Dose Of Nivolumab Research Articles

Impact of Performance Status on Survival Outcomes and Health Care Utilization in Patients With Advanced NSCLC Treated With Immune Checkpoint Inhibitors

IntroductionLandmark trials testing immune checkpoint inhibitors (ICIs) in advanced NSCLC are difficult to extrapolate to real-world practice given the exclusion of patients with poor (i.e., ≥2) Eastern Cooperative Oncology Group performance status (ECOG PS). We sought to evaluate the impact of ECOG PS on clinical outcomes and health care utilization in patients with NSCLC treated with ICIs in real-world practice. MethodsPatients with advanced NSCLC who received at least one dose of pembrolizumab or nivolumab were retrospectively identified from the Alberta Immunotherapy Database. The primary outcome was median overall survival, as stratified by ECOG PS. Secondary outcomes included median time-to-treatment failure and metrics of health care utilization, including emergency department visits, hospitalizations, and death in hospital. ResultsA total of 790 patients were included, with 29.2% having poor ECOG PS at initiation of ICI. These patients had significantly lower median overall survival (3.3 versus 13.4 mo) and median time-to-treatment failure (1.4 versus 4.9 mo) compared with those with favorable ECOG PS (p < 0.0001 for both outcomes). Patients with poor ECOG PS were also more likely to present to the emergency department, be admitted to the hospital, and die in the hospital during their first admission (risk ratio = 1.6, 2.3–2.7, p < 0.001). ConclusionsPatients with NSCLC with poor ECOG PS treated with ICI had significantly worse survival outcomes and were significantly more likely to use health care services than those with favorable ECOG PS. The large proportion of patients with poor ECOG PS further justifies the urgent need for randomized trials evaluating the efficacy of ICI in this high-risk population.

Five-Year Clinical Outcomes after Neoadjuvant Nivolumab in Resectable Non-Small Cell Lung Cancer.

Neoadjuvant anti-PD-1 therapy has shown promise for resectable non-small cell lung cancer (NSCLC). We reported the first phase I/II trial of neoadjuvant nivolumab in resectable NSCLC, finding it to be safe and feasible with encouraging major pathological responses (MPR). We now present 5-year clinical outcomes from this trial, representing to our knowledge, the longest follow-up data for neoadjuvant anti-PD-1 in any cancer type. Two doses of nivolumab (3 mg/kg) were administered for 4 weeks before surgery to 21 patients with Stage I-IIIA NSCLC. 5-year recurrence-free survival (RFS), overall survival (OS), and associations with MPR and PD-L1, were evaluated. With a median follow-up of 63 months, 5-year RFS and OS rates were 60% and 80%, respectively. The presence of MPR and pre-treatment tumor PD-L1 positivity (TPS ≥1%) each trended toward favorable RFS; HR, 0.61 [95% confidence interval (CI), 0.15-2.44] and HR, 0.36 (95% CI, 0.07-1.85), respectively. At 5-year follow-up, 8 of 9 (89%) patients with MPR were alive and disease-free. There were no cancer-related deaths among patients with MPR. In contrast, 6/11 patients without MPR experienced tumor relapse, and 3 died. Five-year clinical outcomes for neoadjuvant nivolumab in resectable NSCLC compare favorably with historical outcomes. MPR and PD-L1 positivity trended toward improved RFS, though definitive conclusions are limited by cohort size.

SAINT: A Phase I/Expanded Phase II Study Using Safe Amounts of Ipilimumab, Nivolumab and Trabectedin as First-Line Treatment of Advanced Soft Tissue Sarcoma.

This Phase 1/2 study is based on the hypothesis that immune checkpoint inhibitors are more effective when given earlier in the course of the disease for advanced soft tissue sarcoma. Phase I endpoints-maximum tolerated dose in previously treated patients; Phase II endpoints-best response, progression free survival and overall survival and incidence of adverse events in previously untreated patients; Phase I treatments-escalating doses of trabectedin (1.0, 1.2, 1.5 mg/m2) as continuous intravenous infusion over 24 h every 3 weeks, 1 mg/kg of ipilimumab given intravenously every 12 weeks, and 3 mg/kg of nivolumab given intravenously every 2 weeks; Phase II treatments-maximum tolerated dose of trabectedin and defined doses of ipilimumab and nivolumab. Phase I (n = 9)-the maximum tolerated dose of trabectedin was 1.2 mg/m2; Phase II (n = 79)-6 complete responses, 14 partial responses, 49 stable disease, 25.3% best response rate, 87.3% disease control rate; median progression-free survival, 6.7 months (CI 95%: 4.4-7.9), median overall survival, 24.6 months (CI 95%: 17.0-.); Grade 3/4 therapy-related adverse events (n = 92)-increased ALT (25%), fatigue (8.7%), increased AST (8.7%), decreased neutrophil count (5.4%) and anemia (4.6%). SAINT is a safe and effective first-line treatment for advanced soft tissue sarcoma.

Phase II multicenter trial combining nivolumab and radiosurgery for NSCLC and RCC brain metastases.

Anti-PD-1 has activity in brain metastases (BM). This phase II open labeled non-randomized single arm trial examined the safety and efficacy of combining nivolumab with radiosurgery (SRS) in the treatment of patients with BM from non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC). This was a multicenter trial (NCT02978404) in which patients diagnosed with NSCLC or RCC, having ≤ 10 cc of un-irradiated BM and no prior immunotherapy were eligible. Nivolumab (240 mg or 480 mg IV) was administered for up to 2 years until progression. SRS (15-21 Gy) to all un-irradiated BM was delivered within 14 days after the first dose of nivolumab. The primary endpoint was intracranial progression free survival (iPFS). Twenty-six patients (22 NSCLC and 4 RCC) were enrolled between August 2017 and January 2020. A median of 3 (1-9) BM were treated with SRS. Median follow-up was 16.0 months (0.43-25.9 months). Two patients developed nivolumab and SRS related grade 3 fatigue. One-year iPFS and OS were 45.2% (95% CI 29.3-69.6%) and 61.3% (95% CI 45.1-83.3%), respectively. Overall response (partial or complete) of SRS treated BM was attained in 14 out of the 20 patients with ≥1 evaluable follow-up MRI. Mean FACT-Br total scores were 90.2 at baseline and improved to 146.2 within 2-4 months (P = .0007). The adverse event profile and FACT-Br assessments suggested that SRS during nivolumab was well tolerated. Upfront SRS with the initiation of anti-PD-1 prolonged the 1-year iPFS and achieved high intracranial control. This combined approach merits validation randomized studies.

Estimated Costs of the Ipilimumab-Nivolumab Therapy and Related Adverse Events in Metastatic Melanoma.

Combined ipilimumab and nivolumab significantly improve outcomes in metastatic melanoma patients but bear an important financial impact on the healthcare system. Here, we analyze the treatment costs, focusing on irAE. We conducted a retrospective analysis of 62 melanoma patients treated with ipilimumab-nivolumab at the Lausanne University Hospital between 1 June 2016 and 31 August 2019. The frequency of irAEs and outcomes were evaluated. All melanoma-specific costs were analyzed from the first ipilimumab-nivolumab dose until the therapy given subsequently or death. A total of 54/62 (87%) patients presented at least one irAE, and 31/62 (50%) presented a grade 3-4 irAE. The majority of patients who had a complete response 12/14 (86%) and 21/28 (75%) of overall responders presented a grade 3-4 toxicity, and there were no responses in patients without toxicity. Toxicity costs represented only 3% of the total expenses per patient. The most significant contributions were medication costs (44%) and disease costs (39%), mainly disease-related hospitalization costs, not toxicity-related. Patients with a complete response had the lowest global median cost per week of follow up (EUR 2425) and patients who had progressive disease (PD), the highest one (EUR 8325). Except for one patient who had a Grade 5 toxicity (EUR 6043/week), we observe that less severe toxicity grades (EUR 9383/week for Grade 1), or even the absence of toxicity (EUR 9922/week), are associated with higher median costs per week (vs. EUR 3266/week for Grade 4 and EUR 2850/week for Grade 3). The cost of toxicities was unexpectedly low compared to the total costs, especially medication costs. Patients with higher toxicity grades had better outcomes and lower total costs due to treatment discontinuation.

Quantitative Diffusion-Weighted Imaging Analyses to Predict Response to Neoadjuvant Immunotherapy in Patients with Locally Advanced Head and Neck Carcinoma.

Neoadjuvant immune checkpoint blockade (ICB) prior to surgery may induce early pathological responses in head and neck squamous cell carcinoma (HNSCC) patients. Routine imaging parameters fail to diagnose these responses early on. Magnetic resonance (MR) diffusion-weighted imaging (DWI) has proven to be useful for detecting HNSCC tumor mass after (chemo)radiation therapy. 32 patients with stage II-IV, resectable HNSCC, treated at a phase Ib/IIa IMCISION trial (NCT03003637), were retrospectively analyzed using MR-imaging before and after two doses of single agent nivolumab (anti-PD-1) (n = 6) or nivolumab with ipilimumab (anti-CTLA-4) ICB (n = 26). The primary tumors were delineated pre- and post-treatment. A total of 32 features were derived from the delineation and correlated with the tumor regression percentage in the surgical specimen. MR-DWI data was available for 24 of 32 patients. Smaller baseline tumor diameter (p = 0.01-0.04) and higher sphericity (p = 0.03) were predictive of having a good pathological response to ICB. Post-treatment skewness and the change in skewness between MRIs were negatively correlated with the tumor's regression (p = 0.04, p = 0.02). Pre-treatment DWI tumor diameter and sphericity may be quantitative biomarkers for the prediction of an early pathological response to ICB. Furthermore, our data indicate that ADC skewness could be a marker for individual response evaluation.

Fatal myocarditis after the first dose of nivolumab.

Thymic carcinoma (TC) is a rare subtype of thymic epithelial malignancy. Surgical resection is a mainstay in the treatment of TC, while radiotherapy and chemotherapy are modalities used in adjuvant or palliative setting. Immune checkpoint inhibitors (ICI) including anti-PD-1 (programmed cell death 1) antibodies represent an emerging treatment modality in TC; however, their administration could be associated with life-threatening toxicity. We present a case of a 59-year-old female with grade III TC, who had received neoadjuvant chemotherapy followed by surgery and subsequent adjuvant radio-immunotherapy with an ICI, nivolumab. We provide our experience with the toxicity of an administered treatment. Fourteen days after the first dose of nivolumab and on 21st day after starting of radiotherapy (total dose of 40 Gy), the patient developed fulminant myocarditis with subsequent heart failure. Despite immunosuppressive therapy with high-dose glucocorticoids and mycophenolate mofetil and intensive support, the patient died within 6 days after the onset of first symptoms. Physicians should be aware of these extremely rare, but potentially fatal complications of immunotherapy.

Selected Articles from This Issue

Davis and colleagues report the first systematic assessment of the safety and pharmacokinetics of dual immune checkpoint inhibition with ipilimumab and nivolumab in pediatric, adolescent, and young adult patients with relapsed or refractory sarcoma. They establish a recommended phase II dose of nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) and found the combination to be generally well tolerated. In expanded phase II cohorts, the authors observed two sustained partial responses. They further demonstrate that increased ipilimumab dosing (3 mg/kg) in combination with nivolumab (1 mg/kg) carries higher toxicity without clinical benefit in this population.Advanced stage head and neck squamous cell carcinoma (HNSCC) patients are at a high risk of recurrent disease. Due to dismal 5-year survival rates, such patients are in dire need of effective adjuvant therapy. Everolimus, an mTOR inhibitor, has documented activity in HNSCC and is well tolerated with minimal long-term toxicity. In this placebo-controlled phase II trial, Nathan and colleagues are the first to show promising results using everolimus as adjuvant therapy after complete response to definitive treatment in a subset of HPV-negative patients with advanced stage disease. In particular, HPV-negative TP53 mutated tumors appear to yield the best benefit. Thus, subsequent trials using everolimus in this patient population are warranted.TLR9 agonists demonstrated efficacy in activation of the innate and adaptive immune system in preclinical models. Babiker and colleagues investigated the activity of tilsotolimod, an investigational synthetic TLR9 agonist, in patients with refractory solid tumors after progression on standard of care therapies. This early phase clinical trial established safety, maximum tolerated dose, and demonstrated early signs of efficacy of tilsotolimod. In addition, translational data revealed activation of the innate and adaptive immune system through the type I interferon (IFN) pathway, IFNγ and IFNα gene upregulation, increase in inflammatory chemokines, activation of myeloid dendritic cells and antigen presentation, and an increase in genes for checkpoint and costimulatory proteins. The translational results suggest further investigation of tilsotolimod in combination with checkpoint inhibitors in solid tumors.Biomarkers are urgently needed to select chemotherapy regimens in pancreatic ductal adenocarcinoma (PDAC). In this study, Perera and colleagues investigated whether mRNA expression levels of hENT1 predict responsiveness to gemcitabinenab-paclitaxel (GnP) in patients with advanced PDAC. The results of this prospective observational clinical trial using tumor-enriched RNA sequencing revealed higher response rates and improved survival in patients receiving GnP, when tumors were considered hENT1high compared to those that were hENT1low. No difference in response or survival were seen in patients receiving modified FOLFIRINOX. An interaction analysis confirmed hENT1 as a predictive biomarker for GnP response. This suggests that hENT1 expression can be used to identify patients who will respond to GnP.

Brentuximab vedotin plus nivolumab after autologous haematopoietic stem-cell transplantation for adult patients with high-risk classic Hodgkin lymphoma: a multicentre, phase 2 trial

After autologous haematopoietic stem-cell transplantation (HSCT), consolidation with brentuximab vedotin in patients with high-risk relapsed or refractory classic Hodgkin lymphoma has been shown to improve progression-free survival compared with placebo. Brentuximab vedotin plus nivolumab is a safe and effective treatment for relapsed or refractory classic Hodgkin lymphoma; therefore, we aimed to evaluate the safety and activity of this drug combination post-autologous HSCT consolidation in patients with high-risk relapsed or refractory classic Hodgkin lymphoma. We did a multicentre phase 2 trial at five centres in the USA. Eligible patients were aged 18 years or older with high-risk relapsed or refractory classic Hodgkin lymphoma, had an ECOG performance status of 0-2, and had adequate organ and bone marrow function. Enrolled patients received brentuximab vedotin (1·8 mg/kg) and nivolumab (3 mg/kg) intravenously starting 30-60 days after autologous HSCT on day 1 of each 21-day cycle for up to 8 cycles. Nivolumab dose reduction was not allowed. Brentuximab vedotin dose reduction to 1·2 mg/kg was permitted. If one drug was discontinued because of a toxic effect, the other could be continued. The primary endpoint was 18-month progression-free survival in all treated patients. This study is registered with ClinicalTrials.gov, number NCT03057795. Between May 3, 2017, and July 13, 2019, 59 patients were enrolled and received the study therapy. Patients initiated brentuximab vedotin plus nivolumab for a median of 54 days (IQR 46-58) after autologous HSCT and received a median of 8 cycles (8-8). 34 (58%) of 59 patients were male, 29 (49%) completed 8 cycles of brentuximab vedotin plus nivolumab, and 45 (76%) completed 8 cycles of at least one drug. The median follow-up time was 29·9 months (IQR 24·6-34·8). The 18-month progression-free survival in all 59 patients was 94% (95% CI 84-98). The most common adverse events were sensory peripheral neuropathy (31 [53%] of 59) and neutropenia (25 [42%]), and immune-related adverse events requiring corticosteroids occurred in 17 (29%) of 59 patients. No treatment-related deaths were observed. Brentuximab vedotin plus nivolumab was highly active post-autologous HSCT consolidation for patients with high-risk relapsed or refractory classic Hodgkin lymphoma, most of whom had previous exposure to either brentuximab vedotin or PD-1 blockade. Combination immunotherapy in this setting should be further studied in patients with classic Hodgkin lymphoma with further refinement of the regimen to mitigate toxic effects, particularly in high-risk patients in whom more intensive therapy to prevent relapse is warranted. Bristol Myers Squibb, Leukemia and Lymphoma Society, Lymphoma Research Foundation, and National Cancer Institute of the National Institutes of Health.

Brentuximab Vedotin, Nivolumab, Doxorubicin, and Dacarbazine (AN+AD) for Advanced Stage Classic Hodgkin Lymphoma: Updated Efficacy and Safety Results from the Single-Arm Phase 2 Study (SGN35-027 Part B)

Introduction Brentuximab vedotin (BV) and nivolumab are well tolerated and active treatments for patients (pts) with classical Hodgkin lymphoma (cHL). These agents were previously studied in first salvage therapy (overall response rate [ORR] 85%; complete response [CR] 67%) (Advani 2021) and as first-line therapy in older adults (ORR 95%) (Yasenchak 2020). In ECHELON-1 study, BV plus doxorubicin, vinblastine, and dacarbazine (A+AVD) improved overall survival (OS) by 4.5 percentage points over doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) (6-year OS estimate of 93.9% vs 89.4%) in pts with previously untreated stage III or IV cHL (Ansell 2022). In pts with limited stage I or II cHL, BV plus doxorubicin and dacarbazine (AD) treatment resulted in a CR rate of 97% at end of treatment (EOT), promising 4-year progression-free survival (PFS) estimate of 88%, and no cases of ≥ Grade 3 peripheral neuropathy (Abramson 2021). In Part B of SGN35-027, treatment with BV, nivolumab, doxorubicin, and dacarbazine (AN+AD) showed promising preliminary activity in pts with bulky stage II or stage III/IV cHL (at EOT: ORR 93%; CR 88%) with no cases of febrile neutropenia or Grade 5 adverse events (AEs) (Lee 2021). Herein, we present updated efficacy and safety results from Part B of this study. Methods SGN35-027 (NCT03646123) is an open-label, multiple part, multicenter, phase 2 clinical trial. In Part B, enrolled pts had Ann Arbor stage I or II cHL with bulky mediastinal disease (defined as ≥10 cm) or stage III or IV cHL. Pts were treated with up to 6 cycles of AN+AD (BV 1.2 mg/kg [A], nivolumab 240 mg [N], doxorubicin 25 mg/m2 [A], and dacarbazine 375 mg/m2 [D]). All study drugs were administered intravenously on Days 1 and 15 of each 28-day cycle. The primary endpoint was CR rate at EOT. Key secondary endpoints included safety, tolerability, ORR, duration of objective response (DOR), duration of complete response (DOCR), and PFS. Disease response and progression were assessed by investigator using Lugano Classification Revised Staging System for malignant lymphoma (Cheson 2014) incorporating Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) for nodal non-Hodgkin and Hodgkin Lymphomas (Cheson 2016). Results In Part B, 58 pts were enrolled of which, 57 received at least 1 dose of study treatment. Most treated pts were White (88%) and <65 years old (95%), and approximately half were male (53%). The median age was 35.0 years (range: 19, 78 years). Thirty percent of treated pts had stage II cHL with bulky mediastinal disease, while the remainder had stage III (18%) or IV (51%) cHL. Of the 57 pts treated, the overall CR rate was 88% (95% CI: 76.3, 94.9) at EOT. ORR (CR or partial response [PR]) was 93% (95% CI: 83.0, 98.1) at EOT. With a median follow-up of 15.1 months, 4 pts (7%) had progressive disease and 1 pt (2%) died. The estimated PFS rate was 93% (95% CI: 81.6, 97.2) at 12 months. As of the data cutoff date (02-May-2022), 93% of pts (95% CI: 81.7, 97.2) had a DOR of least 12 months and 92% of pts (95% CI: 80.0, 96.9) had a DOCR of at least 12 months. Of the 58 pts enrolled, 4 pts had discontinued treatment (study treatment) early due to treatment-emergent adverse events (TEAEs) and 74% of pts had any dose modifications including any dose delay (28%), reduction (25%), and elimination (39%) due to AEs. Within 30 days of last dose of BV or 100 days of last dose of nivolumab, 51% of pts experienced ≥ Grade 3 TEAEs. Nausea, fatigue, and peripheral sensory neuropathy were the most frequently reported treatment-related TEAEs (65%, 47%, and 42% of pts, respectively). Notably, only 2 pts (4%) experienced ≥ Grade 3 peripheral sensory neuropathy, of which were considered treatment-related. No TEAEs led to death, and no cases of febrile neutropenia were reported. Eight pts (14%) experienced treatment-related serious TEAEs; most commonly pneumonitis (5%) and pyrexia (5%). Twenty pts (35%) experienced treatment-emergent immune-mediated AEs; most commonly hypothyroidism (9%), pneumonitis (5%), and maculo-papular rash (5%). Conclusions Efficacy results continue to show that AN+AD is a promising treatment for adult pts with bulky stage II or stage III/IV cHL. Updated safety results demonstrate continued tolerability with AN+AD and no new safety signals observed. Omitting bleomycin and vinblastine may have contributed to the absence of certain AEs, such as febrile neutropenia. This study is ongoing and updated results will be presented.

Results from a Phase I Trial Using Nivolumab in Combination with Dose Adjusted EPOCH in Newly Diagnosed Peripheral T-Cell Lymphomas

Introduction: Dose adjusted (DA)-EPOCH (etoposide, prednisone, vincristine, doxorubicin, and cyclophosphamide) is a first line chemotherapy option for peripheral T-cell lymphomas (PTCLs), but only a minority of patients (pts) are cured. Immune checkpoint blockade (CPB) demonstrated an overall response rate (ORR) of 30% in heavily pre-treated PTCLs in phase I/II studies but rapid or hyperprogression has also been observed in some non-responders. Cytotoxic chemotherapy may be additive to CPB by increasing the expression of neoantigens and therefore overcoming resistance due to weak tumor immunogenicity (Blood Advances. 2021). Methods: We conducted a phase I trial using a flat dose of the anti-PD1 antibody nivolumab (Nivo) in combination with DA-EPOCH in newly diagnosed PTCLs. Pts were allowed to receive one cycle of chemotherapy prior to enrollment. Pts received Nivo (360 mg) followed by DA-EPOCH every 21 days for 6 or 5 cycles (if prior chemotherapy) in the absence of toxicity or lack of efficacy. For immune related adverse event (irAE), Nivo was held until resolution to grade (G)1 and on ≤10 mg prednisone. For any G3 irAE, Nivo was withheld during the subsequent cycle, and if recurrence, Nivo was permanently discontinued. For protocol defined serious G3 irAEs (e.g., pneumonitis) or G4 irAE, Nivo was omitted from remaining cycles. After completing chemotherapy, pts had the option to proceed with autologous stem cell transplant (ASCT). Responses were assessed by PET/CT after 2 cycles of Nivo + DA-EPOCH and after the last cycle, using RECIL criteria. The primary objective was investigator-assessed ORR to Nivo + DA-EPOCH. Secondary objectives included toxicity, event free survival (EFS), progression free survival (PFS), and overall survival (OS). Selected baseline pt and tumor characteristics, as well as targeted next generation sequencing and multiplex immunohistochemistry of diagnostic tumor tissue were assessed and matched to response, EFS, and PFS in an exploratory analysis. Results: Table 1 displays pt characteristics of the 18 pts enrolled. Nine of 18 pts received treatment prior to enrollment as follows: one cycle of anthracycline based chemotherapy (N=6), oral methotrexate (N=1, SPTCL), and systemic steroids (N=2). The EPOCH dose level ranged from -6 to +3 (median dose level -1). All dose level reductions occurred due to G4 thrombocytopenia. In total, 10% (N=8 of 77) of treatment cycles were delayed >3 days; no delays were due to inadequate hematologic recovery. Immune related AEs of all grades occurred in 78% (N=14) of pts and 39% (N=7) of pts experienced ≥ grade 3 irAEs. 44% (N=8) of pts required discontinuation of Nivo due to irAEs. In the 8 pts whose irAEs resulted in discontinuation of Nivo, the irAE occurred prior to the second or third cycle of Nivo + DA-EPOCH. None of the 6 pts who received a cycle of anthracycline based chemotherapy prior to enrolling on trial experienced an irAE that resulted in dose hold or discontinuation of Nivo, whereas 8 of 12 pts who did not receive a prior cycle of anthracycline based chemotherapy experienced an irAE requiring a dose hold or discontinuation of Nivo. Interim and end of induction ORR were 94% (6 CR, 11 PR; 1 (6%) had SD) and 89%, respectively. We observed 11 CR, 5 PR, and 2 PD at the end of induction. Figure 1 displays response to Nivo + DA-EPOCH and duration of response. 2 pts received consolidation with ASCT. The number of doses of Nivo was significantly associated with improved response (CR vs. PR vs. PD); pts who received more doses of Nivo were more likely to achieve CR (p=0.0066). With a median follow up of 707 days (95% CI: 399-962), median EFS is 373 days (95% CI: 214-616), median PFS is 434 days (95% CI: 225-666), and median OS is 714 days (95% CI: 309-NR). Exploratory analyses, including expression of PD-1 and PDL-1 is ongoing. Discussion: As expected, in the entire cohort irAEs were common, often leading to discontinuation of CPB. However, no hyperprogression events were observed and dose-limiting irAEs did not occur in pts who received prior chemotherapy. Pts who were able to receive more Nivo had better efficacy outcomes. Given the high-risk characteristics of this cohort, the observed responses in rare subtypes, the encouraging PFS with a long median follow up, and the acceptable toxicity profile, further investigation of chemoimmunotherapeutic treatment strategies is warranted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Low-dose nivolumab in advanced hepatocellular carcinoma

BackgroundThe approved dose of nivolumab is 3 mg/kg or a flat dose of 240 mg for indications. There is no dose-response relationship for nivolumab; therefore, a low-dose regimen may be an option to reduce financial toxicity. This study was designed to investigate the efficacy and safety of low-dose nivolumab in the management of hepatocellular carcinoma (HCC).MethodsWe retrospectively reviewed patients with HCC who received 20 or 100 mg of nivolumab intravenously every 2 weeks. The objective response rate was determined in accordance with the Response Evaluation Criteria in Solid Tumors criteria version 1.1. The Cox regression model and Kaplan–Meier method were used to analyze hazard factors, progression-free survival (PFS), and overall survival (OS). Adverse events (AEs) were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.ResultsIn total, 78 patients were enrolled, including 49 with hepatitis B virus (HBV) and 23 with hepatitis C virus (HCV). All patients were staged as Barcelona Clinic Liver Cancer stage C, and 20 patients were classified as having Child–Pugh classification B (7). Nivolumab 20 mg was an independent prognostic factor for better PFS, and albumin-bilirubin grade 1 was the independent prognostic factor for superior OS in the multivariate analyses. Patients with better HBV (HBV DNA < 500 IU/ml) and HCV (HCV RNA undetectable) controls had superior OS. All AEs were grade 1–2 in severity, and all patients tolerated nivolumab without treatment interruption or dose adjustment. Additionally, 31 patients underwent subsequent therapy after nivolumab treatment.ConclusionLow-dose nivolumab may be effective with manageable toxicity and can be an alternative option to reduce financial toxicity in patients with advanced HCC who cannot afford the high cost of immune checkpoint inhibitors in real-world practice.

ODP068 A Case Report of Nivolumab Associated Hypercalcemia

Abstract Introduction Nivolumab is a human immunoglobulin G4 (IgG4) antibody which binds to programmed cell death receptor-1 (PD-1) and blocks the binding of PD-1 to either the PD-ligand 1 (PD-L1) or PD-L2 expressed on the surface of cancer cells. It has been approved for the treatment of melanoma, non-small cell lung cancer, renal cell carcinoma etc. Various endocrine immune-related adverse events including thyroiditis, hyper- and hypothyroidism, hypophysitis and type 1 diabetes has been described. We report a case of Nivolumab associated hypercalcemia. Case presentation 67-year-old female with history of CKD stage 3 with secondary hyperparathyroidism, melanoma of right ankle was admitted after one month of receiving the first dose of Nivolumab for her melanoma. She had altered mentation with elevated corrected calcium of 15.94(8.4-10.2) mg/dl. Prior calcium levels were in low to normal range, eGFR was 13, creatinine elevated at 3.4 (0.57-1.11) mg/dl, PTH 84 (10-65) pg/ml, 25 OH vitamin D 54 (30-74) ng/ml, Phosphorus normal, Magnesium normal, 1,25-OH vitamin D was elevated at 103(18-72) pg/ml, PTHrp normal, normal SPEP, normal TSH, no history of fractures, normal DXA, no history of kidney stones, not on any calcium supplements, not on thiazide or lithium. Chest x ray and NM full body PET CT did not show any evidence of granulomatous disease except for recurrence and metastasis of melanoma in right thigh, calf, and ankle. No family history of kidney stones or hypercalcemia. Patient was treated with IV fluids and Calcitonin. Her calcium quickly improved to 9.9 within 48 hours. Within 3 weeks of discharge, she was readmitted for elevated calcium of 14.4 mg/dl, creatinine 2.29 mg/dl, eGFR 21, PTH 96 pg/ml, Mg 1.8 (1.6-2.6) mg/dl. She was treated with IV fluids and calcitonin and calcium normalized within 48 hours. Parathyroid scan did not show any parathyroid adenoma. She was started on prednisone for possible Nivolumab associated immune adverse reaction. She was also briefly treated with cinacalcet which was discontinued. Prednisone was tapered and then stopped over the course of 6 weeks. Calcium remains normal. PTH remains slightly elevated which is thought to be due to secondary hyperparathyroidism from CKD. Normal cortisol level. Discussion This is likely a case of Nivolumab associated hypercalcemia given the onset soon after immunotherapy initiation and improvement with glucocorticoid therapy. Immunotherapy was not resumed after the first dose due to recurrent severe hypercalcemia. The patient is currently under surveillance for melanoma. Calcium level remains normal. Although it is rare, a few cases of Nivolumab associated hypercalcemia have been reported previously. Exact mechanism is not known but it has been speculated that macrophage activation by Nivolumab can cause increased level of 25(OH) D-hydroxylase with increased conversion of 25-OH vitamin D to 1,25-OH vitamin D resulting in calcitriol mediated hypercalcemia. Presentation: No date and time listed

Pancreatic involvement due to immune checkpoint inhibitors: a proposed classification.

Drug-induced acute pancreatitis (AP) is uncommon and pancreatic involvement due to immune checkpoint inhibitors (ICI) in published reports relied on the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE). CTCAE definition of AP differs from the revised Atlanta classification diagnostic criteria. This study aims to classify the spectrum of pancreatic involvement in patients receiving ICI therapy into categories built on the revised Atlanta classification. A retrospective cohort study of cancer patients receiving cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) inhibitors between 2011 and 2020. Pancreas-specific immune-related adverse events (irAEs) were categorized into AP and pancreatic injury. Forty-seven patients on ICI therapy met selection criteria. Twenty patients (43%) had AP, while 27 (57%) had pancreatic injury. Fifteen patients (75%) developed mild AP. Five patients progressed to pancreatic atrophy, and two patients (4%) developed exocrine pancreatic insufficiency. In both groups, most patients received nivolumab therapy (70% vs. 67%, p = 0.08) with no difference in mean number of nivolumab doses (9 vs. 10, p = 0.69). There was no correlation between the mean number of nivolumab or pembrolizumab doses and AP events (OR 0.94, p = 0.26, and OR 0.98, p = 0.86), but the duration of ICI therapy was significantly related to pancreatic atrophy (OR 1.01, p = 0.05; 95% CI 1.00-1.02). Based on the novel classification, majority of pancreatic irAEs were classified as asymptomatic pancreatic injury but with some risk of pancreatic atrophy. This classification can help in assessing patterns of pancreatic involvement, pathogenesis, and treatment decisions.

Sarcomatoid malignant pleural mesothelioma treated with nivolumab: A case series.

Immune checkpoint therapy (ICT) with nivolumab has been widely used to treat malignant pleural mesothelioma (MPM) since clinical trials confirmed its efficacy. However, only a few clinical trials have been conducted for the treatment of sarcomatoid MPM, which is a rare histological type of MPM. Additionally, clinical reports of sarcomatoid MPM are scarce. Therefore, the benefits and risks of nivolumab treatment for sarcomatoid MPM remain unclear. The present report describes the treatment of 3 cases of sarcomatoid MPM (all 3 were men) with nivolumab monotherapy. In all three cases, nivolumab was effective despite variations in the duration of treatment, although side effects were observed in 2 patients. Programmed death ligand 1 (PD-L1) expression was positive in all 3 cases. In particular, the patient with the highest PD-L1 expression had the most rapid response of the 3 patients, and the effect lasted as long as those of the other 2, despite receiving the smallest number of doses of nivolumab. It has been reported that sarcomatoid MPM tends to respond poorly to chemotherapy and express higher levels of PD-L1 than epithelial MPM; thus, ICT may be necessary in these cases. This case series suggests that ICT with nivolumab is a promising treatment option for sarcomatoid MPM.

P06.05.A Repeated intracranial administration of ipilimumab and nivolumab in patients with recurrent glioblastoma (rGB): A multi-cohort adaptive phase I clinical trial

Abstract Background Perioperative intracerebral (iCE) administration of ipilimumab (IPI) and nivolumab (NIVO) in combination with IV NIVO was shown to be feasible, safe and associated with an encouraging survival benefit (Duerinck et al. JITC 2021). In subsequent cohorts, combination of iCE administration with biweekly intracavitary (iCA, via an Ommaya reservoir) administration of increasing doses of IPI and NIVO was investigated. Methods Three cohorts were defined according to resectability and postoperative treatment schedule. Patients (pts) in cohort-A and -C underwent a maximal safe resection, pts in cohort-B stereotactic biopsy only. All pts received iCE administration of 10 mg NIVO and 5 mg IPI at the end of the surgical intervention, after which an OR was implanted and an additional 10mg of NIVO and IPI (1, 5 or 10 mg) was administered iCA in cohort-C. All pts received biweekly postoperative NIVO 10 mg IV and iCA administrations of NIVO (3 dose levels were investigated in cohorts-A and -B: 1, 5, or 10 mg) for up to a maximum of 24w postoperatively. In cohort-C, 10 mg of NIVO was complemented with IPI (1, 5, or 10 mg). NGS and RNA gene expression profiling was performed on all tissue samples. Results In total, 44 pts were included (A: n= 16, B: n= 16, C: n= 12 recruitment ongoing). All pts in cohort-A and -B are off study treatment. All pts received the predefined dose of iCE IPI/NIVO and at least one administration of the predefined iCA dose. AE were infrequent and mostly not immune-related. Most common AE were fatigue(n=37), headache(n=25), confusion(n=18) and postoperative fever(n=15). Bacterial colonization of the Ommaya port occurred in 6 pts, subacute neurological deterioration requiring corticosteroids in 8 pts. There were no grade 5 AEs. Median PFS was 13w for cohort-A, 5w in cohort-B and 13w in cohort-C. Median OS is 43weeks in A, 29w in B and is not yet reached in cohort-C after median follow-up of 23w. OS did not differ significantly between study cohorts. OS of pts who underwent surgical resection (cohorts-A and -C) compared favorably to a historical cohort of 469 Belgian patients with rGB (treated in three prospective phase II clinical trials and a large multicenter early acces program for bevacizumab). Conclusions iCE followed by repeated iCA administrations of increasing doses of NIVO with/without IPI in rGB is feasible and safe without dose limiting AEs. A potential survival benefit seems restricted to pts amenable to surgical resection.

LBA7 Neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer: The NICHE-2 study

Neoadjuvant immunotherapy has shown promising responses in several cancer types. For colon cancer (CC), NICHE was the first neoadjuvant immunotherapy study to show pathologic responses in 100% of dMMR tumors. Importantly, disease-free survival (DFS) in patients (pts) with stage III dMMR CC is similar to that of pMMR pts, with 3-year recurrence risks of over 40% in high-risk (T4 and/or N2) stage III tumors despite adjuvant chemotherapy. Improving outcome for this patient population is urgently needed. In the NICHE-2 study, pts with non-metastatic dMMR CC were treated with one dose of ipilimumab (1mg/kg) and two doses of nivolumab (3mg/kg) and underwent surgery ≤6 weeks of registration. The co-primary endpoints were safety (ITT) and 3-year DFS (PP). Secondary endpoints included major pathologic response (MPR) and complete response (pCR) rates. Pathologic response was defined as ≤50% residual viable tumor (RVT), and MPR as ≤10% RVT. Here we present safety and pathologic response data. A total of 112 pts were treated. Grade 3-4 immune-related adverse events were observed in 3 (3%) patients and only 3 pts experienced delay in surgery, meeting the safety primary endpoint. In the PP population (n=107), baseline radiologic assessment revealed 89% stage III, 77% high-risk stage III (Table), and 64% T4 tumors. With a median time from first dose to surgery of 5 weeks, pathologic response was observed in 106/107 (99%) pts, consisting of 102/107 (95%) MPR and 4 (4%) PR. PCR was observed in 72/107 (67%) pts. At a median follow-up of 13 months (range 1-57), none of the pts had disease recurrence.Table: LBA7Pathologic responseMPRpCRClinical stageI/II (n = 12)11 (92%)9 (75%)Low risk IIIa/b (n = 13)13 (100%)10 (77%)High risk IIIa/b (n = 17)16 (94%)10 (59%)High risk IIIc (n = 65)62 (95%)43 (66%)Total (n = 107)102 (95%)72 (67%) Open table in a new tab In NICHE-2 we confirm the previously reported pathologic responses to short-term neoadjuvant nivolumab plus ipilimumab in a large cohort of dMMR CC pts, with an MPR rate of 95%, including 67% pCR. The first survival data suggest a strong potential for neoadjuvant immunotherapy to become standard of care and allow further exploration of organ-sparing approaches.

LBA37 A randomized, multicentric phase II study of preoperative nivolumab plus relatlimab or nivolumab in patients with resectable non-small cell lung cancer (NEOpredict-Lung)

Preoperative immune checkpoint inhibitor therapy (PICIT) is a promising approach in curative treatment of non-small-cell lung cancer (NSCLC). This study explores the feasibility and efficacy of targeting PD-1 and LAG-3 prior to resection. Patients with histologically confirmed NSCLC stage IB, II or IIIA (UICC 8th edition) were randomized to receive two preoperative doses (q14d) of nivolumab (240 mg, arm A), or nivolumab (240 mg) plus relatlimab (80 mg, arm B). The primary study endpoint was the feasibility of curatively intended surgery within 43 days of start of PICIT. Secondary endpoints include pathological and radiological response rates, disease-free and overall survival rates (DFS, OS) and safety. Exploratory endpoints are addressed by translational research. From March 4, 2020 to July 15, 2022, 60 patients have been randomized. The primary endpoint was met by all patients. R0 resection rate was 98%, excluding 2 patients with pleural carcinosis, which had been undetected by preoperative imaging. PICIT-related adverse events were as expected with grade ≥ 3 events in 4 (arm A) and 2 (arm B) patients. Two patients treated in arm A died within 90 days of surgery. The 12 months OS rate across both arms was 96% (95% CI: 83-99%), the DFS rate was 91% (78-97%). Radiological response rates were 11% (arm A) and 27% (arm B) per RECIST (full population), and 41% (arm A) and 38% (B) per PERCIST (30 patients from one center). Complete or major histopathological response rates were 28% (arm A) and 32% (arm B). In 60% (arm A) and 71% (arm B) of resections after PICIT ≤ 50% vital tumor cells were observed.Table: LBA37Arm A (nivolumab)Arm B (nivolumab/relatlimab)n [female, male]30 (15, 15)30 (13, 17)Age [years] (median, range)64 (43-77)65 (43-81)Histology- adenocarcinoma1315- squamous109- adenosquamous22- other54UICC stage- I B910- II A61- II B1116- III A33- other10PD-L1 [TPS]- 0%89- 1-49%1215- ≥50%106 Open table in a new tab Preoperative immune checkpoint inhibition with nivolumab and relatlimab is safe and feasible in patients with curatively resectable NSCLC. High histopathological response rates indicate clinical efficacy, which merits further study supplementing with biomarker analyses for future patient selection.

Combined nivolumab and ipilimumab with or without stereotactic body radiation therapy for advanced Merkel cell carcinoma: a randomised, open label, phase 2 trial

Merkel cell carcinoma is among the most aggressive and lethal of primary skin cancers, with a high rate of distant metastasis. Anti-programmed death receptor 1 (anti-PD-1) and programmed death ligand 1 (PD-L1) monotherapy is currently standard of care for unresectable, recurrent, or metastatic Merkel cell carcinoma. We assessed treatment with combined nivolumab plus ipilimumab, with or without stereotactic body radiotherapy (SBRT) in patients with advanced Merkel cell carcinoma as a first-line therapy or following previous treatment with anti-PD-1 and PD-L1 monotherapy. In this randomised, open label, phase 2 trial, we randomly assigned adults from two cancer sites in the USA (one in Florida and one in Ohio) to group A (combined nivolumab and ipilimumab) or group B (combined nivolumab and ipilimumab plus SBRT) in a 1:1 ratio. Eligible patients were aged at least 18 years with histologically proven advanced stage (unresectable, recurrent, or stage IV) Merkel cell carcinoma, a minimum of two tumour lesions measureable by CT, MRI or clinical exam, and tumour tissue available for exploratory biomarker analysis. Patients were stratified by previous immune-checkpoint inhibitor (ICI) status to receive nivolumab 240 mg intravenously every 2 weeks plus ipilimumab 1 mg/kg intravenously every 6 weeks (group A) or the same schedule of combined nivolumab and ipilimumab with the addition of SBRT to at least one tumour site (24 Gy in three fractions at week 2; group B). Patients had to have at least two measurable sites of disease so one non-irradiated site could be followed for response. The primary endpoint was objective response rate (ORR) in all randomly assigned patients who received at least one dose of combined nivolumab and ipilimumab. ORR was defined as the proportion of patients with a complete response or partial response per immune-related Response Evaluation Criteria in Solid Tumours. Response was assessed every 12 weeks. Safety was assessed in all patients. This trial is registered with ClinicalTrials.gov, NCT03071406. 50 patients (25 in both group A and group B) were enrolled between March 14, 2017, and Dec 21, 2021, including 24 ICI-naive patients (13 [52%] of 25 group A patients and 11 [44%] of 25 group B patients]) and 26 patients with previous ICI (12 [48%] of 25 group A patients and 14 [56%] of 25 group B patients]). One patient in group B did not receive SBRT due to concerns about excess toxicity. Median follow-up was 14·6 months (IQR 9·1-26·5). Two patients in group B were excluded from the analysis of the primary endpoint because the target lesions were irradiated and so the patients were deemed non-evaluable. Of the ICI-naive patients, 22 (100%) of 22 (95% CI 82-100) had an objective response, including nine (41% [95% CI 21-63]) with complete response. Of the patients who had previously had ICI exposure, eight (31%) of 26 patients (95% CI 15-52) had an objective response and four (15% [5-36]) had a complete response. No significant differences in ORR were observed between groups A (18 [72%] of 25 patients) and B (12 [52%] of 23 patients; p=0·26). Grade 3 or 4 treatment-related adverse events were observed in 10 (40%) of 25 patients in group A and 8 (32%) of 25 patients in group B. First-line combined nivolumab and ipilimumab in patients with advanced Merkel cell carcinoma showed a high ORR with durable responses and an expected safety profile. Combined nivolumab and ipilimumab also showed clinical benefit in patients with previous anti-PD-1 and PD-L1 treatment. Addition of SBRT did not improve efficacy of combined nivolumab and ipilimumab. The combination of nivolumab and ipilimumab represents a new first-line and salvage therapeutic option for advanced Merkel cell carcinoma. Bristol Myers Squibb Rare Population Malignancy Program.

Safety and efficacy of first-line nivolumab plus ipilimumab alternating with nivolumab monotherapy in patients with advanced renal cell carcinoma: the non-randomised, open-label, phase IIIb/IV CheckMate 920 trial

ObjectivesThe non-randomised, open-label, phase IIIb/IV multicohort CheckMate 920 trial explored the safety and efficacy with a less frequent, but continual nivolumab plus ipilimumab (NIVO+IPI) dosing regimen (cohort 1) to determine...