Abstract CT184: Preliminary results of first-line botensilimab (BOT) and balstilimab (BAL) optimization in microsatellite stable colorectal cancer (MSS CRC) without liver, bone, or brain metastasis (BBOpCo)

BACKGROUND: Dysregulation of the WNT-signaling pathway is associated with the development and progression of various tumors. Wnt-β-catenin pathway activating mutations are nearly universally present in selected solid tumors (e.g. desmoid) and in more than 80% of microsatellite stable (MSS) colorectal cancer (CRC). There are no approved agents targeting this pathway. FOG-001 is a Helicon™ peptide that competitively inhibits the interaction between β-catenin and TCF transcription factors in the Wnt-signaling pathway. FOG-001 monotherapy inhibits tumor growth in WPAM+ CRC and other solid tumor patient-derived xenograft (PDX) models. When co-administered with 5-fluorouracil (5-FU), or inhibitors of VEGF or PD-1, FOG-001 showed additive to synergistic efficacy in PDX models. Here we present safety, efficacy, and pharmacokinetic (PK)/pharmacodynamic (PD) results of FOG-001 in patients (pts) with advanced solid tumors. METHODS: This is a first-in-human, phase 1/2, study of FOG-001 alone or in combination in pts with locally-advanced or metastatic solid tumors (NCT05919264). Eligible pts must have received ≥1 prior systemic therapies and either progressed or were unfit for available therapies. Pts with MSS CRC should have received prior 5-FU, oxaliplatin, and irinotecan in the metastatic setting. The primary objective is safety and tolerability. Secondary objectives include anti-tumor activity, PD in paired tumor biopsies and PK. Circulating tumor DNA (ctDNA) assessment is exploratory. RESULTS: As of May 11, 2025, 83 (N=63 MSS CRC, N=20 other WPAM+ solid tumors) pts have received FOG-001 monotherapy at doses ranging from 36–480 mg/m2. Median age was 53 (range 19–79) and 63.9% were male. In pts with MSS CRC, median number of prior treatment lines was 4, with 87.3% and 69.8% of pts having lung and liver metastases, respectively. Grade (Gr) 3 and serious treatment-related adverse events (TRAEs) were uncommon, reported in 20.5% and 2.4% of pts, respectively, primarily at doses at or above 360 mg/m2. There were no Gr 4 or 5 TRAEs and no treatment discontinuations due to TRAEs. FOG-001 showed dose linear exposure with low variability. Anti-tumor activity was assessed in the efficacy-evaluable population. In Wnt-β-catenin driven solid tumors (N=14), objective response rate (ORR) was 43%. Disease control rate (DCR) in this population was 79%. In pts with desmoid tumors (N=5), ORR and DCR were 60% and 100%, respectively. In MSS CRC, the DCR was 50% at the higher dose levels (240–480 mg/m2) with molecular responses (≥50% ctDNA reduction) in 60% of these pts. CONCLUSIONS: FOG-001 monotherapy is well tolerated with a manageable safety profile in pts with desmoid, other WPAM+ tumors and heavily pre-treated MSS CRC. Favorable PK, on-target PD effect, and encouraging anti-tumor activity demonstrate that FOG-001 is a bona fide β-catenin inhibitor with biologic and clinical impact supporting ongoing expansion in desmoid tumors, and evaluation in combination with standard chemotherapy or nivolumab in MSS CRC. Citation Format: Samuel J. Klempner, Michael Cecchini, Moh’d Khushman, Shivaani Kummar, Meredith Pelster, Jordi Rodon, Sunil Sharma, Rona Yaeger, Jonathan Rojo, Amber L. Wells, Megan Tipps, Wade Berry, Amanda Garofalo, Lalith Akella, Laura Strong, Xinwei Han, Ziyang Yu, Jorge D. Ramos, Marie Huong Nguyen, Jonathan Hurov, Keith Orford, Kyriakos P. Papadopoulos. A phase 1/2 trial of FOG-001, a first-in-class direct β-catenin:TCF4 inhibitor, preliminary safety and efficacy in patients with solid tumors bearing Wnt pathway-activating mutations (WPAM+) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B031.

Purpose: The site of metastasis in advanced melanoma patients (pts) influences pt response to immunotherapy and overall prognosis. Liver mets are particularly resistant to immunotherapy and their presence often confers shorter survival and reduced response rates. This study characterised and compared the tumor immune microenvironment of melanoma mets at different anatomical sites. Methods: T-cell and myeloid cell markers were stained using multiplex IHC on FFPE samples from 136 untreated metastatic melanoma pts, from 5 anatomical sites (liver, lung, brain, subcutaneous, and lymph node (LN)). Cell densities, subpopulations and the spatial distribution of cells were compared between sites. Results: CD3+ T cell infiltration was less dense in the liver (med = 154.3 cells/mm2) and brain mets (med = 180.7 cells/mm2) v's lung (med = 434.7 cells/mm2) and LN mets (med = 504.8 cells/mm2) (p<0.05), and T-cells were further away from melanoma cells in liver v's lung mets (med distance = 83µm v's 57µm respectively; P<0.05). The liver displayed a unique T-cell profile, with a significantly lower proportion of CD3+ T cells expressing PD-1 (med = 0.7%) compared to all other sites (P<0.05) while brain mets expressed the highest proportion of PD-1+ T cells (med = 8.9%). There were higher proportions of Tim3+ T cells in liver (10.7%) and lung mets (12.9%) v's brain, subcut and LN mets (P<0.05). Specifically, in liver mets CD3+ T cells within 20um of a melanoma cell had a significantly higher expression of Tim3 (med = 18.57%) v's PD-1 (med = 2%). Brain mets had the lowest density of CD68+ macrophages (med = 33 cells/mm2) v's lung (med = 372 cells/mm2), liver (med = 290 cells/mm2) and Subcut mets (med = 154 cells/mm2). Lung mets also had the highest proportion of PD-L1+ macrophages (med = 18.73%) compared to liver (med = 5.2%) and brain mets (med = 0.65%). While the most highly expressed T cell population varied between sites, CD16+ macrophages were consistently the highest expressed macrophage subpopulation regardless of metastatic site. Conclusion: These data suggest that liver mets are less immunogenic, with fewer T cells and greater distances between CD3+ T cells and melanoma cells, and may account for the poor prognosis of melanoma patients with liver metastases and their reduced response rate to immunotherapy compared to other mets. While liver mets have reduced PD-1 expression, higher Tim3 expression in the liver may provide a therapeutic opportunity to improve outcomes for pts with liver mets by using anti-TIM3 immunotherapy. Overall, these data provide novel insights into the site-specific biology of melanoma mets, heterogeneity in the tumor immune microenvironment, and the need for site specific biomarkers to be considered when selecting treatment targets. Citation Format: Jordan W. Conway, Robert V. Rawson, James S. Wilmott, Georgina V. Long, Richard A. Scolyer, Inês Pires Da Silva. Spatial distribution and immune cell infiltration at different sites of melanoma metastases (mets) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2762.

P-54 Phase 2a study of NT-I7, a long-acting interleukin-7, plus pembrolizumab: Cohort of subjects with checkpoint inhibitor-naïve advanced MSS-colorectal cancer

Microsatellite instability (MSI) has been associated with favourable survival in early stage colorectal cancer (CRC) compared to microsatellite stable (MSS) CRC. The BRAF V600E mutation has been associated with worse survival in MSS CRC. This mutation occurs in 40% of MSI CRC and it is unclear whether it confers worse survival in this setting. The prognostic value of KRAS mutations in both MSS and MSI CRC remains unclear. We examined the effect of BRAF and KRAS mutations on survival in stage II and III MSI colon cancer patients. BRAF exon 15 and KRAS exon 2-3 mutation status was assessed in 143 stage II (n = 85) and III (n = 58) MSI colon cancers by high resolution melting analysis and sequencing. The relation between mutation status and cancer-specific (CSS) and overall survival (OS) was analyzed using Kaplan-Meier and Cox regression analysis. BRAF V600E mutations were observed in 51% (n = 73) and KRAS mutations in 16% of cases (n = 23). Patients with double wild-type cancers (dWT; i.e., BRAF and KRAS wild-type) had a highly favourable survival with 5-year CSS of 93% (95% CI 84-100%), while patients with cancers harbouring mutations in either BRAF or KRAS, had 5-year CSS of 76% (95% CI 67-85%). In the subgroup of stage II patients with dWT cancers no cancer-specific deaths were observed. On multivariate analysis, mutation in either BRAF or KRAS vs. dWT remained significantly prognostic. Mutations in BRAF as well as KRAS should be analyzed when considering these genes as prognostic markers in MSI colon cancers.

2514 Background: Checkpoint inhibitors (CPIs) are usually ineffective in patients (pts) with immune-cold microsatellite stable colorectal cancer (MSS-CRC) or pancreatic cancer (PDAC) and in those who progressed on previously treated with antibodies against PD1 or PD-L1. Here, we report the combination of NT-I7 plus pembrolizumab (pembro) on CPI-naïve MSS-CRC and PDAC cohorts, and patients (pts) with CPI-treated triple-negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), and small cell lung cancer (SCLC) cohorts of this ongoing phase 2a trial. Methods: Pts with CPI-naïve relapsed/refractory (R/R) MSS-CRC and PDAC, and CPI-treated R/R TNBC, NSCLC, and SCLC, were enrolled. NT-I7 (efineptakin alfa) 1200 µg/kg intramuscularly every 6 weeks and 200 mg pembro intravenously every 3 weeks were administered until disease progression/unacceptable toxicity. The primary endpoint of the Phase 2a is the objective response rate (ORR), assessed by RECIST v1.1 and iRECIST. The secondary endpoints are duration of response (DoR), disease control rate, progression-free survival, and overall survival. Results: As of 14 Jan 2022, 92 pts with metastatic or locally advanced cancer who had received a median of 3 prior treatments were enrolled in the study; 32 in PDAC, 28 in MSS-CRC, 22 in NSCLC, 6 in TNBC, and 4 in SCLC. The median age was 62 years [29-81], ECOG PS 0 in 23 (25%), 1 in 68 (74%) and 2 in 1 (1%). Among 71 evaluable pts, the median follow up (months) was 7.7, 5.3, 5.0, 3.7, and 2.4 in TNBC, MSS-CRC, NSCLC, PDAC and SCLC, respectively. The ORR was 50% (1/2) in SCLC, 12% (3/25) in MSS CRC, 8% (2/26) in PDAC 6% (1/16) in NSCLC and 0% (0/2) in TNBC per iRECIST; and 50% (1/2) in SCLC, 4% (1/25) in MSS CRC, and 4% (1/26) in PDAC per RECIST 1.1. All 7 responders are ongoing. The two PDAC pts had DoR over 1.35 months (mos) and 6.64 mos with the best tumor reduction 100% and 72% respectively. The one SCLC pt had DoR over 1.5 mos with the tumor reduction 67%. The one NSCLC pt had DoR over 2.73 mos with the tumor reduction 60%, and the three MSS-CRC pts had DoR 6.34, 2.96, and 0.03 mos with the tumor reduction 60%, 56%, and 43% respectively. A sustained and significant (approximate 3X from baseline) increase of peripheral lymphocytes in all arms was observed as shown in our previous report. Among 92 treated pts, NT-I7-related adverse events (AEs) occurred in 67 (72.8%) pts, including 52 (56.5%) Grade (G)1-2, 13 (14.1%) G3, and 2 (2.2%) G4. There were no NT-I7 related G5 AEs. Additional updated efficacy, safety and biomarker data will be presented. Conclusions: The combination of NT-I7 and pembro demonstrated antitumor activity and manageable toxicity profile in heavily pretreated pts with CPI-naïve MSS-CRC and PDAC and CPI-treated TNBC, NSCLC, and SCLC, suggesting that the addition of NT-I7 to CPI can overcome the primary resistance to CPI in the former group and acquired resistance in the latter. Clinical trial information: NCT04332653.

3533 Background: The randomized METIMMOX trial evaluated short-course oxaliplatin-based chemotherapy (FLOX) alternating with nivolumab for previously untreated, unresectable abdominal metastases (mets) from MSS CRC. A subgroup of patients assigned to this experimental (exp) treatment had remarkably extended progression-free survival (PFS) compared to the control group patients given standard FLOX chemotherapy with median PFS 9.3 months. We explored if the extent of involved organs might be decisive for responsiveness to the METIMMOX regimen. Methods: Patients with measurable infradiaphragmatic (liver, peritoneal, nodal) mets were randomly assigned to the control group of FLOX (oxaliplatin, 5-fluorouracil, folinic acid) Q2W or the exp group of alternating 2 cycles each of FLOX Q2W and nivolumab Q2W, with prespecified break periods. Radiologic response assessment was done every 8 weeks with PFS as the primary endpoint. For this post hoc analysis, at baseline, the principal metastatic site was defined by the 2 largest mets (main lesions) of the dominant infradiaphragmatic organ and the global metastatic pattern by the main and subsidiary lesions of all involved organs. Patients without adverse events leading to treatment discontinuation, thus with conclusive end of treatment (EoT) tumor data, were categorized into discrete outcome groups. Results: Of 36 exp group patients reaching the first radiologic reassessment, enabling formal evaluation, 31 proceeded to EoT tumor data. Of these, 6 patients (3 of 25 with liver main lesions, 3 of 4 with lymph node main lesions) had complete response (CR), including 3 of 3 BRAF -V600E cases. The remaining 3 CR cases had tumor mutational burden (TMB) 9.4-11.8. Of all 25 patients with liver mets, 13 (52%) had objective response and 5 (20%) stable disease. All 16 patients with objective response had improved PFS (median 15.5 months, 95% CI 12.4-18.5; p < 0.001, log-rank test). None of main or subsidiary lesions in peritoneum or lungs responded to the treatment. The 3 outcome groups comprised 7 patients with PFS 19.8-41.6 months (longer than twice the median), 8 with PFS 9.9-16.4 months (above median), and 16 with PFS 1.9-9.2 months (below median). At baseline, the best outcome group cases would have been predicted by the combination of right-sided primary, small main lesions (sum of diameters 42 mm or less), and all mets confined to the liver and/or lymph nodes; the mid group cases by left-sided or rectal primary along with peritoneal or lung subsidiary lesions; and the poor outcome cases by extended organ mets. Conclusions: Alternating short-course oxaliplatin-based chemotherapy and nivolumab was particularly efficient in treating unresectable liver or lymph node mets from right-sided MSS CRC with intermediate TMB or the BRAF driver mutation, but inefficient at peritoneal and lung mets. Clinical trial information: NCT03388190 .

1327P - Clinical factors and overall survival (OS) associated with patterns of metastases (mets) in melanoma patients (pts)

Introduction Immunotherapy with checkpoint inhibition has shown potent antitumor activity in patients with microsatellite instability (MSI) metastatic cancer. Microsatellite stable (MSS) colorectal cancer has long been considered resistant to immunotherapy. Areas covered In this review, we provide an overview of current progress on strategies to overcome the resistance to immunotherapy in MSS colorectal cancer. Expert opinion Emerging evidence suggest that combination of immune modulators such as regorafenib may improve the responsiveness of MSS colorectal cancer to checkpoint blockade. In addition, signs of clinical activity have also been observed in other combination strategies, such as the combination of checkpoint blockade with Stat3 inhibitor, or bispecific T-cell engagers. Nevertheless, predictive biomarkers that can identify patients who may benefit from immunotherapy are key for its implementation in clinical setting. Metastatic disease sites may predict for the response or resistance to checkpoint blockade, with liver metastases emerging as a strong predictive biomarker of lack of benefit from PD-1 targeting, even with combination therapies. Additional efforts are required to study the mechanism of resistance and to develop novel therapeutic strategies to overcome immune resistance. Abbreviations CEA: carcinoembryonic antigen; CR: complete response; CTLA-4: cytotoxic T-lymphocyte-associated protein 4; DCR: disease control rate; MSI-H: microsatellite instability-high; MSS: Microsatellite stable (MSS); OS: overall survival; PD-1: programmed cell death protein 1; PD-L1: programmed death-ligand receptor 1; PR: partial response; PFS: progression-free survival; SD: stable disease; TMB: tumor mutation burden; VEGFR: vascular endothelial growth factor receptor

e16527 Background: Prognostic models based on the heterogeneity of mRCC disease characteristics, including anemia, hypercalcemia, and neutrophilia, are routinely used in clinic. In an attempt to improve these models, we conducted a retrospective analysis of patients(pts) with mRCC to assess the association of overall outcomes with specific sites of metastasis (mets) and clinical complications. Methods: We extracted data from the SEER-Medicare database on pts diagnosed with RCC from 2004 to 2015. Study cohorts included patients who were > 65 years old and had at least 1 of following site-specific mets or complications: ascites, bone mets, brain mets, liver mets, lung mets, pancreatic mets, and hypercalcemia. To accurately delineate the relationship between site-specific/clinical complications and clinical outcomes, pts were stratified into 3 groups by the timing of site-specific mets and complications appearance : A1 (pts with a site-specific mets or complication at the initial diagnosis of mRCC); A2 (pts with a site-specific mets or complication any time after diagnosis of mRCC); and B (pts who have no site-specific mets or complication but have other mets or complications). Kaplan-Meier curves for overall survival(OS) were produced and median(m) OS were reported. Multivariable Cox modeling was performed to assess the association of individual mets or complications with OS between pre-specified subgroups(A1+A2 vs B, A1 vs A2+B and A1 vs B). Results: We identified 4640 RCC pts in the SEER-Medicare database who had at least 1 of the specified sites of mets or complications. At a median follow-up of 8 months(mons), ascites, brain mets and hypercalcemia were associated with worse mOS in all predefined subgroup analysis. In pts with liver mets, groups A1+A2 had shorter OS than B . In pts with lung mets, mOS in A1 was longer than in A2+B or B. bone mets did not show a statistically significant correlation with OS in any stratified analysis. Lastly, pancreatic mets was associated with longer mOS, but this did not reach statistical significance regardless of the comparison groups (table 1). Conclusions: Our data show that ascites, brain mets, hypercalcemia, and liver mets was associated with poor prognosis, and de novo lung mets was associated with better clinical outcome in patients with mRCC. Based on these findings, we are working on comparing the clinical outcome of mRCC pts treated with targeted therapy to that of pts treated with immunotherapy and building a new prognostic model.[Table: see text]

e17046 Background: Brain metastases (BM) in metastatic prostate cancer (mPCa), although rare, are associated with a poor prognosis. Accurate predictors of BMs in mPCa remain largely unknown. This study aims to investigate the prevalence of BMs in mPCa and identify significant clinical and pathological predictors associated with their occurrence. Methods: The National Cancer Database (NCDB) was queried for patients diagnosed with prostate cancer (PCa) from 2004-2021. Patients with cM1 PCa and without missing patient and tumor characteristics were identified. Kaplan-Meier analysis and log-rank test compared overall survival (OS) between patients with and without BMs. Univariable and multivariable logistic regression assessed significant factors associated with the presence of BMs. Results: Among 101,900 patients with cM1 PCa, 1,144 (1.1%) patients had BMs. After excluding missing data, 6,654 patients remained, with 46 (0.7%) having BMs. In chi-square analysis, patients with BMs more often had cT4 tumors (36.8% vs 24.6%, p<0.001), cN+ status (51.9% vs 42.8%, p<0.001), neuroendocrine histology (6.8% vs 1.6%, p<0.001), and higher Gleason grade group (GGG) (p=0.017). Patients with BMs more frequently had liver (17.2% vs 4.1%, p<0.001) and lung mets (27.0% vs 8.0%, p<0.001), while bone mets were less common (80.3% vs 89.8%, p<0.001). Median OS was lower for patients with BMs (15.08 months vs 32.59 months, p<0.001), despite having younger median age. In multivariable analysis, neuroendocrine histology (aOR 3.916, p=0.037), GGG≥3 (aOR 3.699, p=0.016), and liver mets (aOR 3.855, p=0.001) were associated with increased likelihood of BMs. Tumor stage, bone mets, and lung mets were not significantly associated the likelihood BMs. Conclusions: We report specific tumor characteristics associated with BMs, particularly neuroendocrine histology, higher GGG, and liver mets. This analysis is the largest to date to investigate this; however, future studies are needed for validation and further elucidation of patient, tumor, and molecular predictors of BMs in mPCa. Multivariable logistic regression for the presence of brain metastases. Variable aOR (95% CI) p-value Histology (Ref = Adeno) Neuroendocrine Other 3.916 (1.086-14.127)4.557 (0.597-34.819) 0.037 0.144 Gleason (Ref = GG<3) GG≥3 3.699 (1.279-10.699) 0.016 Bone Mets (Ref = No) Yes 0.549 (0.288-1.045) 0.068 Liver Mets (Ref = No) Yes 3.855 (1.681-8.841) 0.001 Lung Mets (Ref = No) Yes 1.833 (0.849-3.958) 0.123 Other Mets (Ref = No) Yes 2.472 (1.103-5.538) 0.028

3584 Background: Immune checkpoint inhibitors (ICIs) have limited efficacy in patients with microsatellite stable (MSS) colorectal cancer (CRC). Radiation therapy (RT) may increase the response rate to ICIs through multiple mechanisms. In our phase 2 trial (NCT03104439), 40 patients with metastatic MSS CRC were enrolled to receive ipilimumab and nivolumab with RT (24 Gy/3 fractions) starting on C2D1. Among the 27 patients who received RT (33% dropout rate), the disease control rate (DCR) was 37% and objective response rate (ORR) was 15%. To confirm this signal and address dropout prior to RT, we conducted a phase 2 study of nivolumab and ipilimumab with RT moved to C1D1. Methods: In this open-label, single-arm, phase 2 study (NCT04361162), eligible patients had histologically confirmed metastatic MSS CRC, ECOG PS 0-1, and progressed on at least one line of chemotherapy. Treatment consisted of ipilimumab 1 mg/kg every 6 weeks for the first 4 cycles, nivolumab 240 mg every 2 weeks on a 6-week cycle, and RT with 24 Gy/3 fractions to one site starting on C1D1. Treatment continued until disease progression, discontinuation, or withdrawal. The primary endpoint was ORR outside of the RT field by RECIST 1.1 with radiological evaluations every 3 months. The treatment regimen was considered to have promising activity if at least 3 of 30 patients achieved an objective response in unirradiated lesions. Secondary endpoints included DCR, PFS, OS, and safety. A single-stage design was used to enroll 30 patients for intention-to-treat analysis of patients receiving at least one dose of study treatment. The per protocol analysis included patients who completed C1D1. The treatment regimen was considered to have promising activity if at least 3 of 30 patients achieved an objective response in unirradiated lesions, providing 85% power to reject 4% ORR in favor of 15% ORR at a significance level of 15%. Results: We enrolled and treated 30 patients (median age 56 years [range 28-85], 60% male, 83% white) from 10/2020 to 05/2022. Patients received a median of 2 (range, 1-7) prior lines of chemotherapy. All patients in the intention-to-treat population also met criteria for inclusion in the per protocol analysis. The ORR was 13% (4/30; 95% CI, 4-31%), DCR was 33% (10/30; 95% CI, 17-53%), median PFS was 2.4 months (95% CI, 1.8-2.9 months), and median OS was 10.6 months (95% CI, 6.8-17.8 months). 16 patients had grade 3+ treatment-related serious adverse events, including lymphopenia (3 patients with grade 4), anemia, diarrhea, colitis, vomiting, alkaline phosphatase increase, hypothyroidism, fatigue, and myositis. Conclusions: Treatment with ipilimumab, nivolumab, and RT starting on C1D1 showed promising activity in patients with traditionally immunoresistant metastatic MSS CRC. Further analyses are ongoing to evaluate optimal patient selection and radiation strategies. Clinical trial information: NCT04361162 .

LBA8 Background: BOT promotes optimized T cell priming, activation and memory formation by strengthening antigen presenting cell/T cell co-engagement. As an Fc-enhanced next-generation anti–CTLA-4 antibody, BOT also promotes intratumoral regulatory T cell depletion and reduces complement fixation. We present results from patients with MSS CRC treated with BOT + BAL in an expanded phase 1a/1b study; NCT03860272. Methods: Patients (pts) with metastatic MSS CRC received BOT 1 or 2 mg/kg every 6 weeks (Q6W) + BAL 3 mg/kg every 2 weeks. Crossover from monotherapy to combination therapy was permitted (rescue) as well as fixed-dosing (150 mg BOT Q6W + 450 mg BAL every 3 weeks). Results: Fifty-nine combination pts were evaluable for efficacy/safety (treated as of 19 May 2022 with ≥1 Q6W imaging assessment), including one rescue and one fixed-dose pt. Median pt age was 57 (range, 25-83), 58% were female, and 76% received at least three prior lines of therapy including prior immunotherapy (34%). Median follow-up was 6.4 months (range, 1.6-29.5). In all pts, objective response rate (ORR) was 22% (95% CI, 12-35), disease control rate (DCR) was 73% (95% CI, 60-84), and median duration of response (DOR) was not reached (NR), with 9/13 responses ongoing. The 12-month overall survival (OS) rate was 61% (95% CI, 42-75), with median OS NR. Of the 13 responders, 9 had RAS mutations (7 KRAS, 2 NRAS), 0 had BRAF mutations, 0/10 had a TMB of ≥10 mutations/Mb, and 1/7 was PD-L1 positive (≥1% combined positive score). A subgroup analysis was conducted by the dose of BOT received . In 1 mg/kg pts (n=8), ORR was 38% (3/8; 95% CI, 9-76) and DCR was 100% (8/8; 95% CI, 63-100); in 2 mg/kg pts (n=50), ORR was 20% (10/50; 95% CI, 10-34) and DCR was 70% (35/50; 95% CI, 55-82). All grade treatment-related adverse events (TRAEs) occurred in 88% of pts, including grade 3 in 32%, and grade 4 in 2% of pts. Diarrhea/colitis was the only grade 3/4 TRAE occurring in more than three pts (15% grade 3, 2% grade 4). The most common grade 3 TRAEs outside of diarrhea/colitis were fatigue (5%) and pyrexia (5%). There were no grade 5 TRAEs reported. Fifteen percent of pts had a TRAE leading to discontinuation of BOT alone and 12% had a TRAE leading to discontinuation of both BOT + BAL. Conclusions: In heavily pretreated metastatic MSS CRC pts, BOT + BAL continues to demonstrate promising clinical activity with durable responses and was well tolerated with no new immune-mediated safety signals. A larger pt set, analyses by subgroup, and additional translational data will be presented at the meeting. A randomized phase 2 trial in MSS CRC pts is enrolling (NCT05608044). Clinical trial information: NCT03860272 .

e15072 Background: The sunitnib approval trials have established this multi-targeted TKI as a standard treatment in patients with metastatic RCC. However, even RCTs may fail to show relevant clinical benefit in wider population, as certain patient subtypes are under-represented, notably those with poorer prognostic factors and pretreated. The purpose of the study was to evaluate effectiveness of sunitinb in unselected RCC patients in real life practice in Italy. Methods: The data were collected through national registry on oncology drugs as part of mandatory surveillance program, which allows prospective investigations of effectiveness. RCC patients receiving sunitinb once daily, on schedule 4/2, between 2007 and 2011, had been included. All patients were checked prospectively for toxicity, clinical outcomes and length of treatment using registry inputs. Retrospective analysis of previous and following treatments and mortality data was performed based on clinical records and hospital databases. Results: A total of 106 patients (median age 64 years, M 70/F 36) were reviewed, 77% had prior nephrectomy and 74% were treatment-naïve. At first evaluation we found 28% partial responses, 25% stable diseases, 46% progressions and one discontinuation due to toxicity. The median TTP and OS were 7 and 11.3 months, respectively. Among 102 RCC patients (pts) with metastases (mets) at first diagnosis, 65% had lung mets, 19% pts had liver mets, 25% had bone mets and 8% had brain mets. The Cox regression model showed in subgroups analysis significantly worse survival prognosis in males, brain and liver mets, ECOG PS>1, non-clear cell histology and non prior nephrectomy. Sorafenib treatment after progression on sunitinib (33% pts) did not improved OS. Grade 3 thrombocytopenia, neutropenia, mucositis and HFS caused dosage reductions. Conclusions: The results on examined RCC study population show that sunitinib clinical benefit was gained in selected responders, but in overall the effectiveness was nearly half of that reported in the approval RCTs. Post-marketing studies in real life practice are required in order to verify both effectiveness and safety in general population, testing for external validity of randomized trials.

854P - Sunitinib in Advanced RCC: Cost-Effectiveness Evaluation Based on Clinical Practice

In sporadic colorectal cancer (CRC), KRAS are alternative to BRAF mutations and occur, respectively, in 30 and 10% of cases. Few reports addressed the association between KRAS-BRAF mutations and tumour progression specifically in sporadic microsatellite-stable (MSS) CRC. We screened KRAS and BRAF in 250 MSS primary CRC and 45 lymph node (LN) metastases and analysed the pathological features of the cases to understand the involvement of KRAS-BRAF activation in progression and metastasis. Forty-five per cent of primary MSS CRCs carried mutations in at least one of these genes and mutations were associated with wall invasion (P=0.02), presence and number of LN metastases (P=0.02 and P=0.03, respectively), distant metastases (P=0.004) and advanced stage (P=0.01). We demonstrated that KRAS and BRAF are alternative events in Tis and T1 MSS CRC and, KRAS rather than BRAF mutations, contributed to the progression of MSS CRC. The frequency of KRAS and/or BRAF mutations was higher in LN metastases than in primary carcinomas (P=0.0002). Mutated LN metastases displayed KRAS associated or not with BRAF mutations. BRAF mutations were never present as a single event. Concomitant KRAS and BRAF mutations increased along progression of MSS CRCs, suggesting that activation of both genes is likely to harbour a synergistic effect.