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.

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.

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.

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.

Clinical outcomes of adjuvant nivolumab in resected stage III melanoma: comparison of CheckMate 238 trial and real-world data.

OBJECTIVES: Nivolumab is approved as adjuvant therapy for resected stage III/IV melanoma based on the phase 3 CheckMate 238 trial. This analysis compared outcomes from CheckMate 238 with those from the real-world Flatiron Health electronic health record-derived de-identified database in patients with resected stage III melanoma (per AJCC-8) treated with adjuvant nivolumab. MATERIALS: Outcomes included baseline characteristics, overall survival (OS) in the CheckMate 238 cohort (randomization until death or last known alive), and real-world overall survival (rwOS) in the Flatiron Health cohort (nivolumab initiation until death or data cutoff). rwOS was compared with OS using unadjusted and adjusted Cox proportional hazards models. Inverse probability of treatment weighting (IPTW) was combined with the adjusted model to reduce baseline discrepancies. RESULTS: The CheckMate 238 and real-world cohorts included 369 and 452 patients, respectively (median age, 56.0 and 63.0 years; median follow-up, 61.4 vs. 25.5 months). rwOS was not different from OS in the unadjusted (hazard ratio [HR] 1.27; 95% CI 0.92-1.74), adjusted (HR 1.01; 95% CI 0.67-1.54), and adjusted IPTW (HR 1.07; 95% CI 0.70-1.63) analyses. In the adjusted analysis, 2-year OS and rwOS rates were 84%. Median OS and rwOS were not reached. After IPTW, OS and rwOS were not different (HR 1.07; 95% CI 0.70-1.64). CONCLUSIONS: In this comparative analysis, OS in the CheckMate 238 trial was similar to rwOS in the Flatiron Health database after adjustments in patients with resected stage III melanoma (per AJCC-8) treated with adjuvant nivolumab, validating the trial results.

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.

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.).

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.

[A Case of Conversion Surgery for Unresectable Advanced Gastric Cancer of Which Metastatic Site Was Disappear by Chemotherapy but the Primary Site Was Enlarged after Five Years].

A 77-year-old man presented to our hospital with a chief complaint of stomachache. He received a diagnosis of unresectable advanced gastric cancer classified as cT3, N+, M1(LYM, HEP, OSS), Stage ⅣB. He underwent first-line chemotherapy with SOX, second-line treatment with PTX plus Ram, and third-line treatment with nivolumab. The primary tumor showed a reduction in size, and liver and lymph node metastases were not detectable. However, after 5 years of chemotherapy, a re- enlargement was observed in the primary gastric lesion without progression of liver and lymph node metastases. Subsequently, conversion surgery was performed. Based on the pathological analysis, the diagnosis was ypT1b2(SM2), N0(0/17), M0, ypStage ⅠA, R0. After nivolumab administration postoperatively for 5 months, chemotherapy was discontinued as there was no recurrence.

Therapeutic Advances and Challenges for the Management of HPV-Associated Oropharyngeal Cancer.

The use of conventional chemotherapy in conjunction with targeted and immunotherapy drugs has emerged as an option to limit the severity of side effects in patients diagnosed with head and neck cancer (HNC), particularly oropharyngeal cancer (OPC). OPC prevalence has increased exponentially in the past 30 years due to the prevalence of human papillomavirus (HPV) infection. This study reports a comprehensive review of clinical trials registered in public databases and reported in the literature (PubMed/Medline, Scopus, and ISI web of science databases). Of the 55 clinical trials identified, the majority (83.3%) were conducted after 2015, of which 77.7% were performed in the United States alone. Eight drugs have been approved by the FDA for HNC, including both generic and commercial forms: bleomycin sulfate, cetuximab (Erbitux), docetaxel (Taxotere), hydroxyurea (Hydrea), pembrolizumab (Keytruda), loqtorzi (Toripalimab-tpzi), methotrexate sodium (Trexall), and nivolumab (Opdivo). The most common drugs to treat HPV-associated OPC under these clinical trials and implemented as well for HPV-negative HNC include cisplatin, nivolumab, cetuximab, paclitaxel, pembrolizumab, 5-fluorouracil, and docetaxel. Few studies have highlighted the necessity for new drugs specifically tailored to patients with HPV-associated OPC, where molecular mechanisms and clinical prognosis are distinct from HPV-negative tumors. In this context, we identified most mutated genes found in HPV-associated OPC that can represent potential targets for drug development. These include TP53, PIK3CA, PTEN, NOTCH1, RB1, FAT1, FBXW7, HRAS, KRAS, and CDKN2A.

Protocol for a phase II study to evaluate the efficacy and safety of nivolumab as a postoperative adjuvant therapy for patients with esophageal cancer treated with preoperative docetaxel, cisplatin plus 5-fluorouracil treatment (PENTAGON trial).

BACKGROUND: In Japan, preoperative adjuvant chemotherapy followed by surgical resection is the standard treatment for patients with locally advanced esophageal squamous cell carcinoma. However, the risk of recurrence after surgical resection remains high. Although a randomized controlled trial evaluating the efficacy of nivolumab, a fully human monoclonal anti-programmed death 1 antibody, as postoperative adjuvant therapy after neoadjuvant chemoradiotherapy and surgery established its superior efficacy as adjuvant therapy, the efficacy for patients who received preoperative adjuvant chemotherapy has not been demonstrated. This study aims to elucidate the efficacy and safety of nivolumab as postoperative adjuvant therapy for patients with esophageal squamous cell carcinoma after preoperative adjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil followed by surgical resection. METHODS: This study is a multi-institutional, single-arm, Phase II trial. We plan to recruit 130 esophageal squamous cell carcinoma patients, who have undergone preoperative adjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil followed by surgical resection. If the patient did not have a pathological complete response, nivolumab is started as a postoperative adjuvant therapy within 4-16 weeks after surgery. The nivolumab dose is 480 mg/day every four weeks. Nivolumab is administered for up to 12 months. The primary endpoint is disease-free survival; the secondary endpoints are overall survival, distant metastasis-free survival, and incidence of adverse events. DISCUSSION: To our knowledge this study is the first trial establishing the efficacy of nivolumab as postoperative adjuvant therapy for patients with esophageal squamous cell carcinoma after preoperative adjuvant chemotherapy with docetaxel and cisplatin plus 5-fluorouracil followed by surgical resection. In Japan, preoperative adjuvant chemotherapy followed by surgery is a well-established standard treatment for resectable, locally advanced esophageal squamous cell carcinoma. Therefore, developing an effective postoperative adjuvant therapy has been essential for improving oncological outcomes.

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.

Understanding and overcoming resistance to immunotherapy in genitourinary cancers.

The introduction of novel immunotherapies has significantly transformed the treatment landscape of genitourinary (GU) cancers, even becoming the standard of care in some settings. One such type of immunotherapy, immune checkpoint inhibitors (ICIs) like nivolumab, ipilimumab, pembrolizumab, and atezolizumab play a pivotal role by disturbing signaling pathways that limit the immune system's ability to fight tumor cells. Despite the profound impact of these treatments, not all tumors are responsive. Recent research efforts have been focused on understanding how cancer cells manage to evade the immune response and identifying the possible mechanisms behind resistance to immunotherapy. In response, ICIs are being combined with other treatments to reduce resistance and attack cancer cells through multiple cellular pathways. Additionally, novel, targeted strategies are currently being investigated to develop innovative methods of overcoming resistance and treatment failure. This article presents a comprehensive overview of the mechanisms of immunotherapy resistance in GU cancers as currently described in the literature. It explores studies that have identified genetic markers, cytokines, and proteins that may predict resistance or response to immunotherapy. Additionally, we review current efforts to overcome this resistance, which include combination ICIs and sequential therapies, novel insights into the host immune profile, and new targeted therapies. Various approaches that combine immunotherapy with chemotherapy, targeted therapy, vaccines, and radiation have been studied in an effort to more effectively overcome resistance to immunotherapy. While each of these combination therapies has shown some efficacy in clinical trials, a deeper understanding of the immune system's role underscores the potential of novel targeted therapies as a particularly promising area of current research. Currently, several targeted agents are in development, along with the identification of key immune mediators involved in immunotherapy resistance. Further research is necessary to identify predictors of response.

Immunotherapy has transformed the treatment landscape for many cancer types, including genitourinary malignancies such as renal and bladder cancers.However, not all patients or tumor types, such as prostate cancer, respond to this type of treatment.Understanding the mechanisms of immunotherapy resistance is critical for developing strategies to overcome these challenges.Primary resistance, which is present at the onset of treatment, can bedue to genetic abnormalities or immune system dysregulation. These factors alter the interactions between host cells and cancer cells.Adaptive resistance develops during therapy due to dynamic changes in the levels of growth factors, cytokines, and the tumor microenvironment (TME).Acquired resistance mainly occurs at the genetic and translational levels, involving the downregulation of critical human leukocyte antigen (HLA) molecules and interference with mutational repair.Future therapies may focus on detailed genetic profiling of patients to guide treatment selection and on the use of immune profile monitoring to assist in assessing responsiveness, alongside developing novel targeted therapies and ICIs.Further research is needed to identify predictors of response to ICIs.

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.

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).

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.

[A Case of Advanced Gastric Cancer Treated with Conversion Surgery followed by Nivolumab Combination Chemotherapy].

The use of nivolumab as first-line therapy for unresectable advanced gastric cancer has now become a standard practice, and its efficacy has been established. This is the first report of a patient with advanced gastric cancer who underwent conversion surgery after first-line nivolumab combination chemotherapy. The patient was a 58-year-old woman. Her medical history included hypertension and dyslipidemia. She had advanced gastric cancer with extensive lymph node metastasis in the left supraclavicular fossa and around the abdominal aorta. After confirming the HER2-negative status and the PD-L1 CPS score to be ≥5, nivolumab was administered in combination with chemotherapy. After the treatment, she underwent a total gastrectomy with D2 dissection, combined splenectomy and pancreatic tail resection for adhesions, and para-aortic lymph node sampling as a conversion surgery. There was no obvious cancerous remnant in the resected specimen, and the pathological response was Grade 3. The patient was alive and recurrence-free at 4 months postoperatively.