First-line Ipilimumab Research Articles

Efficacy of First-Line Nivolumab Plus Ipilimumab in Unresectable Pleural Mesothelioma: A Multicenter Real-World Study (ImmunoMeso LATAM)

BackgroundThe phase 3 CheckMate-743 trial demonstrated a prolonged overall survival (OS) benefit with nivolumab plus ipilimumab over chemotherapy as first-line treatment in patients with unresectable pleural mesothelioma (PM). However, given that Latin American (LATAM) patients were notably underrepresented in this trial, we retrospectively assessed the effectiveness and safety of this regimen in this population. MethodsThis retrospective study included patients from 15 centers in LATAM with unresectable or metastatic PM treated with first-line nivolumab plus ipilimumab in a real-world data (RWD) scenario. Demographic, clinicopathological characteristics, and safety data were collected from medical charts. Progression-free survival (PFS), and OS were calculated using the Kaplan-Meier method. ResultsFrom June 2017, and January 2024 96 patients were included: epithelioid 78% (n = 75), 81% were ECOG 0-1 (n = 78). With a median follow-up of 24.1 months, median PFS and OS were 8 months (95% CI, 6.6-9.4), and 22 months (95% CI, 18.9-25), respectively. No statistical difference in OS was observed between epithelioid versus nonepithelioid histology (median 23 months vs. 19 months, respectively; P = .29). Treatment efficacy was also consistent among different clinical subgroups. Any and grade 3-4 adverse events were found in 43.1% (n = 28), and 18.5% (n = 12) of patients, respectively. Remarkably, no OS impact was observed in patients who had dose delay or treatment discontinuation due to immune-related adverse events, and those who experienced any adverse event. ConclusionsThis multicenter RWD study demonstrated the clinically meaningful benefit of first-line ipilimumab and nivolumab in LATAM patients with unresectable or metastatic PM, and data is consistent with previous trial findings.

Comparative effectiveness of first-line (1L) ipilimumab plus nivolumab (Ipi + Nivo) versus immune checkpoint inhibitors + tyrosine kinase inhibitors (ICI + TKI) in patients (pts) with intermediate or poor (I/P) risk metastatic clear cell renal cell carcinoma (mccRCC).

Comparative effectiveness of first-line (1L) ipilimumab plus nivolumab (Ipi + Nivo) versus immune checkpoint inhibitors + tyrosine kinase inhibitors (ICI + TKI) in patients (pts) with intermediate or poor (I/P) risk metastatic clear cell renal cell carcinoma (mccRCC).

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.

Associations of diet with survival of patients (pts) with metastatic cancer of the urothelium (mUC) and renal cell carcinoma (mRCC) on immune checkpoint blockade (ICB).

4598 Background: The gut microbiome is an emerging modifiable predictor of ICB efficacy. Diet impacts the gut microbiome and fiber intake is associated with longer progression-free survival (PFS) in advanced melanoma treated with ICB. Whether diet impacts ICB benefit in mUC or mRCC remains unknown. Methods: Using a prospective cohort design, baseline dietary data were collected from pts with mUC or mRCC initiating ICB at Memorial Sloan Kettering Cancer Center using the extensively validated Harvard Willett Food Frequency Questionnaire. Tumor mutational burden (TMB) was estimated by next generation sequencing (MSK-IMPACT). The primary endpoint was radiologist assessed PFS, with secondary endpoint of overall survival (OS). Fiber intake was stratified as high or low using the median intake in our cohort. Associations between fiber intake and clinical outcomes were assessed using Kaplan-Meier curves plus univariable (UV) and multivariable (MV) Cox proportional hazards regression. Models were adjusted for prior ICB exposure. Models for mUC controlled for TMB and Bellmunt risk factors. Models for mRCC controlled for histology (clear vs non-clear cell) and IMDC risk score. Results: From 2/2021-6/2022, 88 pts eligible for analysis were enrolled with median follow-up of 10.1 months (mo) (mUC n = 40; mRCC n = 48). Median fiber intake was 17.5 g/day (interquartile range 12.5-24.5). Among pts with mUC, high fiber intake (≥17.5 g/day) was associated with longer PFS (UV hazard ratio [HR] 0.56, 95% CI 0.26-1.19, p = .13; MV HR 0.39, 95% CI 0.16-0.93, p = .03). Similar trends were observed for mRCC. In subgroup analyses, PFS was numerically longer with high fiber intake among mUC pts on maintenance avelumab (median PFS 6.1 vs 3.0 mo, n = 14) and in pts with mRCC treated with first-line (1L) ipilimumab + nivolumab (median PFS 18.0 vs 5.7 mo, n = 14) and 1L ICB + tyrosine kinase inhibitor (median PFS not reached vs 5.1 mo, n = 21). Among pts with mUC on non-maintenance ICB, pts with high fiber intake had numerically higher PFS at 6 mo (38% vs 14%, n = 26). Conclusions: This pilot study indicates that high fiber intake is associated with longer PFS among pts with mUC on ICB. Trends towards longer PFS and OS with high fiber intake were observed among pts with mRCC. Analyses of the gut microbiome are underway to investigate mechanisms of action. [Table: see text]

Relationship Between Pretreatment Body Composition and Clinical Outcomes in Patients With Metastatic Renal Cell Carcinoma Receiving First-Line Ipilimumab Plus Nivolumab

IntroductionBiomarkers are needed to identify patients with metastatic renal cell carcinoma (mRCC) most likely to benefit from immune checkpoint inhibitors. We examined associations between radiographically assessed body composition (BC) variables and body mass index (BMI) with clinical outcomes for patients with mRCC receiving first-line ipilimumab + nivolumab (ipi/nivo). Patients and MethodsWe retrospectively reviewed all patients with mRCC treated with first-line ipi/nivo at one institution before June 1, 2021 with an analyzable baseline computed tomography (CT) scan. BC variables (skeletal muscle index [SMI], subcutaneous adipose tissue index [SATI], and visceral adipose tissue index [VATI]) were measured using baseline CT scans. Relationships between BC variables and clinical outcomes were examined using Cox proportional hazard regression models. ResultsNinety-nine patients were analyzed (74% male, 64% overweight/obese, 75% low SMI). Controlling for age, IMDC risk, and sex (for BMI analyses), high vs. low SMI (HR=2.433, CI: 1.397-4.238, P=.0017), high vs. low SATI (HR=1.641, CI: 1.023-2.632, P=.0398), and obese BMI (≥ 30 kg/m2) vs. normal/overweight BMI (<30 kg/m2) (HR=1.859, CI: 1.156-2.989, P=.0105) were significantly associated with progression-free survival (PFS). Median overall survival (OS) for low SMI patients was higher (42.74 months, CI: 26.84, NR) than median OS for high SMI patients (27.01 months, CI: 15.28, NR) (adjusted HR=1.728, CI: 0.909-3.285, P=.0952). No BC variables were significantly associated with OS or objective response rate. ConclusionsLow SMI and low SATI were associated with significantly better PFS for patients with mRCC receiving first-line ipi/nivo. Radiographic BC variables may be useful prognostic biomarkers in this setting.

Serum C-reactive Protein Level Predicts Overall Survival for Clear Cell and Non-Clear Cell Renal Cell Carcinoma Treated with Ipilimumab plus Nivolumab.

Serum C-reactive protein (CRP) is known to be a biomarker for systemic inflammatory reactions. In the present study, we sought to measure the predictive value of serum CRP level for metastatic renal cell carcinoma (mRCC) treated with first-line ipilimumab and nivolumab using our real-world clinical dataset including non-clear cell RCC (nccRCC). The clinical record of patients who underwent the first-line ipilimumab plus nivolumab treatment for mRCC including ccRCC and nccRCC from 2018 to 2021 was retrospectively analyzed. All patients were diagnosed with either intermediate or poor-risk group defined by IMCD (international metastatic RCC database consortium). In total, 74 patients were involved. The median age was 68 years and 24 (32.4%) patients deceased during the follow-up. Forty-five (61%) and 29 (39%) patients were classified into intermediate and poor-risk groups. The one-year overall survival (OS) rate and objective response rate were 65% and 41% for all 74 mRCC patients, respectively. The receiver operating characteristic curve identified 1.0 mg/dL of serum CRP level as an ideal cut-off for predicting overall survival (OS). Serum CRP &gt; 1.0 mg/dL and nccRCC were the independent predictors for OS in 74 mRCC patients. OS for patients with CRP &gt; 1 mg/dL was significantly shorter than those with CRP &lt; 1 mg/dL in both ccRCC (58 patient: p = 0.009) and nccRCC (16 patients: p = 0.008). The present study indicated that serum CRP level is a prognostic indicator for OS in both ccRCC and nccRCC patients treated with the first-line ipilimumab plus nivolumab treatment.

Association of Immune-Related Adverse Event Management With Survival in Patients With Advanced Melanoma

Management of checkpoint inhibitor-induced immune-related adverse events (irAEs) is primarily based on expert opinion. Recent studies have suggested detrimental effects of anti-tumor necrosis factor on checkpoint-inhibitor efficacy. To determine the association of toxic effect management with progression-free survival (PFS), overall survival (OS), and melanoma-specific survival (MSS) in patients with advanced melanoma treated with first-line ipilimumab-nivolumab combination therapy. This population-based, multicenter cohort study included patients with advanced melanoma experiencing grade 3 and higher irAEs after treatment with first-line ipilimumab and nivolumab between 2015 and 2021. Data were collected from the Dutch Melanoma Treatment Registry. Median follow-up was 23.6 months. The PFS, OS, and MSS were analyzed according to toxic effect management regimen. Cox proportional hazard regression was used to assess factors associated with PFS and OS. Of 771 patients treated with ipilimumab and nivolumab, 350 patients (median [IQR] age, 60.0 [51.0-68.0] years; 206 [58.9%] male) were treated with immunosuppression for severe irAEs. Of these patients, 235 received steroids alone, and 115 received steroids with second-line immunosuppressants. Colitis and hepatitis were the most frequently reported types of toxic effects. Except for type of toxic effect, no statistically significant differences existed at baseline. Median PFS was statistically significantly longer for patients treated with steroids alone compared with patients treated with steroids plus second-line immunosuppressants (11.3 [95% CI, 9.6-19.6] months vs 5.4 [95% CI, 4.5-12.4] months; P = .01). Median OS was also statistically significantly longer for the group receiving steroids alone compared with those receiving steroids plus second-line immunosuppressants (46.1 months [95% CI, 39.0 months-not reached (NR)] vs 22.5 months [95% CI, 36.5 months-NR]; P = .04). Median MSS was also better in the group receiving steroids alone compared with the group receiving steroids plus second-line immunosuppressants (NR [95% CI, 46.1 months-NR] vs 28.8 months [95% CI, 20.5 months-NR]; P = .006). After adjustment for potential confounders, patients treated with steroids plus second-line immunosuppressants showed a trend toward a higher risk of progression (adjusted hazard ratio, 1.40 [95% CI, 1.00-1.97]; P = .05) and had a higher risk of death (adjusted hazard ratio, 1.54 [95% CI, 1.03-2.30]; P = .04) compared with those receiving steroids alone. In this cohort study, second-line immunosuppression for irAEs was associated with impaired PFS, OS, and MSS in patients with advanced melanoma treated with first-line ipilimumab and nivolumab. These findings stress the importance of assessing the effects of differential irAE management strategies, not only in patients with melanoma but also other tumor types.

Relation of overall tumor burden with severe immune-related adverse events in nivolumab plus ipilimumab treatment for lung cancer.

Compared to chemotherapy alone, monoclonal antibodies like ipilimumab and nivolumab, with or without chemotherapy, improve the prognosis of patients with non-small cell lung cancer (NSCLC), albeit with a higher incidence of immune-related adverse events (irAEs) than those with immune checkpoint inhibitor (ICI) monotherapy. Therefore, we aimed to investigate if baseline overall tumor burden was associated with the development of Grade ≥ 3 irAEs (severe irAEs) when treated with first-line ipilimumab plus nivolumab with or without chemotherapy.We retrospectively examined consecutive patients with advanced NSCLC who received nivolumab plus ipilimumab with or without chemotherapy at Hakodate Goryoukaku Hospital between December 2020 and December 2021. Baseline overall tumor burden was measured as the sum of unidimensional diameters of up to five target lesions according to the Response Evaluation Criteria in Solid Tumors, version 1.1. We defined irAEs as ICI therapy-related toxicities according to the Common Terminology Criteria for Adverse Events, version 5.0.A significant difference in tumor burden was observed between patients with and without severe irAEs (100mm vs. 67.5mm, p = 0.001). We evaluated various clinical parameters, including baseline overall tumor burden, before treatment initiation. Of the various parameters, only high tumor burden correlated with severe irAEs, independent of complementary chemotherapy. The multivariate odds ratio of severe irAEs and high tumor burden was 6.62.Conclusively, baseline overall tumor burden may be a risk factor for severe irAEs in patients treated with first-line combination ICI therapy. Therefore, patients with large tumor burden should be carefully monitored to prevent irAEs.

Real-world cost effectiveness of first-line pembrolizumab for advanced melanoma: A population-based study by the Canadian Real-world Evidence Value for Cancer Drugs (CanREValue) Collaboration.

17 Background: Randomized controlled trials (RCTs) demonstrate large survival benefits with anti-PD-1 checkpoint inhibitors compared to anti-CTLA4 therapy for advanced melanoma. However, it remains unclear if patients in routine practice derive a similar survival benefit or if real-world health utilization differs from trials. Outcomes are needed to inform life-cycle health technology reassessment (HTA) with real-world cost-effectiveness analysis. Methods: This study compared patients with advanced melanoma treated with publicly funded first-line ipilimumab (September 2012 - December 2014) or pembrolizumab (June 2016 - March 2018) in Ontario, Canada. These periods were chosen to reflect distinct eras of access to treatment. Linked administrative databases were used to identify cases, covariates, health-utilization and all-cause death. Inverse probability of treatment weighting (IPTW) with stabilizing weights was used to adjust for covariates (including: age, sex, melanoma site, rurality, income, comorbidity, stage at diagnosis, cancer history, prior brain metastasis treatment). Using a three-year time horizon, individual patient-level censoring-adjusted costs in 2019 Canadian dollars with a 1.5% annual discount rate were determined from the public payer’s perspective. The outcome was quality-adjusted life-years (QALY) measured at the individual patient level. Health utilities were based on accepted Canadian values from the initial HTA. The incremental cost-effectiveness ratio (ICER) was determined with bootstrap confidence intervals (CI). Results: Ninety patients treated with first-line ipilimumab, and 300 with pembrolizumab were identified. Those receiving pembrolizumab were older (median 70 vs.63 years), more likely to have multiple comorbidities (12% vs. 8%), and no prior brain radiation (83% vs. 74%). Covariates were balanced after weighting. Pembrolizumab was associated with improved OS (43.1% vs. 22.1% with ipilimumab at 3 years, IPTW adjusted hazard ratio: 0.52, 95% CI: 0.39-0.70; p &lt; 0.001). Mean costs for pembrolizumab and ipilimumab were $212,706 (95% CI 196,122 - 229,290) and $158,352 ($143,218 - 173,484), and mean survival 1.20 QALY (95%CI 1.11 – 1.29) and 0.66 QALY (0.52 – 0.80) respectively. The ICER was $101,183/QALY (65,375 – 139,298). The probability of cost-effectiveness was 0%, 48% and 99% at willingness-to-pay thresholds of $50k, $100k and $150k respectively. Conclusions: In real-world patients, first-line pembrolizumab for advanced melanoma was associated with improved OS compared to ipilimumab. The real-world cost-effectiveness estimate of $101,183/QALY is similar to the model-based cost-effectiveness estimates ($114,389/QALY to $151,369/QALY) used in the initial health technology assessment recommendation prior to reimbursement.

Role of the Systemic Immune-Inflammation Index in Patients with Metastatic Renal Cell Carcinoma Treated with First-Line Ipilimumab plus Nivolumab.

Simple SummaryThe aim of this study was to evaluate the predictive and prognostic value of the systemic immune-inflammation index (SII), which is based on peripheral blood platelet, neutrophil, and lymphocyte counts, in patients with metastatic renal cell carcinoma (mRCC) treated with ipilimumab plus nivolumab in the first-line setting. High SII score was an independent prognostic factor for worse progression-free survival and overall survival. The clinical benefit rate was higher for patients with a low SII index if compared to a high SII index. An increase in SII of >20% from baseline after 12 weeks of therapy was significantly associated with tumor progression at first imaging. The SII index is both prognostic and predictive and could refine decision making in patients treated with ipilimumab plus nivolumab.Background: The aim of this study was to evaluate the predictive and prognostic value of the systemic immune-inflammation index (SII) in patients with metastatic renal cell carcinoma (mRCC) treated with first-line ipilimumab plus nivolumab. Methods: This retrospective study included forty-nine mRCC patients treated with first-line ipilimumab plus nivolumab at the Department of Urology of the University of Tuebingen, Germany. SII was assessed before starting ipilimumab plus nivolumab therapy at the time of first imaging and at tumor progression. Optimal SII cut-off was stratified by ROC-analysis. Univariable and multivariable Cox regression analyses were used to evaluate the predictive and prognostic value of SII. Results: Optimal SII cut-off was 788. Twenty-nine/forty-nine patients had high SII (≥788) before initiation of ipilimumab plus nivolumab. High SII was an independent prognostic factor for worse progression-free (HR 2.70, p = 0.014) and overall survival (HR 10.53, p = 0.025). The clinical benefit rate was higher for patients with low SII if compared to high SII (80% vs. 32.1%). An increase in SII > 20% from baseline after twelve weeks of therapy was associated with progression at first imaging (p = 0.003). Conclusions: SII is both prognostic and predictive and could refine decision making in patients with unclear imaging on therapy with ipilimumab plus nivolumab.

Distinct outcomes in Hispanic/Latinx and non-Hispanic/Latinx patients with metastatic renal cell carcinoma (mRCC) treated with first-line ipilimumab plus nivolumab (ipi/nivo).

4554 Background: Subgroup analyses have reported differences in clinical outcomes by ethnicity in patients (pts) receiving immune checkpoint inhibitors (Cheng et al Ann Oncol 2019; Peravali et al World J Clin Oncol 2021). We sought to compare real-world outcomes between Hispanic/Latinx and non-Hispanic/Latinx mRCC pts treated with first-line ipi/nivo within a safety-net healthcare system and at a tertiary care center in Southern California. Methods: We performed a retrospective analysis of mRCC pts who received ipi/nivo within the Los Angeles County Department of Health Services (a safety-net healthcare system) and the City of Hope Comprehensive Cancer Center (a tertiary oncology center) between Jan 1, 2015 and Dec 31, 2021. Pts were identified using institutional databases and clinical data were compiled from electronic health records. Pts with pathologic diagnosis of stage IV mRCC, age &gt; 18 years and receipt of ipi/nivo as first-line therapy were included. Progression-free survival (PFS) was analyzed using the Kaplan-Meier method and covariates were adjusted using multivariate Cox proportional hazards regression. Results: Of 96 pts, 67 (70%) were male, 90 (94%) had clear-cell histology, and 89 (93%) had intermediate/poor IMDC risk. Forty-two pts (44%) were Hispanic/Latinx while the remainder were non-Hispanic/Latinx (44 pts [46%] White, 7 pts [7%] Asian, and 3 pts [3%] Other). Fifty (52%) and 46 (48%) pts received their care at a tertiary care center and within a safety-net healthcare system, respectively. Median age, IMDC risk classification, BMI, and number of comorbidities were similar between both groups. Pooled analysis by ethnicity revealed significantly shorter PFS in Hispanic/Latinx vs non-Hispanic/Latinx pts (HR 1.60, 95% CI 1.04-2.48, p = 0.03). At 12 months, 19% of Hispanic/Latinx pts (95% CI, 9-32) and 35% of non-Hispanic/Latinx pts (95% CI, 23-48) were alive and progression-free. There was no difference in PFS between pts at the safety-net hospital system vs tertiary care center (HR 1.32, 95% CI 0.87-2.02, p = 0.19). Conclusions: Our real-world analysis of mRCC pts demonstrated poorer outcomes with ipi/nivo in Hispanic/Latinx pts. We are currently interrogating multiple social determinants of health that may contribute to these concerning disparities.

Utilization and Safety of Ipilimumab Plus Nivolumab in a Real-World Cohort of Metastatic Renal Cell Carcinoma Patients.

Ipilimumab plus nivolumab was associated with a survival benefit in a phase III clinical trial of first-line treatment for metastatic renal cell carcinoma (mRCC). In this study, mRCC patients from the Canadian Kidney Cancer Information System (CKCis) database who received first-line ipilimumab plus nivolumab were analyzed to determine the safety and outcomes in a real-world setting. Patients who received ipilimumab plus nivolumab as first-line therapy for mRCC in CKCis, were identified, and the amount of treatment received, discontinuation rates, and reasons for discontinuing treatment were determined. Toxicity data, including type and grade, were collected. Efficacy outcomes of interest included overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). The cohort included 195 patients, the majority with clear cell histology (74%). All 4 cycles of ipilimumab plus nivolumab were administered in 124 patients (64%). Progressive disease (n=87; 45%) and toxicity (n=36; 18%) were the most common causes for discontinuing treatment. Several patients (n=18) did not receive all 4 doses of ipilimumab but received single agent nivolumab. The estimated median OS was 54.5 months (95% CI, 17.7 - NE) and 12-month OS was 72.2% (95% CI, 65.0 - 79.3). Median PFS was 7.4 months (95% CI 5.3 - 10.2) and ORR was 42.5%. Patients who received all 4 cycles of ipilimumab plus nivolumab had better ORR (50% vs. 28%) and a longer PFS and OS than those who received less than 4 cycles (P < .0001). Ninety-five AEs were documented in 72 patients who required dose reduction/change, with colitis being the most frequent. In this real-world cohort of treatment-naïve mRCC patients, outcomes, and safety were comparable to previously reported clinical trial data.

Early primary tumor response in metastatic RCC patients treated with immune checkpoint inhibitors-based combinations.

349 Background: 25-30% of renal cell carcinoma presents with metastases (mRCC) at diagnosis. The activity of immune checkpoint inhibitor (ICI)-combinations on the primary tumor (PT) is debated. Patients and Methods: mRCC patients (pts) with PT who received first-line nivolumab plus ipilimumab (N/I) or pembrolizumab plus axitinib (P/A) were included. We investigated the early primary tumor response (EPTR) at the first radiological assessment. Results: 73 pts were included. The median early reduction of the PT longest diameter was 12.4% with P/A versus 6.2% with N/I (p = 0.42). We evaluated if the type of EPTR could affect the metastases response. Among pts with PT stable disease (SD), 8.3% had metastatic disease progression (PD) with P/A and 34.8% with N/I. Early PT partial response (PR) was associated with no metastatic PD with both N/I and P/A. The 2 pts with PT PD had also metastatic PD to P/A. Of the 3 PT with PD to N/I, 1 had metastatic SD and 2 PD. In the overall population, of the 94.1% without PT progression (PR+SD), 47.5% had metastatic PR, 35.6% SD, 16.9% PD. Conclusions: ICIs-combinations achieved an early PT PR in about 10-20%, without any complete responses. Only a small percentage of PT had an early PD, mainly associated with metastatic PD. However, among those PT without an early progression, metastatic PR can be achieved in approximately 50% of cases.[Table: see text]

Real-world evidence for option value in metastatic melanoma.

BACKGROUND: The concept of real option value (ROV) suggests there is added value in treatments that extend life because they enable a patient to live long enough to benefit from future innovative treatments. Real-world evidence of this novel value element is scant, limiting its consideration in formal value assessments. OBJECTIVE: To calculate the ROV in clinical practice of ipilimumab for treatment of advanced melanoma, with evaluation of survival until availability of cancer immunotherapy (CIT). METHODS: This was a retrospective analysis of electronic health records from a US nationwide deidentified database including data from approximately 280 cancer clinics. Participants were patients with advanced or metastatic melanoma diagnosed after January 1, 2011, who initiated treatment before April 19, 2015, and were treated with first-line and second-line ipilimumab or chemotherapy, up to availability of CIT. The proportions of patients surviving and receiving CIT and overall survival by line of therapy were calculated. Baseline demographics were used to weight Kaplan-Meier curves using stabilized inverse probability of treatment weighting. ROV was estimated for patients receiving first-line or second-line ipilimumab with or without subsequent CIT and first-line or second-line chemotherapy with or without subsequent CIT. RESULTS: Overall, 721 patients were included in the study, with a total sample size of 733 (12 patients in both groups). For first-line ipilimumab, 50% of patients survived to the availability of CIT, while only 18% of first-line chemotherapy users survived to the same date. For second-line ipilimumab, 37% of patients survived to availability of CIT vs 21% of patients using second-line chemotherapy. 45% of first-line ipilimumab and 52% of second-line ipilimumab patients who survived to the availability date received CIT. ROV for first-line ipilimumab averaged 3.7 months of additional survival, while those who initiated second-line ipilimumab averaged 4.8 months. The combined estimated ROV was 3.9 months. CONCLUSIONS: This study provides real-world evidence of ROV and adds to the growing literature that may support inclusion of this novel value concept for innovative therapies alongside more traditional measures of value. Further evaluation of ROV in clinical areas with varying survival and innovation is warranted. DISCLOSURES: This study was funded by Genentech, Inc., which was involved in conducting the study. Wong and To are employees of Genentech, Inc. Veenstra, Garrison, Li, and Lee have served as consultants to Genentech, Inc. Data were presented at ISPOR 2021; May 17-20, 2021; as a virtual podium presentation.

Melanoma brain metastases that progress on BRAF-MEK inhibitors demonstrate resistance to ipilimumab-nivolumab that is associated with the Innate PD-1 Resistance Signature (IPRES)

BackgroundMelanoma brain metastases (MBMs) are a challenging clinical problem with high morbidity and mortality. Although first-line dabrafenib–trametinib and ipilimumab–nivolumab have similar intracranial response rates (50%–55%), central nervous system (CNS) resistance...

EC2 Modeling Approaches to Estimate Realized Real Option Value of Ipilimumab in Metastatic Melanoma

Real option value (ROV) is created when a drug enables a patient to live long enough to benefit from a future innovation, but few if any studies have quantified ROV observed in the real world. We aimed to estimate the realized ROV using real-world data (RWD) using ipilimumab in melanoma as a case study. We developed a framework for calculating ROV using RWD that accounted for the health gain in the standard therapy arm as well as the actual uptake of future innovative drugs. We developed a Markov model to estimate the quality-adjusted life-years (QALYs) gained with ipilimumab compared to chemotherapy for patients with or without subsequent cancer immunotherapy (CIT). The realized ROV of ipilimumab and chemotherapy was the additional health gain due to the CIT. To inform the model parameters, we used the nationwide Flatiron Health electronic health record-derived de-identified database to estimate real-world progression-free survival (PFS) and overall survival (OS) curves for patients stratified by the first- and subsequent-lines of therapy. Patients diagnosed with metastatic or advanced unresectable melanoma and started treatment between 1/1/2011 and date of 1st CIT approval (9/4/2014) were included. The incremental QALYs gained for ipilimumab vs. chemotherapy without subsequent CIT were 1.74. With subsequent CIT, the incremental QALYs increased by 0.92, 0.60, 0.33, 0.18, 0.10, and 0.02 when CIT became available 0, 3, 6, 9, 12, and 24 months after the initiation of first-line ipilimumab, respectively. The results were sensitive to the survival benefit of ipilimumab, the survival benefit of subsequent CIT, and the uptake of CIT. This is the first study to demonstrate the realized ROV using RWD. The realized ROV was between 1%–54% of conventional value for patients diagnosed within 2 years before CIT availability. Further studies are needed to understand ROV in other diseases, particularly those with longer survival times.

Sequential immunotherapy in melanoma: is it a realistic alternative to dual immunotherapy?

The treatment of metastatic melanoma has been revolutionised with the emergence of checkpoint inhibitors. The combination of Ipilimumab and Nivolumab offers the longest overall survival but is considerably more toxic than single-agent therapy. For patients who received single-agent immunotherapy it is unclear whether second-line immunotherapy is efficacious or tolerable. This study looked at outcomes for patients treated with sequential immunotherapy and compared them to patients who received dual immunotherapy. Fifty-eight patients received both Ipilimumab and an anti-PD-1 agent during the 5-year period, twenty-seven received dual immunotherapy, twenty received first-line Ipilimumab and eleven received an anti-PD-1 agent first line. The median overall survival (OS) was 24.8 months. The 5 year survival was greatest in patients treated with dual immunotherapy (42%) compared to first-line anti-PD-1 (33.3%) and first-line Ipilimumab (0%). As second-line treatments, anti-PD-1 agents had a median OS of 16.5 months compared to Ipilimumab at 3.4 months. 77.8% of patients had grade 3/4 toxicity with dual immunotherapy compared to 10% of patients treated with first-line Ipilimumab and 0% with anti-PD-1 agents. In the second line, 72.7% of patients treated with Ipilimumab experienced grade 3/4 toxicity, compared to 20% of patients treated with second-line anti-PD-1 agents. This study suggests Ipilimumab is not efficacious in patients who progress after anti-PD-1 agents, and this sequential approach does not avoid toxicity. The emergence of new checkpoint inhibitors will hopefully provide more efficacious treatment options for patients unable to tolerate Ipilimumab.

Outcomes of first-line (1L) ipilimumab and nivolumab (IPI-NIVO) and subsequent therapy in metastatic renal cell carcinoma (mRCC): Results from the International mRCC Database Consortium (IMDC).

4554 Background: IPI NIVO is approved for 1L treatment of IMDC intermediate/poor risk mRCC based on the CHECKMATE 214 trial. Herein, we report the clinical effectiveness of 1L IPI NIVO and second line (2L) therapy in the real-world setting. Methods: Using the IMDC dataset, patients (pts) treated with 1L IPI NIVO were identified. The outcomes of interest were 1L and 2L overall response rate (ORR), treatment duration (TD), time to next treatment (TTNT), and overall survival (OS). Results: 706 pts were included: 9% (57/614), 58% (354/614), and 33% (203/614) were IMDC favorable (fav), intermediate (int), and poor risk, respectively. Median age was 61 years. The majority of pts were males (71%), had clear cell histology (85%), and underwent nephrectomy (61%). 36%, 19%, and 8% of patients had bone, liver, and brain metastases, respectively. The 12-month OS for pts with IMDC fav, int, and poor risk disease was 92%, 79%, and 56%, respectively (p&lt;0.01). The corresponding estimates for 24 months were 80%, 69%, and 38% (p&lt;0.01). Pts who responded (39%) were more likely to have better IMDC risk category (p=0.02), received nephrectomy (p=0.04), normal neutrophil count (p&lt;0.01), and clear cell histology (p=0.01). Pts with progressive disease as best response (27%) were more likely to have not received nephrectomy (p&lt;0.01), worse IMDC risk category (p=0.02), bone metastases (p=0.01), liver metastases (p=0.04), and non-clear cell histology (p=0.01). Of the 66% (466/706) of pts who discontinued 1L IPI NIVO, 51% (236/466) received 2L therapy: sunitinib (40%), cabozantinib (25%), pazopanib (18%), axitinib (8%), and others (9%). The ORR, median TD, and median OS for those who received either sunitinib, cabozantinib, pazopanib or axitinib was 16%, 4.5 months (mo) (95% CI 3.7-5.6), and 14.5 mo (95% CI 10.9-25.9), respectively. 33% (129/386) of pts discontinued IPI NIVO due to irAEs. Conclusions: Our study benchmarks the real-world experience of 1L IPI NIVO in mRCC. IMDC criteria is prognostic for clinical outcome. Tyrosine kinase inhibitors have clinical activity post IPI NIVO.[Table: see text]

Patterns and management of progression on first-line ipilimumab combined with anti-PD-1 (IPI+PD1) in metastatic melanoma (MM) patients.

9533 Background: First line IPI+PD1 induces long-term response in 36% of MM patients (pts); however, the majority of pts will progress and may require further treatment, which is yet to be established. We studied the patterns of progressive disease (PD) on 1st line IPI+PD1, and the management and outcomes in MM pts. Methods: Demographics, disease characteristics, nature of PD, subsequent treatments and outcomes were examined in MM pts with PD on 1st line IPI+PD1. Multivariable analyses (MVA) identified factors associated with patterns of PD: innate resistance (IR) = PD as best response or stable disease (SD) &lt; 6 mo; acquired resistance (AR) = PD after initial response or SD ≥ 6 mo. Results: 310 MM pts from 14 melanoma centres were included; 208 (67%) had PD during and 102 (33%) after ceasing IPI+PD1. Overall med. progression-free survival (mPFS) was 2.8 mo (CI 95% 2.7 – 3.0); 187 pts (60%) had IR (mPFS 2.2 [2.1 – 2.5]), 112 pts (36%) had AR (mPFS 8.5 [7.2 – 10.2]) and 11 pts (4%) had pseudoprogression, i.e. PD followed by response without changing treatment (mPFS 2.7 mo [1.4 – NA]). On MVA, pts with ECOG PS ≥ 1 were more likely to have IR vs AR; and within IR pts, those with head &amp; neck primary melanomas and lung metastases were more likely to have PD &lt; 1.5 mo. Most pts with IR (68%) had PD in multiple sites, while 61% AR pts had PD in a single site. Brain was most common site of single organ PD; 49% of IR and 41% of AR. Med. follow-up from PD was 32.7 mo (28.1 – 36.8). After PD, 61 pts (20%) had best supportive care (26% of IR and 11% of AR pts). 259 pts (80%) received further treatment: 39% IR pts had systemic treatment (ST) only and 27% had ST + local; 31% AR pts had ST only and 39% had ST + local. Of 200 pts (65%) who had ST(+/-local), 54% had 1 line of ST and 46% had ≥ 2; 1st line ST (ST1) was BRAF/MEKi in 36% of pts, PD1 in 32%, IPI+PD1 in 7%, investigational drugs in 11%, chemotherapy in 9% and others in 5%. ORR in IR pts was lower than in AR pts for every type of ST1 (see Table). Med. OS from PD was 11.4 mo (CI 95% 9.6 – 16.1); IR 6.4 mo (CI 95% 5.6 – 10.2) and AR 26.1 mo (CI 95% 17.1 – NA). Conclusions: These data suggest longer OS from PD for AR vs IR pts independent of ST type. BRAF/MEKi, rechallenge with PD1+/-IPI and investigational drugs showed activity after PD on IPI+PD1, while chemotherapy has no role in this context.[Table: see text]

Retrospective analysis of immune-related adverse events (irAE) in metastatic renal cell carcinoma (mRCC) patients treated with first-line ipilimumab and nivolumab (I+N).

e17094 Background: Incidence of irAEs has grown with increasing use of immunotherapies and can affect multiple organ systems: I+N followed by N maintenance is approved as front-line therapy for intermediate &amp; poor-risk mRCC. Most common associated irAEs are gastrointestinal, dermatologic &amp; hepatic. The purpose of this retrospective, single-institution analysis is to describe irAE incidence and identify risk factors in mRCC pts treated with I+N. Methods: Patients with mRCC started on first-line I+N at the Cleveland Clinic between March 2018 and April 2019 were retrospectively reviewed. Patient demographics, tumor characteristics, radiologic response and irAE history were collected. IRAE incidence was estimated with cumulative incidence. Risk factors for IRAE were assessed with Fine and Gray competing risk regression. Results: Of forty-six (N = 46) pts with mRCC treated with 1L I+N, median age 60 (range: 34-81): 95% clear cell histology; IMDC risk 20%/56%/24% favorable/intermediate/poor respectively. 67% (N = 31) experienced ≥ 1 irAE with total of N = 44 irAEs. Most common systems affected included Gastrointestinal (27%), Musculoskeletal (23%), Dermatologic (14%) &amp; Renal (9%). Most common irAEs were colitis (23%), arthralgia (16%), transaminitis (9%). 82% of irAEs were treated with front-line glucocorticoids and 14% required additional immunosuppressants. 82% of irAEs were attributed to the I+N induction phase and 32% required discontinuation of I+N. 1 pt died as result of irAEs. Incidence of irAEs at 1, 3 and 6 months was 20%, 52%, 59% respectively. Among 31 pts who developed irAEs, median onset from start of I+N was 1.6 months (range 0-11.7). None of the variables examined (i.e. age at I+N initiation, gender, race, IMDC risk, ECOG status, stage at diagnosis, prior nephrectomy, prior radiation therapy) were identified as statistically-significant risk factors for irAEs. Development of irAEs was not associated with progression-free survival (PFS). Conclusions: IRAEs from I+N in mRCC tend to occur early in treatment course and are associated with high rates of treatment discontinuation and need for corticosteroids and other immunosuppressants. The lack of association between baseline factors and development of irAEs should increase physician alertness to potential irAEs with any change in clinical status.