Nivo Monotherapy Research Articles

Advanced Renal Cell Cancer Combination Immunotherapy Clinical Trial (ARCITECT; HCRN GU 22-587)

Abstract Background First-line treatment for patients with metastatic clear cell renal cell carcinoma (mccRCC) often includes an anti-PD1 inhibitor in combination with either an anti-CTLA inhibitor (IO/IO) or a VEGF receptor tyrosine kinase inhibitor (TKI) (IO/TKI). Although some patients treated with nivolumab/ipilimumab (Nivo/Ipi) (IO/IO) experience durable responses leading to treatment free intervals, over two-thirds experience disease progression. Resistance to Nivo (anti-PD1) monotherapy has been associated with increased presence of a subpopulation of Tregs in the tumor microenvironment. Botensilimab (Bot) is an IO agent that leverages novel FcyR-associated mechanisms of action to enhance T cell priming, deplete intratumoral Tregs and enhance myeloid activation. Combination botensilimab/balstilimab (Bot/Bal) (anti-CTLA/anti-PD1) has shown impressive anti-tumor activity in diseases where Nivo/Ipi has shown little to no efficacy. Methods ARCITECT is a phase II, multicenter study evaluating the efficacy and safety of Bot/Bal relative to Nivo/Ipi. Patients with mccRCC (favorable, intermediate, or poor risk), no prior systemic therapy (including adjuvant or neoadjuvant), and at least one measurable lesion as defined by RECIST 1.1 are eligible for enrollment. 120 patients will be randomized in a 2:1 fashion to Arm A (Bot/Bal induction followed by Bal maintenance) or Arm B (Nivo/Ipi induction followed by Nivo maintenance) each for a maximum of 2 years. Stratification factors include IMDC risk groups and sarcomatoid histology. The primary endpoint is overall response rate (ORR) per RECIST 1.1. We hypothesize that Bot/Bal will lead to a superior ORR (55%) relative to Nivo/Ipi (40%). This trial has > 90% power to detect the alternative hypothesis while maintaining a one-sided significance level of not more than 0.10 using the exact binomial. The study will be monitored for early stopping in favor of the null hypothesis based on a Simon’s two stage design. In the first stage, 69 patients will be enrolled (Arm A:46 and Arm B:23). If at the end of the first stage, Arm A has either at least 18/42 (42.8%) of eligible patients responding or an ORR at least numerically equivalent to that for eligible patients in Arm B, then the trial will progress to the second stage. The primary endpoint will be met if there are 38/80 responders (ORR > 47.5%) in Arm A. Key secondary endpoints include landmark progression-free survival, treatment-free survival and rates of immune-related adverse events. Correlative studies will explore immune and molecular predictors of response and resistance to IO/IO in tumor and blood. Clinical trial information: NCT05928806. Results

Advanced renal cell cancer combination immunotherapy clinical trial (ARCITECT; HCRN GU 22-587).

TPS4614 Background: First-line treatment for patients with metastatic clear cell renal cell carcinoma (mccRCC) often includes an anti-PD1 inhibitor in combination with either an anti-CTLA inhibitor (IO/IO) or a VEGF receptor tyrosine kinase inhibitor (TKI) (IO/TKI). Although some patients treated with nivolumab/ipilimumab (Nivo/Ipi) (IO/IO) experience durable responses leading to treatment free intervals, over two-thirds experience disease progression. Resistance to Nivo (anti-PD1) monotherapy has been associated with increased presence of a subpopulation of Tregs in the tumor microenvironment. Botensilimab (Bot) is an IO agent that leverages novel FcyR-associated mechanisms of action to enhance T cell priming, deplete intratumoral Tregs and enhance myeloid activation. Combination botensilimab/balstilimab (Bot/Bal) (anti-CTLA/anti-PD1) has shown impressive anti-tumor activity in diseases where Nivo/Ipi has shown little to no efficacy. Methods: ARCITECT is a phase II, multicenter investigator initiated trial evaluating the efficacy and safety of Bot/Bal relative to Nivo/Ipi. Patients with mccRCC (favorable, intermediate, or poor risk), no prior systemic therapy (including adjuvant or neoadjuvant), and at least one measurable lesion as defined by RECIST 1.1 are eligible for enrollment. 120 patients will be randomized in a 2:1 fashion to Arm A (Bot/Bal induction followed by Bal maintenance) or Arm B (Nivo/Ipi induction followed by Nivo maintenance) each for a maximum of 2 years. Stratification factors include IMDC risk groups and sarcomatoid histology. The primary endpoint is overall response rate (ORR) per RECIST 1.1. We hypothesize that Bot/Bal will lead to a superior ORR (55%) relative to Nivo/Ipi (40%). This trial has > 90% power to detect the alternative hypothesis while maintaining a one-sided significance level of not more than 0.10 using the exact binomial. The study will be monitored for early stopping in favor of the null hypothesis based on a Simon’s two stage design. In the first stage, 69 patients will be enrolled (Arm A:46 and Arm B:23). If at the end of the first stage, Arm A has either at least 18/42 (42.8%) of eligible patients responding or an ORR at least numerically equivalent to that for eligible patients in Arm B, then the trial will progress to the second stage. The primary endpoint will be met if there are 38/80 responders (ORR > 47.5%) in Arm A. Key secondary endpoints include landmark progression-free survival, treatment-free survival and rates of immune-related adverse events. Correlative studies will explore immune and molecular predictors of response and resistance to IO/IO in tumor and blood. Clinical trial information: NCT05928806 .

Molecular analysis of the HCRN GU16-260-Cohort A phase II study of first-line (1L) nivolumab (nivo) and salvage nivo + ipilimumab (ipi) in patients (pts) with advanced clear cell renal cell carcinoma (accRCC).

4546 Background: Seven molecular subsets of ccRCC have been proposed: 1: Angiogenic/Stromal; 2: Angiogenic; 3: Complement/Ω-oxidation; 4: T-effector/Proliferative; 5: Proliferative; 6: Stromal/Proliferative; and 7: snoRNA (Motzer et al. Can Cell 2020). In an analysis of IMmotion 151, which compared 1L atezolizumab/bevacizumab to sunitinib, combination immune checkpoint blockade (ICB) and anti-VEGF therapy was associated with improved progression-free survival (PFS) and overall survival (OS) in clusters (CLs) 4 and 5, increased PFS in CL 7, and decreased OS in CL 2 (Motzer Can Cell 2020, Motzer JAMA Onc 2022). CL 4 was also associated with higher PFS and objective response rate (ORR) in >1L nivo compared to everolimus in an analysis of CheckMate-025 (Denize CCR 2022). To date, outcomes have not been compared among accRCC subtypes in pts who received 1L pure ICB. Methods: In HCRN GU16-260-Cohort A, pts with accRCC received 1L nivo monotherapy until progressive disease (PD), unacceptable toxicity, or completion of 96 weeks of therapy. Pre-treatment FFPE tumor samples were obtained. A machine learning model (random forest) was trained on annotated transcriptomic data from bulk RNA-seq and used to classify tumors that passed quality control into one of the 7 molecular subtypes. Results: 70 tumor samples contained adequate RNA quality and were classified as outlined in the table. IMDC rates and ORR (40%) for the RNAseq population closely matched those of the whole study (Atkins JCO 2022). No tumors were classified in CL 7 and only 3 in CL 5. Tumors in each IMDC group contained a mix of subtypes. The highest ORR occurred in CL 4 (6/10, 60.0%); CL 4 median PFS was 15.2 months and 1-year PFS was 60%. ORR was also high in CLs 1 and 3 at 52.4% and 40.0%, respectively and lowest in CL 2 (12.5%). PD as best response (5/10, 50.0%) and short PFS (5.1 months) were seen in CL 6. Conclusions: Consistent with prior analyses with combination ICB + anti-VEGF and >1L ICB, CL 4 was associated with robust 1L ICB monotherapy antitumor efficacy. Surprisingly, ORR was also high in CLs 1 and 3. In this small dataset, transcriptomic signatures enriched for but did not fully predict ORR. Future prospective trials are needed to identify more discriminative biomarkers of efficacy for pure ICB therapy.[Table: see text]

Neutralizing GDF-15 in muscle-invasive bladder cancer (MIBC): A neoadjuvant immunotherapy trial of visugromab (CTL-002) in combination with the anti-PD1 antibody nivolumab (GDFather-Neo).

TPS712 Background: Neoadjuvant chemotherapy (NACT) is a well-established treatment modality in MIBC but suffers from limited activity and significant toxicity. Neoadjuvant immunotherapy (I/O) demonstrated clinical safety and efficacy in various solid tumors including MIBC, with potentially less toxicity. Results from previous studies of single-agent I/O indicated a proportion of pathologic complete responses (ypT0N0) similar to that reported with NACT. Therefore, improving ypT0N0 responses remains a major task for treatment of MIBC. Increasing evidence emerged that Growth and Differentiation Factor 15 (GDF-15) plays a critical local immunosuppressive role. Apart from blocking immune-cell entry into tissues GDF-15 also has major impact on the formation of the immune synapse. Many tumors overexpress GDF-15 and have hijacked this mechanism to block I/O therapy success. Various translational research efforts indicated that GDF-15 may play a significant role for immunosuppression and T-cell exclusion in urothelial carcinoma (UC). Visugromab (CTL-002) is a GDF-15 neutralizing IgG4 monoclonal antibody that demonstrated in Phase 1 a favorable safety profile and promising clinical activity with durable and deep responses in PD-1/PD-L1 relapsed/refractory metastatic solid tumors in combination with the anti-PD1 antibody Nivolumab (Nivo)*. The Neo-GDFather trial is intended to investigate the combination of Visugromab with Nivo vs. Nivo monotherapy as neoadjuvant therapy for MIBC in patients (pts) who are ineligible for or elect not to undergo NACT. Primary endpoints are the complete pathologic response rate and radiologic response. Methods: Multi-center, parallel-cohorts and single-blinded Phase 2 study of neoadjuvant therapy in pts planned for radical cystectomy (RC). A total number of 30 subjects with stage T2-T4N0M0 MIBC will be enrolled and assigned 1:1 to receive either Nivo + Visugromab or Nivo + Placebo after stratification for CPS PD-L1 expression and cT-stage. Other inclusion criteria comprise an ECOG performance status 0-1 and a pure/predominant UC histology. No statistical assumptions were undertaken at this stage.Treatment consists of three 4-week cycles [i.v., Q4Wk], and RC is planned 4-8 weeks after last dose of study drug. After RC, pts will follow standard recommendations of EAU guidelines. Primary endpoints are the proportion of ypT0N0 response and radiologic response rate. Secondary endpoints comprise additional efficacy parameter, surgical and medical safety, PK and PD assessments. Translational research includes evaluation of immunologic parameters in the tumor, other immune-correlates and molecular profiles, as well as evaluation of treatment-emergent cytokine and chemokine profiles in peripheral blood. * Melero et al., #2501 ASCO Annual Meeting 2023 Oral Abstract Session. Clinical trial information: Not yet available.

A Phase 2 Study of Nivolumab for Relapsed/Refractory Multiple Myeloma or Non-Hodgkin Lymphoma Following CAR-T Therapy

Background: Treatment options are limited for patients with relapsed multiple myeloma (MM) or non-Hodgkin lymphoma (NHL) after CAR-T failure. While checkpoint inhibition may theoretically improve T-cell effector activity following CAR-T, a prospective trial of pembrolizumab (a monoclonal antibody targeting PD-1 on T-cells) following CD19 CAR-T in NHL showed an ORR of only 25% (Chong Blood 2022). In a recent multicenter NHL cohort (Major Blood Advances 2023), responses were similarly low with both pembrolizumab and nivolumab (nivo). However, nivo has not been studied prospectively in this setting, and the efficacy of checkpoint inhibition after CAR-T failure in MM has not been characterized. Methods: We conducted a single-center phase 2 trial (NCT04205409) of nivo for MM or NHL pts with relapse following any CAR-T product (including investigational products) as their last line of therapy. Nivo monotherapy was dosed 480mg IV every 4 weeks until PD or toxicity. The primary endpoint was overall response rate (ORR) by IMWG or Lugano criteria. Secondary endpoints included safety data for AEs and immune-related AEs (irAEs) using CTCAE v5.0 as well as post-nivo CRS/ICANS using ASTCT criteria. Other endpoints included duration of response (DoR), PFS, CAR-T expansion following first nivo dose, and PD-L1/PD-1 IHC expression on tumor biopsies. Results: We enrolled 20 pts (11 MM, 9 NHL) as detailed in Table 1. Prior to nivo, the best response to CAR-T had been CR in 64% of MM pts and 44% of NHL pts, while 1 MM pt and 1 NHL pt had experienced PD as best response. Median time between CAR-T infusion & C1D1 nivo was 624 days (range 59-1211) in MM and 149 days (range 34-506) in NHL. The ORR was 15% overall: 18% (2/11) for MM and 11% (1/9) for NHL. Characteristics of the 3 responders are detailed in Table 2. Both responders with MM had previously received fully human CAR-T therapies; in NHL, the sole response was in a patient who had received commercial axi-cel. In all 3 cases, clinical benefit was evident following a single nivo dose. Both MM patients achieved a VGPR by light chains (>95% reduction) within 4 weeks; in one patient, PET-CT showed complete resolution of a plasmacytoma that had measured 8.6cm one week before C1D1 nivo. DoR was 687 days for this patient and ≥198 days (ongoing) in the other responder with MM. In NHL, the responding patient - who had had a DS4 response at Day +30 then a DS5 response at Day +60 following axi-cel before starting nivo one month later - achieved a complete response (DS3) including resolution of hepatic and splenic lymphomatous lesions. Conversely, in all non-responders, PD was uniformly evident within a month of nivo as well. The most common Grade 3+ AEs were neutropenia (25%), anemia (15%), and sepsis (15%). One MM patient developed secondary MDS. Two irAEs (one Gr2 pneumonitis, one Gr2 rash) occurred, both in non-responders, and both resolved with brief courses of prednisone. CRS or ICANS did not occur following nivo in any pt. There were 3 deaths within 100 days of nivo initiation, all unrelated to treatment and, all in non-responders: two clearly due to PD and one due to hypotensive cardiac arrest (no evidence of myocarditis). The results of ongoing correlative analyses will be presented at the meeting, including post-nivo CAR T-cell expansion data, nivolumab binding assays on T-cells, and PD-L1 tissue expression on tumor biopsies. Conclusions: We found that responses to PD-1 blockade following CAR-T failure are uncommon, confirming prior studies in NHL which demonstrate poor activity in this setting. Our 18% ORR with post-CAR-T nivo in R/R MM (2/11 pts) is notably higher than the 4% ORR (1/27 pts) reported with nivo monotherapy in R/R MM (Lesokhin JCO 2016), although conclusions are difficult to draw with small n. Day +28 responses following a single dose of nivo 480mg were uniformly predictive of long-term efficacy. irAEs were relatively uncommon and manageable with steroids, while CRS and ICANS did not occur. To our knowledge, this is the first prospective evaluation of nivo following CAR-T failure. Given the non-curative nature of BCMA CAR-T, there may be certain pts with MM for whom checkpoint inhibition leads to a meaningful clinical benefit without unacceptable risks. Better tools to identify such patients are needed, and novel correlative data to help identify pre-nivolumab features of responders - particularly in MM - will be presented at the meeting.

Determinants of resistance to nivolumab (nivo) monotherapy investigated through genomic and transcriptomic analysis of renal cell carcinoma (RCC) tumors from the HCRN GU16-260 study.

4524 Background: Nivo monotherapy demonstrated anti-tumor activity in treatment-naïve RCC in Part A of HCRN GU16-260 across all IMDC groups and in multiple histologies. Patient tumor samples were collected to characterize the tumor-immune microenvironmental determinants of effective anti-tumor immunity with nivo. Methods: Whole exome sequencing (WES) was performed on formalin-fixed, paraffin-embedded tissue collected within one year prior to nivo. For single-cell RNA-sequencing (scRNA-seq), eligible patients (pts) with any RCC histology underwent tumor biopsy prior to and/or at resistance to nivo monotherapy. Gene expression signatures discovered through scRNA-seq were used to interrogate previously published bulk transcriptomic data of nivo in the treatment-refractory setting. Results: WES analysis (n = 96 tumors) identified recurrent focal amplifications within chromosome 11q13 (amp11q13), which was observed in 6 of 18 (33.3%) of tumors from pts with progressive disease (PD) compared to 0 of 20 (0%) of tumors from pts with complete or partial response (CR/PR; p = 0.005). amp11q13 was associated with worse progression free survival (PFS; p = 0.008) and overall survival (OS; p = 0.010). ScRNA-seq was performed on tumors from 17 pts (8 with baseline only, 7 with progression only, and 2 with paired baseline and progression samples) across 7 trial sites. Trajectory inference analysis of tumor-infiltrating T cells revealed a bifurcating structure, starting with naïve T cells and ending either in terminally exhausted CD8+ T cells or SLAMF7+ CD8+ T cells. Surprisingly, the SLAMF7+ T cell population expressed high levels of cytotoxic genes (including GZMA, GZMB, GNLY) and markers of tissue residency ( ZNF683/HOBIT and ITGAE/CD103). Of the 14 pts with at least 100 sequenced tumor-infiltrating T cells, the presence of a higher percentage of SLAMF7+ CD8+ T cells (relative to total T cells) was associated with primary resistance to nivo (mean percentage in PD [n = 4] pts 32.7%; stable disease [n = 4] pts, 9.1%; CR/PR [n = 6] pts, 2.2%; p = 0.019 for CR/PR vs PD). Of 172 pre-treatment tumors from the nivo arms of the CheckMate-009/010/025 trials that we analyzed by bulk RNA-seq, a signature score derived using genes expressed in the SLAMF7+ CD8+ T cell trajectory branch was enriched in pts with PD compared to CR/PR as best response (p = 0.032). Conclusions: Bulk genomic and single-cell transcriptomic analyses uncovered somatic alterations (amp11q13) and infiltrating T cell populations ( SLAMF7+ CD8+) associated with resistance to frontline nivo monotherapy in a phase II study in RCC. Additional independent and functional validation studies are in progress.

Economic evaluation for the US of relatlimab and nivolumab (RELA+NIVO) versus nivolumab (NIVO) monotherapy in untreated advanced melanoma.

9539 Background: The RELATIVITY-047 trial demonstrated longer median progression-free survival (PFS) with the combination of RELA+NIVO (10.1 months, 95% CI = 6.4 to 15.7) over NIVO (4.6 months, 95%CI = 3.4 to 5.6) in patients with untreated advanced melanoma (hazard ratio for progression or death = 0.75, 95%CI = 0.62 to 0.92). This economic evaluation aimed to estimate the cost-effectiveness/utility of RELA+NIVO vs. NIVO monotherapy in this setting. Methods: A two state partitioned survival model (PFS, progressed/death) was developed to compare costs and PFS outcome associated with both treatments. PFS curves were digitized and parametric functions fitted. A 5-year time horizon from a US payer perspective with a 3% discount rate/year was considered. Costs of treatment (average sales price), administration and monitoring parameters were derived from Centers for Medicare & Medicaid Services databases; cost of adverse events (grade 3/4 with rate >5%) were derived from prior advanced melanoma economic evaluations. Incremental costs, PFS life years (PFSLY), and PFS quality adjusted life years (PFSQALY) gained (g) were estimated in base case (BCA) and probabilistic sensitivity analyses (PSA). A cost-effectiveness acceptability curve (CEAC) was plotted to determine the probability of either treatment to be cost-effective over the other at different willingness to pay (WTP) thresholds. Results: Exponential regression was used to extrapolate RELA+NIVO and NIVO survival curves. According to the result table shown below, the BCA (PSA) shows an incremental cost of RELA+NIVO over NIVO of $405,663 ($402,936), incremental PFSLY of 0.326 (0.325), and incremental PFSQALY of 0.260 (0.256). The BCA (PSA) ICERs indicated an additional $1,244,365 ($1,239,803) per PFSLY gained (g) and an additional $1,560,242 ($1,573,969) per PFSQALYg. The CEAC curve shows that RELA+NIVO treatment had a 50% probability of being cost-effective regimen at a WTP threshold value of $1,525,000 and 100% probability at a threshold of $3,050,000 or above. Conclusions: In the setting of advanced melanoma, this economic evaluation showed that RELA+NIVO is associated with improvement in LY and QALY, however, at a marked incremental cost, requiring a very high WTP threshold. [Table: see text]

Real-world outcomes in advanced melanoma patients treated with first-line nivolumab plus ipilimumab.

e21552 Background: Nivolumab plus ipilimumab (NIVO+IPI), a first-in-class combination immunotherapy, has dramatically changed the treatment paradigm for melanoma in recent years. The aim of this study was to analyze treatment patterns, treatment response, survival, safety, and healthcare resource utilization with this first-line combination therapy in patients (pts) with advanced melanoma under real-world conditions. Methods: This retrospective analysis included pts with stage 3 unresectable and stage 4 melanoma treated 01/2021-06/2022 with NIVO+IPI at 6 centers in Poland according to uniform criteria. Pts received up to 4 cycles of IPI 3 mg/kg + NIVO 1 mg/kg Q3W followed by maintenance NIVO (240 mg Q2W or 480 mg Q4W) until disease progression, unacceptable toxicity or at the request of the patient or physician. Kaplan-Meier estimator and Log-rank test were used in survival analysis. Results: A total of 291 adults were identified. The median age was 53 years, 42.5% of pts were female, 47% were BRAF-mutated, and 24% of pts received prior adjuvant treatment. At baseline, 19.5% of pts had stage III disease, 14.1% stage M1a, 13.7% stage M1b, 30.1% stage M1c and 23% had M1d disease. Median follow-up time was 11.9 months. The median number of cycles of NIVO+IPI administered was 3, with 47.9% of pts completing 4 cycles. Maintenance NIVO was continued in 52.7% pts who discontinued the combination therapy due to toxicity. Median progression-free survival (mPFS) was 9.8 months (95% CI 6.9–13.4). The longest mPFS was observed in pts with stage M1a (15 months; 95%Cl 3.1–NA) and the shortest in stage M1d pts (5 months; 95%CI 2.8–NA). We observed a statistically significant longer mPFS in pts who continued NIVO monotherapy after discontinuation of combination therapy due to toxicity (13 months, 95% Cl 10.4–NA) compared to those who discontinued immunotherapy (7.1 months, 95% Cl 3.4 –12; p < 0.0001). Median overall survival (OS) was not achieved, with an OS rate of 70% at 12 months (95%Cl 64–76). The objective response rate (ORR) was 39%, with 7.8% of pts achieving a complete response. For pts who received prior adjuvant therapy, the ORR was 24.2%. Treatment-related adverse events (TRAEs) of any grade were observed in 97% of pts and grade 3/4 TRAEs occurred in 29.6% of pts. The most common TRAEs were liver toxicity, colitis, hyperthyroidism, hypothyroidism, and hypopituitarism; the treatment-related hospitalization rate was 23.8% and the median length of hospital stay was 9 days. Conclusions: This real-world study confirms the high efficacy of NIVO+IPI in real-world settings with grade 3/4 toxicity lower than observed in clinical trials. Maintenance of NIVO despite early toxicity during combination treatment appears to have a beneficial effect on patient survival. Therefore, it is extremely important to carefully monitor pts for toxicity, as early intervention helps to avoid severe toxicity and premature discontinuation of treatment.

Phase II study of nivolumab (nivo) in combination with relatlimab (rela) in patients (pts) with active melanoma brain metastases (MBM).

TPS9605 Background: More than half of all pts diagnosed with metastatic melanoma (MM) will develop brain metastases. Despite this prevalence, pts with MBM are excluded from the majority of clinical trials, preventing them from potential benefit of novel therapies. Long-term outcomes of the CheckMate 204 study combining ipilimumab (ipi) (3mg/kg) plus nivo (1 mg/kg) for asymptomatic MBM reported an intracranial (IC) response in 54% of pts. The 36-month IC progression-free survival (PFS) was 54% and overall survival (OS) was 72%. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 55% of pts. RELATIVITY-047, a global phase II/III randomized study, reported on the fixed-dose combination of nivo (480 mg) and rela (a LAG-3–blocking antibody,160 mg) compared to nivo (480 mg) alone for pts with advanced unresectable and untreated melanoma. The combination demonstrated significantly improved PFS and improved OS and objective response rate (ORR) compared to monotherapy. At 19.3 months of median follow-up, only the PFS benefit was statistically significant with a hazard ratio (HR) of 0.78 (95% CI 0.64-0.94). The OS benefit was not statistically significant (HR 0.8, 95% CI 0.64-1.01), and the descriptive ORR was 43.1% compared to 32.6% for single agent nivo. Grade 3 or 4 TRAEs occurred in 21% of pts in the combination group compared to 11% in the monotherapy group with no new safety signals. The nivo/rela combination has been FDA approved for the treatment of pts with MM but has not been studied in pts with MBM. We hypothesize that nivo/rela will be safe and tolerable for pts with MBM and demonstrate favorable outcomes compared to nivo monotherapy with fewer AEs in contrast to ipi/nivo combination. Methods: This single arm, single center, open-label phase II trial will evaluate the safety and efficacy of nivo/rela in pts with MBM (NCT05704647). 30 MBM pts who are treatment naïve to anti-PD-1 therapy will be enrolled. At least one unirradiated parenchymal brain metastasis at least 5 mm or larger is required for inclusion. Asymptomatic pts not requiring steroids for the management of their neurological symptoms are eligible. Pts requiring urgent local therapy with radiation or surgery are not eligible. Pts will be treated with nivo (480 mg)/rela (160 mg) every 4 weeks for up to 25 cycles, disease progression, or unacceptable toxicity. The primary objective is to evaluate IC ORR (CR + PR) by MRI per modified RECIST 1.1 criteria. Monitoring for futility will be performed using the Bayesian Optimal Phase 2 (BOP2) design. Thirty evaluable patients will provide 82% power to detect a difference between the historical IC ORR of 20% for nivo alone to a targeted ORR of 40% for nivo/rela. Longitudinal research blood, tissue, and microbiome samples will be collected along with neurocognitive assessment and quality of life surveys. Clinical trial information: NCT05704647 .

Neoadjuvant nivolumab alone or in combination with relatlimab or ipilimumab in resectable head and neck squamous cell carcinoma (HNSCC).

6018 Background: PD-1 inhibition using nivolumab (nivo) monotherapy is modestly effective in metastatic HNSCC. Neoadjuvant trials using nivo may permit development of more effective combinations in surgically resectable HNSCC. We evaluated combinations with nivo plus additional immune checkpoints, CTLA-4 (ipilimumab, ipi) and LAG-3 (relatlimab, rela). Methods: Phase II randomized trial of neoadjuvant nivo alone (240 mg q2 weeks), or with ipi (1 mg/kg q3 weeks) or rela (160 mg q4 weeks) for 4 weeks prior to surgery. Response was scored using RECIST and standard pathologic response criteria. Patients were stratified by p16, PD-L1, and LAG-3, with staining assessed by immunohistochemistry. Freshly digested tumors were subjected to single cell RNA sequencing (scRNAseq) for T cell receptors and gene pathways to identify biomarkers of response or progression. The Cochran-Armitage trend test was used to explore associations with increasing pathological response efficacy. Results: 41 patients (pts) have been enrolled, with 33 evaluable for this analysis. Of these 33, median age is 63 (32-81), primary site oral cavity (n=25), oropharynx (n=5, 3 HPV), larynx (n=3), clinical T2 (n = 5), T3 (n = 12), T4 (n = 13), and cN0/1 (n = 22), cN2 (n = 9), and PD-L1 CPS > 1 (n=25). There were no serious study drug-related AEs or unexpected surgical delays/complications. Pathologic response (Table) was more frequent with nivo/rela (11/13) vs. nivo/ipi (6/10) or nivo (4/10). Partial (>50%) or major (>90%) pathologic responses were more frequent and deeper in the combination arms. Minor (<50%) pathologic responses were more frequent with nivo/rela, and similar between nivo/ipi and nivo. There was no association between RECIST response, PD-L1, or LAG3 and pathologic response. Combined PD-L1 and LAG3 expression was not associated with pathologic response in the nivo/rela arm, however more patients with combined positivity had a >50% response (4 vs. 0). Expansion of CD8+ T cells, as well as expanded proportion of CD8+ CXCL13+ T cells in responder tumors were identified in post-treatment specimens using scRNAseq. Conclusions: Neoadjuvant nivo/ipi or nivo/rela combinations were safe and associated with promising pathologic responses compared to nivo monotherapy. Anti-tumor CD8+ T cell populations and targetable pathways are emerging in responder patients. The trial continues to enroll and further evaluation of this strategy is warranted. Clinical trial information: NCT04080804 . [Table: see text]

Neutralizing GDF-15 in muscle-invasive bladder cancer (MIBC): A neoadjuvant immunotherapy trial of visugromab (CTL-002) in combination with the anti-PD1 antibody nivolumab (NEO-GDFATHER).

TPS595 Background: Neoadjuvant chemotherapy (NACT) is a well-established treatment modality in MIBC but suffers from limited activity and significant toxicity. Recently, neoadjuvant immunotherapy (I/O) has demonstrated clinical safety and efficacy in various solid tumor indications including MIBC, with potentially less toxicity. Results from previous studies of single-agent I/O indicated a proportion of pathologic complete responses (ypT0N0) similar to that reported with NACT. Therefore, improving ypT0N0 responses remains a major task for successful treatment of MIBC in the future. Increasing evidence has emerged that Growth and Differentiation Factor 15 (GDF-15) plays a critical local immunosuppressive. Apart from blocking immune-cell entry into tissues GDF-15 also has major impact on the formation of the immune synapse. Many tumors overexpress GDF-15 and have hijacked this mechanism to block I/O therapy success. Various translational research efforts have indicated that GDF-15 may play a significant role for immunosuppression and T-cell exclusion in urothelial carcinoma (UC). Visugromab (CTL-002) is a GDF-15 neutralizing IgG4 monoclonal antibody that has demonstrated in Phase 1 a favorable safety profile and promising clinical activity with durable and deep responses in PD-1/PD-L1 relapsed/refractory metastatic solid tumors in combination with the anti-PD1 antibody Nivolumab (Nivo)*. This clinical trial is intended to investigate the combination of Visugromab with Nivo vs. Nivo monotherapy as neoadjuvant therapy for MIBC in patients (pts) who are ineligible for or elect not to undergo NACT. Primary endpoints are the complete pathologic response rate and radiologic response. Methods: This is a multi-center, parallel-cohorts and single-blinded Phase 2 study of neoadjuvant therapy in pts planned for radical cystectomy (RC). A total number of 30 subjects with stage T2-T4N0M0 MIBC will be enrolled and assigned 1:1 to receive either Nivo + Visugromab or Nivo + Placebo after stratification for CPS PD-L1 expression and cT-stage. No statistical assumptions have been undertaken at this stage. Treatment consists of three 4-week cycles [i.v., Q4Wk], and RC is planned 4-8 weeks after last dose of study drug. After RC, pts will follow standard recommendations according to EAU guidelines. Primary endpoints are the proportion of ypT0N0 response and radiologic response rate. Secondary endpoints comprise additional efficacy parameter, surgical and medical safety, PK and PD assessments. Translational research includes evaluation of immunologic parameters in the tumor, other immune-correlates and molecular profiles, as well as evaluation of treatment-emergent cytokine and chemokine profiles in peripheral blood. * Melero et al., Annals of Oncology (2022) 33 (suppl_7): S331-S355.

P062: The efficacy and safety of nivolumab 40 mg therapy versus 3 mg/kg in patients with relapsed and refractory classic Hodgkin lymphoma

Table 1: Patient’s characteristics Background: The efficacy of nivolumab (Nivo) at a fixed dose of 40 mg in patients with relapsed and refractory classic Hodgkin lymphoma (r/r cHL) was demonstrated in previous studies. Nevertheless, comparison of the efficacy of low doses of PD1 inhibitors with standard dose 3 mg/kg is currently required. Aims: To compare the results of Nivo 40 mg therapy versus standard dosing regimen of 3 mg/kg for patients with r/r cHL. Methods: The Nivo40 trial (NCT03343665) expanded prospective cohort of patients (group 1, n=51) treated with Nivo 40 mg was compared with the retrospective group 2 (n=116) of patients treated with Nivo 3 mg/kg. The response was evaluated every 3 months by PET-CT using LYRIC criteria. Adverse events (AE) were analyzed by NCI CTCAE 4.0.3. Overall response rate (ORR), progression-free survival (PFS), overall survival (OS) were compared between group 1 and 2. During the survival analysis the PFS was censored by the time of additional therapy initiation. Results: Patient’s characteristics are demonstrated in the table 1. Median follow up was 48 (2–60) months in group 1 and 60 (6–70) months in group 2. Median Nivo cycles was 19 (2–49) and 20 (1–32) respectively. The best response to Nivo therapy was detected at 6 (2–24) and 6 (1–27) cycles respectively. ORR was 68% in group 1 and 67% in group 2. The structure of response in group 1 was: complete response (CR) in 40% of patients, partial response (PR) in 28%, stable disease (SD) in 6%, indeterminate response (IR) in 20% and progressive disease (PD) in 6%; in group 2: CR in 34%, PR in 33%, SD in 5%, IR in 20% and PD in 8%. Median OS was not achieved in both groups, 3-year OS was 97,9% and 96,5% respectively (p=0.243). Median PFS was 21,9 months (95%CI: 16,8–26,9) in group 1 and 18,8 months (95%CI: 13,4–24,2) in group 2, 3-year PFS was 23,6% and 27% respectively (p=0.356). Any grade AE were detected in 65% of patients in group 1 and in 79% in group 2 (p=0.068), 3–4 grade AE were detected in 10% and 19% respectively (p=0.151). Additional therapy after Nivo monotherapy was started in 78% of patients after Nivo 40 mg and in 84% after Nivo 3 mg/kg. Allogeneic stem cell transplantation after Nivo therapy was performed in 5 (10%) patients in group 1 and in 26 (22%) patients in group 2. Conclusion: The efficacy of Nivo 40 mg therapy is comparable to the standard dose of 3 mg/kg in patients with r/r cHL. However, a direct comparison of different doses of Nivo in a prospective study is required.

LBA4 Adjuvant nivolumab plus ipilimumab (NIVO+IPI) vs placebo (PBO) for localized renal cell carcinoma (RCC) at high risk of relapse after nephrectomy: Results from the randomized, phase III CheckMate 914 trial

CheckMate 914 (NCT03138512) is a phase III, randomized, double-blind, multicenter, 2-part trial evaluating NIVO+IPI vs PBO (part A) or NIVO monotherapy vs NIVO+IPI vs PBO (part B) in mutually exclusive patients (pts) with localized RCC at high risk of post-nephrectomy relapse. We report the primary analysis for part A of this trial. CheckMate 914 key inclusion criteria: radical or partial nephrectomy with negative surgical margins > 4 and ≤ 12 weeks before randomization; predominant clear cell histology; pathological TNM stage T2a (grade [G] 3 or 4) N0M0, T2b (any G) N0M0, T3 (any G) N0M0, T4 (any G) N0M0, or any T (any G) N1M0; and no clinical/radiological evidence of residual disease or distant metastases. Pts were randomized 1:1 to NIVO 240 mg Q2W (× 12 doses) + IPI 1 mg/kg Q6W (× 4 doses) or equivalent PBO for 24 weeks or until disease recurrence/unacceptable toxicity. Stratification factors: TNM stage and type of nephrectomy. Primary endpoint: disease-free survival (DFS) per blinded independent central review; secondary endpoints include overall survival and safety. 816 pts were randomized to NIVO+IPI (n = 405) vs PBO (n = 411). With 37.0 months of median follow-up (range, 15.4–58.0), the primary efficacy endpoint of DFS was not met (HR, 0.92; 95% CI, 0.71–1.19; P = 0.5347). Median DFS was not reached with NIVO+IPI and 50.7 months with PBO; DFS probabilities at 24 months were 76.4% and 74.0%, respectively. Median (Q1, Q3) treatment duration was 5.1 (2.8, 5.3) months and 5.1 (5.1, 5.3) months, respectively. Any-grade treatment-related adverse events (AEs) were reported in 88.9% vs 56.8% of pts treated with NIVO+IPI vs PBO; grade ≥ 3 treatment-related AEs were reported in 28.5% vs 2.0%, respectively. Treatment-related AEs led to discontinuation of NIVO+IPI in 29.0% of pts and of PBO in 1.0% of pts. The CheckMate 914 trial of NIVO+IPI vs PBO in pts with localized RCC at high risk of relapse after nephrectomy did not meet the primary endpoint of DFS. Safety of NIVO+IPI was consistent with its known profile in advanced RCC, although the rate of discontinuation due to treatment-related AEs was higher with adjuvant NIVO+IPI vs PBO in this trial.

Cost-Utility of Nivolumab Plus Ipilimumab in First-Line Treatment of Advanced Melanoma in the United States: An Analysis Using Long-Term Overall Survival Data from Checkmate 067.

ObjectiveThe aim of this study was to evaluate the cost-utility of nivolumab plus ipilimumab (NIVO + IPI) versus other first-line therapies for advanced melanoma in the United States (US) from the third-party payer perspective.MethodsThis analysis estimated total expected life-years (LYs), quality-adjusted LYs (QALYs), and costs for first-line treatments of advanced melanoma during a 30-year time horizon using indirect treatment comparisons based on time-varying hazard ratios (HRs) and a three-state partitioned survival model. Overall survival (OS) and progression-free survival reference curves were extrapolated based on 5-year follow-up from the phase III Checkmate 067 trial (NCT01844505). Comparators of NIVO + IPI were NIVO, IPI, pembrolizumab, dabrafenib plus trametinib, encorafenib plus binimetinib (ENCO + BINI), and vemurafenib plus cobimetinib. Drug acquisition costs, treatment administration costs, follow-up time, subsequent therapy data, and adverse event frequencies were obtained from published sources. Utility weights were estimated from Checkmate 067, which compared NIVO + IPI or NIVO monotherapy with IPI monotherapy as first-line therapy in advanced melanoma. A 3% annual discount rate was applied to costs and outcomes. Sensitivity scenarios for BRAF-mutant subgroups were conducted.ResultsNIVO + IPI was estimated to generate the longest OS and the highest total costs versus all comparators, accruing 6.99 LYs, 5.70 QALYs, and $469,469 over the 30-year time horizon. The incremental cost utility of NIVO + IPI versus comparators ranged from $2130 per QALY (versus ENCO + BINI) to $76,169 per QALY (versus NIVO). In all base-case and most sensitivity analyses, the incremental cost-utility ratios for NIVO + IPI were below $100,000 per QALY.ConclusionsNIVO + IPI is estimated to be a life-extending and cost-effective treatment versus other therapies in the US, with base-case incremental cost-utility ratios below $100,000 per QALY.Supplementary InformationThe online version contains supplementary material available at 10.1007/s41669-022-00348-0.

P1080: COMPARISON OF NIVOLUMAB 40 MG EFFICACY VERSUS 3 MG/KG IN PATIENTS WITH RELAPSED AND REFRACTORY CLASSIC HODGKIN LYMPHOMA

Background: Nivolumab 3 mg/kg was shown to be effective in patients with relapsed and refractory classic Hodgkin lymphoma (r/r cHL). However, previously obtained data on pharmacokinetics, as well as financial toxicity of therapy, raised the issue of studying necessity of efficacy of reduced doses of PD-1 inhibitors. Efficacy of nivolumab 40 mg has previously been demonstrated in patients with r/r cHL in a prospective phase 2 study (Lepik KV et al., 2020). Continued accumulation of experience in the use of low-dose PD-1 inhibitors in patients with r/r cHL is required to support previous data. Aims: To compare the efficacy of nivolumab (Nivo) 40 mg therapy with 3 mg/kg for patients with r/r cHL. Methods: The Nivo40 trial (NCT03343665) expanded prospective cohort of patients (group 1, n=50) treated with Nivo 40 mg was compared with the retrospective group 2 (n=116) of patients treated with Nivo 3 mg/kg. Patients characteristics are demonstrated in the Table 1. The response was evaluated every 3 months by PET-CT using LYRIC criteria. Adverse events (AE) were analyzed by NCI CTCAE 4.0.3. Overall response rate, progression-free survival (PFS) and overall survival (OS) were compared between group 1 and 2. During the survival analysis the PFS was censored by the time of additional therapy initiation. - Variable Nivo 40 mgN=50 Nivo 3 mg/kgN=116 p Median age, years (range) 36 (20-54) 38 (14-65) 0.129 Male/female, n (%) 17/33 (34/66) 56/60 (48/52) 0.089 Primary chemoresistance, n (%) 38 (76) 74 (64) 0.124 Early relapse, n (%) 7 (14) 14 (12) 0.731 Prior autologous stem cell transplantation, n (%) 17 (34) 44 (38) 0.630 Prior brentuximab vedotin, n (%) 18 (36) 62 (53) 0.039 Therapy lines before Nivo therapy, n (range) 4 (1-8) 5 (2-10) 0.011 B symptoms at Nivo therapy initiation, n (%) 26 (52) 71 (61) 0.269 Disease stage at Nivo therapy initiation, n (%) 2 8 (16) 11 (9) 0.294 3 5 (10) 7 (6) 4 37 (74) 97 (84) Progression at Nivo therapy initiation, n (%) 46 (92) 92 (79) 0.272 ECOG status at Nivo therapy initiation, n (%) 0-1 31 (62) 70 (60) 0.758 2 14 (28) 29 (25) 3 4 (8) 14 (12) 4 1 (2) 2 (2) Results: Median follow up was 44 (11-55) months in group 1 and 60 (6-70) months in group 2. Median Nivo cycles was 19 (2-49) and 20 (1-32) respectively. The best response to Nivo therapy was detected at 6 (2-24) and 6 (1-27) cycles respectively. Overall response rate was 66% in group 1 and 67% in group 2. The structure of response in group 1 was: complete response (CR) in 38% of patients, partial response (PR) in 28%, stable disease (SD) in 6%, indeterminate response (IR) in 22% and progressive disease (PD) in 6%; in group 2: CR in 34%, PR in 33%, SD in 5%, IR in 20% and PD in 8%. Median OS was not achieved in both groups, 3-year OS was 97,8% and 96,5% respectively (p=0.356). Median PFS was 21,9 months (95%CI: 16,75-27,05) in group 1 and 18,8 months (95%CI: 13,44-24,16) in group 2, 3-year PFS was 25,6% and 27% respectively (p=0.356). Additional therapy after Nivo monotherapy was started in 78% of patients after Nivo 40 mg and in 84% after Nivo 3 mg/kg. Allogeneic stem cell transplantation after Nivo therapy was performed in 5 (10%) patients in group 1 and in 26 (22%) patients in group 2. Any grade adverse events were detected in 66% of patients in group 1 and in 79% in group 2 (p=0.068), 3-4 grade AE were detected in 10% and 19% respectively (p=0.151). Summary/Conclusion: Nivolumab 40 mg therapy is comparable to the standard dose of 3 mg/kg in terms of overall response rate as well as survival in patients with r/r cHL. However, a direct comparison of different doses of nivolumab in a prospective study is required.

Phase II study of nivolumab and salvage nivolumab + ipilimumab in treatment-naïve patients (pts) with advanced clear cell renal cell (HCRN GU16-260-Cohort A): Final report.

288 Background: Nivolumab (nivo) is FDA approved for patients (pts) with VEGFR TKI-resistant RCC and the nivo + ipilimumab (nivo/ipi) combination is FDA approved for treatment naïve pts with IMDC intermediate and poor risk renal cell carcinoma (RCC). Little information was available on the efficacy and toxicity of nivo monotherapy in treatment naïve RCC or the efficacy of nivo/ipi salvage in pts with tumors resistant to initial nivo monotherapy. Methods: Eligible pts with treatment naïve RCC received nivo 240mg IV q2 wk x 6 doses followed by 360mg IV q3 wk x 4 doses followed by 480 mg q4 wk until progressive disease (PD), toxicity, or completion of 96 wks of treatment (Part A). Pts with PD prior to, or stable disease (SD) at 48 wks (pSD) were potentially eligible to receive salvage nivo (3mg/kg)/ipi (1 mg/kg) q3 wk x 4 doses followed by q4 wk nivo maintenance for up to 48 wks (Part B). All pts were required to submit tissue from a metastatic lesion obtained within 12 months (mos) prior to study entry and prior to Part B for correlative studies. Results: 123 pts with clear cell(cc) RCC were enrolled between 5/2017 and 12/2019 at 12 participating HCRN sites. Data lock was 04/07/2021. Median Follow-up 26.9 mos. Median age 65 (32-86) years; 72% male. IMDC risk: favorable (Fav) 35 (28%), intermediate (I) 76 (62%) and poor (P) 12 (10%). 22 (18%) had a component of sarcomatoid histology (SARC). RECIST defined ORR was: 34.1% (25.8-43.2%) (CR 6.5%, PR 27.6%), SD 47 (35.8%). ORR by irRECIST was 39%. ORR by IMDC was: Fav 20/35 (57.1%) (39-74%), (I/P) 22/88 (25%) and for SARC 36.4%. ORR by PD-L1 status was 21/78 (27%), 8/16 (50%) and 6/8 (75%) for pts with tumor PD-L1 of 0, 1-20 or > 20%, respectively (trend test p-value 0.002). 5/7 (71.4%) Fav pts with PD-L1 > 1 responded. Median DOR was 27.6 (13.7, NA) mos with 26/42 responders including 17/20 (85%) with Fav Risk remaining progression free. Median PFS was 8.2 (5.5, 10.9) mos; (30.3 for IMDC Fav and 5.4 for I/P). 91 pts remain alive with 24 mos OS rate of 78%. 65 patients (59 PD, 6 pSD) were potentially eligible for salvage nivo/ipi (Part B), but 25 did not enroll due to symptomatic PD (6), grade 3-4 toxicity on nivo (17), or other (2) and 5 were not treated due to inability to confirm residual disease on a biopsy. ORR for Part B by RECIST was 11.4% (4/35) and by irRECIST 17.2%. Grade 3-5 treatment-related AEs (TrAE) (not including asymptomatic amylase/lipase) were seen in 20.3% in Part A and 14.2% in Part B with 1 death in each cohort. Conclusions: Nivo monotherapy is active in treatment naïve ccRCC across all IMDC groups. Although efficacy appears less than combination nivo/ipi in I/P pts, Fav pts had a notably high ORR and DOR. Efficacy appeared to correlate with tumor PD-L1 status, although at least half the responders had a tumor PD-L1 of 0. Salvage treatment with nivo/ipi after nivo was frequently not feasible and of limited benefit. Clinical trial information: NCT03117309.

Tailored immunotherapy approach with nivolumab in advanced transitional cell carcinoma (TITAN-TCC).

441 Background: Nivolumab (nivo) is an approved 2nd line treatment after platinum-based chemotherapy in metastatic urothelial carcinoma (mUC). Recent studies suggest improved outcomes for dual checkpoint inhibition in mUC in particular with higher ipilimumab (ipi) doses (nivo 1mg/kg + ipi 3mg/kg). TITAN-TCC uses a response-based approach starting with 4 doses of nivo (8 weeks) followed by nivo+ipi boosts in non-responders. Here we report cohort 2 of TITAN-TCC applying nivo1/ipi3 boost doses in patients after prior platinum-based chemotherapy (2nd/3rd line). Methods: Between April 2019 and February 2021 83 patients with histologically confirmed mUC (TITAN-TCC cohort 2) started with nivo 240mg Q2W induction. After 4 doses and tumor assessment at week 8 (i) non-responders (stable (SD)/ progressive disease (PD)) received 2-4 doses nivo1+ipi3 while (ii) responders (complete (CR)/ partial response (PR)) continued with nivo maintenance but could receive nivo1+ipi3 for later PD. Primary endpoint was confirmed investigator-assessed ORR per RECIST1.1. Using a Fleming single-stage phase II design 77 evaluable patients would provide a 90% power to reject the null-hypothesis that ORR was ≤20% at a one-sided 5% type I error if the true ORR was ≥35%. Secondary endpoints included activity of nivo monotherapy at week 8, remission rate with nivo+ipi boosts, progression-free survival (PFS), overall survival (OS), and safety. Results: Median follow-up time was 5.6 months. Of the patients, 78 (94%) were 2nd line. Median age was 68 years (range 37-84) and 57 patients (69%) were male. ORR with nivo monotherapy at first assessment (week 8) was 20.5%. Of the patients, 44 and 6 received nivo+ipi boosts after week 8 and for later PD, respectively. Confirmed objective response with nivo induction ± nivo+ipi boosts was achieved in 27/83 (32.5%) of the patients (significant > 20%, p < 0.01). Patients with PD-L1 expression in ≥1% of tumor cells had a numerically higher ORR (46% vs. 24% for PD-L1 negatives). Of the patients with initial SD after nivo induction, 4/13 (31%) achieved response upon boost. Of the patients boosted for PD, 9/37 (24%) improved. Median PFS was 1.9 months (95% CI 1.8-3.2), median OS was 7.6 months (95% CI 5.1-14.9). No new safety signals emerged. Conclusions: In patients after prior platinum-based chemotherapy treatment with nivo and nivo+ipi boosts in non-responders significantly improved ORR compared to the one reported for nivo as 2nd line monotherapy. Patients with PD-L1 positive tumors appear to benefit most. Our study provides further evidence for the added value of high dose (3mg/kg) ipilimumab in mUC. Clinical trial information: NCT0321977.[Table: see text]

Primary analysis from DS8201-A-U105: A phase 1b, two-part, open-label study of trastuzumab deruxtecan (T-DXd) with nivolumab (nivo) in patients (pts) with HER2-expressing urothelial carcinoma (UC).

438 Background: HER2 overexpression has been found in invasive UC, suggesting a role for HER2 in disease progression and prognosis (Kruger Int J Oncol 2002). T-DXd is an antibody-drug conjugate comprising an anti-HER2 antibody, a cleavable linker, and a topoisomerase I inhibitor payload. Preclinical models showed that T-DXd combined with an anti-PD-1 antibody had greater efficacy versus either agent alone (Iwata Mol Cancer Ther 2018). We conducted a phase 1b, 2-part, open-label, multicenter study of T-DXd in combination with nivo in pts with HER2-expressing advanced/metastatic UC (NCT03523572). Methods: Pts aged ≥18 y had pathologically documented advanced/metastatic UC with centrally confirmed HER2 expression by immunohistochemistry (IHC) 2+/3+ (cohort 3; high expression) or IHC 1+ (cohort 4; low expression) who received prior platinum-based therapy with documented progression. Pts received T-DXd at 5.4 mg/kg and nivo 360 mg IV every 3 weeks (recommended dose for expansion). The primary endpoint was confirmed objective response rate (ORR) assessed by independent central review (ICR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints (assessed by ICR) included duration of response (DOR), progression-free survival (PFS), time to response (TTR), and overall survival (OS), and safety. Results: At the primary analysis data cutoff (July 22, 2021), 34 pts (cohort 3, n = 30; cohort 4, n = 4) received T-DXd and nivo. Median age was 70.9 y (range, 41.4-80.5), 88.2% were male, 61.8% received ≥1 prior regimens for locally advanced/metastatic disease, and 26.5% had a history of liver metastases. Median treatment duration (all pts) was 3.2 mo (range, 1-21) for T-DXd and 4.1 mo (range, 1-20) for nivo. In cohort 3, ORR by ICR was 36.7% (95% CI, 19.9-56.1; complete response, 13.3%; partial response, 23.3%), median DOR was 13.1 mo (95% CI, 4.1- NE), median PFS was 6.9 mo (95% CI, 2.7-14.4), median TTR was 1.9 mo (range 1.2-6.9), and median OS was 11.0 mo (95% CI, 7.2-NE). Grade (G) ≥3 treatment-emergent adverse events (TEAEs) occurred in 73.5% of all pts (44.1% related to T-DXd; 26.5% related to nivo). TEAEs leading to drug discontinuation occurred in 32.4% of all pts (17.6% related to T-DXd; 23.5% related to nivo). The most common any-grade TEAEs were nausea (73.5%), fatigue (52.9%), and vomiting (44.1%). Adjudicated drug-related interstitial lung disease (ILD)/pneumonitis occurred in 23.5% of all pts (2 G1; 4 G2; 1 G3; 1 G5). Conclusions: T-DXd combined with nivo showed antitumor activity in pts with high-expressing HER2 UC. The safety profile was consistent with prior studies for T-DXd in other indications and nivo monotherapy in UC pts. Adjudicated ILD/pneumonitis was within the range observed in other T-DXd monotherapy studies. Ongoing clinical trials are further exploring T-DXd in this population. Clinical trial information: NCT03523572.

Adaptive Dosing of Nivolumab + Ipilimumab Immunotherapy Based Upon Early, Interim Radiographic Assessment in Advanced Melanoma (The ADAPT-IT Study).

Nivolumab + ipilimumab (nivo + ipi) is highly efficacious but has high toxicity. Standard treatment in advanced melanoma is four doses of nivo + ipi followed by nivo alone. Whether four doses of nivo + ipi are needed is unclear. The Adaptively Dosed ImmunoTherapy Trial (ADAPT-IT) study (NCT03122522) is a multicenter, single-arm phase II clinical trial. Patients received two doses of nivo (1 mg/kg) + ipi (3 mg/kg) followed by a computed tomography scan at week 6. Patients without new lesions or index lesion tumor growth of > 4% had protocol-defined early favorable antitumor effect (FATE) and ceased nivo + ipi, transitioning to nivo monotherapy. Patients without FATE at week 6 received the standard third and fourth doses of nivo + ipi followed by nivo monotherapy. The primary end point was response rate by RECIST 1.1 at week 12. Secondary end points included additional efficacy assessments and safety. Sixty patients were enrolled; 41 patients (68%) had FATE at week 6 and met criteria for stopping nivo + ipi. Best overall response rates by RECIST at week 12 or any time afterward were 48% (95% CI, 35 to 62) and 58% (95% CI, 45 to 71), respectively. With a median follow-up of 25 months, the estimated 18-month progression-free survival and overall survival are 52% and 80%, respectively. Fifty seven percent of patients had grade 3-5 treatment-related toxicity. The efficacy and toxicity of standard four dose nivo + ipi induction therapy in melanoma is likely driven by the first two doses. An interim computed tomography scan after two doses guided cessation of combination dosing and identified almost all responders. Longer follow-up and further study are needed to fully understand the implications of a shortened induction course of nivo + ipi.

First-line Nivolumab plus Ipilimumab Versus Sunitinib in Patients Without Nephrectomy and With an Evaluable Primary Renal Tumor in the CheckMate 214 Trial

We present an exploratory post hoc analysis from the phase 3 CheckMate 214 trial of first-line nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib in a subgroup of 108 patients with advanced renal cell carcinoma (aRCC) without prior nephrectomy and with an evaluable primary tumor, a population under-represented in clinical trials. Patients with clear cell aRCC were randomized to NIVO+IPI every 3 wk for four doses followed by NIVO monotherapy, or sunitinib every day for 4 wk (6-wk cycle). Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and primary tumor shrinkage were assessed. PFS and ORR were assessed per independent radiology review committee using RECIST version 1.1. With minimum study follow-up of 4 yr for intent-to-treat patients, OS favored NIVO+IPI (n = 53) over sunitinib (n = 55; hazard ratio 0.63, 95% confidence interval 0.40–1.0) among patients without prior nephrectomy. ORR was higher (34% vs 15%; p = 0.0041) and median duration of response was longer with NIVO+IPI versus sunitinib (20.5 vs 14.1 mo); the best overall response was partial response in either arm. A ≥30% reduction in the diameter of intact target renal tumors was achieved in 35% of patients with NIVO+IPI versus 20% with sunitinib. Safety was consistent with the global study population. In conclusion, in patients with aRCC without prior nephrectomy and with an evaluable primary tumor, NIVO+IPI showed survival benefits and renal tumor reduction versus sunitinib. This trial is registered at ClinicalTrials.gov as NCT02231749. Patient summaryIn an exploratory analysis of a large global trial (CheckMate 214), we observed positive outcomes (both survival and tumor response to treatment) with nivolumab plus ipilimumab over sunitinib in a subgroup of patients with advanced kidney cancer who did not undergo removal of their primary kidney tumor. This subset of patients represents a population that has not been studied in clinical trials and for whom outcomes with new immunotherapy combination regimens are not yet known. We conclude that treatment with nivolumab plus ipilimumab offers these patients a survival benefit versus sunitinib, consistent with that observed in the overall study, as well as a notable kidney tumor reduction.