanoma that have progressed during or after immune checkpoint inhibitor therapy. Intratumoral (IT) immunotherapy may improve tumor-specific immune activation by promoting local tumor antigen presentation while avoiding systemic toxicities. The phase 3 ILLUMINATE-301 study (ClinicalTrials.gov identifier: NCT03445533) evaluated tilsotolimod, a Toll-like receptor-9 agonist, with or without ipilimumab in patients with anti-PD-1 advanced refractory melanoma. METHODS: Patients with unresectable stage III-IV melanoma that progressed during or after anti-PD-1 therapy were randomly assigned 1:1 to receive 24 weeks of tilsotolimod plus ipilimumab or 10 weeks of ipilimumab alone. Nine IT injections of tilsotolimod were administered to a single designated lesion over 24 weeks. Intravenous ipilimumab 3 mg/kg was administered once every 3 weeks from week 2 in the tilsotolimod arm and week 1 in the ipilimumab arm. The primary end point was efficacy measured using objective response rate (ORR; independent review) and overall survival (OS). RESULTS: A total of 481 patients received tilsotolimod plus ipilimumab (n = 238) or ipilimumab alone (n = 243). ORRs were 8.8% in the tilsotolimod arm and 8.6% in the ipilimumab arm, with disease control rates of 34.5% and 27.2%, respectively. Median OS was 11.6 months in the tilsotolimod arm and 10 months in the ipilimumab arm (hazard ratio, 0.96 [95% CI, 0.77 to 1.19]; P = .7). Grade ≥3 treatment-emergent adverse events occurred in 61.1% and 55.5% of patients in the tilsotolimod and ipilimumab arms, respectively. CONCLUSION: Combining IT tilsotolimod with ipilimumab did not significantly improve the ORR or OS compared with ipilimumab alone in patients with anti-PD-1 advanced refractory melanoma.

• MeSH
• Adult MeSH
• Ipilimumab * administration & dosage   adverse effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• Melanoma * drug therapy   pathology   immunology   mortality   MeSH
• Skin Neoplasms * drug therapy   pathology   immunology   MeSH
• Oligonucleotides MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   adverse effects   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH

• MeSH
• Doxorubicin pharmacology   therapeutic use   MeSH
• Immune Checkpoint Inhibitors classification   therapeutic use   MeSH
• Ipilimumab pharmacology   therapeutic use   MeSH
• Leiomyosarcoma drug therapy   MeSH
• Melanoma diagnosis   drug therapy   MeSH
• Stomach Neoplasms drug therapy   MeSH
• Nivolumab pharmacology   therapeutic use   MeSH
• Antineoplastic Protocols MeSH
• Trabectedin pharmacology   therapeutic use   MeSH
• Publication type
• Overall MeSH

Východiska: Léčba checkpoint inhibitory (immune checkpoint inhibitor – ICI) přinesla v léčbě pokročilého nemalobuněčného karcinomu plic (non-small cell lung cancer – NSCLC) revoluční pokrok. Nemálo pacientů s NSCLC má komorbidní onemocnění. U pacientů, kteří již mají poškozenou funkci ledvin, je třeba věnovat zvláštní pozornost renální toxicitě, což je vzácná imunitně podmíněná nežádoucí příhoda. Ačkoli bylo publikováno několik kazuistik léčby ICI u pacientů s pokročilým NSCLC podstupujících hemodialýzu, informace o léčbě ICI u pacientů s chronickým onemocněním ledvin (chronic kidney disease – CKD) jsou limitované. Případ: Uvádíme zde případ úspěšně léčeného 75letého pacienta s CKD a pokročilým NSCLC. Odhadovaná rychlost glomerulární filtrace na začátku protinádorové léčby byla 40 ml/min/1,73 m2. Byl podán nivolumab a ipilimumab, jednak s ohledem na očekáváný terapeutický účinek a jednak kvůli zamezení nežádoucím účinkům. Ipilimumab byl vysazen 1 rok po zahájení léčby a podávání nivolumabu bylo také ukončeno, a to 2 roky od zahájení léčby kvůli dysfunkci štítné žlázy jako imunitně podmíněnému nežádoucímu účinku. Bez toho, aby se u pacienta zhoršilo CKD, byla možná léčba NSCLC dvěma checkpoint inhibitory po dobu ≥ 3 let. Závěr: Režim nivolumab a ipilimumab se může stát jednou z možností léčby pacientů s NSCLC a současně s CKD. Tento článek by mohl poskytnout návrh léčby budoucích pacientů, u kterých je možné předpokládat podobný průběh.

Background: Immune checkpoint inhibitor (ICI) therapy has brought about a revolutionary advance in the treatment of advanced non-small cell lung cancer (NSCLC). Not a few patients with NSCLC have comorbid diseases. In patients who already have impaired renal function, particular attention must be paid to renal toxicity, a rare immune-related adverse events. Although there have been some case reports of ICI therapy for patients with advanced NSCLC undergoing hemodialysis, information on ICI therapy in patients with chronic kidney disease (CKD) is limited. Case: We show herein a case with a successfully treated 75-year-old male patient with CKD and advanced NSCLC. His estimated glomerular filtration rate at the start of anticancer treatment was 40 mL/min/1.73 m2. Nivolumab and ipilimumab were administered, considering both the expectation of therapeutic efficacy and the avoidance of side effects. Ipilimumab was discontinued 1 year after the start of the treatment, and nivolumab was also terminated 2 years after the initiation of the treatment due to thyroid dysfunction as immune-related adverse event. Without worsening of CKD, the patient was able to control NSCLC with two immune checkpoint inhibitors for ≥ 3 years. Conclusion: Nivolumab and ipilimumab regimen might become one of the options for NSCLC patients with CKD. This report could provide some suggestions for the treatment of future patients who might experience a similar course of the therapy.

• MeSH
• Renal Insufficiency, Chronic chemically induced   diagnosis   MeSH
• Immune Checkpoint Inhibitors * pharmacology   adverse effects   therapeutic use   MeSH
• Ipilimumab pharmacology   adverse effects   therapeutic use   MeSH
• Humans MeSH
• Lung Neoplasms drug therapy   classification   MeSH
• Carcinoma, Non-Small-Cell Lung * drug therapy   complications   MeSH
• Nivolumab pharmacology   adverse effects   therapeutic use   MeSH
• Positron Emission Tomography Computed Tomography methods   MeSH
• Aged MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged MeSH
• Publication type
• Case Reports MeSH

• Keywords
• studie CheckMate 9LA,
• MeSH
• Survival Analysis MeSH
• Progression-Free Survival MeSH
• Ipilimumab pharmacology   therapeutic use   MeSH
• Humans MeSH
• Neoplasm Metastasis MeSH
• Carcinoma, Non-Small-Cell Lung * drug therapy   MeSH
• Nivolumab pharmacology   therapeutic use   MeSH
• Antineoplastic Combined Chemotherapy Protocols MeSH
• Randomized Controlled Trials as Topic MeSH
• Check Tag
• Humans MeSH

Karcinom žaludku je v naprosté většině případů diagnostikován ve stadiu metastatického onemocnění. Nicméně i u pacientů, kteří jsou diagnostikováni v časnějších stadiích onemocnění, dochází k relapsu v podobě systémové generalizace. Možnosti léčby metastatického onemocnění se odvíjí od řady proměnných. V současnosti je nepodkročitelným minimem vyšetření prediktivních markerů (Her2, MMR, PD-L1 CPS). V případě Her2 negativních nádorů byla dlouho standardem samotná chemoterapie. Pokroky v molekulární biologii, genetice společně s rozvojem imunoterapie vedly ke změně terapeutických možností u těchto pacientů. Cílem článku je podat přehled současných možností léčby Her2 negativního metastatického onemocnění napříč liniemi.

In the vast majority of cases, gastric cancer is diagnosed at the metastatic stage. However, even patients who are diagnosed at earlier stages of the disease experience relapse in the form of systemic generalization. Treatment options for metastatic disease depend on a number of variables. At present, the unsurpassed minimum is testing for predictive markers (Her2, MMR, PD-L1 CPS). For Her2-negative tumors, chemotherapy alone has long been the standard of care. Advances in molecular biology, genetics, together with the development of immunotherapy have led to a change in therapeutic options for these patients. The aim of this article is to provide an overview of the current treatment options for Her2 negative metastatic disease across multiple lineages.

• MeSH
• Immunotherapy methods   MeSH
• Ipilimumab administration & dosage   MeSH
• Clinical Studies as Topic MeSH
• Drug Therapy, Combination methods   MeSH
• Humans MeSH
• Neoplasm Metastasis * MeSH
• Stomach Neoplasms * drug therapy   therapy   MeSH
• Nivolumab administration & dosage   MeSH
• Antineoplastic Agents administration & dosage   MeSH
• Randomized Controlled Trials as Topic MeSH
• Check Tag
• Humans MeSH

Terapie metastazujícího kolorektálního karcinomu doznala v posledních letech zásadních změn. Kromě cílené léčby na základě proběhlých klinických studií u pacientů s vysokou mikrosatelitovou instabilitou (microsatellite instability-high, MSI-H) / deficiencí mismatch repair genů (deficient mismatch repair, dMMR) je možno nově podle podmínek úhrady indikovat také imunoterapii. Pembrolizumab v monoterapii získal registraci i úhradu z veřejného zdravotního pojištění v první linii paliativní léčby a kombinace nivolumabu s ipilimumabem získala úhradu u pacientů předléčených. Imunoterapie jednoznačně patří do léčebného algoritmu metastazujícího kolorektálního karcinomu na základě vyšetření prediktivních markerů.

The therapy of metastatic colorectal cancer changed significantly in recent years. Besides already known targeted therapy immunotherapy gained registration as well as health insurance reimbursement for the treatment of the patients with microsatellite instability-high (MSI-H) / deficient mismatch repair (dMMR) tumors. Monotherapy with pembrolizumab is now available for the previously untreated colorectal cancer and the combination of nivolumab with ipilimumab has indication for the later lines of the treatment. Immunotherapy without any doubts represents treatment standard for the patients with metastatic colorectal cancer based on the predictive markers.

• Keywords
• dMMR/MSI-H karcinom, pembrolizumab,
• MeSH
• Ipilimumab pharmacology   therapeutic use   MeSH
• Clinical Trials as Topic MeSH
• Colorectal Neoplasms * drug therapy   genetics   MeSH
• Combined Antibody Therapeutics * MeSH
• Humans MeSH
• Meta-Analysis as Topic MeSH
• Neoplasm Metastasis MeSH
• Microsatellite Instability drug effects   MeSH
• Biomarkers, Tumor MeSH
• Nivolumab pharmacology   therapeutic use   MeSH
• Check Tag
• Humans MeSH