Giant cell arteritis and therapeutic response: a dual facet of immunotherapy in metastatic clear cell renal carcinoma.

Immune checkpoint inhibitors have emerged as a promising cancer treatment, allowing significant and long-term therapeutic responses. Nivolumab, an anti-programmed cell death protein-1, is one of the molecules of this therapeutic class with known and manageable side effects. Giant cell arteritis is a rare immune-related adverse event most often manifested by headaches poorly released by common antalgics and can result in visual loss. We report its occurrence in an 80-year-old patient on maintenance nivolumab for metastatic clear cell renal carcinoma. Prompt diagnosis and initiation of glucocorticoid therapy led to symptom improvement and visual recovery.

Major response of a peritoneal mesothelioma to nivolumab and ipilimumab: a case report, molecular analysis and review of literature.

Malignant peritoneal mesothelioma (MPM) is a rare tumor associated with a poor prognosis and a lack of consensus regarding treatment strategies. While the Checkmate 743 trial demonstrated the superiority of first-line nivolumab and ipilimumab over chemotherapy in malignant pleural mesothelioma (MPlM), few studies have assessed the effectiveness of immunotherapy against MPM, due to its rarity. Here, we report a major and sustained 12-month response in a 74-year-old female patient who received the anti-PD-1 nivolumab and the anti-CTLA4 ipilimumab as first-line therapy for diffuse MPM. PD-L1 was expressed and BAP1 expression was lost, as shown by immunohistochemistry, however the BAP1 gene was not mutated. Our findings suggest a role for ICI in non-resectable diffuse MPM exhibiting PD-L1 overexpression and loss of BAP1 expression, and instill new hope in their treatment. To our knowledge, this is the second reported case of dual immunotherapy used as first-line in MPM with a major clinical response. To investigate the clinical outcome, we conducted additional molecular analyses of the MPM tumor and we reviewed the literature on immunotherapy in MPM to discuss the role of PD-L1 and BAP1.

Functional status and quality of life in older patients with advanced esophageal squamous cell cancer receiving second-line nivolumab ± ipilimumab therapy: A post hoc analysis of the phase 2, multicenter RAMONA study.

INTRODUCTION: The phase 2 RAMONA study demonstrated that second-line nivolumab ± ipilimumab immunotherapy was feasible and effective in older patients with advanced esophageal squamous cell cancer (ESCC). Here, we presented results from functional status (FS) and quality-of-life (QoL) analyses. MATERIALS AND METHODS: Patients aged ≥65 years with advanced ESCC and disease progression following first-line therapy were enrolled for study treatment with nivolumab ± ipilimumab. Geriatric assessments (GA) consisting of G8 and GoGo/SlowGo evaluation, and quality of life (QoL) assessments with EORTC QLQ-C30 questionnaires were conducted at baseline and during the treatment. A post hoc analysis was performed to compare therapy efficacy, toxicity, and QoL between age groups (≥70 years vs. <70 years) and functionality groups (G8 > 14 vs. ≤14 and GoGo vs. SlowGo). RESULTS: In 66 treated patients with a median age of 70.5 years, older patients had non-inferior overall survival and tumor response compared to younger patients, with no increased treatment-related adverse events. Fitter patients (G8 > 14, GoGo) had a clinically, yet not statistically significant, survival advantage than less fit patients (G8 ≤ 14, SlowGo) patients. Moreover, FS by G8 and GoGo/SlowGo significantly correlated with QoL. Overall, QoL was impaired at baseline but remained stable in all scales over the course of immunotherapy. DISCUSSION: The administration of nivolumab ± ipilimumab second-line immunotherapy in older patients with ESCC did not show age-dependent effects and maintained QoL. GA could identify functional deficits and limitations of QoL and should be implemented in the context of immunotherapy. CLINICALTRIALS: gov: NCT03416244.

Nivolumab plus chemotherapy in patients with HER2-negative, previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: 3-year follow-up of the ATTRACTION-4 randomized, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Nivolumab + chemotherapy is now a standard of care for HER2-negative, previously untreated, unresectable or recurrent gastric/gastroesophageal junction cancer (advanced gastric cancer), but long-term follow-up data of clinical trials are limited. METHODS: ATTRACTON-4 was a phase 3, double-blind, placebo-controlled trial in Japan, South Korea, and Taiwan. Patients were randomized to either nivolumab or placebo, both combined with the physician's choice of SOX (oral S-1 [tegafur-gimeracil-oteracil potassium] + oxaliplatin) or CAPOX (capecitabine + oxaliplatin). We report the primary endpoints-centrally assessed progression-free survival (PFS) and overall survival (OS)-and landmark analyses of OS among patients alive using 3-year follow-up data. RESULTS: At the cutoff date (May 10, 2021), 17/359 patients in the nivolumab + chemotherapy group and 6/358 in the placebo + chemotherapy group were continuing study treatment. PFS (centrally assessed) was longer in the nivolumab + chemotherapy group (median 10.94 vs. 8.48 months; hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.55-0.82). Although OS did not differ between the two groups (median 17.45 vs. 17.15 months; HR 0.89, 95% CI 0.75-1.05), the landmark analysis of OS, calculating HRs at each landmark time point (every month), was getting numerically better in the nivolumab + chemotherapy group over time. Approximately 80% of patients who achieved complete response in the nivolumab + chemotherapy group were alive at 3 years. No new safety signals or major late-onset select treatment-related adverse events were observed for nivolumab + chemotherapy. CONCLUSION: This 3-year follow-up of ATTRACTION-4 confirmed the long-term clinical benefit and manageable safety of nivolumab + chemotherapy in patients with previously untreated advanced gastric cancer. TRIAL REGISTRATION: NCT02746796.

Prognostic value of type of prior TKI in pretreated metastatic renal cell carcinoma patients receiving nivolumab.

Aim: To define the prognostic significance of first-line TKI in mRCC patients receiving nivolumab.Materials and methods: A total of 571 mRCC patients who received ≥second line nivolumab were included in this subanalysis. The correlation between prior TKI (sunitinib vs. pazopanib) and overall response rate (ORR), disease control rate, progression-free survival and overall survival were investigated. Additionally, the impact of TKI choice according to the International Metastatic RCC Database Consortium prognostic score was examined.Results: There was no significant difference between sunitinib and pazopanib groups in terms of mPFS, mOS, overall response rate and disease control rate. Moreover, no difference between sunitinib and pazopanib was found according to the International Metastatic RCC Database Consortium prognostic score.Conclusion: There is no conclusive evidence favoring pazopanib or sunitinib treatment before initiating nivolumab therapy in metastatic renal cell carcinoma patients.

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A Case of Cholangitis as a Nivolumab-Induced Immune-Related Adverse Event in a Patient with Pulmonary Metastasis After Surgery for Oral Cancer.

We report a case of cholangitis, an immune-related adverse event (irAE), caused by the administration of nivolumab in a patient with lung metastasis of oral cancer. A 72-year-old man developed pulmonary metastasis after surgery for oral cancer. Hepatic enzyme abnormalities were observed after the second session of treatment, and irAE cholangitis was diagnosed based on the results of the blood test results and endoscopy findings. We suggested steroid treatment, but the patient refused it. Therefore, he was treated with ursodeoxycholic acid. The cholangitis gradually deteriorated, the patients' general condition worsened, and he died 169 days after the onset of cholangitis.

Efficacy of timing­dependent infusion of nivolumab in patients with advanced gastric cancer.

Although an association exists between the timing of immune checkpoint inhibitor (ICI) administration and therapeutic efficacy in several types of cancer, to the best of our knowledge, no reports exist regarding this relationship in gastric cancer (GC). The present study aimed to evaluate the optimal timing of ICI (nivolumab) administration in patients with advanced GC. A total of 58 consecutive patients with advanced GC who received nivolumab monotherapy after ≥2 chemotherapy regimens were retrospectively evaluated. These patients were divided into two groups according to the median time of nivolumab administration: i) Early-timing and (ii) late-timing groups, and the efficacy was assessed in both groups. The early-timing group had significantly longer overall survival (OS) than the late-timing group [median OS 8.2 months; 95% confidence interval (CI), 4.2-12.9 vs. median OS 5.4 months; 95% CI, 3.6-6.1]. Moreover, patients in the early-timing group had significantly longer progression-free survival (PFS) than those in the late-timing group (median PFS 2.6 months; 95% CI, 1.3-3.9 months vs. median PFS 1.6 months; 95% CI, 0.9-2.1 months). Furthermore, univariate analysis showed that early timing, immune-related adverse events and nonsteroidal anti-inflammatory drug administration were associated with longer OS and PFS. Cutoff Finder analysis revealed that the optimal timing of nivolumab administration for achieving better outcomes was before 12:06 p.m. Nivolumab administration in the morning, especially before 12:06 p.m., had a better clinical impact on patients with advanced GC.

A Rare Case of Metastatic Adrenal Melanoma.

Metastatic melanoma presents a significant clinical challenge, characterized by its aggressive nature and propensity to spread to multiple organ systems. Despite advances in detection and treatment, managing metastatic disease remains complex. Here, we present the case of a 43-year-old male with metastatic melanoma displaying an unusual pattern of involvement, affecting the adrenal gland, liver, spleen, and bones. The diagnostic process was intricate, involving atypical hormonal profiles and a negative BRAF status, necessitating a comprehensive approach for accurate characterization and treatment selection. Immunotherapy demonstrated efficacy but also highlighted the emergence of immune-related adverse events, notably hyperglycemia. This case discusses the heterogeneous nature of metastatic melanoma and underscores the importance of a multidisciplinary approach, close monitoring, and consideration of evolving treatment strategies in its management.

Nivolumab-Induced Diabetic Ketoacidosis: A Case Report.

Nivolumab, an investigational monoclonal antibody targeting a specific immune pathway, has shown promise in treating various autoimmune diseases. However, like other immunomodulatory agents, it has potential side effects. This case report describes a rare adverse event of nivolumab-induced diabetic ketoacidosis (DKA) in a patient with a history of adrenal insufficiency secondary to nivolumab. The patient presented with symptoms of hyperglycemia, metabolic acidosis, and ketosis after receiving nivolumab therapy for 12 cycles. Prompt recognition and management of nivolumab-induced DKA are crucial to prevent complications and ensure patient safety.

Cabozantinib plus ipilimumab/nivolumab in patients with previously treated advanced differentiated thyroid cancer.

BACKGROUND: This investigator-initiated phase II trial aimed to evaluate the efficacy of cabozantinib in combination with nivolumab and ipilimumab (CaboNivoIpi) in previously treated patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) (NCT03914300). METHODS: Eligible patients with RAI-refractory DTC who progressed on 1 prior line of VEGFR-targeted therapy received a 2-week run-in of cabozantinib monotherapy followed by CaboNivoIpi for 4 cycles (cycle length = 6 weeks), followed by cabozantinib plus nivolumab (cycle length = 4 weeks) until disease progression. The primary endpoint was objective response rate (ORR) within the first 6 months of treatment. A Simon optimal 2-stage design allowed for an interim analysis after accrual of 10 evaluable patients. At least 5 responses were needed to proceed to stage 2. RESULTS: Among 11 patients enrolled, the median age was 69 years. Prior VEGFR-targeted therapies included lenvatinib, pazopanib, and sorafenib plus everolimus. Median follow-up was 7.9 months. Among 10 evaluable patients, ORR within the first 6 months of treatment was 10% (1 partial response). Median progression-free survival was 9 months [95% CI: 3.0, not reached] and median overall survival was 19.2 months [(95% CI: 4.6, not reached]. Grade 3/4 treatment-related adverse events (AEs) were noted in 55% (6/11) and grade 5 AEs in 18% (2/11) of patients. The most common treatment-related AE was hypertension. The study did not reach its prespecified efficacy threshold. CONCLUSION: CaboNivoIpi had low ORRs and a high rate of grade ≥3 treatment-related AEs. CLINICAL TRIAL REGISTRATION: NCT03914300.

Immune checkpoint inhibitors and the orbit; two cases of reactive dacryoadenitis.

Immune checkpoints refer to mechanisms entrusted with the modulation of immune responses in peripheral tissues and are required for minimising collateral damage. Immune checkpoint inhibitors (ICPi) work through numerous pathways, including the anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), anti-PD-1 (programmed cell death protein 1) and the PD-L1 (protein cell death protein-ligand-1) pathways. They are proving to be an exciting therapeutic avenue in the attempt to activate anti-tumour activity. Ipilimumab is a fully human monoclonal antibody working on the anti-CTLA-4 pathway, while nivolumab and pembrolizumab are humanised monoclonal IgG4 antibodies that work on the PD-1 pathway. Despite a growing body of research pertinent to these novel therapies, early indications show that they are limited by their side effect profile. Furthermore, their efficacy appears to be greater in cancers with a high mutational burden. We present two female patients with bilateral reactive dacryoadenitis secondary to ICPi therapy, a finding that to the best of our knowledge was not previously described in the literature.

Clinical, genomic and immune microenvironmental determinants of nivolumab response in head and neck squamous cell carcinoma.

Background: In view of improving biomarkers predicting the efficacy of immunotherapy for head and neck squamous cell carcinoma (R/M HNSCC), this multicenter retrospective study aimed to identify clinical, tumor microenvironmental, and genomic factors that are related to therapeutic response to the anti- Programmed cell death protein 1 (PD-1) antibody, nivolumab, in patients with R/M HNSCC. Methods: The study compared 53 responders and 47 non-responders, analyzing formalin-fixed paraffin-embedded samples using 14-marker multiplex immunohistochemistry and targeted gene sequencing. Results: Of 100 patients included, responders had significantly lower smoking and alcohol index, higher incidence of immune related adverse events, and higher PD-1 ligand (PD-L1) expression in immune cells as well as PD-L1 combined positive score (CPS) than non-responders. The frequency of natural killer cells was associated with nivolumab response in patients with prior cetuximab use, but not in cetuximab-naïve status. Age-stratified analysis showed nivolumab response was linked to high CPS and lymphoid-inflamed profiles in patients aged ≥ 65. In contrast, lower NLR in peripheral blood counts was associated with response in patients aged < 65. Notably, TP53 mutation-positive group had lower CPS and T cell densities, suggesting an immune-excluded microenvironment. Patients with altered tumor suppressor gene pathways, including TP53, CDKN2A, and SMAD4 mutations, had lower CPS, higher smoking index, and were associated with poor responses. Conclusion: Nivolumab treatment efficacy in HNSCC is influenced by a combination of clinical factors, age, prior treatment, immune environmental characteristics, and gene mutation profiles.

Long-Term Temporal Trends of Real-World Healthcare Costs Associated with Nivolumab Plus Ipilimumab and Pembrolizumab Plus Axitinib as First-Line Treatment for Advanced or Metastatic Renal Cell Carcinoma.

INTRODUCTION: Nivolumab plus ipilimumab (NIVO + IPI) and pembrolizumab plus axitinib (PEM + AXI) are first-line (1L) treatments for advanced or metastatic renal cell carcinoma (aRCC), although the long-term trends in their associated real-world healthcare costs are not well defined. We compared the real-world healthcare costs of patients with aRCC who received 1L NIVO + IPI or PEM + AXI over 24 months. METHODS: Adults with RCC and secondary malignancy who initiated 1L NIVO + IPI or PEM + AXI were identified in the Merative MarketScan Commercial and Medicare Supplemental Databases (01/01/2004 to 09/30/2021). All-cause and RCC-related healthcare costs (unadjusted and adjusted) were assessed per patient per month (PPPM) at 6-month intervals post-treatment initiation (index date) up to 24 months, and differences between the NIVO + IPI and PEM + AXI cohorts were compared. RESULTS: Of 325 patients with aRCC, 219 received NIVO + IPI and 106 received PEM + AXI as the 1L treatment. According to patients' follow-up length, the analyses for months 7-12 included 210 patients in the NIVO + IPI cohort and 103 in the PEM + AXI cohort; months 13-18 included 119 and 48 patients, respectively; and months 19-24 included 81 and 25 patients. PPPM unadjusted all-cause total costs were $46,348 for NIVO + IPI and $38,097 for PEM + AXI in months 1-6; $26,840 versus $27,983, respectively, in months 7-12; $22,899 versus $25,137 in months 13-18; and $22,279 versus $27,947 in months 19-24. PPPM unadjusted RCC-related costs were $44,059 for NIVO + IPI and $36,456 for PEM + AXI in months 1-6; $25,144 versus $26,692, respectively, in months 7-12; $21,645 versus $23,709 in months 13-18; and $20,486 versus $25,515 in months 19-24. PPPM costs declined more rapidly for patients receiving NIVO + IPI compared to those receiving PEM + AXI, resulting in significantly lower all-cause costs associated with NIVO + IPI during months 19-24 (difference - $10,914 [95% confidence interval - $21,436, - $1091]) and RCC-related costs during months 7-12 (- $4747 [(- $8929, - $512]) and 19-24 (- $10,261 [- $20,842, - $421]) after adjustment. Cost savings for NIVO + IPI versus PEM + AXI were driven by differences in drug costs which, after adjustment, were significantly lower in months 7-12 (difference - $5555 [all-cause], - $5689 [RCC-related]); 13-18 (- $7217 and - $6870, respectively); and 19-24 (- $16,682 and - $16,125). CONCLUSION: Although the real-world PPPM healthcare costs of 1L NIVO + IPI were higher compared with PEM + AXI in the first 6 months of treatment, the costs associated with NIVO + IPI rapidly declined thereafter, resulting in significantly lower costs vs. PEM + AXI from months 7 to 24.

A case of rapidly progressive insulin-dependent diabetes mellitus without islet autoantibodies developed over two years after the first dose of nivolumab.

The case was an 80-year-old Japanese man. He was diagnosed with right renal cell carcinoma when he was 74. After laparoscopic radical nephrectomy, the patient received interferon, sorafenib, axitinib, and nivolumab therapy. The patient developed rapid progressive insulin-dependent diabetes mellitus (DM) after 46 courses of nivolumab monotherapy (772 days from the first nivolumab treatment). Glutamic acid decarboxylase antibody, islet cell cytoplasmic antibody, islet cell antigen-2 antibody, insulin antibody, and zinc transporter 8 antibody were all negative. Human leukocyte antigen (HLA) typing showed DRB1*09:01, DRB1 *13:02, DQB1*03:03, and DQB1 *06:04. Multiple daily insulin injections were started. However, controlling his blood glucose by standard multiple daily insulin injection treatments was difficult. The patient survived more than two years after the onset of immune checkpoint inhibitor-associated DM (ICI-DM). This is a valuable report of late-onset ICI-DM with a detailed patient background and clinical course over two years after the first dose of nivolumab.

Adjuvant Therapy with Immune Checkpoint Inhibitors after Carbon Ion Radiotherapy for Mucosal Melanoma of the Head and Neck: A Case-Control Study.

The development of new treatment strategies to improve the prognosis of mucosal malignant melanoma of the head and neck (MMHN) after carbon ion radiotherapy (CIRT) is essential because of the risk of distant metastases. Therefore, our objective was to evaluate the outcomes of immune checkpoint inhibitor (ICI) treatment to justify its inclusion in the regimen after CIRT. Thirty-four patients who received CIRT as an initial treatment were included in the analysis and stratified into three groups: those who did not receive ICIs (Group A), those who received ICIs after recurrence or metastasis (Group B), and those who received ICIs as adjuvant therapy after CIRT (Group C). In total, 62% of the patients (n = 21) received ICIs. The 2-year local control and overall survival (OS) rates for all patients were 90.0% and 66.8%, respectively. The 2-year OS rates for patients in Groups A, B, and C were 50.8%, 66.7%, and 100%, respectively. No significant differences were observed between Groups A and B (p = 0.192) and Groups B and C (p = 0.112). However, a significant difference was confirmed between Groups A and C (p = 0.017). Adjuvant therapy following CIRT for MMHN may be a promising treatment modality that can extend patient survival.

Adjuvant Therapy for High-Risk Stage II Melanoma: Current Paradigms in Management and Future Directions.

Melanoma is the fifth most common cancer in the United States and accounts for the majority of all skin cancer-related deaths, making it the most lethal cutaneous malignancy. Systemic adjuvant therapy for stage IIB-IV melanoma is now approved for patients who have undergone surgical resection, given the appreciable risk of recurrence and mortality in this patient population. Despite the lower stage, high-risk stage II melanoma (stage IIB/IIC) can often exhibit an even more aggressive course when compared to stage IIIA/IIIB disease, thus justifying consideration of adjuvant therapy in these patients. In this review, we highlight the current standard of practice for the treatment of stage IIB/C melanoma, with a focus on adjuvant therapies supported by published landmark clinical trials, including anti-PD-1 therapy. Notably, adjuvant therapies approved thus far in this patient population have demonstrated an improvement in recurrence-free survival, while their impact on overall survival is pending. Finally, this review highlights currently ongoing trials and future directions for research and treatment possibilities for high-risk clinical stage II melanoma.

Clinical features associated with immune checkpoint inhibitor nephritis: a single-center clinical case series.

BACKGROUND: Acute kidney injury (AKI) has been well described as a complication of immune checkpoint inhibitor therapy. We present a series of patients, the majority with lung adenocarcinoma, who developed AKI while actively receiving immune checkpoint inhibitors. METHODS: This is a retrospectively analyzed clinical case series of six patients treated at City of Hope Comprehensive Cancer Center. Data were collected on gender, age, ethnicity, comorbidities, concomitant medications, type of malignancy, treatments, and renal function. All patients underwent renal biopsy for classification of the mechanism of AKI. Comprehensive genomic profiling (CGP) was performed on tumor tissue for all patients. RESULTS: Patterns of AKI included acute interstitial nephritis and acute tubular necrosis. Contributing factors included the use of concomitant medications known to contribute to AKI. All but two patients had full resolution of the AKI with the use of steroids. There were several mutations found on CGP that was notable including an Exon 20 insertion as well as multiple NF1 and TP53 mutations. There was high PD-L1 expression on tumor tissue noted in two out of six patients. In addition to AKI, a subset of patients had proteinuria with biopsies revealing corresponding glomerular lesions of minimal change disease and focal and segmental glomerulosclerosis. CONCLUSIONS: Our case series demonstrates that AKI from immune checkpoint inhibitors has a variable presentation that may require an individualized treatment approach. Further studies are needed to identify biomarkers that may help identify those at risk and guide the management of this condition.

Extracellular vesicles miR-574-5p and miR-181a-5p as prognostic markers in NSCLC patients treated with nivolumab.

Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced non-small cell lung cancer (NSCLC), although patient survival is still unsatisfactory. Accurate predictive markers capable of personalizing the treatment of patients with NSCLC are still lacking. Circulating extracellular vesicles involved in cell-to-cell communications through miRNAs (EV-miRs) transfer are promising markers. Plasma from 245 patients with advanced NSCLC who received nivolumab as second-line therapy was collected and analyzed. EV-miRnome was profiled on 174/245 patients by microarray platform, and selected EV-miRs were validated by qPCR. A prognostic model combining EV-miR and clinical variables was built using stepwise Cox regression analysis and tested on an independent patient cohort (71/245). EV-PD-L1 gene copy number was assessed by digital PCR. For 54 patients with disease control, EV-miR changes at best response versus baseline were investigated by microarray and validated by qPCR. EV-miRNome profiling at baseline identified two EV-miRs (miR-181a-5p and miR-574-5p) that, combined with performance status, are capable of discriminating patients unlikely from those that are likely to benefit from immunotherapy (median overall survival of 4 months or higher than 9 months, respectively). EV-PD-L1 digital evaluation reported higher baseline copy number in patients at increased risk of mortality, without improving the prognostic score. Best response EV-miRNome profiling selected six deregulated EV-miRs (miR19a-3p, miR-20a-5p, miR-142-3p, miR-1260a, miR-1260b, and miR-5100) in responding patients. Their longitudinal monitoring highlighted a significant downmodulation already in the first treatment cycles, which lasted more than 6 months. Our results demonstrate that EV-miRs are promising prognostic markers for NSCLC patients treated with nivolumab.

Changes in outcome of patients with advanced non-clear cell renal cell carcinoma from the tyrosine kinase inhibitor era to the immuno-oncology era.

BACKGROUND: The therapeutic benefit of immuno-oncology (IO) therapy for patients with advanced non-clear-cell renal cell carcinoma (nccRCC) remains unclear. PATIENTS AND METHODS: We reviewed clinical data from 93 patients with advanced nccRCC who received first-line systemic therapy including IO combination therapy and tyrosine kinase inhibitor (TKI) monotherapy at our affiliated institutions. Patients were divided based on the period when the treatment was implemented as the standard of care into the IO and TKI eras. Survival and tumor response outcomes were compared between the IO and TKI eras. RESULTS: Of the 93 patients, 50 (54%) and 43 (46%) were categorized as IO era and TKI era groups, respectively. Progression-free survival (PFS) and overall survival (OS) were significantly longer in the IO era than in the TKI era (median PFS: 8.97 vs. 4.96 months, p = 0.0152; median OS: 38.4 vs. 13.5 months, p = 0.0001). After the adjustment using other covariates, the treatment era was an independent factor for PFS (hazard ratio: 0.59, p = 0.0235) and OS (hazard ratio: 0.27, p < 0.0001). Objective response and disease control rates was not significantly different between the treatment eras (26% vs. 16.3%, p = 0.268; 62% vs. 62.8%, p = 0.594). CONCLUSION: The implementation of IO therapy was significantly associated with longer survival in the nccRCC population. Further studies are needed to establish a more effective treatment strategy in this population using multiple regimens of IO combination therapy.