Neoadjuvant Immunotherapy in Locally Advanced Mismatch Repair-Deficient Colon Cancer.

BACKGROUND: Mismatch repair-deficient (dMMR) tumors can be found in 10 to 15% of patients with nonmetastatic colon cancer. In these patients, the efficacy of chemotherapy is limited. The use of neoadjuvant immunotherapy has shown promising results, but data from studies of this approach are limited. METHODS: We conducted a phase 2 study in which patients with nonmetastatic, locally advanced, previously untreated dMMR colon cancer were treated with neoadjuvant nivolumab plus ipilimumab. The two primary end points were safety, defined by timely surgery (i.e., ≤2-week delay of planned surgery owing to treatment-related toxic events), and 3-year disease-free survival. Secondary end points included pathological response and results of genomic analyses. RESULTS: Of 115 enrolled patients, 113 (98%; 97.5% confidence interval [CI], 93 to 100) underwent timely surgery; 2 patients had surgery delayed by more than 2 weeks. Grade 3 or 4 immune-related adverse events occurred in 5 patients (4%), and none of the patients discontinued treatment because of adverse events. Among the 111 patients included in the efficacy analysis, a pathological response was observed in 109 (98%; 95% CI, 94 to 100), including 105 (95%) with a major pathological response (defined as ≤10% residual viable tumor) and 75 (68%) with a pathological complete response (0% residual viable tumor). With a median follow-up of 26 months (range, 9 to 65), no patients have had recurrence of disease. CONCLUSIONS: In patients with locally advanced dMMR colon cancer, neoadjuvant nivolumab plus ipilimumab had an acceptable safety profile and led to a pathological response in a high proportion of patients. (Funded by Bristol Myers Squibb; NICHE-2 ClinicalTrials.gov number, NCT03026140.).

Time-dependent efficacy analysis of first-line immunotherapies for advanced non-small cell lung cancer.

BACKGROUND: Many randomized controlled trials (RCTs) and network meta-analyses have demonstrated that the progression-free survival (PFS) and overall survival (OS) of advanced non-small cell lung cancer (NSCLC) patients can be improved through combination immunotherapy or monotherapies. However, time-dependent analysis of the treatment effect is currently lacking. Thus, we aimed to evaluate the efficacy of first-line immunotherapy, and establish a hazard ratio function to reflect the time-varying progression or mortality risk of patients with NSCLC. METHODS: Seventeen clinical trials were selected based on search strategy. Baseline characteristics, including the age, sex, smoking status, geographical region, and Eastern Cooperative Oncology Group (ECOG) performance status of patients, were balanced, resulting in ten immunotherapies from nine appropriate clinical trials to conduct treatment effect comparison. RESULTS: We found that nivolumab plus ipilimumab (nivo + ipi) improved the PFS and OS over time. The hazard ratio of nivo + ipi, relative to that of pembrolizumab, decreased from 1.11 to 0.36 for PFS, and from 0.93 to 0.49 for OS over a 10-year period. In terms of the response to immunotherapy in patients with different PD-L1 expression levels, patients with PD-L1 > = 50% experienced lower rates of progression and a reduced mortality risk over time. The hazard ratio of patients with PD-L1 > = 50% relative to all of the patients decreased from 0.73 to 0.69 for PFS, and from 0.78 to 0.67 for OS. CONCLUSIONS: Based on the fact that time-dependent progression and mortality risk existed during the treatment duration, physicians should select a suitable treatment regimen for patients based on the hazard ratio.

Nivolumab plus ipilimumab combination therapy in patients with advanced hepatocellular carcinoma previously treated with sorafenib: 5-year results from CheckMate 040.

BACKGROUND: Nivolumab plus ipilimumab demonstrated promising clinical activity and durable responses in sorafenib-treated patients with advanced hepatocellular carcinoma (HCC) in the CheckMate 040 study at 30.7-month median follow-up. Here, we present 5-year results from this cohort. PATIENTS AND METHODS: Patients were randomized 1 : 1 : 1 to arm A [nivolumab 1 mg/kg plus ipilimumab 3 mg/kg Q3W (four doses)] or arm B [nivolumab 3 mg/kg plus ipilimumab 1 mg/kg Q3W (four doses)], each followed by nivolumab 240 mg Q2W, or arm C (nivolumab 3 mg/kg Q2W plus ipilimumab 1 mg/kg Q6W). The primary objectives were safety, tolerability, investigator-assessed objective response rate (ORR), and duration of response (DOR) per RECIST version 1.1. RESULTS: A total of 148 patients were randomized across treatment arms. At 60-month minimum follow-up (62.6-month median follow-up), the ORR was 34% (n = 17), 27% (n = 13), and 29% (n = 14) in arms A, B, and C, respectively. The median DOR was 51.2 months [95% confidence interval (CI) 12.6 months-not estimable (NE)], 15.2 months (95% CI 7.1 months-NE), and 21.7 months (95% CI 4.2 months-NE), respectively. The median overall survival (OS) was 22.2 months (34/50; 95% CI 9.4-54.8 months) in arm A, 12.5 months (38/49; 95% CI 7.6-16.4 months) in arm B, and 12.7 months (40/49; 95% CI 7.4-30.5 months) in arm C; 60-month OS rates were 29%, 19%, and 21%, respectively. In an exploratory analysis of OS by response (6-month landmark), the median OS was meaningfully longer for responders versus nonresponders for all arms. No new safety signals were identified with longer follow-up. There were no new discontinuations due to immune-mediated adverse events since the primary analysis. CONCLUSIONS: Consistent with the primary analysis, the arm A regimen of nivolumab plus ipilimumab continued to demonstrate clinically meaningful responses and long-term survival benefit, with no new safety signals in patients with advanced HCC following sorafenib treatment, further supporting its use as a second-line treatment in these patients.

Case report: Strong GAD antibody positivity and type 1 diabetes-HLA-susceptible haplotype-DRB1*04:05-DQB1*04:01 in a Japanese patient with immune checkpoint inhibitor-induced type 1 diabetes.

Immune checkpoint inhibitors (ICIs) are widely used in cancer treatment; however, they can lead to immune-related adverse events, including immune checkpoint inhibitor-induced type 1 diabetes mellitus (ICI-T1DM). While fulminant T1DM is common in East Asia, ICI-T1DM has predominantly been reported in Western countries. In this report, we present the case of a 66-year-old Japanese man with type 2 diabetes mellitus undergoing dialysis for diabetic nephropathy. The patient was diagnosed with left upper lobe lung cancer, and treatment with nivolumab and ipilimumab was initiated. After 48 days, the patient experienced impaired consciousness and difficulty moving. His blood glucose levels were 815 mg/dL, and metabolic acidosis was detected, leading to a diagnosis of diabetic ketoacidosis. The patient was subsequently treated with continuous intravenous insulin. However, his C-peptide levels rapidly depleted, and new-onset ICI-T1DM was diagnosed. Although most Japanese patients with ICI-T1DM test negative for glutamic acid decarboxylase (GAD) antibodies, this case exhibited a strong positivity. Thus, we reviewed the literature on 15 similar Japanese cases, revealing a mean HbA1c level at onset of 8.7% and a mean time from ICI administration to onset of 9.7 weeks, which was shorter than that in GAD-negative cases. Moreover, human leukocyte antigen typing revealed five cases of DRB1*04:05-DQB1*04:01, including the present case, and one case of DRB1*09:01-DQB1*03:03, both of which were susceptible to T1DM haplotypes. These findings suggest that GAD antibody positivity may be associated with acute onset and disease progression in some cases of Japanese patients with ICI-T1DM. Given that the prediction of new-onset ICI-T1DM is challenging, monitoring GAD antibody levels might be useful. However, further studies with large sample sizes and validation across different racial and ethnic populations are warranted.

Nivolumab plus chemotherapy or ipilimumab versus chemotherapy in patients with advanced esophageal squamous cell carcinoma (CheckMate 648): 29-month follow-up from a randomized, open-label, phase III trial.

BACKGROUND: First-line nivolumab plus chemotherapy and nivolumab plus ipilimumab both demonstrated significant overall survival (OS) benefit versus chemotherapy in previously untreated patients with advanced esophageal squamous cell carcinoma (ESCC) in the CheckMate 648 trial, leading to approvals of both nivolumab-containing regimens in many countries. We report longer-term follow-up data. METHODS: This open-label, phase III trial (NCT03143153) enrolled adults with previously untreated, unresectable, advanced, recurrent, or metastatic ESCC. Patients were randomized 1:1:1 to nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy. Primary endpoints were OS and progression-free survival (PFS) by blinded independent central review. Hierarchical testing was performed first in patients with tumor cell programmed death ligand 1 (PD-L1) expression of ≥1% and then in the overall population. RESULTS: A total of 970 patients were randomly assigned. After 29 months of minimum follow-up, nivolumab plus chemotherapy continued to demonstrate improvement in OS versus chemotherapy (hazard ratio [HR] = 0.59 [95% CI: 0.46-0.76]) in patients with tumor cell PD-L1 expression of ≥1% and in the overall population (HR = 0.78 [95% CI: 0.65-0.93]) and with nivolumab plus ipilimumab versus chemotherapy (HR = 0.62 [95% CI: 0.48-0.80]) in patients with tumor cell PD-L1 expression of ≥1% and in the overall population (HR = 0.77 [95% CI: 0.65-0.92]). In patients with tumor cell PD-L1 expression of ≥1%, nivolumab plus chemotherapy demonstrated PFS benefit versus chemotherapy (HR = 0.67 [95% CI: 0.51-0.89]); PFS benefit was not observed with nivolumab plus ipilimumab versus chemotherapy (HR = 1.04 [95% CI: 0.79-1.36]). Among all treated patients (n = 936), Grade 3-4 treatment-related adverse events were reported in 151 (49%, nivolumab plus chemotherapy), 105 (32%, nivolumab plus ipilimumab), and 110 (36%, chemotherapy) patients. CONCLUSIONS: Nivolumab plus chemotherapy and nivolumab plus ipilimumab continued to demonstrate clinically meaningful OS benefit versus chemotherapy with no new safety signals identified with longer follow-up, further supporting use as first-line standard treatment options for patients with advanced ESCC.

Evaluating the efficacy and safety of nivolumab and ipilimumab combination therapy compared to nivolumab monotherapy in advanced cancers (excluding melanoma): a systemic review and meta-analysis.

BACKGROUND: Nivolumab (Nivo) and ipilimumab (Ipi) have revolutionized cancer treatment by targeting different pathways. Their combination shows promising results in various cancers, including melanoma, but not all studies have demonstrated significant benefits. A meta-analysis was performed to assess the effectiveness and safety of Nivo-Ipi compared to Nivo alone in advanced cancer types (excluding melanoma). METHODS: Following PRISMA guidelines, we conducted a meta-analysis up to September 30, 2023, searching databases for randomized controlled trials (RCTs). We focused on advanced solid malignancies (excluding melanoma) with specific Nivo and Ipi dosing. Primary outcomes were overall survival (OS), progression-free survival (PFS), grades 3-4 adverse events (AEs), and treatment-related discontinuations. Secondary outcomes included specific adverse events. Statistical analysis in Review Manager included hazard ratio (HR) and risk ratio (RR), assessing heterogeneity (Higgins I2). RESULTS: Nine RCTs, involving 2152 patients covering various malignancies, were analyzed. The Nivo plus Ipi group exhibited a median OS of 12.3 months and a median PFS of 3.73 months, compared to monotherapy with 11.67 months and 3.98 months, respectively. OS showed no significant difference between Nivo and Ipi combination and Nivo alone (HR = 0.97, 95% CI: 0.88 to 1.08, p = 0.61). PFS had a slight improvement with combination therapy (HR = 0.91, 95% CI: 0.82 to 1.00, p = 0.04). Treatment-related cumulative grades 3-4 adverse events were higher with Nivo and Ipi (RR = 1.52, 95% CI: 1.30 to 1.78, p < 0.00001), as were treatment-related discontinuations (RR = 1.99, 95% CI: 1.46 to 2.70, p < 0.0001). Hepatotoxicity (RR = 2.42, 95% CI: 1.39 to 4.24, p = 0.002), GI toxicity (RR = 2.84, 95% CI: 1.44 to 5.59, p = 0.002), pneumonitis (RR = 2.29, 95% CI: 1.24 to 2.23, p = 0.008), dermatitis (RR = 2.96, 95% CI: 1.08 to 8.14, p = 0.04), and endocrine dysfunction (RR = 6.22, 95% CI: 2.31 to 16.71, p = 0.0003) were more frequent with Nivo and Ipi. CONCLUSIONS: Combining nivolumab and ipilimumab did not significantly improve overall survival compared to nivolumab alone in advanced cancers (except melanoma). However, it did show slightly better PFS at the cost of increased toxicity, particularly grades 3-4 adverse events. Specific AEs occurred more frequently in the combination group. Further trials are needed to fully assess this combination in treating advanced cancers.

Distinct autoantibody profiles across checkpoint inhibitor types and toxicities.

Immune checkpoint inhibitors (ICI) are increasingly used in combination. To understand the effects of different ICI categories, we characterized changes in circulating autoantibodies in patients enrolled in the E4412 trial (NCT01896999) of brentuximab vedotin (BV) plus ipilimumab, BV plus nivolumab, or BV plus ipilimumab-nivolumab for Hodgkin Lymphoma. Cycle 2 Day 1 (C2D1) autoantibody levels were compared to pre-treatment baseline. Across 112 autoantibodies tested, we generally observed increases in ipilimumab-containing regimens, with decreases noted in the nivolumab arm. Among 15 autoantibodies with significant changes at C2D1, all nivolumab cases exhibited decreases, with more than 90% of ipilimumab-exposed cases showing increases. Autoantibody profiles also showed differences according to immune-related adverse event (irAE) type, with rash generally featuring increases and liver toxicity demonstrating decreases. We conclude that dynamic autoantibody profiles may differ according to ICI category and irAE type. These findings may have relevance to clinical monitoring and irAE treatment.

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.

BACKGROUND: Patients 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. METHODS: The 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. DISCUSSION: From 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 REGISTRATION: ClinicalTrials.gov ID NCT05652673, registration date: 08-12-2022.

Case report: Durable complete response of a mucosal melanoma of the rectum after neoadjuvant immunotherapy with ipilimumab plus nivolumab.

Melanoma causes the majority of skin cancer-related deaths. Despite novel therapy options, metastatic melanoma still has a poor prognosis. Immune checkpoint inhibition (ICI) therapy has been shown to prolong overall survival in patients with advanced melanoma, but mucosal melanomas respond less favorably compared to melanomas of cutaneous origin. We report on a patient with a mucosal melanoma of the rectum diagnosed in June 2020. Since a surgical intervention in order to achieve a tumor-free situation would have required an amputation of the rectum, a neo-adjuvant systemic immunotherapy with ipilimumab and nivolumab was initiated. As restaging and colonoscopy after four doses of this combination immunotherapy showed a partial response, the patient decided against the pre-planned surgery and a maintenance therapy with nivolumab was started. Repeated colonoscopy showed a complete response after four doses of nivolumab. After ongoing ICI therapy with nivolumab and no evidence of tumor relapse, immunotherapy was stopped in July 2022 after nearly 2 years of continuous treatment. The patient remained tumor-free during further follow-up. Neo-adjuvant immunotherapy is getting more explored in advanced melanoma. By administering ICI therapy before surgical resection of an essentially operable tumor, a stronger and more diverse immunological response is supposed to be achieved. Our reported case demonstrates that this approach could also be effective in mucosal melanoma despite of its generally lower response to immunotherapy.

Prognostic impact of FAN score in patients receiving nivolumab plus ipilimumab for metastatic renal cell carcinoma.

FAN score is reportedly associated with prognostic outcomes in patients with urothelial carcinoma being treated with immune check point inhibitors. However, the prognostic impact of pre-treatment FAN score in patients with metastatic renal cell carcinoma (RCC) treated with nivolumab plus ipilimumab remains unclear. We retrospectively evaluated the association between pre-treatment FAN score and prognostic outcomes in 154 patients with metastatic RCC treated with nivolumab plus ipilimumab. The pre-treatment FAN score was '0' in 56 patients (36%), '1' in 60 patients (40%), '2' in 37 patients (24%) and '3' in one patient (1%). Progression-free survival was not significantly different between patients with different FAN scores, but second progression-free survival (PFS2), cancer-specific survival (CSS) and overall survival (OS) were significantly different. In multivariable Cox proportional hazard analyses, FAN score ≥ 2 was a significant predictor of poor PFS2 (vs. FAN score 0, HR: 2.43, 95% CI 1.21-4.87, P = 0.01), poor CSS (vs. FAN score 0, HR: 2.71, 95% CI 1.13-6.47, P = 0.02) and poor OS (vs. FAN score 0, HR: 2.42, 95% CI 1.11-5.25, P = 0.02). High pre-treatment FAN score could be a significant independent predictor of poor prognosis in patients receiving nivolumab plus ipilimumab for metastatic RCC.

Efficacy of dual checkpoint inhibitors in a patient with a mixed hepatocellular cholangiocarcinoma.

A woman in her 60s was diagnosed with a metastatic, unresectable rare histological type of liver cancer; combined hepatocellular cholangiocarcinoma. She had palliative chemotherapy, initially with gemcitabine and cisplatin, and then with oxaliplatin, L-folinic acid and fluorouracil. Both treatment strategies demonstrated disease progression, and somatic mutation profiling revealed no actionable mutations. The patient was started on immuno-oncology (IO) with nivolumab and ipilimumab, followed by maintenance nivolumab. She has achieved a sustained ongoing partial response since the start of this therapy for at least 12 months. The outcome in this patient is in keeping with the growing evidence of the role that IO agents have in metastatic biliary tract cancer and also serves to highlight their importance in mixed histology liver tumours.

ELISA assay for the quantification of ipilimumab in human serum, plasma, milk, and cerebrospinal fluid.

Ipilimumab is an immune checkpoint inhibitor of the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Ipilimumab has become part of the standard of care for different types of cancer. The efficacy of these treatments is limited due to immune-related toxicity and high economic costs. Dose rationalization studies based on pharmacokinetic data may help to address these limitations. For this purpose, more sensitive analytical methods are needed. We report the development and validation of the first enzyme-linked immunosorbent assay (ELISA) for sensitive determination of ipilimumab concentrations in human serum, plasma, cerebrospinal fluid (CSF), and milk. Our assay is based on the specific capture of ipilimumab by immobilized CTLA-4. The lower limit of quantifications of ipilimumab in serum, plasma, and milk are 50 ng/mL and 10 ng/mL in CSF. The ELISA method showed long-term storage stability for at least one year at -80°C and was successfully cross-validated with ultraperformance liquid chromatography coupled with tandem mass spectrometry. The ELISA method is reliable, relatively inexpensive, and can be used in serum, plasma, CSF, and milk from patients treated with ipilimumab, as evidenced by the analysis of real clinical samples.

Immune checkpoint inhibitor-induced hypophysitis with transient ACTH-dependent hypercortisolism.

A woman in her 70s with metastatic melanoma presenting with refractory hypokalaemia on combined immune checkpoint inhibitors, nivolumab-ipilimumab, was diagnosed with adrenocorticotropic hormone (ACTH)-dependent hypercortisolism 11 weeks following the initiation of her immunotherapy. Investigations also demonstrated central hypothyroidism and hypogonadotropic hypogonadism. She underwent imaging studies of her abdomen and brain which revealed normal adrenal glands and pituitary, respectively. She was started on levothyroxine replacement and had close pituitary function monitoring. Two weeks later, her cortisol and ACTH levels started to trend down. She finally developed secondary adrenal insufficiency and was started on hydrocortisone replacement 4 weeks thereafter.This report highlights a case of immunotherapy-related hypophysitis with well-documented transient central hypercortisolism followed, within weeks, by profound secondary adrenal insufficiency. Healthcare professionals should remain vigilant in monitoring laboratory progression in these patients. Early recognition of the phase of hypercortisolism and its likely rapid transformation into secondary adrenal insufficiency can facilitate timely hormonal replacement and prevent complications.

Comparison of Cabozantinib and Axitinib as Second-line Therapy After Nivolumab Plus Ipilimumab in Patients With Metastatic Clear Cell Renal Cell Carcinoma: A Comparative Analysis of Retrospective Real-world Data.

BACKGROUND: To date, no studies have compared the treatment outcomes of second-line therapies in patients with metastatic clear cell renal cell carcinoma (ccRCC). This study retrospectively evaluated the efficacy of cabozantinib and axitinib as second-line treatments in patients with metastatic ccRCC who previously received immune-oncology combination therapy. PATIENTS AND METHODS: Patients with metastatic ccRCC treated with cabozantinib and axitinib as second-line therapy after nivolumab-ipilimumab treatment were identified among 243 patients with RCC treated between August 1, 2018 and January 31, 2022 at 34 institutions belonging to the Japanese Urological Oncology Group. Patients were assessed for treatment outcomes, including progression-free survival (PFS), overall survival, objective response rate (ORR), and incidence rate of treatment-related adverse events (AEs). RESULTS: Forty-eight patients treated with cabozantinib and 60 treated with axitinib as second-line therapy after nivolumab-ipilimumab treatment for metastatic ccRCC were identified. The median PFS (95% confidence interval) was 11.0 months (9.0-16.0) with cabozantinib and 9.5 months (6.0-13.0) with axitinib. The ORRs were 37.5% (cabozantinib) and 38.3% (axitinib). The rates of any-grade AEs and grade ≥3 AEs were 79.2% (cabozantinib) versus 63.3% (axitinib; P = .091) and 35.4% (cabozantinib) versus 23.3% (axitinib; P = .202), respectively. In the poor-risk group, PFS was longer in the cabozantinib group than in the axitinib group (P = .033). CONCLUSION: The efficacy and safety of cabozantinib and axitinib were comparable. In the poor-risk group, cabozantinib was more effective than axitinib. These findings provide valuable insights into the selection of second-line treatment options after nivolumab-ipilimumab treatment in patients with metastatic ccRCC.

Treatment-free survival outcomes from the phase II study of nivolumab and salvage nivolumab/ipilimumab in advanced clear cell renal cell carcinoma (HCRN GU16-260-Cohort A).

BACKGROUND: As part of a partitioned survival analysis, treatment-free survival (TFS) can characterize the overall survival time patients spend between the cessation of immunotherapy and the start of subsequent therapy; both with and without toxicity. Significant TFS was reported for the nivolumab/ipilimumab arms of the CheckMate 067 and 214 trials for patients with advanced melanoma or renal cell carcinoma (aRCC), respectively, where immunotherapy was often halted for toxicity rather than a predefined treatment endpoint. We therefore sought to assess TFS in the HCRN GU16-260 trial, which was designed to reduce toxicity and cap immunotherapy duration. METHODS: Data were analyzed from 128 patients with clear-cell aRCC treated with first-line nivolumab monotherapy for up to 2 years. Salvage nivolumab/ipilimumab for up to 1 year was provided to eligible patients with disease progression at any point or stable disease at 48 weeks (29% of patients). TFS was defined as the area between Kaplan-Meier curves for a time from registration to protocol therapy cessation and for a time from registration to subsequent systemic therapy initiation or death, estimated from 36-month mean times. The time on or off protocol treatment with grade 3+treatment-related adverse events (TRAEs) was also captured. RESULTS: At 36 months from enrollment, 68.3% of patients were alive: 96.8% of International Metastatic RCC Database Consortium (IMDC) favorable-risk patients and 56.6% of those with intermediate/poor-risk, respectively. The 36-month mean time on protocol therapy was 11.5 months including 0.6 months with grade 3+TRAEs (16.0 months for favorable-risk patients and 9.6 months for intermediated/poor-risk patients). The 36-month mean TFS for the whole population was 9.4 months (12.9 months including 1.5 months with grade 3+TRAEs for favorable-risk and 8.0 months including 1.0 months with grade 3+TRAEs for intermediate/poor-risk). At 36 months, 65.6% of favorable-risk patients and 27.1% of intermediate/poor-risk patients were alive and subsequent systemic treatment-free. CONCLUSIONS: Nivolumab monotherapy with salvage nivolumab/ipilimumab in non-responders is an active treatment approach in treatment-naïve patients with aRCC and, similar to nivolumab/ipilimumab in CheckMate 214, results in substantial TFS and toxicity-free TFS. TFS was greatest in patients with favorable-risk disease, supporting the use of an immunotherapy-only regimen in this population.

Successful treatment of immune checkpoint inhibitor-related periaortitis.

We report a 64-year-old patient with melanoma receiving ipilimumab and nivolumab therapy who presented with a periaortic soft tissue mass around the abdominal aorta on restaging fluorodeoxyglucose positron emission tomography/computed tomography imaging. Clinical, laboratory, and radiologic findings resulted in a diagnosis of immune checkpoint inhibitor-related periaortitis. Periaortitis is a rare disease presenting with fibro-inflammatory tissue around the aorta and may lead to serious complications. Immune checkpoint inhibitors were discontinued, and the patient was treated with glucocorticoids, leading to a complete resolution of the periaortitis. To our knowledge, this is only the third reported case of immune checkpoint inhibitor-related periaortitis.

Binimetinib in combination with nivolumab or nivolumab and ipilimumab in patients with previously treated microsatellite-stable metastatic colorectal cancer with RAS mutations in an open-label phase 1b/2 study.

BACKGROUND: In patients with previously treated RAS-mutated microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), a multicenter open-label phase 1b/2 trial was conducted to define the safety and efficacy of the MEK1/MEK2 inhibitor binimetinib in combination with the immune checkpoint inhibitor (ICI) nivolumab (anti-PD-1) or nivolumab and another ICI, ipilimumab (anti-CTLA4). METHODS: In phase 1b, participants were randomly assigned to Arm 1A (binimetinib 45 mg twice daily [BID] plus nivolumab 480 mg once every 4 weeks [Q4W]) or Arm 1B (binimetinib 45 mg BID plus nivolumab 480 mg Q4W and ipilimumab 1 mg/kg once every 8 weeks [Q8W]) to determine the maximum tolerable dose (MTD) and recommended phase 2 dose (RP2D) of binimetinib. The MTD/RP2D was defined as the highest dosage combination that did not cause medically unacceptable dose-limiting toxicities in more than 35% of treated participants in Cycle 1. During phase 2, participants were randomly assigned to Arm 2A (binimetinib MTD/RP2D plus nivolumab) or Arm 2B (binimetinib MTD/RP2D plus nivolumab and ipilimumab) to assess the safety and clinical activity of these combinations. RESULTS: In phase 1b, 21 participants were randomized to Arm 1A or Arm 1B; during phase 2, 54 participants were randomized to Arm 2A or Arm 2B. The binimetinib MTD/RP2D was determined to be 45 mg BID. In phase 2, no participants receiving binimetinib plus nivolumab achieved a response. Of the 27 participants receiving binimetinib, nivolumab, and ipilimumab, the overall response rate was 7.4% (90% CI: 1.3, 21.5). Out of 75 participants overall, 74 (98.7%) reported treatment-related adverse events (AEs), of whom 17 (22.7%) reported treatment-related serious AEs. CONCLUSIONS: The RP2D binimetinib regimen had a safety profile similar to previous binimetinib studies or nivolumab and ipilimumab combination studies. There was a lack of clinical benefit with either drug combination. Therefore, these data do not support further development of binimetinib in combination with nivolumab or nivolumab and ipilimumab in RAS-mutated MSS mCRC. TRIAL REGISTRATION: NCT03271047 (09/01/2017).

Facial palsy after administration of immune checkpoint inhibitors: case report, literature review and clinical care management.

Neurological immune-related adverse events (irAEs) due to immune checkpoint inhibitors (ICI) are rare complications of immunotherapy, particularly dreadful for patients and clinical teams. Indeed, neurological irAEs are potentially severe and their diagnosis require prompt recognition and treatment. Additionally, the spectrum of neurological irAEs is broad, affecting either neuromuscular junction, peripheral or central nervous system. Here, we described the case of a 55-year man with metastatic melanoma, facing a brutal right peripheral cerebral palsy after his third ipilimumab/nivolumab infusion. After the case presentation, we reviewed the literature about this rare complication of immunotherapy, and described its diagnosis work-up and clinical management.

Neoadjuvant in Situ and Systemic Immunotherapy with Lymph Node Cryoablation in Resectable Stage III Melanoma Metastasis: a Proof-of-Concept Study.

PURPOSE: Complete lymph node dissection is the recommended treatment for clinically detectable lymph nodes in stage III melanoma. This surgery is associated with substantial morbidity. We hypothesize that combining percutaneous imaging-guided cryoablation of locoregional lymph nodes metastases with neoadjuvant in situ and systemic immunotherapy could allow disease control and evaluate the feasibility of this combination in this proof-of-concept study. METHODS: We enrolled 15 patients with stage IIIB/IIIC melanoma. Patients were treated as follows: a single 240 mg flat dose infusion of nivolumab on day 1, cryoablation under local anesthesia using CT on day 2, and a single intralesional injection of 10-20 mg of ipilimumab into the lymphadenopathy treated by cryotherapy on day 3. Five-eight weeks after this procedure, complete lymph node dissection was performed according to routine care. The primary outcome measure of this study was feasibility, measured as the number of failures (i.e., inability to complete the entire procedure). RESULTS: The procedure was carried out successfully in 15 out of 15 patients with an observed number of failures of 0. The Bayesian analysis showed an estimated failure rate of 4.2% [0.2-20.6]. Eight patients (53%) had adverse events secondary to either immunotherapy or cryotherapy. Grade 3/4 events occurred in three patients, but all resolved quickly and patients could proceed to surgery as scheduled. Eight patients (53%) had a pathological complete or near complete response. CONCLUSION: Combining percutaneous cryotherapy with in situ ipilimumab and systemic nivolumab for stage III resectable melanoma is feasible with tolerable toxicity.

Nivolumab with or without ipilimumab in patients with recurrent or metastatic cervical cancer (CheckMate 358): a phase 1-2, open-label, multicohort trial.

BACKGROUND: In preliminary findings from the recurrent or metastatic cervical cancer cohort of CheckMate 358, nivolumab showed durable anti-tumour responses, and the combination of nivolumab plus ipilimumab showed promising clinical activity. Here, we report long-term outcomes from this cohort. METHODS: CheckMate 358 was a phase 1-2, open-label, multicohort trial. The metastatic cervical cancer cohort enrolled patients from 30 hospitals and cancer centres across ten countries. Female patients aged 18 years or older with a histologically confirmed diagnosis of squamous cell carcinoma of the cervix with recurrent or metastatic disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and up to two previous systemic therapies were enrolled into the nivolumab 240 mg every 2 weeks group, the randomised groups (nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks [NIVO3 plus IPI1] or nivolumab 1 mg/kg every 3 weeks plus ipilimumab 3 mg/kg every 3 weeks for four cycles then nivolumab 240 mg every 2 weeks [NIVO1 plus IPI3]), or the NIVO1 plus IPI3 expansion group. All doses were given intravenously. Patients were randomly assigned (1:1) to NIVO3 plus IPI1 or NIVO1 plus IPI3 via an interactive voice response system. Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal, or for up to 24 months. The primary endpoint was investigator-assessed objective response rate. Anti-tumour activity and safety were analysed in all treated patients. This study is registered with ClinicalTrials.gov (NCT02488759) and is now completed. FINDINGS: Between October, 2015, and March, 2020, 193 patients were recruited in the recurrent or metastatic cervical cancer cohort of CheckMate 358, of whom 176 were treated. 19 patients received nivolumab monotherapy, 45 received NIVO3 plus IPI1, and 112 received NIVO1 plus IPI3 (45 in the randomised group and 67 in the expansion group). Median follow-up times were 19·9 months (IQR 8·2-44·8) with nivolumab, 12·6 months (7·8-37·1) with NIVO3 plus IPI1, and 16·7 months (7·2-27·5) with pooled NIVO1 plus IPI3. Objective response rates were 26% (95% CI 9-51; five of 19 patients) with nivolumab, 31% (18-47; 14 of 45 patients) with NIVO3 plus IPI1, 40% (26-56; 18 of 45 patients) with randomised NIVO1 plus IPI3, and 38% (29-48; 43 of 112 patients) with pooled NIVO1 plus IPI3. The most common grade 3-4 treatment-related adverse events were diarrhoea, hepatic cytolysis, hyponatraemia, pneumonitis, and syncope (one [5%] patient each; nivolumab group), diarrhoea, increased gamma-glutamyl transferase, increased lipase, and vomiting (two [4%] patients each; NIVO3 plus IPI1 group), and increased lipase (nine [8%] patients) and anaemia (seven [6%] patients; pooled NIVO1 plus IPI3 group). Serious treatment-related adverse events were reported in three (16%) patients in the nivolumab group, 12 (27%) patients in the NIVO3 plus IPI1 group, and 47 (42%) patients in the pooled NIVO1 plus IPI3 group. There was one treatment-related death due to immune-mediated colitis in the NIVO1 plus IPI3 group. INTERPRETATION: Nivolumab monotherapy and nivolumab plus ipilimumab combination therapy showed promise in the CheckMate 358 study as potential treatment options for recurrent or metastatic cervical cancer. Future randomised controlled trials of nivolumab plus ipilimumab or other dual immunotherapy regimens are warranted to confirm treatment benefit in this patient population. FUNDING: Bristol Myers Squibb and Ono Pharmaceutical.