Ipilimumab Therapy Research Articles

Primary resistance to nivolumab plus ipilimumab therapy affects second-line treatment outcomes in patients with metastatic renal cell carcinoma.

Nivolumab plus ipilimumab (NIVO+IPI) has a long-term response rate of 30% for patients with metastatic renal cell carcinoma (mRCC). However, 20% of patients develop primary resistant disease (PRD) to NIVO+IPI and show poor survival outcomes. In this study, we aimed to evaluate the effect of PRD as a second-line treatment in patients with mRCC. The data used in this multi-institutional, retrospective cohort were collected between August 2015 and January 2023. In total, 189 patients with mRCC were treated with NIVO+IPI and then with a vascular endothelial growth factor receptor-tyrosine kinase inhibitor. Associations between PRD and progression-free survival of second-line treatment (PFS), progression-free survival 2 (PFS2), and overall survival (OS) were analyzed. The median age at NIVO+IPI initiation was 67 years in the male-dominant population (n = 140, 74.1%), and most patients had clear cell histology (n = 140, 74.1%). PRD was recorded in 42 (22.2%) of 189 patients during NIVO+IPI therapy. Patients who experienced PRD showed poor PFS (hazard ratio [HR], 1.788; 95% confidence interval [CI], 1.176-2.718; p = 0.007), PFS2 (HR, 4.127; 95% CI, 2.649-6.431; p < 0.001), and OS (HR, 3.330; 95% CI, 2.040-5.437; p < 0.001). Before starting second-line therapy, patients with PRD tended to have a poor performance status compared with non-PRD patients and a higher IMDC risk. Second-line drug therapy was not associated with treatment outcomes in patients with PRD. PRD in patients with mRCC receiving NIVO+IPI as first-line treatment was associated with poor clinical course, even with second-line therapy.

Acute Interstitial Nephritis in the Setting of Ipilimumab and Nivolumab Therapy

Acute Interstitial Nephritis in the Setting of Ipilimumab and Nivolumab Therapy

Comparison of efficacy between anti-PD-1 antibody monotherapy and nivolumab plus ipilimumab therapy as first-line immunotherapy for advanced mucosal melanoma in Japanese patients: A single-center, retrospective cohort study.

Mucosal malignant melanoma (MMM) is a rare subtype of malignant melanoma with a more aggressive biological behavior than cutaneous melanoma (CM). Owing to its rarity, it is necessary to accumulate information on treatments, especially in Asians, in whom MMM occurs more frequently than in Caucasians. In this study, we investigated the efficacy and adverse events (AEs) of nivolumab plus ipilimumab therapy (NIVO+IPI) versus immune checkpoint inhibitor (ICI) monotherapy (PD-1) in Japanese patients with MMM. We reviewed patients with advanced or recurrent MMM who received ICIs as first-line systematic therapy between February 2012 and February 2024 at the Shizuoka Cancer Center. We enrolled a total of 57 patients: 10 (17.5%) were treated with NIVO+IPI, and 47 (82.5%) were treated with PD-1 as first-line systemic therapy. Objective response rates (ORR) did not differ significantly between the NIVO+IPI and PD-1 groups (40.0% vs 27.7%; p = 0.176). There was also no statistically significant difference in progression-free survival (PFS) (median PFS time: 4.3 months vs 9.9 months, log-rank test, p = 0.578) or overall survival (OS) (median OS time: 33.1 months vs. 22.8 months, log-rank test, p = 0.697) between the two groups. However, regarding AEs, grade ≥3 AEs leading to discontinuation of first-line treatment occurred in 80% of patients in the NIVO+IPI group and in 22.6% of patients in the PD-1 group (p = 0.002). No difference was found in the efficacy of NIVO+IPI therapy and anti-PD-1 antibody monotherapy as the first-line treatment for MMM in Japanese patients, but an increase in AEs was observed with combination therapy. This study suggests that patients with MMM may receive less benefit from NIVO+IPI than from PD-1.

External validation of hemoglobin and neutrophil levels as predictors of the effectiveness of ipilimumab plus nivolumab for treating renal cell carcinoma.

Pretreatment hemoglobin and neutrophil levels were previously reported to be important indicators for predicting the effectiveness of ipilimumab plus nivolumab (IPI + NIVO) therapy for renal cell carcinoma (RCC). Therefore, we aimed to validate this in a large external cohort. In total, 172 patients with RCC who underwent IPI + NIVO treatment at a multicenter setting were divided into three groups according to their pretreatment hemoglobin and neutrophil levels (group 1: non-anemia; group 2: anemia and low-neutrophil; and group 3: anemia and high-neutrophil). Group 1 showed better survival than groups 2 and 3 (overall survival: 52.3 vs. 21.4 vs. 9.4 months, respectively; progression-free survival: 12.1 vs. 7.0 vs. 3.4 months, respectively). In this large cohort, we validated our earlier observation that hemoglobin and neutrophil levels can be reliable predictors of the effectiveness of IPI + NIVO in advanced RCC. Thus, our approach may aid in selecting the optimal first-line therapy for RCC.

Association between immune checkpoint inhibitor and cytomegalovirus infection: A pharmacovigilance study based on the adverse event reporting system.

Immune checkpoint inhibitor (ICI)-induced adverse events due to excessive immune stimulation are problematic in immunotherapy. The activation of viral infection triggered by ICI-induced dysregulated immunity has been proposed; however, this association remains inconsistent. This study investigated the association between ICI administration and cytomegalovirus (CMV) infections, a pathogen linked to immune abnormalities and reactivation, using the Food and Drug Administration Adverse Event Reporting System. We used the crude data set and immunocompromise-free data set from the fourth quarter of 2012 to 2023. The disproportionality between CMV infection and ICI was analyzed using reporting odds ratio (ROR) and information component (IC) methodologies. Disproportionality between ipilimumab and nivolumab combination case and CMV infection was observed in the crude (ROR: 2.83, 95% confidence interval [CI]: 2.32-3.47; IC: 1.48, 95% CI: 1.14-1.73) and immunocompromise-free data set (ROR: 1.76, 95% CI: 1.33-2.33; IC: 0.80, 95% CI: 0.33-1.14), whereas disproportionality between other ICI and CMV infection was not observed in the immunocompromise-free data set. Multiple sensitivity analyses and time-scan analysis also revealed the consistent disproportionality between ipilimumab and nivolumab combination cases and CMV infection, regardless of the host's immune status. While further research is warranted to validate our findings, these results highlight new insights into ICI-induced viral infections and suggest the importance of considering the possibility of CMV infections during ipilimumab and nivolumab combination therapy, regardless of the host's immune status.

Immune checkpoint inhibitor-associated sick sinus syndrome and cardiogenic shock.

Immune checkpoint inhibitors (ICI) represent a major advance in the treatment of cancer. Most studies of ICI have underestimated their cardiotoxicity; however, an increasing number of cases of cardiotoxicity are being reported. Herein we discussed a 67-year-old, male, Japanese patient who presented with cardiogenic shock accompanied by sick sinus syndrome 4days into his second course of ipilimumab plus nivolumab combination therapy. A temporary transvenous pacemaker was subsequently placed, and a permanent pacemaker was implanted for persistent, symptomatic, intermittent bradycardia. The permanent implantation of the pacemaker improved his symptoms and allowed him to continue his ICI therapy.

37 Cost-effectiveness of treatment sequences with front-line nivolumab+ipilimumab therapy vs immuno-oncology+tyrosine kinase inhibitor therapies in intermediate/poor-risk metastatic renal cell carcinoma

Abstract Background Immuno-oncology (IO) and vascular endothelial growth factor (VEGF) targeted tyrosine kinase inhibitor (TKI) combinations have transformed the treatment of metastatic renal cell carcinoma (mRCC). However, there is a lack of evidence regarding the most cost-effective sequencing of these systemic therapies. This study aimed to assess the expected health and economic outcomes of various treatment sequences for newly diagnosed patients with intermediate/poor-risk RCC from a US payer perspective. Methods We developed a model using a continuous time micro-simulation framework. First-line treatment options included: nivolumab+ipilimumab, nivolumab+cabozantinib, pembrolizumab+lenvatinib, and pembrolizumab+axitinib. Second-line treatment options included: cabozantinib and everolimus+lenvatinib. In both lines, the source data for the overall survival (OS) and progression-free survival (PFS) distributions were obtained from the registrational randomized controlled trials (RCTs) of each therapy. The analysis included costs associated with drug acquisition in the US wholesale setting, drug administration and monitoring, management of treatment-related adverse events, disease management, and terminal care. Treatment duration for all first-line IO and TKI therapies was capped at 2 years. Quality-adjusted life-years (QALYs) were estimated by multiplying time in each phase of the disease by phase-specific utility values estimated from the CheckMate 214 trial data using US tariffs. The analysis was run 1000 times for cohorts of 100 patients over a 20-year time horizon. All costs and health outcomes were discounted annually at a 3% rate. Results Average per-patient QALYs were estimated for each sequence of interest: nivolumab+ipilimumab followed by cabozantinib (3.59), nivolumab+ipilimumab followed by lenvatinib+everolimus (3.26), pembrolizumab+axitinib followed by cabozantinib (3.14), pembrolizumab+axitinib followed by lenvatinib+everolimus (2.97), pembrolizumab+lenvatinib followed by cabozantinib (3.51), and nivolumab+cabozantinib followed by lenvatinib+everolimus (2.99). Average per-patient costs were estimated for each sequence of interest: nivolumab+ipilimumab followed by cabozantinib ($468,856), nivolumab+ipilimumab followed by lenvatinib+everolimus ($491,259), pembrolizumab+axitinib followed by cabozantinib ($675,714), pembrolizumab+axitinib followed by lenvatinib+everolimus ($700,411), pembrolizumab+lenvatinib followed by cabozantinib ($837,888), nivolumab+cabozantinib followed by lenvatinib+everolimus ($873,377). First-line drug acquisition costs accounted for the majority of costs for all sequences. Conclusions Based upon our model using data from registrational RCTs, first-line nivolumab+ipilimumab followed by cabozantinib represents the dominant treatment strategy for intermediate/poor-risk mRCC patients in the US, offering estimated cost savings of up to 45% when compared to IO+TKI options. Additional studies are needed to elucidate whether these cost savings translate to the real-world setting.

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

IntroductionThe 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 MethodsPatients 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). ResultsIn 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. DiscussionThe 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.

Prognostic significance of inflammatory markers in patients with advanced renal cell carcinoma receiving nivolumab plus ipilimumab.

A useful biomarker for the efficacy of immune checkpoint inhibitors (ICIs) in advanced renal cell carcinoma (RCC) has not yet been established. This study aims to investigate whether inflammatory markers are associated with the efficacy of nivolumab plus ipilimumab therapy before and during treatment. Data from patients with advanced clear cell RCC who received a combination treatment of nivolumab plus ipilimumab were retrospectively analyzed. The neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and C-reactive protein (CRP) levels were assessed at baseline and 3, 6, and 9weeks after treatment initiation. The correlation between these inflammatory markers and the patient's prognosis was investigated. Eighty-four patients were identified. The multivariate analysis identified NLR at week 3, CRP at week 6, and NLR and CRP at week 9 as the consistent predictor associated with poor overall survival (OS) at each time point. The survival analysis and receiver operating characteristic (ROC) curve analysis revealed that an NLR of ≥ 2.4 at week 3, CRP of ≥ 1.4mg/dL at week 6, and NLR of ≥ 4.8 and CRP of ≥ 1.0mg/dL at week 9 were associated with worse OS (hazard ratios (HR) = 5.70, P = 0.008, HR = 3.23, P = 0.004, HR = 7.38, P < 0.001 and HR = 3.55, P = 0.002). Both NLR and CRP were considered useful biomarkers for understanding the prognosis during nivolumab plus ipilimumab therapy. Furthermore, an NLR of ≥ 4.8 and CRP of ≥ 1.0mg/dL at week 9 are helpful in reconsidering treatment continuation.

Risk factors for severe immune-related pneumonitis after nivolumab plus ipilimumab therapy for non-small cell lung cancer.

The efficacy of anti-CTLA-4 antibody (ipilimumab) plus anti-programmed cell death 1 antibody (nivolumab) in treating advanced non-small cell lung cancer (NSCLC) is impeded by an elevated risk of severe immune-related adverse events. However, our understanding of associations among pre-existing fibrosis, emphysematous changes, and objective indicators as predictive factors is limited for severe pneumonitis in NSCLC patients receiving this combination therapy. Thus, we retrospectively investigated these associations, including overall tumor burden, before treatment initiation in the Japanese population. We focused on patients (n = 76) with pre-existing interstitial lung disease (ILD) to identify predictors of severe pneumonitis. Variables included age, sex, smoking status, programmed cell death ligand 1 expression, overall tumor burden, chest computed tomography-confirmed fibrosis, serum markers, and respiratory function test results. Severe pneumonitis was more frequent in patients with squamous cell carcinoma, fibrosis, low diffusing capacity for carbon monoxide (%DLCO), and high surfactant protein D (SP-D) level. Notably, squamous cell carcinoma, baseline %DLCO, and SP-D level were significant risk factors. Our findings revealed the nonsignificance of tumor burden (≥85 mm) in predicting severe pneumonitis, emphasizing the importance of pre-existing ILD. Conversely, in cases without pre-existing fibrosis, severe pneumonitis was not associated with %DLCO or SP-D level (93.2% vs. 91.9%, and 63.3 vs. 40.9 ng/mL, respectively) and was more common in patients with a large overall tumor burden (97.5 vs. 70.0 mm). Vigilant monitoring and early intervention are crucial for patients with squamous cell carcinoma, high SP-D level, or low %DLCO undergoing ipilimumab plus nivolumab therapy.

A randomized, controlled, multicenter, phase 3 study of vusolimogene oderparepvec (VO) combined with nivolumab vs treatment of physician’s choice in patients with advanced melanoma that has progressed on anti–PD-1 and anti–CTLA-4 therapy (IGNYTE-3).

TPS9604 Background: Melanoma is the 5th most common cancer type, with ~100,000 new cases and ~8,000 deaths estimated in the US for 2024. First-line systemic treatment with immune checkpoint inhibitors improved the objective response rate (ORR) and extended progression-free survival (PFS) and overall survival (OS) for patients with advanced disease. The combination of anti–PD-1 nivolumab (nivo) + anti–CTLA-4 ipilimumab (ipi) therapy is associated with the highest ORR and best PFS and OS in this setting. However, only about half of patients respond, and there is no standard of care for patients who progress after anti–PD-1–based therapy. VO (also referred to as RP1) is a selectively replication-competent HSV-1 oncolytic virus that expresses human GM-CSF and a fusogenic glycoprotein (GALV-GP-R–). Preliminary data from the phase 1/2 study (IGNYTE) showed that intratumoral (IT) VO plus intravenous (IV) nivolumab (nivo) was well tolerated and had meaningful antitumor activity (ORR, 31.4%) with durable responses in patients with advanced melanoma who progressed on prior anti–PD-1 therapy. This phase 3 study will evaluate the overall survival and clinical benefit as well as the safety of VO plus nivo for patients with advanced melanoma whose disease has progressed after receiving anti–PD-1 and anti–CTLA-4 therapy (or who are not eligible for anti–CTLA-4 therapy in addition to anti–PD-1) versus physician’s choice. Methods: This is a randomized, controlled, multicenter, phase 3 clinical trial comparing VO in combination with nivo vs physician’s choice of treatment in patients with unresectable or metastatic melanoma. Key eligibility criteria include age ≥12 years, stage IIIb–IV/M1a–M1d cutaneous melanoma, confirmed disease progression on an anti–PD–1 and anti–CTLA-4 treatment (administered in combination or in sequence with anti–PD-1 last), at least 1 measurable tumor (≥1 cm), and adequate hematologic, hepatic, and renal function. Patients who are not candidates for anti–CTLA-4 therapy may enroll if they have confirmed progression on anti–PD-1 therapy. Patients with BRAF V600 mutant melanoma must have received an anti-BRAF + anti-MEK targeted therapy prior to enrollment. Patients (N = ~400) will be randomized 1:1 to receive VO plus nivo or physician’s choice (nivo + relatlimab, anti–PD–1 monotherapy rechallenge [nivo or pembrolizumab], or single-agent chemotherapy [dacarbazine, temozolomide, or paclitaxel/albumin-bound paclitaxel]). VO is given IT Q2W; nivo is administered IV at 240 mg Q2W or 480 mg Q4W starting with the 2nd dose of VO. The primary endpoint of the study is OS; the key secondary endpoints are PFS and ORR. Additional endpoints include complete response rate, duration of response, disease control rate, and safety. Clinical trial information: NCT06264180 .

The lymphocyte-to-monocyte ratio as a significant inflammatory marker associated with survival of patients with metastatic renal cell carcinoma treated using nivolumab plus ipilimumab therapy.

Nivolumab plus ipilimumab (NIVO + IPI) is the first-line treatment for patients with metastatic renal cell carcinoma (mRCC). While approximately 40% of patients treated with NIVO + IPI achieve a durable response, 20% develop primary resistance with severe consequences. Therefore, there is a clinical need for criteria to select patients suitable for NIVO + IPI therapy to optimize its therapeutic efficacy. Accordingly, our aim was to evaluate the association between candidate biomarkers measured before treatment initiation and survival. This was a multi-institutional, retrospective, cohort study of 183 patients with mRCC treated with systematic therapies between August 2015 and July 2023. Of these, 112 received NIVO + IPI as first-line therapy: mean age, 68years; men, 83.0% (n = 93), and clear cell histology, 80.4% (n = 90). Univariable and multivariable analyses were used to evaluate associations between biomarkers and survival. On univariate analysis, high C-reactive protein and systemic index, a high neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio, and a low lymphocyte-to-monocyte ratio (LMR) were associated with shorter overall survival (OS). On multivariable analysis, a LMR ≤ 3 was retained as an independent factor associated to shorter OS with the highest accuracy (C-index, 0.656; hazard ratio, 7.042; 95% confidence interval, 2.0-25.0; p = 0.002). A low LMR may identify patients who would be candidate for NIVO + IPI therapy for mRCC.

The relationship between immune-related adverse events during ipilimumab monotherapy and survival outcomes among melanoma patients: A systematic review.

Ipilimumab disinhibits immune system activity which results in the elimination of malignant cells. An unintended consequence of ipilimumab therapy is off-target immune-related adverse events (irAEs). It has therefore been proposed that the incidence of irAEs is a manifestation of treatment effectiveness. The objective of this systematic review is to examine the relationship between irAEs and survivability among melanoma patients administered ipilimumab monotherapy. A comprehensive search was conducted across several databases which yielded a total of 2381 studies. Clinical trials and prospective studies administering ipilimumab monotherapy to melanoma patients were included. Furthermore, there was no restriction placed on publication date. After screening, five studies were included for data extraction. The primary outcome of median overall survival (OS) and the secondary outcome of OS hazard ratio were extracted from the included studies. Based on qualitative analysis of the included studies, there seemed to be an association between the occurrence of non-lethal irAEs and improved survival outcomes among melanoma patients administered ipilimumab monotherapy. With that being said, the poorer survivability among patients who experienced high-grade irAEs may be the result of subsequent treatment discontinuation. Potential confounders such as corticosteroid use should be accounted for. Finally, landmark analyses may be conducted to account for immortal time bias. The findings from this systematic review provide evidence suggesting that the incidence of irAEs is a marker of an improved anti-tumor response.

218 A case of Toxic Epidermal Necrolysis secondary to combination Ipilimumab and Nivolumab therapy for Pleural Mesothelioma, successfully treated with Ruxolitinib

218 A case of Toxic Epidermal Necrolysis secondary to combination Ipilimumab and Nivolumab therapy for Pleural Mesothelioma, successfully treated with Ruxolitinib

Early Serum Markers for Immune Checkpoint Inhibitor Induced Hypophysitis in Melanoma Patients.

Immune checkpoint inhibitors (ICIs) have shown promising anti-tumor activities and are widely used for the treatment of advanced cancers. However, they may lead to immune-related adverse events (irAEs) and some of them, such as hypophysitis, can be life-threatening. Here, early diagnosis is critical. We retrospectively analyzed 40 melanoma patients who developed hypophysitis during ICI treatment with either ipilimumab and/or anti-PD1 therapy and compared them to 40 control patients who did not develop hypophysitis during the ICI treatment, matched for age, gender, type of immunotherapy, and stage. Clinical data and blood values such as LDH, CRP, TSH, T3, T4, and absolute immune cell counts were retrieved from the medical records. Patient characteristics, laboratory values, progression-free survival, and overall survival were compared between the two groups. Patients with ir-hypophysitis had a median age of 59 years, and most of them were male. Clinically, frequent symptoms were fatigue, headache, dizziness, and gastrointestinal symptoms such as nausea or abdominal pain. The onset of ir-hypophysitis differed much between ipilimumab- (median 8 weeks) and anti-PD1 (median 40 weeks)-induced hypophysitis (p < 0.001). At baseline, besides a slightly increased CRP level (p = 0.06), no differences were observed in patients who later developed hypophysitis compared to the control. After treatment started, hypophysitis patients showed a constant and significant decline in T4 levels from the start of therapy until diagnosis (p < 0.05), independent of the ICI treatment regime. However, a decline in T3 and TSH was only noted in patients with ipilimumab-induced ir-hypophysitis. Furthermore, serum sodium levels declined rapidly at the diagnosis of hypophysitis (p < 0.001). In addition, there was a constant increase in the absolute counts of eosinophils and lymphocytes from baseline in hypophysitis patients (p < 0.05). Ir-hypophysitis reveals different clinical pictures and onset times depending on the ICI regime used. Whereas a drop in T4 levels was indicative of developing hypophysitis independent of the ICI regime, TSH levels only declined in patients under ipilimumab-based ICI regimes. To best monitor our patients, it is important to recognize these differences.

Abstract 7380: Predicting immunotherapy outcomes from H&amp;E images in lung cancer

Abstract Checkpoint blockade immunotherapy is a cornerstone of lung cancer treatment, but there is a need to improve the identification of patients who will respond favorably. Here, we explored a deep learning approach to predict immunotherapy outcomes from hematoxylin and eosin (H&amp;E) images in non-small cell lung cancer (NSCLC). We included 150 unique cases with metastatic NSCLC (113 adenocarcinoma, 29 squamous cell, 8 other) treated with anti-PD-1/PD-L1 immunotherapy (56 nivolumab, 49 atezolizumab, 44 pembrolizumab, 1 durvalumab) as mono or combination (14 with chemotherapy, 1 with ipilimumab) therapy in a single institution. Each case consisted of a representative H&amp;E whole slide image (53 biopsies, 50 needle core biopsies, 47 resections) obtained prior to immunotherapy, and the outcome reported as the 1-year overall survival (OS). PD-L1 status (tumor proportion score ≥ 1%) was known for 70 cases. We preprocessed the H&amp;E images using two deep learning models previously developed using The Cancer Genome Atlas dataset. First, we used a classification model to identify tumor regions and randomly sampled a fixed number of tumor patches for each case. Then, we used a self-supervised pathology foundation model to obtain a compressed visual representation of each patch, known as an embedding. Next, using our dataset, we trained a deep multiple instance learning (DeepMIL) model with a gated attention mechanism to predict the binary 1-year OS status (0=deceased, 1=alive) for each case. As a baseline, we also trained a linear-probe (logistic regression) model using the averaged embeddings. Given the small dataset size, 5-fold cross-validation was used to train and evaluate both the DeepMIL and linear-probe models, with cases randomly split across folds. For evaluation, we used survival analysis to compare the 0/1 case groups. Overall, across all 150 cases, univariable Cox regression showed that 1-year OS was more strongly associated with the DeepMIL status (46/104, HR=0.55, p=0.03) than the linear-probe status (55/95, HR=0.81, p=0.44). Results were consistent on the subset of 70 cases with known PD-L1 status, whereby OS was most strongly associated with the DeepMIL status (19/51, HR=0.40, p=0.04) compared to the linear-probe status (31/39, HR=0.46, p=0.09) and PD-L1 status (30/40, HR=0.65, p=0.32). In multivariable Cox regression adjusting for age group and smoking status, OS remained more strongly associated with the DeepMIL status (HR=0.45, p=0.08) than PD-L1 status (HR=0.72, p=0.47). In conclusion, the DeepMIL status predicted from H&amp;E images showed a stronger association with outcomes compared to PD-L1 status, a standard biomarker for immunotherapy in NSCLC. These exploratory results demonstrate the potential of deep learning using pathology foundation models to improve immunotherapy outcomes prediction, even with small datasets. Such approaches may even enable the discovery of novel biomarkers from H&amp;E images to advance precision medicine. Citation Format: Jessica Loo, Yang Wang, Pok Fai Wong, Ellery Wulczyn, Jeremy Lai, Peter Cimermancic, David F. Steiner, Shamira S. Weaver. Predicting immunotherapy outcomes from H&amp;E images in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7380.

Nephrotic syndrome with acute kidney injury due to combination therapy of immune checkpoint inhibitors: a case report and review of the literature

BackgroundRecent studies have focused on immune checkpoint inhibitors. Renal complications associated with the use of immune checkpoint inhibitors are uncommon compared with other immune-related adverse events. Acute interstitial nephritis accounts for most of these renal complications, with nephrotic syndrome quite rare. We herein report a case of nephrotic syndrome associated with immune checkpoint inhibitors that was more severe than that in previous cases. By comparing this case with previous reports, the possible reasons for the particular severity of this case are discussed.Case presentationA 75-year-old man developed nephrotic syndrome with acute kidney injury after the first combination therapy of nivolumab and ipilimumab for malignant pleural mesothelioma. The results of a kidney biopsy indicated minimal change disease with mild atherosclerosis, acute interstitial nephritis, and fusion of nearly all podocyte foot processes. Nivolumab and ipilimumab therapy were stopped, and treatment with corticosteroids was initiated. We investigated previously reported cases of nephrotic syndrome using immune checkpoint inhibitors. Seventeen cases of immune checkpoint inhibitor-related nephrotic syndrome, including ours, have been reported. Two of the 17 patients with immune checkpoint inhibitor-related nephrotic syndrome required hemodialysis treatment for acute kidney injury. Unlike many previously reported cases, the present patient was administered two different immune checkpoint inhibitors, which may be one of the reasons for the development of severe nephrotic syndrome.ConclusionsIn addition to previously reported risk factors, immune checkpoint inhibitor combination therapy can exacerbate nephrotic syndrome compared to immune checkpoint inhibitor monotherapy.

Genomic and Transcriptomic Characteristics of Tumors of Patients with Metastatic Clear Cell Renal Cell Carcinoma Clinically Benefiting from First-Line Treatment with Ipilimumab Plus Nivolumab

Background: Ipilimumab plus nivolumab is approved as a first-line treatment for intermediate or poor risk metastatic renal cell carcinoma (mRCC). However, ∼35% of patients progress within six months on ipilimumab plus nivolumab, and no validated genomic biomarkers predict the benefit. In this study, we explore the genomic and transcriptomic differences among patients with clear cell mRCC patients who either did or did not experience clinical benefit from first-line ipilimumab plus nivolumab therapy. Method: Patients with clear cell mRCC intermediate or poor IMDC risk scores, with available tumor whole exome with/without transcriptome sequencing before starting systemic therapy were included. Patients who developed a complete response, partial response, or stable disease for at least six months after initiating treatment were categorized into the ‘clinical benefit’ group, whereas the rest were classified as ‘no clinical benefit.’ Genomic alteration frequencies between the groups were assessed with a chi-square test. Differentially expressed genes and gene sets were identified via DeSeq2 and GSEA v4.2.3, respectively. Result: 53 patients with clear cell mRCC (37 clinical benefit and 16 no clinical benefit) were eligible and included. No significant difference was found in the genomic alteration frequencies between these groups. Baseline tumor transcriptomic data were available for 14 patients (9 clinical benefit and 5 no clinical benefit). The apical surface and pathways downregulated by KRAS signaling were enriched in the clinical benefit group, whereas inflammatory pathways were enriched in the no clinical benefit group. Conclusion: These findings suggest that tumor specific gene expression as assessed by RNA sequencing could serve as a potential biomarker of response to ipilimumab plus nivolumab therapy.

532P The changes of the serum SMRP levels is useful to predict the antitumor efficacy of ipilimumab plus nivolumab combination therapy in patients with malignant pleural mesothelioma

532P The changes of the serum SMRP levels is useful to predict the antitumor efficacy of ipilimumab plus nivolumab combination therapy in patients with malignant pleural mesothelioma

THU018 Remarkable Response Of ACTH-secreting Pituitary Carcinoma To Immune Checkpoint Inhibitors: A Case Report

Abstract Disclosure: J. Park: None. W. Choi: None. A. Hong: None. J. Yoon: None. H. Kim: None. H. Kang: None. Background: ACTH-secreting pituitary carcinoma transformed from Cushing’s disease is very rare and has aggressive characteristics with limited treatment options. We report a case of ACTH-secreting pituitary carcinoma patient who showed a excellent response to immune checkpoint inhibitors (ICIs). Clinical Case: A 70-year-old female presented with a rapidly growing pituitary carcinoma transformed from Cushing’s disease after bilateral adrenalectomy. Her tumor initially responded to 6 cycles of temozolomide and 7 cycles of temozolomide plus capecitabine. However, multiple brain and pulmonary metastases were newly seen on following imaging studies and the patient had worsening generalized pigmentation on her whole body with newly developed headache, diplopia, and ptosis of the left eye. After introduction of three cycles of ipilimumab plus nivolumab therapy, her plasma ACTH level decreased dramatically from 58,000 pg/ml to 198 pg/ml with improving skin pigmentation and headache episodes. We maintained nivolumab and observed that the plasma ACTH level be normalized to 44 pg/ml (normal range: 6 – 60 pg/ml). Her follow-up brain MRI and chest CT scan also showed marked response, some of the chest lesions even showed nearly complete response (figure 1). On the last follow-up visit, we confirmed that she was in good general condition and tolerable to nivolumab maintenance therapy with glucocorticoid replacement. Conclusion: Immune checkpoint inhibitors (ICIs) may be effective therapeutic options in aggressive pituitary carcinoma and can be considered in temozolomide resistant cases. Moreover, because of the excessively high cost, we emphasize the necessity of clinical trials of ICIs for rare diseases like pituitary carcinomas to expand insurance coverage and reduce the unmet needs of medical care.