5058 Background: Hypoxia-inducible factor 2α (HIF-2α) is an established oncogenic driver, and HIF-2α expression in prostate cancer is positively correlated with aggressive disease. Belzutifan is a selective HIF-2α inhibitor approved for use in clear cell renal cell carcinoma. Cohort J of the multicohort, phase 1b/2 KEYNOTE-365 study (NCT02861573) evaluated the safety and efficacy of belzutifan in participants (pts) with mCRPC. Methods: Eligible adults had histologically or cytologically confirmed adenocarcinoma of the prostate without small cell histology, had an Eastern Cooperative Oncology Group performance status score of 0 or 1, and had received prior docetaxel for mCRPC. Prior treatment with 1 other chemotherapy and ≤2 second-generation hormonal agents were allowed. Pts received oral belzutifan 120 mg daily. Primary end points were safety and tolerability, prostate-specific antigen (PSA) response rate (PSA decline ≥50%), and objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points included time to PSA progression, ORR, and radiographic progression-free survival (rPFS) per PCWG3-modified RECIST v1.1, duration of response and disease control rate (DCR; complete response + partial response + stable disease ≥6 mo) per RECIST v1.1 and PCWG3-modified RECIST v1.1 by BICR, and overall survival (OS). Results: A total of 21 pts were allocated to receive belzutifan. Median age was 69.0 y (range, 56-84). Median study follow-up was 17.6 mo (range, 15.9-21.8). All pts discontinued treatment as of the data cutoff (August 25, 2025), most commonly due to progressive disease (n = 12; 57%). Median duration of belzutifan therapy was 2.8 mo (range, 0.7-8.7). Treatment-related adverse events (AEs) occurred in 20 pts (95%); grade 3 or 4 treatment-related AEs occurred in 11 pts (52%), most commonly anemia (n = 8; 38%). A total of 2 pts (10%) discontinued treatment, and no pts died due to treatment-related AEs. Among pts with a baseline PSA measurement (n = 20), PSA response rate was 0% (95% CI, 0-17) and median time to PSA progression was 3.0 mo (95% CI, 2.8-not reached [NR]). Among 12 pts with RECIST-measurable disease, ORR and DCR per RECIST v1.1 were both 0%; ORR and DCR per PCWG3-modified RECIST v1.1 were 0% and 8%, respectively. In all pts, median rPFS was 3.7 mo (95% CI, 1.9-NR) and median OS was 16.9 mo (95% CI, 10.8-NR). Conclusions: In cohort J of the KEYNOTE-365 trial, belzutifan monotherapy had a manageable safety profile but did not show meaningful antitumor activity in mCRPC. Future research is needed to determine effective treatments for pts with mCRPC. Clinical trial information: NCT02861573 .

BACKGROUND:OBI-999 is an antibody-drug conjugate consisting of the Globo H-targeting antibody OBI-888 linked to the cytotoxic payload monomethyl auristatin E. In a dose-escalation study, the OBI-999 recommended phase 2 dose (RP2D) was 1.2 mg/kg every 3 weeks. This dose-expansion study evaluated the efficacy and safety of OBI-999 in patients with pancreatic cancer, colorectal cancer (CRC), or other tumor types ("basket cohort") and tumoral Globo H H-scores ≥100 (NCT04084366). PATIENTS AND METHODS:Patients were treated at RP2D of OBI-999. We assessed response, progression-free survival (PFS), treatment-emergent adverse events (TEAEs), and pharmacokinetics of OBI-999. RESULTS:Of 29 patients treated, 23 were evaluable for response. Eight (34.8%) had stable disease): pancreatic cancer, 4 of 7; CRC, 2 of 8; basket cohort, 2 of 8. No objective response was noted. The median time on treatment was 22 days. No association between H-score and tumor size reduction was noted. Median PFS was 3.3 months, 1.3 months, and 1.4 months in the pancreatic, CRC, and basket cohorts, respectively. One patient (3.4%) experienced a serious TEAE related to OBI-999 (febrile neutropenia) that led to discontinuation of OBI-999; the TEAE resolved 3 days after onset. OBI‑999 showed consistent pharmacokinetics with comparable exposure at RP2D across cohorts. CONCLUSIONS:OBI-999 had a favorable safety profile. Although 34.8% of patients had disease stabilization, no objective response was noted, likely owing to inefficient antigen binding, suboptimal systemic exposure at the tolerated dose, and complex tumor biology.

TAC-001 is a novel next-generation antibody-drug conjugate designed for systemic delivery of a potent Toll-like Receptor (TLR)-9 agonist payload. It selectively targets TLR9 to CD22+ B cells, triggering their activation and inducing anti-tumor responses by harnessing the immunological functions of B cells. The mouse surrogate of TAC-001 induced tumor infiltration of activated B cells, effector T cells, and TLS-like structures, leading to sustained anti-tumor activity, including in models resistant to anti-PD-1 therapy. This Phase 1 trial (INCLINE 101; NCT05399654) evaluated the safety, tolerability, pharmacokinetics (PK), immunogenicity, tumor biopsy pharmacodynamic (PD) effects, and preliminary efficacy of TAC-001 across multiple solid tumors with ECOG-PS 0-1. Eligible patients (pts; ≥18 years) received TAC-001 IV Q2W at 3-fold escalating doses (0.1-12 mg/kg) with monitoring for 28-day dose-limiting toxicities (DLTs). Doses were reduced 2-fold or to the next lower tolerated dose level in the event of DLTs. TAC-001 was evaluated in select tumor types at two doses at and below the maximum tolerable dose (MTD). As of September 11, 2024, 72 heavily pre-treated pts (median age 62, range 37-79) with a median of 6 (range 1 to 12) prior therapies were enrolled in the study, including 52 (72%) PD-(L)1 refractory/resistant pts. Treatment-related adverse events (TRAE) were reported in 66 (92%) pts, with 54 (75%) experiencing mild-moderate (Gr 1-2) events. The most frequent TRAEs included chills (61%), fatigue (35%), and pyrexia (35%). Gr ≥ 3 toxicities occurred in 12 (17%) pts, leading to treatment discontinuation in one pt (1.4%). DLTs occurred at 3 mg/kg (1 pt Gr ≥3 bilirubin and elevated ALT) and 12 mg/kg (1 pt transient Gr 3 transaminitis, and 1 pt Gr ≥3 bilirubin with Gr 4 acute kidney injury). The MTD was established at 6mg/kg, with 3mg/kg and 6mg/kg selected for dose expansion. TAC-001 PK exposures (Cmax and AUC) exhibited dose-dependent increases over the dose range tested. Preliminary PD assessment demonstrated dose-dependent CD22 engagement, with activation of circulating B cells observed across dose levels. Among 68 response-evaluable pts, 24 achieved stable disease (≥2 months), 2 (melanoma and cholangiocarcinoma) had confirmed durable partial responses, and 32 had progressive disease. Final results will be presented at the meeting. TAC-001 showed a favorable safety profile, dose-dependent PK/PD activity, and anti-tumor activity in PD- (L)1 refractory pts. Jason T. Henry, Anna C. Pavlick, Timothy Humphries, Sunnie Kim, Martin Gutierrez, Sarina A. Piha-Paul, Daniel Vaena, Shiraj Sen, Alexander Spira, Guru Sonpavde, Ons Harrabi, Feng Jin, Sangeetha Bollin, Laura QM Chow, Hong I. Wan, Cesar A. Perez. A phase 1/2 trial of TAC-001 (TLR9 agonist-CD22 mAb) in advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT045.

5059 Background: Patients with NEPC are often treated with platinum-based chemotherapy but novel therapies with favorable efficacy and safety profiles are needed. Cohort I of the phase 1b/2 KEYNOTE-365 study (NCT02861573) was designed to evaluate the safety and efficacy of adding pembro to chemo in participants (pts) with NEPC. Preliminary data are presented. Methods: Adultpts with pathologically (morphology and immunohistochemistry) confirmed treatment-emergent (t-NE) or de novo metastatic NEPC (small cell, large cell, or mixed morphology per central review), disease progression ≤6 mo before screening, and ECOG PS of 0 or 1, with or without prior androgen deprivation therapy, are included. Enrollment is ongoing. Prior treatment (Tx) with ≤2 chemo regimens for metastatic castration-resistant prostate cancer and ≤2 next-generation hormonal agents are allowed. Prior Tx with platinum-containing regimens is not permitted. Pts are randomly assigned 1:1 to receive 4-6 cycles of carboplatin AUC 5 IV on day 1 Q3W + etoposide 100 mg/m 2 IV on days 1-3 Q3W with or without pembro 200 mg IV Q3W for ≤35 cycles. Primary end points are safety, ORR per RECIST v1.1 by blinded independent central review (BICR), and confirmed prostate-specific antigen (PSA) response rate (≥50% decrease from baseline [BL] measured twice ≥3 wk apart). Secondary end points include rPFS per PCWG3-modified RECIST v1.1 by BICR and OS. No formal hypothesis testing was performed. Results: As of August 26, 2024, 40 pts have been randomized; 19 pts received ≥1 dose of pembro + chemo and 18 pts ≥1 dose of chemo. Of treated pts, 29 (78%) had t-NE. Median follow-up was 11.7 mo (range, 0.5-28.7); 7 and 2 pts remain on Tx with pembro + chemo or chemo, respectively. For pts with RECIST-measurable disease, confirmed ORR was 33% (6/18; 95% CI, 13-59; 6 partial responses [PRs]) with pembro + chemo versus 6% (1/16; 0-30; 1 PR) with chemo. For pts with a BL PSA measurement, confirmed PSA response rate was 37% (7/19; 95% CI, 16-62) versus 18% (3/17; 4-43). In all treated pts, median rPFS was 5.1 mo (95% CI, 3.9-8.1) with pembro + chemo versus 4.0 mo (2.0-4.3) with chemo; 6-mo rPFS rate was 49% versus 21%. Median OS was 11.4 mo (95% CI, 5.1-not reached) versus 7.8 mo (3.6-8.5); 6-mo OS rate was 80% versus 65%. Grade 3 or 4 Tx-related AEs (TRAEs) occurred in 58% of pts with pembro + chemo versus 78% with chemo, most commonly anemia (32% vs 39%); no grade 5 TRAEs occurred. Immune-mediated AEs and infusion reactions occurred in 32% of pts with pembro + chemo versus 11% with chemo, most commonly hyperthyroidism (16% vs 6%) and infusion reactions (16% vs 6%). Conclusions: Based on these preliminary data in pts with NEPC, the addition of pembro to chemo is associated with promising efficacy outcomes compared with chemo alone and does not result in new or unexpected safety signals. Updated data from cohort I will be presented at the meeting. Clinical trial information: NCT02861573 .

3597 Background: There is a high unmet need for the treatment of patients [pts] with metastatic microsatellite stable colorectal cancer [MSS-CRC]. We reported encouraging preliminary antitumor activity with the combination of COM701 + nivolumab in patients with MSS-CRC and liver metastases [12/22(77%)], [ORR 2/17 (12%); disease control rate [DCR] 5/17 (29%)]1. COM701 is a novel, 1st-in-class immune checkpoint inhibitor [ICI] that binds to PVRIG, a DNAM-1 axis member, leading to activation of T and NK-cells; COM902 is an ICI of TIGIT. Pembrolizumab is an ICI of PD-1. We hypothesized that in pts with metastatic MSS-CRC, the triple combination by inhibiting the DNAM-1 axis would demonstrate antitumor activity with a favorable safety and tolerability profile. We present encouraging preliminary results. Methods: We enrolled 20 pts with metastatic MSS-CRC who all received COM701 15 mg/kg + COM902 3 mg/kg + pembrolizumab 200 mg all IV Q3W. Primary objectives were safety/tolerability, with secondary objective of antitumor activity of the combination. Key inclusion criteria: Age ≥ 18 yrs, measurable disease, MSS by IHC or genomic testing, ≤3 prior lines including fluroropyrimidines, irinotecan, and oxaliplatin. Key exclusion criteria: prior receipt of ICI including anti-PVRIG, anti-TIGIT. Investigator assessed responses were per RECIST v1.1, safety per CTCAE v5.0. Results: Median age 57.5yrs, 11/20 [F], 15/20 [75%] pts with liver metastases. Median of 3 prior lines of therapy. Objective response rate [ORR] 1/20 [5%] pts; 7 pts with SD. Disease control rate [CR + PR + SD] 8/20 [40%]. In pts with liver mets ORR 1/15 [7%], DCR 6/15 (40%); 6/8 [75%] pts with best response ≥SD had liver mets. Treatment related AEs were reported in 11/20 [55%] pts, the majority were ≤G2 7/20 [35%] with the most frequent TRAE of 4 pts each with ≤G2 fatigue, myalgia, 4/20 pts with G3 TRAE, there were no ≥G4 TRAEs. Strong peripheral IFNɣ induction was observed after treatment. Three pts [1 PR, 2 SD] are ongoing at the time of data cut. Conclusions: The data further supports the antitumor activity of the combination of COM701 + COM902 + pembrolizumab in pts with MSS-CRC and specifically in patients with liver metastases. Of note the data further reinforces the data previously disclosed in a similar pt population of 22 pts that received COM701 + nivolumab1. No new safety signals are reported. Additional clinical and translational data will be presented at the conference. Data cut 01/09/2024. Reference: 1. Rasco D, Dumbrava E, Sharma M, et al659 COM701 plus nivolumab demonstrates preliminary antitumor activity and immune modulation of tumor microenvironment in patients with metastatic MSS-CRC and liver metastases. Journal for ImmunoTherapy of Cancer 2022;10:doi: 10.1136/jitc-2022-SITC2022.0659. Clinical trial information: NCT04354246 .

PURPOSE Patients with no evidence of disease (NED) after metastasectomy for renal cell carcinoma are at high risk of recurrence. Pazopanib is an inhibitor of vascular endothelial growth factor receptor and other kinases that improves progression-free survival in patients with metastatic RCC (mRCC). We conducted a randomized, double-blind, placebo-controlled multicenter study to test whether pazopanib would improve disease-free survival (DFS) in patients with mRCC rendered NED after metastasectomy. PATIENTS AND METHODS Patients with NED after metastasectomy were randomly assigned 1:1 to receive pazopanib 800 mg once daily versus placebo for 52 weeks. The study was designed to observe an improvement in DFS from 25% to 45% with pazopanib at 3 years, corresponding to 42% reduction in the DFS event rate. RESULTS From August 2012 to July 2017, 129 patients were enrolled. The study was unblinded after 83 DFS events (92% information). The study did not meet its primary end point. An updated analysis at 60.5-month median follow-up from random assignment (95% CI, 59.3 to 71.0) showed that the 3-year DFS was 27.4% (95% CI, 17.9 to 41.7) for pazopanib and 21.9% (95% CI, 13.3 to 36.2) for placebo. Hazard ratio (HR) for DFS was 0.90 ([95% CI, 0.60 to 1.34]; Pone-sided = .29) in favor of pazopanib. Three-year overall survival (OS) was 81.9% (95% CI, 72.7 to 92.2) for pazopanib and 91.4% (95% CI, 84.4 to 98.9) for placebo. The HR for OS was 2.55 (95% CI, 1.23 to 5.27) in favor of placebo ( Ptwo-sided = .012). Health-related quality-of-life measures deteriorated in the pazopanib group during the treatment period. CONCLUSION Pazopanib did not improve DFS as the primary end point compared with blinded placebo in patients with mRCC with NED after metastasectomy. In addition, there was a concerning trend favoring placebo in OS.

BACKGROUND:Belzutifan is a first-in-class hypoxia-inducible factor subunit 2α (HIF-2α) inhibitor approved at a dose of 120 mg once daily for certain adults with VHL disease and adults with advanced renal cell carcinoma (RCC) following therapy with a programmed cell death protein 1 (PD-1) [or programmed death ligand 1 (PD-L1)] inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor. However, whether the belzutifan dose could be optimized is unclear. PATIENTS AND METHODS:The phase II LITESPARK-013 study (NCT04489771) enrolled patients with advanced clear cell RCC whose disease progressed after one to three prior systemic therapies, including an anti-PD-(L)1 regimen. Patients were randomly assigned 1 : 1 to receive belzutifan 120 or 200 mg once daily. The primary endpoint was the objective response rate (ORR) per RECIST version 1.1. The secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS:Overall, 154 patients were enrolled (120 mg: n = 76; 200 mg: n = 78). The median follow-up was 20.1 months (range 14.8-28.4). The ORR was 23.7% versus 23.1% for the 120 mg and 200 mg groups, respectively [P = 0.5312; -0.5%, 95% confidence interval (CI) -14.0% to 12.9%]. The median DOR was not reached for the 120 mg arm and was 16.1 months (2.1+ to 23.5+) for the 200 mg arm. No between-group differences were observed for PFS [hazard ratio (HR) 0.94, 95% CI 0.63-1.40] or OS (medians not reached; HR 1.11, 95% CI 0.65-1.90). Grade 3 or 4 treatment-related adverse events were observed in 35 patients (46.1%) in the 120 mg group and 36 patients (46.2%) in the 200 mg group. CONCLUSIONS:The efficacy of belzutifan was similar between the 120 mg dose and the 200 mg dose for previously treated clear cell RCC. Safety at both doses was consistent with the known safety profile of belzutifan. These results further support 120 mg once daily as the preferred dose for belzutifan.

Importance In metastatic hormone-sensitive prostate cancer (mHSPC), new first-line combination therapies have enhanced overall survival (OS), but clinical outcomes for individual patients vary greatly and are difficult to predict. Peripheral blood circulating tumor cell (CTC) count is the most extensively validated prognostic liquid biomarker in metastatic castration-resistant prostate cancer (mCRPC), and recent studies have suggested that it may also be informative in mHSPC. Objective To examine the prognostic value of CTC count in men with mHSPC. Design, Setting, and Participants In this prognostic study, peripheral blood was drawn at registration (baseline) and at progression to mCRPC in the S1216 study (March 1, 2013, to July 15, 2017), a phase 3, prospective, randomized clinical trial in men with mHSPC. The CTCs were enumerated using a US Food and Drug Administration-cleared isolation platform. Counts were categorized as 0, 1 to 4, or 5 or more CTCs per 7.5 mL based on the prognostic value of these cut points in prior studies. The data analysis was performed between October 28, 2022, and June 15, 2023. Exposure Metastatic hormone-sensitive prostate cancer. Main Outcomes and Measures Circulating tumor cell count was evaluated for an association with 3 prespecified trial end points: OS, progression-free survival, and 7-month prostate-specific antigen, after adjusting for other baseline covariates using proportional hazards and logistic regression models. Results Of 1313 S1216 participants (median [IQR] age, 68 [44-92] years), evaluable samples from 503 (median [IQR] age, 69 [46-90] years) with newly diagnosed mHSPC were collected at baseline, and 93 samples were collected at progression. Baseline counts were 5 or more CTCs per 7.5 mL in 60 samples (11.9%), 1 to 4 CTCs per 7.5 mL in 107 samples (21.3%), and 0 CTCs per 7.5 mL in 336 samples (66.8%). Median OS for men with 5 or more CTCs per 7.5 mL was 27.9 months (95% CI, 24.1-31.2 months) compared with 56.2 months (95% CI, 45.7-69.8 months) for men with 1 to 4 CTCs per 7.5 mL and not reached at 78.0 months follow-up for men with 0 CTCs per 7.5 mL. After adjusting for baseline clinical covariates, men with 5 or more CTCs per 7.5 mL at baseline had a significantly higher hazard of death (hazard ratio, 3.22; 95% CI, 2.22-4.68) and disease progression (hazard ratio, 2.46; 95% CI, 1.76-3.43) and a lower likelihood of prostate-specific antigen complete response (odds ratio, 0.26; 95% CI, 0.12-0.54) compared with men with 0 CTCs per 7.5 mL at baseline. Adding baseline CTC count to other known prognostic factors (covariates only: area under the curve, 0.73; 95% CI, 0.67-0.79) resulted in an increased prognostic value for 3-year survival (area under the curve, 0.79; 95% CI, 0.73-0.84). Conclusions and Relevance In this prognostic study, the findings validate CTC count as a prognostic biomarker that improved upon existing prognostic factors and estimated vastly divergent survival outcomes regardless of subsequent lines of therapy. As such, baseline CTC count in mHSPC may serve as a valuable noninvasive biomarker to identify men likely to have poor survival who may benefit from clinical trials of intensified or novel regimens.

6507 Background: Recent real-world studies observed that some aNSCLC pts with ADO initiated non-targeted therapy (non-TT) before biomarker test results became available. This study assesses the clinical impact of the timing of first line (1L) TT in aNSCLC pts with ADO. Methods: In a retrospective analysis of the nationwide Flatiron Health electronic health record-derived de-identified database, pts aged ≥18 years, diagnosed (Dx) with aNSCLC between 1/1/2015-10/18/2022, had ADO (ALK, BRAF, EGFR, RET, MET, ROS-1, or NTRK) based on biomarker testing ≤ 90 days of advanced Dx, and received 1L treatment (tx) were included. Cohorts were defined by tx patterns after test result: Cohort 1 received 1L TT ≤ 42 days; Cohort 2 initiated 1L non-TT before or after testing but switched to TT ≤ 42 days; Cohort 3 initiated non-TT before or after testing and did not switch to TT ≤ 42 days. Pts were followed from test results + 42 days until 11/30/2022 or death, whichever earliest. Multivariate Cox regression evaluated real-world progression-free survival (rwPFS) and overall survival (OS) between cohorts. Results: A total of 5156 aNSCLC pts with ADO were included: 79% were treated in the community setting and 56% received NGS testing. Most common ADO were EGFR and ALK for both Cohort 1 (78% and 13%) and Cohort 2 (67% and 24%); EGFR (39%) and BRAF (35%) for Cohort 3. Cohort 3 included more rare mutations (MET, NTRK, RET). Statistically significant differences were observed in gender, race/ethnicity, practice type, and area-level socioeconomic status across all cohorts. There was no significant difference in outcomes observed between Cohort 2 and 1, but significantly inferior outcomes in Cohort 3 vs 1. Conclusions: Our findings demonstrated better outcomes with upfront 1L TT vs non-TT in aNSCLC pts with ADO. The comparable outcomes between pts who received 1L TT after test result and pts who switched to TT ≤ 42 days of test result available underscore the importance of timely tx decisions based on ADO detection in lieu of tx-switch at progression. Opportunities remain to improve utilization of NGS to identify all ADO upfront to inform the appropriate 1L TT when indicated. [Table: see text]

4534 Background: In the randomized phase 2 LITESPARK-013 study (NCT04489771), the first-in-class HIF-2α inhibitor belzutifan showed comparable antitumor activity in patients with pretreated advanced ccRCC at 200 mg and 120 mg doses (objective response rate [ORR]: 23.1% vs 23.7%; 1-sided P= 0.5312). We present results of a post hoc analysis of the pooled population (200 mg and 120 mg arms) across patient subgroups based on prior therapy and IMDC risk group. Methods: Patients with advanced ccRCC, measurable disease per RECIST v1.1, a Karnofsky Performance Scale score of ≥70%, ≤3 prior systemic regimens for advanced ccRCC (including an anti–PD-(L)1 regimen), and disease progression during or after an anti–PD-(L)1 regimen were randomly assigned 1:1 to receive belzutifan 200 mg or 120 mg QD. End points in the pooled population and subgroups were ORR and duration of response per RECIST v1.1 by blinded independent central review. Data cutoff was February 10, 2023. Results: A total of 154 patients were enrolled (200 mg, n = 78; 120 mg, n = 76). In the pooled population, the median age was 64.0 years, 127 patients (82.5%) had intermediate/poor risk per IMDC criteria, 110 patients (71.4%) received 1-3 prior tyrosine kinase inhibitor (TKI) regimens, and 81 patients (52.6%) received 2 or 3 prior lines of therapy. As of the data cutoff date, 39 patients (25.3%) in the pooled population remained on treatment. Median follow-up was 20.1 months (range, 14.8-28.4). In the pooled population, ORR was 23.4% (95% CI, 16.9-30.9; 4 complete responses [CRs], 32 partial responses [PRs]) and median duration of response (DOR) was 16.1 months (range, 2.1+ to 23.5+). Additional efficacy analyses for subgroups are presented in the table. Conclusions: This post hoc analysis from the LITESPARK-013 study of patients with pretreated advanced ccRCC suggests that belzutifan has antitumor activity regardless of prior lines of therapies and prognostic risk category. These results further support belzutifan as a treatment option for advanced RCC. Clinical trial information: NCT04489771 . [Table: see text]

ADAPT study group and participating centers

Aim: Biomarker testing detects actionable driver mutations to inform first-line treatment in advanced non-small-cell lung cancer (aNSCLC) and metastatic colorectal cancer (mCRC). This study evaluated biomarker testing in a nationwide database (NAT) versus the OneOncology (OneOnc) community network. Patients & methods: Patients with aNSCLC or mCRC with ≥1 biomarker test in a de-identified electronic health record-derived database were evaluated. OneOnc oncologists were surveyed. Results: Biomarker testing rates were high and comparable between OneOnc and NAT; next-generation sequencing (NGS) rates were higher at OneOnc. Patients with NGS versus other biomarker testing were more likely to receive targeted treatment. Operational challenges and insufficient tissue were barriers to NGS testing. Conclusion: Community cancer centers delivered personalized healthcare through biomarker testing.

subsequent standard of care treaments

542 Background: Detection of minimal residual disease (MRD) is emerging as a potential risk stratification and surveillance tool in patients with resected bladder cancer to potentially direct adjuvant therapy and early intervention. Recently, the sensitivity of MRD testing for early detection of recurrence has been questioned. We sought to evaluate the real world diagnostic performance characteristics of the Signatera ctDNA assay in patients with stage 1-4 bladder cancer who either had transurethral resection of bladder tumor (TURBT) in addition to either chemoradiation or radical cystectomy. Methods: Patients with bladder cancer who underwent ctDNA MRD testing after resection for stage 1-4 disease from 03/2021 to 09/2022 were evaluated retrospectively. Both patients with single and serial ctDNA assays were included. Individual chart review was performed to collect demographic and clinical variables such as diagnosis, stage, pathology, imaging results, and treatment course. Results: MRD results from 19 patients were available, 9 of which had serial assays. 13/19 patients were found to have ctDNA positive results at any time point. The positivity rate at initial testing was associated with stage: Stage 1: 3/5 patients, of which 2 had TURBT and 1 Radical cystectomy, stage 2: 2/5, stage 3: 6/8, and stage 4: 0/1. Notably, of the 9 patients with serial assays, one patient’s result converted from negative to highly positive during surveillance, with subsequent decrease to low positive after adjuvant therapy. One patient had a result of 2 consecutive low positives initially, which was converted to negative after systemic therapy and radiation. 7/19 patients completed testing 3 or more times over a span of approximately 4-13 months, 2 of whom had negative results throughout. Most patients who were found to have positive ctDNA did demonstrate radiographic recurrence within 2-3 months of ctDNA detection. Conclusions: Positive ctDNA MRD after resection is common in bladder cancer. Tumor-informed ctDNA MRD testing has very high sensitivity, but a one-time negative test result does not exclude the presence of metastatic disease. The above data shows an association between cancer stage and positivity results, particularly for advanced stages. Stage I cases with positive results can likely be explained by inadequate resection. Increases in ctDNA may represent early recurrence and can potentially be salvaged with early systemic therapy reverting to negative ctDNA. Prospective randomized and non-randomized studies are evaluating the clinical utility of ctDNA MRD testing in bladder cancer, and analysis of Signatera ctDNA assays will largely contribute to these efforts.

In the phase 1 LITESPARK-001 study of the HIF-2α inhibitor belzutifan for ccRCC, the MTD was not reached for dosages up to 240 mg per day, and the RP2D was 120 mg QD based on PD, PK, and safety. The phase 2 LITESPARK-013 study (NCT04489771) examined if a higher belzutifan dose could improve efficacy while maintaining an acceptable safety profile. Pts with advanced ccRCC, measurable disease per RECIST v1.1, ≤3 prior systemic regimens for advanced ccRCC including an anti–PD-1/L1 agent, and disease progression during or after an anti–PD-1/L1 agent were randomly assigned 1:1 to belzutifan 120 mg or 200 mg QD. Pts were stratified by IMDC risk score (0 vs 1-2 vs 3-6) and number of prior TKI therapies for advanced ccRCC (0 vs 1 vs 2-3). Primary end point was ORR per RECIST v1.1 by blinded independent central review. Secondary end points included DOR, PFS, OS, safety, and PK. Database cutoff was February 10, 2023. 154 pts were enrolled (120 mg: n=76; 200 mg: n=78). Baseline characteristics were well balanced between arms. Median follow-up was 20.1 months (range 14.8-28.4). ORR was 23.7% (18 PR) vs 23.1% (4 CR; 14 PR) for the 120 mg and 200 mg arms, respectively (P=0.5312; −0.5% [95% CI, −14.0 to 12.9] using the Miettinen-Nurminen method stratified by IMDC risk). PFS (median 7.3 vs 9.1 months; HR 0.94 [95% CI 0.63-1.40]) and OS (medians not reached; HR 1.11 [95% CI, 0.65-1.90]) did not differ between arms. Median DOR was not reached for the 120 mg arm (range 2.6+ to 16.1+) and was 16.1 mo (2.1+ to 23.5+) for the 200 mg arm; 64.7% and 51.3% of pts had ongoing responses ≥15 mo, respectively. 142 pts had a treatment-related AE (TRAE; 70 [92.1%] with 120 mg; 72 [92.3%] with 200 mg]. 2 pts (2.6%) in the 120 mg arm and 7 (9.0%) in the 200 mg arm discontinued treatment due to a TRAE. Treatment-related anemia (81.6% with 120 mg and 83.3% with 200 mg) and hypoxia (23.7% with 120 mg and 26.9% with 200 mg) was similar between arms. The efficacy of belzutifan was similar between the RP2D of 120-mg dose and the 200-mg dose and was consistent with prior reports of antitumor activity in ccRCC. Safety at both doses was consistent with the known safety profile of belzutifan. These results further support 120 mg QD as the preferred dose for belzutifan.

5595 Background: There is a high unmet medical need for the treatment of patients [pts] with microsatellite stable [MSS], recurrent, metastatic, endometrial cancer [EC]. We reported encouraging preliminary antitumor activity with the triple combination of COM701 + BMS-986207 + nivolumab in patients with platinum resistant epithelial ovarian cancer [1]. COM701 is a novel, 1st-in-class immune checkpoint inhibitor [ICI] that binds to PVRIG, a DNAM-1 axis member, leading to activation of T-and NK-cells; BMS-986207 is an ICI of TIGIT. Nivolumab is an ICI of PD-1. We hypothesized that in pts with EC, the triple combination would demonstrate antitumor activity with a favorable safety and tolerability profile. We present encouraging preliminary results. Methods: As part of an expansion cohort, we enrolled 9 patients [pts] with EC. All pts received COM701 20 mg/kg + BMS-986207 480 mg + nivolumab 480 mg all IV Q4W. Primary objectives were safety/tolerability, with secondary objective of antitumor activity in pts with EC. Key inclusion criteria: Age ≥ 18 yrs, measurable disease, MSS by IHC or genomic testing, ≤2 prior systemic cytotoxic therapies, prior PD-1/PD-L1 permissible. Key exclusion criteria: prior receipt of anti-PVRIG, anti-TIGIT. Investigator assessed responses were per RECIST v1.1, safety per CTCAE v5.0. Results: Median age 71yrs, median of 2 prior lines of therapy, prior PD-1/PD-L1 3/9 [33%]. All pts received prior cytotoxic therapy. Objective response rate (ORR) 2/9 [22%] pts; 2 pts with SD. Disease control rate [CR + PR + SD] 4/9 [44%]. There were 2 pts with confirmed PR; 1 of these pts was refractory to prior receipt of lenvatinib + pembrolizumab [best response assessment of progressive disease]. Treatment related AEs were reported in 6/9 [67%] pts, the majority 4/6 [67%] were Grade 1 [1 pt each with chills, pyrexia, back pain and pruritus, lipase increased]. No new safety signals are reported. Conclusions: The combination of COM701 + BMS-986207 + nivolumab demonstrates encouraging preliminary signal of antitumor activity in pts with EC including in a pt refractory to prior exposure to lenvatinib + pembrolizumab. The triplet combination has a favorable safety/tolerability profile. Additional data analyses and pt follow up are ongoing and will be presented at the conference. Data extract 01/24/2023. 1. Moroney JW, Yeku O et al. Triple blockade of the DNAM-axis with COM701 + BMS-986207 + nivolumab demonstrates preliminary antitumor activity in patients with platinum resistant OVCA. Annals of Oncology (2022) 16 (suppl_1): 100104-100104. 10.1016/iotech/iotech100104. Clinical trial information: NCT04570839 .