Kochenderfer, Mark D.

TPS3675 Background: Multi-agent chemotherapy regimens (eg, mFOLFOX6) ± anti-vascular endothelial growth factor (VEGF) or anti-epidermal growth factor regimens are currently the standard of care for patients (pts) with mCRC without targetable mutations. However, the 5-year survival rate remains low at approximately 16% (SEER, 2025). The addition of biological therapies (eg, bevacizumab [bev], an anti-VEGF monoclonal antibody) to immune checkpoint inhibitors (ICIs) has demonstrated a synergistic antitumor effect in solid tumors. However, ICI monotherapy has limited activity in mismatch repair proficient (pMMR)/microsatellite stable (MSS) mCRC. Simultaneous bispecific targeting of programmed death 1 (PD-1) and VEGF in conjunction with cytotoxic chemotherapy has the potential to enhance antitumor activity. PF-08634404 is a fully human immunoglobulin G4 (IgG4) bispecific antibody targeting PD-1 and VEGF. A phase 2 study of PF-08634404 with XELOX or mFOLFOX6 demonstrated promising antitumor activity with a manageable safety profile in first-line (1L) mCRC (Xu X, ESMO 2025; Abstract 796P). Methods: Symbiotic-GI-03 (NCT07222800) is an ongoing, double-blind, randomized, phase 3 study evaluating the efficacy and safety of 1L PF-08634404 + mFOLFOX6 vs bev + mFOLFOX6. Inclusion criteria are age ≥18 y; mCRC with measurable disease per RECIST 1.1; no prior systemic therapy for metastatic disease; ECOG PS 0 or 1; and adequate hematologic, hepatic, and renal function. Pts with BRAF V600E-mutant or mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) CRC, active central nervous system metastases, or clinically significant risk of hemorrhage/fistula will be excluded. Approximately 800 pts will be randomized 1:1 to receive PF-08634404 + mFOLFOX6 or bev + mFOLFOX6 until disease progression, unacceptable toxicity, withdrawal of consent, or death. Randomization will be stratified by region (North America, Europe, or rest of world), RAS status (mutant or wildtype), and presence of liver metastasis (yes or no). The dual primary endpoints are progression-free survival (PFS) by blinded independent central review and overall survival; for each, a stratified log-rank test will be used to compare arms. Hazard ratios with corresponding 2-sided 95% CIs will be estimated using a stratified Cox proportional hazards model, and medians will be estimated using the Kaplan-Meier method with corresponding 2-sided 95% CIs calculated using the log(-log) method. Secondary endpoints include PFS by investigator, objective response rate, duration of response, PFS after next-line therapy, safety/tolerability, pharmacokinetics, immunogenicity, and patient-reported outcomes. Enrollment began in December 2025. Clinical trial information: NCT07222800 .

PURPOSE Tumor treating fields (TTFields) use alternating electric fields to disrupt cancer cell proliferation. Feasibility of TTFields therapy with gemcitabine/nab-paclitaxel was previously demonstrated in patients with advanced pancreatic adenocarcinoma. PANOVA-3 was designed to confirm safety and efficacy of TTFields in patients with unresectable locally advanced pancreatic adenocarcinoma (LA-PAC). METHODS In this global phase III trial, 571 patients with newly diagnosed LA-PAC were randomly assigned to receive gemcitabine 1,000 mg/m 2 and nab-paclitaxel 125 mg/m 2 by intravenous infusion once a day on days 1, 8, and 15 of a 28-day cycle with or without TTFields. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), local PFS, pain-free survival, and overall response rate (ORR). Distant PFS was analyzed post hoc. RESULTS OS was significantly prolonged using TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel (median, 16.2 months [95% CI, 15.0 to 18.0] v 14.2 months [95% CI, 12.8 to 15.4]; hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.99]; P = .039). PFS, local PFS, and ORR were not improved. Pain-free survival was significantly prolonged with TTFields with gemcitabine/nab-paclitaxel (median, 15.2 months [95% CI, 10.3 to 22.8] v 9.1 months [95% CI, 7.4 to 12.7]; HR, 0.74 [95% CI, 0.56 to 0.97]; P = .027), as was distant PFS (median, 13.9 months [95% CI, 12.2 to 16.8] v 11.5 months [95% CI, 10.4 to 12.9]; HR, 0.74 [95% CI, 0.57 to 0.96]; P = .022). Device-related skin adverse events (AEs) were experienced by 76.3% of patients. Most device-related skin AEs were mild to moderate, with 7.7% of patients reporting a grade 3 AE. CONCLUSION This study demonstrated significant OS, pain-free survival, and distant PFS benefits for TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in patients with unresectable LA-PAC, with no additive systemic toxicity.

Background Standard first-line therapies for metastatic colorectal cancer (mCRC) include fluoropyrimidine-containing regimens with oxaliplatin and/or irinotecan and a biologic agent. Immunotherapy may enhance antitumor activity in combination with standard therapies in patients with mCRC. Here, we present phase 2 results of nivolumab plus standard-of-care therapy (SOC; 5-fluorouracil/leucovorin/oxaliplatin/bevacizumab) versus SOC in the first-line treatment of patients with mCRC (CheckMate 9X8). Methods CheckMate 9X8 was a multicenter, open-label, randomized, phase 2/3 trial. Eligible patients were at least 18 years of age with unresectable mCRC and no prior chemotherapy for metastatic disease. Patients were randomized 2:1 to receive nivolumab 240 mg plus SOC or SOC alone every 2 weeks. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors V.1.1. Secondary endpoints included PFS by investigator assessment; objective response rate (ORR), disease control rate, duration of response, and time to response, all by BICR and investigator assessments; overall survival; and safety. Preplanned exploratory biomarker analyses were also performed. Results From February 2018 through April 2019, 310 patients were enrolled, of which 195 patients were randomized to nivolumab plus SOC (n=127) or SOC (n=68). At 21.5-month minimum follow-up, PFS with nivolumab plus SOC versus SOC did not meet the prespecified threshold for statistical significance; median PFS by BICR was 11.9 months in both arms (HR, 0.81 (95% CI, 0.53 to 1.23); p=0.30). Higher PFS rates after 12 months (18 months: 28% vs 9%), higher ORR (60% vs 46%), and durable responses (median 12.9 vs 9.3 months) were observed with nivolumab plus SOC versus SOC. Grade 3–4 treatment-related adverse events were reported in 75% versus 48% of patients; no new safety signals were identified. Conclusions The CheckMate 9X8 trial investigating first-line nivolumab plus SOC versus SOC in patients with mCRC did not meet its primary endpoint of PFS by BICR. Nivolumab plus SOC showed numerically higher PFS rates after 12 months, a higher response rate, and more durable responses compared with SOC alone, with acceptable safety. Further investigation to identify subgroups of patients with mCRC that may benefit from nivolumab plus SOC versus SOC in the first-line setting is warranted. Trial registration number NCT03414983 .

8 Background: Standard 1L therapies for mCRC include a fluoropyrimidine with oxaliplatin and/or irinotecan, and a biologic agent. NIVO may enhance antitumor activity in combination with 1L standard therapies within a subset of patients (pts) with mCRC. CheckMate 9X8 evaluated NIVO + mFOLFOX6/BEV vs mFOLFOX6/BEV in 1L mCRC (NCT03414983). Methods: Adults with previously untreated, unresectable, mCRC were randomized 2:1 to NIVO 240 mg + mFOLFOX6/BEV Q2W (NIVO + standard-of-care [SOC]) or mFOLFOX6/BEV Q2W (SOC). Primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR) per RECIST v1.1. Key secondary endpoints included objective response rate (ORR), disease control rate (DCR), time to response (TTR), duration of response (DOR), overall survival (OS), and safety. Results: 195 pts were randomized to NIVO + SOC (n = 127) or SOC (n = 68). Median (range) follow-up was 23.7 (0–33.2) months (mo; NIVO + SOC) vs 23.2 (0–32.3) mo (SOC). Median (range) duration of therapy was 9.9 (0.1–31.8+) mo (NIVO + SOC) and 7.7 (0.1–26.7+) mo (SOC). The HR (95% CI) for PFS was 0.81 (0.53–1.23; P = 0.30), which did not meet the prespecified threshold for statistical significance (median PFS, 11.9 mo in both arms; Table). PFS rates after 12 mo were higher with NIVO + SOC vs SOC (Table). ORR was 60% (NIVO + SOC) and 46% (SOC; odds ratio 1.72 [95% CI 0.96–3.10]) and median (95% CI) DOR was 12.9 (9.0–13.1) mo (NIVO + SOC) and 9.3 (7.5–11.3) mo (SOC; Table). Rates of grade 3−4 treatment-related adverse events (TRAEs) were higher with NIVO + SOC; however, no new safety signals were identified (Table). Biomarker analyses, including tumor mutational burden and baseline CD8 levels, will be presented. Conclusions: The primary endpoint of PFS was not met; however, NIVO + SOC showed higher PFS rates after 12 mo, a higher response rate, and more durable responses compared with SOC, along with acceptable safety, in 1L mCRC. Clinical trial information: NCT03414983. [Table: see text]