Perioperative Nivolumab in Resectable Lung Cancer.

BACKGROUND: Standard treatment with neoadjuvant nivolumab plus chemotherapy significantly improves outcomes in patients with resectable non-small-cell lung cancer (NSCLC). Perioperative treatment (i.e., neoadjuvant therapy followed by surgery and adjuvant therapy) with nivolumab may further improve clinical outcomes. METHODS: In this phase 3, randomized, double-blind trial, we assigned adults with resectable stage IIA to IIIB NSCLC to receive neoadjuvant nivolumab plus chemotherapy or neoadjuvant chemotherapy plus placebo every 3 weeks for 4 cycles, followed by surgery and adjuvant nivolumab or placebo every 4 weeks for 1 year. The primary outcome was event-free survival according to blinded independent review. Secondary outcomes were pathological complete response and major pathological response according to blinded independent review, overall survival, and safety. RESULTS: At this prespecified interim analysis (median follow-up, 25.4 months), the percentage of patients with 18-month event-free survival was 70.2% in the nivolumab group and 50.0% in the chemotherapy group (hazard ratio for disease progression or recurrence, abandoned surgery, or death, 0.58; 97.36% confidence interval [CI], 0.42 to 0.81; P<0.001). A pathological complete response occurred in 25.3% of the patients in the nivolumab group and in 4.7% of those in the chemotherapy group (odds ratio, 6.64; 95% CI, 3.40 to 12.97); a major pathological response occurred in 35.4% and 12.1%, respectively (odds ratio, 4.01; 95% CI, 2.48 to 6.49). Grade 3 or 4 treatment-related adverse events occurred in 32.5% of the patients in the nivolumab group and in 25.2% of those in the chemotherapy group. CONCLUSIONS: Perioperative treatment with nivolumab resulted in significantly longer event-free survival than chemotherapy in patients with resectable NSCLC. No new safety signals were observed. (Funded by Bristol Myers Squibb; CheckMate 77T ClinicalTrials.gov number, NCT04025879.).

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.

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.

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.

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.

Nivolumab for mismatch-repair-deficient or hypermutated gynecologic cancers: a phase 2 trial with biomarker analyses.

Programmed death-1 (PD-1) inhibitors are approved for therapy of gynecologic cancers with DNA mismatch repair deficiency (dMMR), although predictors of response remain elusive. We conducted a single-arm phase 2 study of nivolumab in 35 patients with dMMR uterine or ovarian cancers. Co-primary endpoints included objective response rate (ORR) and progression-free survival at 24 weeks (PFS24). Secondary endpoints included overall survival (OS), disease control rate (DCR), duration of response (DOR) and safety. Exploratory endpoints included biomarkers and molecular correlates of response. The ORR was 58.8% (97.5% confidence interval (CI): 40.7-100%), and the PFS24 rate was 64.7% (97.5% one-sided CI: 46.5-100%), meeting the pre-specified endpoints. The DCR was 73.5% (95% CI: 55.6-87.1%). At the median follow-up of 42.1 months (range, 8.9-59.8 months), median OS was not reached. One-year OS rate was 79% (95% CI: 60.9-89.4%). Thirty-two patients (91%) had a treatment-related adverse event (TRAE), including arthralgia (n = 10, 29%), fatigue (n = 10, 29%), pain (n = 10, 29%) and pruritis (n = 10, 29%); most were grade 1 or grade 2. Ten patients (29%) reported a grade 3 or grade 4 TRAE; no grade 5 events occurred. Exploratory analyses show that the presence of dysfunctional (CD8+PD-1+) or terminally dysfunctional (CD8+PD-1+TOX+) T cells and their interaction with programmed death ligand-1 (PD-L1)+ cells were independently associated with PFS24. PFS24 was associated with presence of MEGF8 or SETD1B somatic mutations. This trial met its co-primary endpoints (ORR and PFS24) early, and our findings highlight several genetic and tumor microenvironment parameters associated with response to PD-1 blockade in dMMR cancers, generating rationale for their validation in larger cohorts.ClinicalTrials.gov identifier: NCT03241745 .

Checkpoint inhibitor immunotherapy induced inflammatory arthritis secondary to Nivolumab and Ipilimumab: a pediatric first.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have expanded the arsenal of cancer therapeutics over the last decade but are associated with a spectrum of immune-related adverse events (irAEs), including inflammatory arthritis. While these complications are increasingly recognized in the adult population, no cases of inflammatory arthritis irAEs have been reported in the pediatric literature. CASE PRESENTATION: A 14-year-old female with metastatic epithelioid mesothelioma was referred to the pediatric rheumatology clinic after developing progressive inflammatory joint pain in her bilateral shoulders, hips, and small joints of hands following the second cycle of Nivolumab and Ipilimumab. Initial examinations showed bilateral shoulder joint line tenderness, positive FABERs test bilaterally, tenderness over bilateral greater trochanters, and bilateral second PIP effusions. Her serological profile was notable for positive HLA-B27, positive anti-CCP, negative Rheumatoid Factor, and negative ANA. PET-CT scan performed for disease response following immunotherapy showed symmetric increased metabolic activity primarily involving the supraspinatus, gluteus medius and minimus, and semimembranosus tendon insertions. Her presentation was consistent with a grade 1 irAE that worsened to a grade 2 irAE despite NSAID therapy, prompting a short course of oral prednisolone. She achieved clinical remission of her mesothelioma following six cycles of Nivolumab and Ipilimumab and her inflammatory arthritis was controlled on Celebrex monotherapy. CONCLUSIONS: To our knowledge, this is the first pediatric case of ICI-induced inflammatory arthritis and enthesitis. This case highlights the importance of increasing awareness of diagnosis and management of irAEs in children.

Nivolumab-associated immune-related filamentary keratitis.

A woman in her late 50s presented to the ophthalmology clinic having bilateral eye pain and discharge for the last month. Her medical history was significant for lung adenocarcinoma, for which she was being treated with nivolumab. Filamentary keratitis was evident at the slit-lamp examination. Regardless of ophthalmic reasons, nivolumab was suspended. Prednisolone ointment was started, with a complete remission. We present a case of steroid-responsive filamentary keratitis triggered by nivolumab. We aim to highlight the importance of prompt ophthalmology referral and the use of therapies targeting ocular surface inflammation in immune checkpoint inhibition therapy.

Systemic Scleroderma Induced by Nivolumab in Malignant Melanoma.

BACKGROUND: Immunotherapy using immune checkpoint inhibitors is not devoid of immune-related adverse events (irAEs) including rheumatological conditions. CASE REPORT: We report a rare case of a 47-year-old woman with metastatic melanoma who developed systemic scleroderma after initiating nivolumab. The patient displayed inflammatory arthralgias, morning stiffness, and classical cutaneous manifestations of the disease. Clinical evaluations also revealed carpal tunnel syndrome, cardiac involvement, and dyspnea. RNA-Polymerase III antibodies were positive. Nivolumab, an anti-PD-1 antibody, was considered as a potential trigger for this condition. CONCLUSION: To our knowledge, this is the first case of nivolumab-induced systemic scleroderma in the context of melanoma described in the literature that fulfills the classification criteria of the disease. This case underscores the need for increased awareness of immune-related adverse events in patients receiving immune checkpoint inhibitors, emphasizing timely intervention and further research.

Adverse events of nivolumab plus ipilimumab versus nivolumab plus cabozantinib: a real-world pharmacovigilance study.

BACKGROUND: No head-to-head clinical trials have compared the differences in adverse events (AEs) between nivolumab plus ipilimumab (NIVO-IPI) and nivolumab plus cabozantinib (NIVO-CABO) in the treatment of metastatic renal cell carcinoma (mRCC). AIM: We analysed the two largest real-world databases, the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and the World Health Organization's VigiBase, to elucidate the differences in AEs between NIVO-IPI and NIVO-CABO. METHOD: In total, 40,376 and 38,022 records were extracted from FAERS and VigiBase, and 193 AEs were analysed. The reporting odds ratios (ROR) with 95% confidence interval were calculated using a disproportionality analysis (NIVO-CABO/NIVO-IPI). RESULTS: The reported numbers of immune-related AEs, including myocarditis, colitis, and hepatitis, were significantly higher with NIVO-IPI (ROR = 0.18 for FAERS and 0.13 for VigiBase). Contrarily, the reported numbers of other AEs, including gastrointestinal disorders (ROR = 2.68 and 2.92) and skin and subcutaneous tissue disorders (ROR = 2.94 and 3.55), considered to be potentiated by the combination of NIVO and CABO, were higher with NIVO-CABO. CONCLUSION: Our findings contribute to the selection and clinical management of NIVO-IPI and NIVO-CABO, which minimizes the risk of AEs for individual patients with mRCC by considering distinctive differences in the AE profiles.

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.

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.

Nivolumab-Induced Cytokine Release Syndrome: A Case Report and Literature Review.

BACKGROUND CRS (cytokine release syndrome) is a massive activation of the inflammatory system characterized by a supra-physiological rate of inflammatory cytokines. The interleukin 6 cytokine plays a central role in CRS. The main clinical sign of CRS is fever, but CRS can lead to multiple organ failure in severe cases. CRS is usually described in sepsis, more recently in SARS COV-2 infection, and in chimeric antigen receptor T-cell therapy. However, it can also be associated with immune checkpoint inhibitors (ICIs), which is infrequently described. ICI have growing indications and can lead to CRS by causing an uncontrolled activation of the immune system. There are currently no treatment guidelines for ICI-induced CRS. CASE REPORT We report a rare case of grade 3 CRS induced by nivolumab associated with 5-fluorouracil and oxaliplatin for gastric cancer. The patient was 65-year-old man with an adenocarcinoma of the cardia. CRS developed during the tenth course of treatment and was characterized by fever, hypotension requiring vasopressors, hypoxemia, acute kidney injury, and thrombopenia. The patient was transferred quickly to the Intensive Care Unit. He was treated for suspected sepsis, but it was ruled out after multiple laboratory examinations. There was rapid resolution after infusion of hydrocortisone. CONCLUSIONS The use of ICIs is expanding. Nivolumab-induced CRS is rarely described but can be severe and lead to multiple organ dysfunction; therefore, intensive care practitioners should be informed about this adverse effect. More studies are needed to better understand this condition and establish treatment guidelines.

Profound postinduction hypotension precipitated by immune checkpoint inhibitors: a case report.

BACKGROUND: With the increasing use of immune checkpoint inhibitors (ICIs) in cancer therapy, perioperative healthcare professionals need to be vigilant about potential immune-related adverse events (irAEs). We report a case of severe postinduction hypotension in a patient undergoing laparotomy due to suspected intraabdominal bleeding from gastric cancer and Krukenberg tumors, caused by unrecognized hypothyroidism precipitated by ICIs. CASE PRESENTATION: A 65-year-old Chinese female with a history of gastric adenocarcinoma and Krukenberg tumors, previously treated with nivolumab, presented to the emergency room with abdominal pain and hypotension. Despite ruling out other causes, including hypovolemia and anaphylaxis, her hypotension persisted. The patient was found to have severe hypothyroidism, likely an irAE from the use of nivolumab. Thyroxine replacement therapy resolved the hypotension, and the patient recovered uneventfully after surgery. CONCLUSIONS: This case underscores the importance of considering irAEs, such as hypothyroidism, in patients treated with ICIs. Perioperative healthcare providers must remain vigilant for potential complications and promptly recognize and manage irAEs to optimize patient outcomes.

A phase Ib study evaluating the recommended phase II dose, safety, tolerability, and efficacy of mivavotinib in combination with nivolumab in advanced solid tumors.

Mivavotinib (TAK-659/CB-659), a dual SYK/FLT3 inhibitor, reduced immunosuppressive immune cell populations and suppressed tumor growth in combination with anti-PD-1 therapy in cancer models. This dose-escalation/expansion study investigated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of mivavotinib plus nivolumab in patients with advanced solid tumors. Patients received oral mivavotinib 60-100 mg once-daily plus intravenous nivolumab 3 mg/kg on days 1 and 15 in 28-day cycles until disease progression or unacceptable toxicity. The dose-escalation phase evaluated the recommended phase II dose (RP2D; primary endpoint). The expansion phase evaluated overall response rate (primary end point) at the RP2D in patients with triple-negative breast cancer (TNBC). During dose-escalation (n = 24), two dose-limiting toxicities (grade 4 lipase increased and grade 3 pyrexia) occurred in patients who received mivavotinib 80 mg and 100 mg, respectively. The determined RP2D was once-daily mivavotinib 80 mg plus nivolumab 3 mg/kg. The expansion phase was terminated at ~50% enrollment (n = 17) after failing to meet an ad hoc efficacy futility threshold. Among all 41 patients, common treatment-emergent adverse events (TEAEs) included dyspnea (48.8%), aspartate aminotransferase increased, and pyrexia (46.3% each). Common grade ≥3 TEAEs were hypophosphatemia and anemia (26.8% each). Mivavotinib plasma exposure was generally dose-proportional (60-100 mg). One patient had a partial response. Mivavotinib 80 mg plus nivolumab 3 mg/kg was well tolerated with no new safety signals beyond those of single-agent mivavotinib or nivolumab. Low response rates highlight the challenges of treating unresponsive tumor types, such as TNBC, with this combination and immunotherapies in general. TRIAL REGISTRATION ID: NCT02834247.

Neoadjuvant Dual Checkpoint Inhibitors vs Anti-PD1 Therapy in High-Risk Resectable Melanoma: A Pooled Analysis.

Importance: Despite the clear potential benefits of neoadjuvant therapy, the optimal neoadjuvant regimen for patients with high-risk resectable melanoma (HRRM) is not known. Objective: To compare the safety and efficacy of dual checkpoint inhibitors with anti-programmed cell death protein-1 (anti-PD1) therapy in a neoadjuvant setting among patients with HRRM. Design, Setting, and Participants: In this pooled analysis of clinical trials, studies were selected provided they investigated immune checkpoint inhibitor treatment, were published between January 2018 and March 2023, and were phase 1, 2, or 3 clinical trials. Participant data included in the analysis were derived from trials evaluating the efficacy and safety of anti-PD1 monotherapy and the combination of anti-cytotoxic T lymphocyte-associated protein-4 with anti-PD1 in the neoadjuvant setting, specifically among patients with HRRM. Interventions: Patients were treated with either anti-PD1 monotherapy; dual checkpoint inhibition (DCPI) with a conventional dose of 3-mg/kg ipilimumab and 1-mg/kg nivolumab; or DCPI with an alternative-dose regimen of 1-mg/kg ipilimumab and 3-mg/kg nivolumab. Main Outcomes and Measures: The main outcomes were radiologic complete response (rCR), radiologic overall objective response (rOOR), and radiologic progressive disease. Also, pathologic complete response (pCR), the proportion of patients undergoing surgical resection, and occurrence of grade 3 or 4 immune-related adverse events (irAEs) were considered. Results: Among 573 patients enrolled in 6 clinical trials, neoadjuvant therapy with DCPI was associated with higher odds of achieving pCR compared with anti-PD1 monotherapy (odds ratio [OR], 3.16; P < .001). DCPI was associated with higher odds of grade 3 or 4 irAEs compared with anti-PD1 monotherapy (OR, 3.75; P < .001). When comparing the alternative-dose ipilimumab and nivolumab (IPI-NIVO) regimen with conventional-dose IPI-NIVO, no statistically significant difference in rCR, rOOR, radiologic progressive disease, or pCR was noted. However, the conventional-dose IPI-NIVO regimen was associated with increased grade 3 or 4 irAEs (OR, 4.76; P < .001). Conventional-dose IPI-NIVO was associated with greater odds of achieving improved rOOR (OR, 1.95; P = .046) and pCR (OR, 2.99; P < .001) compared with anti-PD1 monotherapy. The alternative dose of IPI-NIVO also was associated with higher odds of achieving rCR (OR, 2.55; P = .03) and pCR (OR, 3.87; P < .001) compared with anti-PD1 monotherapy. The risk for grade 3 or 4 irAEs is higher with both the conventional-dose (OR, 9.59; P < .001) and alternative-dose IPI-NIVO regimens (OR, 2.02; P = .02) compared with anti-PD1 monotherapy. Conclusion and Relevance: In this pooled analysis of 6 clinical trials, although DCPI was associated with increased likelihood of achieving pathological and radiologic responses, the associated risk for grade 3 or 4 irAEs was significantly lower with anti-PD1 monotherapy in the neoadjuvant setting for HRRM. Additionally, compared with alternative-dose IPI-NIVO, the conventional dose of IPI-NIVO was associated with increased risk for grade 3 or 4 irAEs, with no significant distinctions in radiologic or pathologic efficacy.

Phase 1b study of intraperitoneal ipilimumab and nivolumab in patients with recurrent gynecologic malignancies with peritoneal carcinomatosis.

BACKGROUND: Intravenous immune checkpoint blockade (ICB) has shown poor response rates in recurrent gynecologic malignancies. Intraperitoneal (i.p.) ICB may result in enhanced T cell activation and anti-tumor immunity. METHODS: In this phase 1b study, registered at Clinical. TRIALS: gov (NCT03508570), initial cohorts received i.p. nivolumab monotherapy, and subsequent cohorts received combination i.p. nivolumab every 2 weeks and i.p. ipilimumab every 6 weeks, guided by a Bayesian design. The primary objective was determination of the recommended phase 2 dose (RP2D) of the combination. Secondary outcomes included toxicity, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). FINDINGS: The trial enrolled 23 patients: 18 with ovarian cancer, 2 with uterine cancer, and 3 with cervical cancer. Study evaluable patients (n = 16) received a median of 2 prior lines of therapy (range: 1-8). Partial response was observed in 2 patients (12.5%; 1 ovarian, 1 uterine), and complete response was observed in 1 patient (6.3%) with cervical cancer, for an ORR of 18.8% (95% confidence interval: 4.0%-45.6%). The median duration of response was 14.8 months (range: 4.1-20.8), with one complete response ongoing. Median PFS and OS were 2.7 months and not reached, respectively. Grade 3 or higher immune-related adverse events occurred in 2 (8.7%) patients. CONCLUSIONS: i.p. administration of dual ICB is safe and demonstrated durable responses in a subset of patients with advanced gynecologic malignancy. The RP2D is 3 mg/kg i.p. nivolumab every 2 weeks plus 1 mg/kg ipilimumab every 6 weeks. FUNDING: This work was funded by Bristol Myers Squibb (CA209-9C7), an MD Anderson Cancer Center Support Grant (CA016672), the Ovarian Cancer Moon Shots Program, the Emerson Collective Fund, and a T32 training grant (CA101642).

Immune Checkpoint Inhibitor-Associated Kelch-Like Protein-11 IgG Brainstem Encephalitis.

OBJECTIVES: Kelch-like protein-11 (KLHL11)-IgG is associated with rhombencephalitis and seminoma. It has not previously been described as a neurologic immune checkpoint inhibitor (ICI)-related adverse event (nirAE) or in association with esophageal adenocarcinoma. METHODS: We describe a 61-year-old man with metastatic esophageal adenocarcinoma treated with folinic acid, fluorouracil, oxaliplatin (FOLFOX), and nivolumab, who subsequently developed diplopia, vertigo, and progressive gait ataxia after 8 weeks of treatment. RESULTS: Owing to a concern for ICI-associated myasthenia gravis, nivolumab was held and he was treated with prednisone and pyridostigmine. EMG showed no neuromuscular junction dysfunction, and acetylcholine-receptor antibodies were negative. Brain MRI was unrevealing. Murine brain tissue immunofluorescence assay revealed KLHL11-IgG in both serum and CSF, confirmed by cell-based assay. Tumor histopathology demonstrated poorly differentiated, highly proliferative adenocarcinoma with increased mitotic figures and cytoplasmic KLHL11 immunoreactivity. He was initiated on 6 months of cyclophosphamide in addition to FOLFOX for post-ICI-associated KLHL11-IgG rhombencephalitis. DISCUSSION: We report KLHL11-IgG rhombencephalitis associated with poorly differentiated esophageal cancer as a novel nirAE. Tumor staining revealed KLHL11 immunoreactivity, supporting a cancer-antigen-driven ICI-associated paraneoplastic syndrome. Recognition of novel nirAEs can expedite treatment and potentially prevent progressive neurologic disability.