Discontinuation Of Nivolumab Research Articles

1140TiP Safe stop IPI-NIVO trial: Early discontinuation of nivolumab upon achieving a complete or partial response in patients with irresectable stage III or metastatic melanoma treated with first-line ipilimumab-nivolumab

1140TiP Safe stop IPI-NIVO trial: Early discontinuation of nivolumab upon achieving a complete or partial response in patients with irresectable stage III or metastatic melanoma treated with first-line ipilimumab-nivolumab

Safe Stop IPI-NIVO trial: early discontinuation of nivolumab upon achieving a complete or partial response in patients with irresectable stage III or metastatic melanoma treated with first-line ipilimumab-nivolumab – study protocol

BackgroundPatients with irresectable stage III or metastatic melanoma presenting with poor prognostic factors are usually treated with a combination of immune checkpoint inhibitors (ICIs), consisting of ipilimumab and nivolumab. This combination therapy is associated with severe immune related adverse events (irAEs) in about 60% of patients. In current clinical practice, patients are usually treated with ICIs for up to two years or until disease progression or the occurrence of unacceptable AEs. The incidence of irAEs gradually increases with duration of treatment. While durable tumour responses have been observed after early discontinuation of treatment, no consensus has been reached on optimal treatment duration. The objective of the Safe Stop IPI-NIVO trial is to evaluate whether early discontinuation of ICIs is safe in patients with irresectable stage III or metastatic melanoma who are treated with combination therapy.MethodsThe Safe Stop IPI-NIVO trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 80 patients with irresectable stage III or metastatic melanoma who are treated with combination therapy of ipilimumab-nivolumab and have a complete or partial response (CR/PR) according to RECIST v1.1 will be included to early discontinue maintenance therapy with anti-PD-1. The primary endpoint is the rate of ongoing response at 12 months after start of ICI. Secondary endpoints include ongoing response at 24 months, disease control at different time points, melanoma specific and overall survival, the incidence of irAEs and health-related quality of life.DiscussionFrom a medical, healthcare and economic perspective, overtreatment should be prevented and shorter treatment duration of ICIs is preferred. If early discontinuation of ICIs is safe for patients who are treated with the combination of ipilimumab-nivolumab, the treatment duration of nivolumab could be shortened in patients with a favourable tumour response.Trial registrationClinicalTrials.gov ID NCT05652673, registration date: 08–12-2022.

Evaluation of the efficacy and safety of nivolumab in the second- or later-line treatment of patients with locally advanced/metastatic non-small cell lung cancer in Türkiye: a retrospective multicenter non-interventional registry study

Objective To evaluate the efficacy and safety of nivolumab in the second-line (2L) or later-line (LL) treatment of patients with locally advanced/metastatic non-small cell lung cancer (NSCLC) in real-life setting in Türkiye. Methods This study was designed as a national, multi-center, retrospective study. The study population was evaluated in two groups for the line of nivolumab therapy: those receiving nivolumab in the 2L (Group 2L) and third-line (3L) or LL (Group 3L/LL). Efficacy was evaluated based on one-year overall survival (OS) and progression-free survival (PFS). Safety was evaluated based on treatment-related adverse events (AEs) and nivolumab discontinuation rate. Results Of 244 patients, 52.9% were in Group 2L and 47.1% were in Group 3L/LL. Demographic and clinical characteristics did not differ between the groups. In Group 2L and Group 3L/LL, one-year OS and PFS rates were 60.8% and 61.4% (p = 0.592) and 31.2% and 21.3% (p = 0.078), respectively. The objective response rate (ORR) was 34.7% in Group 2L and 27.3% in Group 3L/LL (p = 0.262). The percentage of patients reporting at least one AE in Groups 2L and 3L/LL was 34.9% and 43.5%, respectively (p = 0.169). Fatigue was the most common (16.4%) treatment-related AE in each group. The groups were comparable regarding the AE frequency. Nivolumab was discontinued in 61 patients in Group 2L and 53 patients in Group 3L/LL, with the most common reason being disease progression (57.4% and 66.0%, respectively). Conclusion Nivolumab is safe and effective in the 2L or 3L/LL treatment of locally advanced/metastatic NSCLC and associated with acceptable AEs in real-life setting.

Clinical characteristics, diagnosis and management of nivolumab-induced myocarditis.

Nivolumab can cause fatal myocarditis. We aimed to analyze the clinical characteristics of nivolumab-induced myocarditis and provide evidence for clinical diagnosis, treatment, and prevention. Studies involving nivolumab-induced myocarditis were identified in electronic databases from 2000 to 2023 for retrospective analysis. A total of 66 patients were included, with a median age of 68 years. The median onset time of myocarditis is 11.5 days. The main organs affected in persons presented with myocarditis are heart (100.0%) and skeletal muscle (22.7%). The main clinical manifestations are dyspnea (49.2%), fatigue (47.6%), and myalgias (25.4%). The levels of troponin, troponin T, troponin I, creatine kinase, creatine kinase myocardial band, creatine phosphokinase, C-reactive protein, brain natriuretic peptide, and N-terminal brain natriuretic peptide precursor were significantly increased. Histopathology often shows lymphocyte infiltration, myocardial necrosis, and fibrosis. Myocardial immunological parameters usually present positive. Cardiac imaging often suggests complete heart block, intraventricular conduction delay, arrhythmia, myocardial infarction, edema, left ventricular ejection fractions reduction, ventricular dysfunction, and other symptoms of myocarditis. Forty-two (63.6%) patients achieved remission within a median time of 8 days after discontinuation of nivolumab and treatment with systemic corticosteroids, immunoglobulins, plasmapheresis, and immunosuppressant. Thirty-five patients eventually died attributed to myocarditis (68.6%), cancer (20.0%), respiratory failure (5.7%), and other reasons (5.7%). Nivolumab-induced myocarditis should be comprehensively diagnosed based on clinical symptoms, histopathological manifestations, immunological parameters, and cardiac function imaging examinations. Nivolumab should be discontinued immediately, plasmapheresis and systemic corticosteroids combined with immunoglobulins or immunosuppressants may be an effective treatment.

Safety and short-term efficacy of adjuvant nivolumab after neoadjuvant docetaxel, cisplatin, and fluorouracil for locally advanced esophageal squamous cell carcinoma.

271 Background: Efficacy and safety of adjuvant nivolumab has been demonstrated in patients with locally advanced esophageal cancer who received neoadjuvant chemoradiotherapy followed by surgery and had residual pathological disease in the CheckMate-577 trial. Although neoadjuvant docetaxel, cisplatin, and fluorouracil (DCF) is the standard neoadjuvant therapy for patients with locally advanced esophageal squamous cell carcinoma (ESCC) in Japan based on the JCOG1109 study, the safety and efficacy of adjuvant nivolumab in this population remains unclear. Here, we report the short-term safety and efficacy of adjuvant nivolumab after neoadjuvant DCF in patients with locally advanced ESCC. Methods: We retrospectively reviewed medical records of patients who received adjuvant nivolumab after neoadjuvant DCF and surgery for locally advanced ESCC from Nov 2021 to Jun 2023 at National Cancer Center Hospital East. Pathological stage was classified by UICC-TNM 8th edition. Adverse events were assessed according to CTCAE v5.0. Disease-free survival (DFS) was calculated by Kaplan-Meier method. Results: The study included a total of 33 patients with a median age of 67 years (range, 56-77), of which 29 patients were male. All patients had residual pathological disease, with ypStage I/II/III/IV of 5/1/16/11 patients. Median time from surgery to the initiation of adjuvant nivolumab was 10.6 weeks (range, 7.1-16.4 weeks). Treatment-related adverse events (TRAEs) occurred in 27 patients (82%), with pruritus (n = 13, 39%), rash (n = 7, 21%), hypothyroidism (n=7, 21%), xerosis (n = 6, 18%), diarrhea (n = 5, 15%), hypopituitarism (n = 5, 15%), pneumonitis (n = 1, 3%), and hepatic dysfunction (n = 1, 3%). Among these TRAEs, one patient developed grade 3 of hepatic dysfunction, which resolved with corticosteroid. TRAEs which led to discontinuation of nivolumab were hepatic dysfunction (n = 1, 3%), diarrhea (n = 1, 3%), and pneumonitis (n = 1, 3%). No treatment-related death was observed. With a median follow-up of 10.3 months, 1-year DFS rate was 63.3% (95% CI, 39.8-79.7%). Among 9 patients who experienced recurrence (locoregional; n = 3, distant; n = 6), 8 patients received subsequent therapy, including systemic chemotherapy (n = 5) and salvage chemoradiotherapy (n = 3). Conclusions: The safety and short-term efficacy of adjuvant nivolumab after neoadjuvant DCF and surgery was comparable to the results of the CheckMate-577 trial. Our study suggests that adjuvant nivolumab might be a possible treatment option in patients with locally advanced ESCC patients with residual pathological disease after neoadjuvant DCF followed by surgery.

A case of stage Ⅳ malignant melanoma that maintained a partial response after nivolumab discontinuation

A case of stage Ⅳ malignant melanoma that maintained a partial response after nivolumab discontinuation

High-Dose Methotrexate Containing Induction Chemotherapy Followed By Nivolumab Consolidation in Older (≥ 65) Patients with Previously Untreated Primary CNS Lymphoma

Introduction: High-dose methotrexate (HD-MTX)-containing chemotherapy followed by either autologous stem cell transplant (ASCT) or whole-brain irradiation (WBI) is widely considered the standard for primary CNS lymphoma (PCNSL) treatment. However, many older frail patients with PCNSL are unable to undergo ASCT or WBI due to increased risk of treatment-related toxicity, such as infections and neurotoxicity. Without consolidation, survival outcomes are significantly worse, with a 3-year progression free survival (PFS) rate of ~ 30%. Therefore, novel therapeutic approaches are urgently needed for older PCNSL patients. Recently, nivolumab, an anti-PD1 antibody, showed promising clinical activities in relapsed/refractory PCNSL, and we hypothesized that addition of nivolumab in the frontline setting would be safe and improve survival outcomes of older PCNSL patients who are deemed poor candidates for ASCT or WBI. Methods: In this phase 1/1B single-arm multicenter study, patients ≥ 65, who were deemed poor candidates for ASCT and WBI, with previously untreated PCNSL received at least 3 cycles of HD-MTX-containing chemotherapy followed by nivolumab consolidation for 6 cycles (NCT 04022980). Patients with systemic lymphoma or known ocular involvement were excluded from the study. Stage 1 was designed to evaluate the safety of nivolumab consolidation after HD-MTX-containing induction chemotherapy. A 3+3 design was used as safety run-in, initiating 6 patients on nivolumab at the FDA-approved single-agent dose and monitoring for dose-limiting toxicities (DLTs) during Cycle 1. If less than 2 out of 6 subjects experienced a DLT, then the stage 2 part of study would initiate to evaluate the efficacy of nivolumab consolidation in terms of the 2-year PFS. The patient's neurological function was assessed at baseline and throughout the study follow-up using the Neurologic Assessment in Neuro-Oncology (NANO) scale. Results: A total of 14 patients enrolled in the study between April 2020 and December 2022 at 4 US sites. In 14 evaluable patients who underwent the study treatment, the median age was 72 years (range, 65-79), 71% patients were female, and 35% patients had ECOG score of 2 or 3. Variations of the following regimens were used for induction: 43% R-MPV (rituximab, methotrexate, procarbazine, and vincristine) (43%), 29% MRT (methotrexate, rituximab, and temozolomide), 21% MR (methotrexate and rituximab), and 7% MATRix (methotrexate, cytarabine, thiotepa, and rituximab). After induction, 58% achieved a complete response (CR), 33% achieved a partial response (PR), and 8% had a stable disease (SD). Patients received a median of 6 cycles of nivolumab consolidation. Patients who received at least 1 cycle of nivolumab consolidation achieved an overall response rate of 83% with a CR rate of 75%. With a median follow-up duration of 18 months, the 1-year overall survival (OS) and PFS rates were 91.7% and 66.1%, respectively. No DLTs were observed during Cycle 1 of nivolumab consolidation in Stage 1. The most common grade ≥ 3 Adverse Events (AEs) associated with nivolumab consolidation included neutropenia (14%) and fatigue (7%). One patient (7%) developed a grade 4 Stevens-Johnson syndrome associated with sepsis and acute kidney injury, requiring discontinuation of nivolumab after Cycle 1. Conclusion: The current study demonstrates encouraging safety and clinical outcomes of nivolumab consolidation in older PCNSL patients who are deemed poor candidates for ASCT or WBI. No DLT was observed during the safety run-in phase, and there was no unexpected toxicity associated with nivolumab although 1 patient discontinued the study treatment due to Stevens-Johnson syndrome, a rare but known AE associated with nivolumab, after Cycle 1. Overall, nivolumab consolidation was associated with favorable survival rates in a group of patients with poor-risk PCNSL. We are in the process of identifying various clinical and biological factors, including 9p24.1 copy number alteration, in association with the response to nivolumab consolidation. Furthermore, changes in the neurological function based on the NANO scale assessed before and after the nivolumab consolidation are being analyzed.

Role of eosinophilia in patients with recurrent/metastatic head and neck squamous cell carcinoma treated with nivolumab: Prediction of immune-related adverse events and favorable outcome.

Immune-related adverse events (irAEs) are prognostic factors for patients on nivolumab. However, predictors of irAEs have not yet been identified. We aimed to investigate the predictors of irAEs occurrence and nivolumab discontinuation due to irAEs. Sixty-two patients with recurrent/metastatic head and neck squamous cell carcinoma received nivolumab therapy between June 2017 and December 2020. Treatment outcome was compared between the groups with or without irAEs. The irAE (+) group was further divided by nivolumab discontinuation. Progression-free survival (PFS) and overall survival (OS) were compared between the groups. Predictors of irAE occurrence were analyzed. Twenty-one patients (33.9%) developed irAEs, and six (28.6%) discontinued nivolumab due to severe irAEs. The irAE (+) group had significantly longer PFS and OS than the irAE (-) group (median PFS, 12.7 vs. 1.9 months; median OS, 33.1 vs. 12.8 months). The treatment outcomes in the discontinuation group were comparable to those in the non-discontinuation group. The maximum absolute eosinophil count (AEC) during nivolumab therapy was significantly higher in the irAE (+) group than in the irAE (-) group (548.8 vs. 182) and higher in the discontinuation group than in the non-discontinuation group (729.3 vs. 368.6). The receiver operating characteristic curve showed that the maximum AEC had a moderate-to-high accuracy for predicting irAE occurrence (area under the curve [AUC], 0.757) and nivolumab discontinuation (AUC, 0.893). Monitoring AEC during nivolumab therapy may be useful in predicting irAE occurrence, nivolumab discontinuation, and disease prognosis.

Complete response of metastatic papillary renal cell carcinoma with inferior vena cava tumor thrombus to nivolumab plus cabozantinib

IntroductionThe effectiveness of nivolumab plus cabozantinib for metastatic papillary renal cell carcinoma with inferior vena cava tumor thrombus remains unclear.Case presentationA 77‐year‐old male was diagnosed with right papillary renal cell carcinoma with a metastatic lesion on Gerota's fascia, lymph node metastasis, and inferior vena cava tumor thrombus. He was treated with nivolumab plus cabozantinib. As all lesions regressed enough to permit complete resection, radical nephrectomy, thrombectomy, and retroperitoneal lymph node dissection were performed. No viable malignant cells were identified histopathologically. Despite the discontinuation of nivolumab plus cabozantinib, there has been no recurrence for 9 months.ConclusionNivolumab plus cabozantinib has effectiveness for metastatic papillary renal cell carcinoma with inferior vena cava tumor thrombus.

Anti-Ma2 Antibody Paraneoplastic Cerebellar Degeneration Associated with Renal Cell Carcinoma: A Case Report. (P8-11.013)

<h3>Objective:</h3> To highlight a unique case of Anti-Ma2 antibody paraneoplastic cerebellar degeneration (PCD) associated with renal cell carcinoma (RCC). <h3>Background:</h3> Paraneoplastic neurologic syndromes are a group of immune mediated disorders with a multitude of presentations. PCD is a rare presentation of a rapidly progressive ataxia associated with a variety of antibodies. In 0.5–1% of patients, anti-Ma2 antibody has been known to cause PCD in the setting of neoplasms. <h3>Design/Methods:</h3> NA <h3>Results:</h3> A 70-year-old male presented with three-month history of progressive gait difficulty, poor balance and recurrent falls. He had a history of metastatic RCC for which he underwent a total left nephrectomy, radiation therapy and chemotherapy with nivolumab and axitinib. Initial evaluation noted end-gaze nystagmus, limb dysmetria, truncal ataxia and wide-based gait. Chemotherapy was discontinued at the onset of symptoms. Work-up demonstrated cerebellar atrophy and cerebrospinal fluid (CSF) studies revealed mildly elevated protein and oligoclonal bands. He was hospitalized one month later for rapidly worsening ataxia. Repeat serum and CSF studies were positive for anti-Ma2 antibodies. He underwent 5 sessions of plasmapheresis with minimal improvement. Despite treatment, disease continued to progress with patient becoming wheelchair bound. Further treatment with immunotherapies were discussed, but patient elected to pursue palliative care. <h3>Conclusions:</h3> Anti-Ma2 antibodies have been well characterized in PCD in the setting of neoplasms. Immune checkpoint inhibitors (ICI) have also been associated with anti-Ma2 antibodies, causing immune related adverse events including encephalitis and cranial neuropathies. Nivolumab has been reported with cerebellar ataxia in the absence of anti-Ma2 antibodies with symptoms starting shortly after the initiation of therapy. However, symptoms improved after discontinuation of nivolumab and treatment with steroids. In our case, symptoms started almost one year after the initiation of ICI and patient continued to decline even after discontinuation of ICI. This presentation demonstrates a unique case of anti-Ma2 antibody PCD associated with RCC. <b>Disclosure:</b> Dr. Zahra has nothing to disclose. Dr. Ahmed has nothing to disclose. Dr. Sivakumar has nothing to disclose. Dr. Urrea-Mendoza has nothing to disclose. Dr. Veerappan has nothing to disclose.

P027 Immune checkpoint inhibitor associated vasculitis: a limitation to cancer therapy

Abstract Background/Aims The increasing use of immune checkpoint inhibitors (ICIs) underlies the importance of close monitoring and recognition of associated adverse events. We report a rare case of nivolumab-related peripheral vasculitis with digital gangrene and auto-amputation in a patient treated for mesothelioma. Methods A 69-year-old male with T4M0N0 pulmonary sarcoid mesothelioma was commenced on second-line Nivolumab therapy. 11 days later, he presented with worsening dyspnoea and dry cough. CTPA demonstrated new bilateral lower zone and peripheral predominant ground glass patchy consolidation consistent with acute pneumonitis. He sustained a significant clinical benefit from IV methylprednisolone and cessation of Nivolumab. 20 days after the pneumonitis episode, the patient re-presented with extremely tender, blue-black discoloration of the 2nd, 3rd and 4th fingers bilaterally, accompanied by localised sensory loss. Petechiae were also seen distributed across the digital pulp and nailbeds. Although bilateral, the left side was notably worse, with clear evidence of digital ischaemia and dry gangrene. Urine dipstix was bland. Immunology revealed normal C3/C4, ANCA and dsDNA serology, but mildly raised ANA (1.5). An echocardiogram excluded infective emboli. High dose IV methylprednisolone and iloprost infusion was commenced to treat ICI-associated peripheral vasculitis. Concurrently, dalteparin was required for a non-occlusive right subclavian venous thrombus. Nevertheless, his digital ischaemia progressed proximally to the left middle distal phalanx. MDT decision was made to avoid Cyclophosphamide given the infection risk. Sildenafil was introduced alongside a reduction regime of oral prednisolone. Unfortunately, the patient was subsequently hospitalised for acute PCP infection requiring high flow oxygen and intravenous antimicrobials. Following this stormy course, a slow but consistent and substantial clinical improvement was noted with respect to his digital ischaemia with minimal tissue loss. 7 months on, the patient’s digits remain free from ischaemia, infection and pain with good functional ability on Sildenafil treatment. Results Reports of PD-1 blockade-associated vasculitides mention ANCA-vasculitis, IgA vasculitis, leukocytoclastic vasculitis, eGPA and granulomatous vasculitis; however, drug-induced digit necrosis and auto-amputation is not widely reported. In this rare presentation of digital gangrene, immediate discontinuation of nivolumab treatment with initiation of high dose steroids and sildenafil, allowed eventual recovery of digits with limited auto-amputation and minimal sequelae. Management of nivolumab-associated vasculitis and pneumonitis required a multidisciplinary approach involving oncology, rheumatology, plastics and respiratory medicine. In the context of nivolumab discontinuation, the patient remains only on symptomatic treatment and follow up with no active cancer therapy meaning that prognosis is poor, in keeping with other reports of vasculitic reactions to nivolumab in cancer patients. Conclusion ICIs have revolutionised the management and outcomes across a range of malignancies. However, their mechanism can inadvertently induce undesired toxicity, the awareness of which is paramount. Disclosure M. Au: None. A. Faher: None. E. Htut: None.

Clinical characteristics, treatment and outcome of nivolumab-induced myasthenia gravis.

To investigate the clinical features of nivolumab-induced myasthenia gravis (MG) and provide evidence for the rational use of nivolumab in the clinic. We collected case reports and case series of nivolumab-induced MG for retrospective analysis by searching Chinese and English databases from 2014 to October 31, 2022. Of the 67 patients included, the median age was 72.5 years (range 34-86), including 44 males (65.7%). MG occurred in the median 2nd treatment cycle (range, 1st-6th) after nivolumab treatment, being mild in 12 patients (17.9%) and moderate to severe in 44 patients (65.7%). Ptosis (n = 48,71.6%), diplopia (n = 34,50.7%), dyspnea (n = 30, 44.8%), limb muscle weakness (n = 30, 44.8%) and dysphagia (n = 27, 40.3%) were the most common symptoms. Fifty-six patients (83.6%) were classified as having generalized myasthenia gravis (GMG), the remaining 11 patients (16.4%) isolated ocular myasthenia gravis (OMG). Twenty-one patients (31.3%) had MG combined with myositis, 10 patients (14.9%) had myocarditis, and 9 patients (13.4%) had both myositis and myocarditis. Forty patients (59.7%) were positive for anti-acetylcholine receptor antibodies. The serum creatine kinase level was significantly increased in 37 patients (55.2%), with a median value of 4000 IU/L (219,14229). After discontinuation of nivolumab and immunosuppressive therapy, 46 patients (68.7%) finally recovered or improved their MG symptoms, while 15 patients (22.4%) did not recover. Eleven patients (16.4%) died of MG complications. MG is a serious and rare adverse reaction to nivolumab. Nivolumab-induced MG should be timely and correctly identified, and immunotherapy should be given.

Immune checkpoint inhibitors associated granulomatous small vessel vasculitis accompanied with tubulointerstitial nephritis: a case report

BackgroundImmune checkpoint inhibitors (ICIs) have provided significant benefits in cancer treatment, but they could develop immune-related adverse events (irAE). ICI-associated renal adverse effects are rare and tubulointerstitial nephritis (TIN) is the most common in the renal irAE. However, only a few case reports of renal vasculitis associated with ICI have been reported. In addition, the characteristics of infiltrating inflammatory cells of ICI-associated TIN and renal vasculitis have been uncertain.Case presentationA 65-year-old man received immune checkpoint inhibitors (ICIs), anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) and anti-PD-1 (programmed cell death 1) antibodies for aggravated metastatic malignant melanoma. About 1 week after the second administration of nivolumab and ipilimumab, acute kidney injury developed. A renal biopsy was performed that showed TIN and non-necrotizing granulomatous vasculitis in interlobular arteries. Massive CD3+ T cells and CD163+ macrophages infiltrated both tubulointerstitium and interlobular arteries. Many infiltrating cells tested positive for Ki-67 and PD-1 ligand (PD-L1), but negative for PD-1. In CD3+ T cells, CD8+ T cells were predominantly infiltrated, and these cells were positive for Granzyme B (GrB) and cytotoxic granule TIA-1, but negative for CD25, indicating antigen-independent activated CD8+ T cells. Infiltration of CD4+ T cells was noted without obvious CD4+ CD25+ regulatory T (Treg) cells. His renal dysfunction recovered within 2 months of treatment with prednisolone in addition to discontinuation of nivolumab and ipilimumab.ConclusionsWe herein reported a case of ICI-related TIN and renal granulomatous vasculitis with infiltration of massive antigen-independent activated CD8+ T cells and CD163+ macrophages, and none or few CD4+ CD25+ Treg cells. These infiltrating cells might be a characteristic of the development of renal irAE.

Adjuvant nivolumab plus ipilimumab versus placebo for localised renal cell carcinoma after nephrectomy (CheckMate 914): a double-blind, randomised, phase 3 trial

Effective adjuvant therapy for patients with resected localised renal cell carcinoma represents an unmet need, with surveillance being the standard of care. We report results from part A of a phase 3, randomised trial that aimed to assess the efficacy and safety of adjuvant nivolumab plus ipilimumab versus placebo. The double-blind, randomised, phase 3 CheckMate 914 trial enrolled patients with localised clear cell renal cell carcinoma who were at high risk of relapse after radical or partial nephrectomy between 4-12 weeks before random assignment. Part A, reported herein, was done in 145 hospitals and cancer centres across 20 countries. Patients were randomly assigned (1:1) to nivolumab (240 mg) intravenously every 2 weeks for 12 doses plus ipilimumab (1 mg/kg) intravenously every 6 weeks for four doses, or matching placebo, via an interactive response technology system. The expected treatment period was 24 weeks, and treatment could be continued until week 36, allowing for treatment delays. Randomisation was stratified by TNM stage and nephrectomy (partial vs radical). The primary endpoint was disease-free survival according to masked independent central review; safety was a secondary endpoint. Disease-free survival was analysed in all randomly assigned patients (intention-to-treat population); exposure, safety, and tolerability were analysed in all patients who received at least one dose of study drug (all-treated population). This study is registered with ClinicalTrials.gov, NCT03138512. Between Aug 28, 2017, and March 16, 2021, 816 patients were randomly assigned to receive either adjuvant nivolumab plus ipilimumab (405 patients) or placebo (411 patients). 580 (71%) of 816 patients were male and 236 (29%) patients were female. With a median follow-up of 37·0 months (IQR 31·3-43·7), median disease-free survival was not reached in the nivolumab plus ipilimumab group and was 50·7 months (95% CI 48·1 to not estimable) in the placebo group (hazard ratio 0·92, 95% CI 0·71-1·19; p=0·53). The number of events required for the planned overall survival interim analysis was not reached at the time of the data cutoff, and only 61 events occurred (33 in the nivolumab plus ipilimumab group and 28 in the placebo group). 155 (38%) of 404 patients who received nivolumab plus ipilimumab and 42 (10%) of 407 patients who received placebo had grade 3-5 adverse events. All-cause adverse events of any grade led to discontinuation of nivolumab plus ipilimumab in 129 (32%) of 404 treated patients and of placebo in nine (2%) of 407 treated patients. Four deaths were attributed to treatment with nivolumab plus ipilimumab and no deaths were attributed to treatment with placebo. Adjuvant therapy with nivolumab plus ipilimumab did not improve disease-free survival versus placebo in patients with localised renal cell carcinoma at high risk of recurrence after nephrectomy. Our study results do not support this regimen for the adjuvant treatment of renal cell carcinoma. Bristol Myers Squibb and Ono Pharmaceutical.

P060: Prognosis of patients with relapsed and refractory classic Hodgkin lymphoma after nivolumab discontinuation and efficacy of nivolumab retreatment

P060: Prognosis of patients with relapsed and refractory classic Hodgkin lymphoma after nivolumab discontinuation and efficacy of nivolumab retreatment

Effectiveness and Safety of Molecular-Targeted Therapy after Nivolumab Plus Ipilimumab for Advanced or Metastatic Renal Cell Carcinoma: A Multicenter, Retrospective Cohort Study.

Simple SummaryWe evaluated the efficacy and safety of molecular-targeted therapies (MTTs) in 29 patients who discontinued the combination therapy of nivolumab plus ipilimumab (NIVO+IPI) for advanced or metastatic renal cell carcinoma as real-world outcomes. Patients receiving MTTs had a median follow-up of 8 months. The objective response rate was 44.8%, and the disease control rate was 72.4%. After NIVO+IPI, the median overall survival was 18 months, and progression-free survival (PFS) was 8 months. Patients with bone metastases had a significantly shorter median PFS when treated with MTTs after NIVO+IPI than those without bone metastases (4 vs. 12 months, p = 0.012). MTTs may be a useful secondary treatment option after the discontinuation of NIVO+IPI.This study aimed to evaluate the effectiveness and safety of molecular-targeted therapies (MTTs) after the discontinuation of nivolumab and ipilimumab (NIVO+IPI) combination therapy in patients who had been diagnosed with advanced/metastatic renal cell carcinoma as real-world outcomes. We enrolled patients treated with MTTs following initial therapy with NIVO+IPI at nine institutions in Japan. We evaluated the objective response rate (ORR) as the primary endpoint and disease control rate (DCR), best overall response, and oncological outcomes (overall survival (OS) and progression-free survival (PFS)) as the secondary endpoints. We also evaluated factors predictive of disease progression after the administration of MTTs. Patients were followed up for a median of 8 months. The ORR was 44.8%, and the DCR was 72.4%. The median OS and PFS of MTTs after NIVO+IPI were 18 months and 8 months, respectively. A total of 31% of patients experienced grade 3/4 MTT-related adverse events. The median PFS in patients with bone metastases was significantly shorter than that in those without bone metastases (4 vs. 12 months, p = 0.012). MTTs may be a useful secondary treatment option after the discontinuation of NIVO+IPI.

New-onset type 1 diabetes mellitus as a delayed immune-related event after discontinuation of nivolumab: A case report

Rationale:Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. However, they may cause immune-related adverse events. Although there have been a few reports of new-onset type 1 diabetes mellitus (T1DM) during ICI treatment, T1DM as a delayed immune-related event after discontinuing immunotherapy is extremely rare. Herein, we report the case of an elderly veteran who presented with diabetic ketoacidosis 4 months after the discontinuation of treatment with nivolumab.Patient concerns:A 74-year-old veteran was treated with second-line nivolumab for advanced non–small cell lung cancer. After 9 treatment cycles, the administration was discontinued due to fatigue. Four months later, he was admitted to the emergency department in a stuporous mental state and hyperglycemia, with high glycosylated hemoglobin levels (10.6%). C-peptide levels were significantly decreased, with negative islet autoantibodies.Diagnoses:We diagnosed nivolumab-induced T1DM. There were no laboratory results indicating a new thyroid dysfunction or adrenal insufficiency, which are typical endocrine adverse reactions.Interventions:Since the hypothalamic and pituitary functions were preserved and only the pancreatic endocrine capacity was impaired, we administered continuous intravenous insulin injections, with fluid and electrolyte replacement.Outcomes:His serum glucose levels decreased, and symptoms improved; hence, on the 8 day of hospitalization, we switched to multiple daily insulin injections.Lessons:The present case indicates that regular glucose monitoring and patient education are needed for diabetic ketoacidosis after the discontinuation of ICI therapy.

LBA75 RACE IT: A prospective, single arm, multicenter, phase II-trial to assess safety and efficacy of preoperative RAdiation therapy before radical CystEctomy combined with ImmunoTherapy in locally advanced urothelial carcinoma of the bladder (AB 65/18) – first results

Patients (Pts) with locally advanced bladder cancer (BC) have a poor prognosis despite radical surgical therapy. Early data on neoadjuvant immunotherapy in muscle invasive BC is promising, while there are indications of synergistic effects of radiation and immunotherapy. This trial evaluates the feasibility, safety and efficacy of neoadjuvant radio-immunotherapy (RIT) following radical cystectomy (RCX) in patients with locally advanced, muscle invasive BC. Patients with locally advanced urothelial BC (cT3/4 cN0/N+ cM0, eligible for RCX, unfit for or refusing neoadjuvant chemotherapy) were included in this prospective, single arm, phase II-trial. Pts were treated with Nivolumab 240mg intravenously every two weeks for 4 cycles, starting one week before radiotherapy of the bladder/pelvis with 50.4 Gy, followed by RCX with standardized pelvic lymphadenectomy. Primary endpoint is the rate of Pts with completed treatment (RIT and RCX) at the end of week 15. Secondary endpoints include overall response rate (ORR), pathological response rates, disease free survival (DFS) and toxicity. Of 33 treated Pts, 32 (97%) were ≥cT3/4 and 10 (30.3%) were lymph node positive (cN+). For primary endpoint and efficacy analysis, 31 Pts were eligible. Primary endpoint of completed treatment (RIT and RCX) in time at the end of week 15 was reached in 27/31 (87.1%) Pts. Median number of nivolumab cycles was 4. The radiological ORR was 70.9% (CR 16.1%, PR 54.8%, SD 25.8% and PD 3.2%). Pathological response rate was ypT0 38.7% and ≤ ypT1 58.1%. While survival data is immature, DFS rate at 12 months was 90.6%. Any-grade treatment-related AEs (TRAEs) occurred in 54.5 % of all 33 patients. TRAEs were mostly grade 1-2. Most common TRAEs were thyroid and gastrointestinal disorders (each 15.2%) and skin reactions (33.3%). TRAEs led to Nivolumab discontinuation in 8 (25.8%) Pts. The trial met its primary endpoint. Neoadjuvant radio-immunotherapy followed by radical cystectomy in locally advanced bladder cancer patients is feasible and safe.

P61-5 Examination of patients with advanced non-small cell lung cancer (NSCLC) responding to nivolumab monotherapy over 1 year

Nivolumab, a PD-1 immune-checkpoint-inhibitor antibody, was approved six years ago as 2nd line therapy for advanced NSCLC. The 5-year survival rate for NSCLC is 13.4% according to phase III trials Checkmate 017 and 057. Although some cases responding favorably to long-term treatment with nivolumab have been reported, few studies have investigated the reasons for discontinuation of nivolumab.

Recurrent advanced rectal malignant melanoma that discontinued anti‐PD‐1 antibody after complete response and was refractory to rechallenge

We report a case of 70-year-old woman with rectal malignant melanoma that recurred in the pelvic lymph node one year after surgery. Nivolumab was initiated and she achieved complete response after one year, but she discontinued nivolumab at her instance. At a follow-up 21 months after the discontinuation of nivolumab, a pelvic lymph node metastasis recurrence and a lung metastasis discovered. Nivolumab rechallenge was initiated, but it was not successful.