Manageable Safety Profile Research Articles

Efficacy and safety of albumin-bound docetaxel vs. docetaxel in patients with previously treated advanced gastric or gastroesophageal junction adenocarcinoma: A multicenter, randomized, phase II study.

333 Background: Docetaxel has demonstrated promising activity in gastric cancer, both as monotherapy and in combination with other agents. Albumin-bound docetaxel (HB1801) is a new kind of taxane and has many advantages compared with docetaxel. Previous phase I study has demonstrated that HB1801 showed preliminary efficacy in patients with gastric cancer. Methods: In this phase II study, eligible patients were aged 18-75 years with histologically confirmed gastric or gastroesophageal junction (G/GEJ) adenocarcinoma, who progressed on at least first line of combined chemotherapy of platinum and fluorouracil. Patients were randomized (1:1) to receive HB1801 (100 mg/m 2 ) or docetaxel (Taxotere, 75 mg/m 2 ) administered every 3 weeks by intravenous infusion. Stratified factors included previous treatment with immunotherapy (yes or no) and ECOG PS (0 or 1). Primary endpoint was progression free survival (PFS). Results: As of June 25, 2024, 128 patients were randomized to the HB1801 group ( n =65) or the docetaxel group ( n =63). The two groups were comparable on baseline characteristics. Overall, the median age was 59.0 (range 27-75) years, 106 (82.8%) patients had ECOG PS of 1. 76 (59.4%) patients had received previous treatment with immunotherapy. 76 (59.4%) patients had ≥ 2 metastatic sites. Median PFS was 4.0 months (95%CI 2.8-4.2) with HB1801 versus 2.7 months (95%CI 1.8-3.0) with docetaxel, HR = 0.81(95%CI 0.53, 1.21). Objective response rate and disease control rate were 21.5% (1CR and 13 PRs, 95%CI 12.3-33.5) and 56.9% (20 SDs, 95%CI 44.0-69.2) in the HB1801 group, compared with 14.3% (1 CR and 8 PRs, 95%CI 6.8-25.4) and 42.9% (17 SDs, 95%CI 30.5-56.0) in the docetaxel group. Median overall survival was 11.3 months with HB1801 versus 7.8 months with docetaxel (HR = 0.59 [95%CI 0.35, 1.01], p=0.025). Treatment-related adverse events (TRAEs) occurred in 93.8% of patients receiving HB1801, and 93.7% of patients receiving docetaxel. Alopecia (46.2% vs. 39.7%), fatigue (43.1% vs 23.8%), anemia (40.0% vs 39.7%), hypoalbuminemia (29.2% vs 12.7%), decreased appetite (21.5% vs 12.7%), peripheral edema (16.9% vs 12.7%) and nausea (15.4% vs 19.0%) were the most common TRAEs in the HB1801 group and the docetaxel group. 20 patients (30.8%) in the HB1801 group and 19 patients (30.2%) in the docetaxel group experienced ≥grade 3 TRAEs, with the most common being anemia and fatigue. 3 patients in the docetaxel group experienced treatment emergent adverse events (TEAEs) leading to death, which one was considered to be treatment-related. No patients in the HB1801 group had TEAEs leading to death. No new safety signal was observed in HB1801 group. Conclusions: Compared with Taxotere, HB1801 results in 41% reduction in risk of death with a manageable safety profile in patients with previously treated advanced G/GEJ cancer. Clinical trial information: NCT05705635 .

Zanidatamab dose optimization in patients with HER2-positive biliary tract cancer (BTC).

546 Background: Zanidatamab (zani) is a dual HER2-targeted bispecific antibody that binds 2 distinct HER2 domains, resulting in receptor crosslinking, clustering, and internalization as well as leading to reductions in cell-surface levels of HER2, phosphorylation of HER family members (EGFR, HER2, and HER3), downstream signaling, and ligand-dependent and -independent proliferation. Zani also induces complement-dependent cytotoxicity as well as antibody-dependent cellular cytotoxicity and phagocytosis. In the phase 2 HERIZON-BTC-01 study (Study 203), zani 20 mg/kg Q2W demonstrated a 41.3% confirmed objective response rate (cORR) and a manageable safety profile in patients (pts) with previously treated HER2+ BTC (IHC3+/2+ and ISH+). The objective of this analysis is to report optimal dose selection for zanidatamab in patients with HER2+ BTC through pharmacokinetic modeling. Methods: Source data included the phase 1 ZW25-101 study (Study 101; NCT02892123), Study 203 (NCT04466891), and in vitro study for ligand-dependent growth inhibition (LDGI) in HER2-expressing human cancer cell lines. In the LDGI study, cancer cells were cultured in media containing epidermal growth factor and were treated with different zani concentrations. The IC90 value for LDGI was obtained by nonlinear regression using the logistic dose-response model. To assess target saturation, the population pharmacokinetic model was used to simulate clearance at steady state following 5-30 mg/kg Q2W. The clinical utility of zani was evaluated based on the correlation of zani concentrations with both efficacy and safety. Results: Study 101 included 192 patients with HER2-expressing solid tumors (dose ranged from 5-30 mg/kg including QW, Q2W, and Q3W). The Ctrough values following the first zani 5 mg/kg QW dose were below the IC90 (25.0 μg/mL) for LDGI, and no confirmed responses were observed at this dose. The Ctrough values following the first zani dose of 10 mg/kg QW or 20 mg/kg Q2W were above IC90 and the 2 dose levels demonstrated a cORR of 25% and 28.6%, respectively. The simulated clearance suggests that the target-mediated elimination pathway was saturated at the dose level of 20 mg/kg Q2W, since clearance was comparable to that of the higher dose of 30 mg/kg Q2W. The efficacy and safety of 20 mg/kg Q2W was further evaluated in 87 pts with HER2-amplified BTC enrolled in Study 203. The clinical utility analysis based on the data from Study 203 demonstrated that the majority of pts had an exposure range on the plateau part of the efficacy curve. Conclusions: The zani dose of 20 mg/kg Q2W is expected to maximize the clinical benefit for pts with HER2+ BTC based on: reaching the desired target exposure (IC90 for LDGI), saturating target-mediated elimination pathway, and the clinical utility analysis of safety and efficacy. Higher exposures are not expected to result in higher responses. Clinical trial information: NCT02892123 , NCT04466891 .

Anlotinib combined with penpulimab and nab-paclitaxel as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): A single-arm, open-label phase II clinical trial.

367 Background: Recently, PD-1 blockades combined with dual chemotherapy regimens in first-line setting exhibited encouraging efficacy for patients with ESCC. However, the safety profile of conventional dual chemotherapy remained unsatisfactory. Therefore, PD-1 blockades combined with anti-angiogenic tyrosine kinase inhibitors (TKIs) and single chemotherapy regimen might offer a promising strategy. Anlotinib, a novel multitarget TKI primarily targeting VEGFR1-3, demonstrated promising therapeutic activity as first-line combination therapy or second-line monotherapy for ESCC patients in China clinically. Therefore, this study was designed to explore the efficacy and safety of anlotinib combined with penpulimab (PD-1 blockade) and nab-paclitaxel as first-line therapy in advanced ESCC. Methods: Patients with previously untreated metastatic or locally advanced ESCC were recruited and treated with anlotinib (12mg, po, d1~14, q3w) and penpulimab (200mg, iv, d1, q3w) plus nab-paclitaxel (220mg/m 2 , iv, d1, q3w) until disease progression or unacceptable toxicity. The tumor response was assessed according to RECIST 1.1 using CT scans every two cycles. Adverse events were recorded by severity in accordance with the NCI CTC AE Version 5.0. The predefined sample size was 30. Primary endpoint was PFS and secondary endpoints included safety, ORR, DCR and OS. Results: From Jul 2022 to Sep 2024, a total of 30 patients were enrolled, with 29 patients who had received first tumor response were included in this analysis. The best overall response indicated that there were 1 CR (3.4%), 23 PR (79.3%), 2 SD (6.9%) and 3 NE (10.3%). Therefore, the preliminary ORR was 82.8% (95%CI: 64.2%-94.2%), DCR was 89.7% (95%CI: 72.6%-97.8%). The primary median PFS of the 29 patients was 10.84 months (95%CI: 7.57-14.11). Additionally, safety profile exhibited that the regimen was tolerable. The most common treatment-emergent adverse events among the 29 patients with the incidence >20% were anemia (62%), leukopenia (31%), peripheral neurotoxicity (28%) and rash (21%). Common grade ≥3 treatment-emergent adverse events were leukopenia (7%), glutamic-pyruvic transaminase was elevated (3%), glutamic oxalacetic transaminase increased (3%), hypertension (3%), diarrhea (3%) and rash (3%). Conclusions: The combination of anlotinib plus penpulimab and nab-paclitaxel as first-line therapy for advanced ESCC demonstrated promising efficacy and manageable safety profile. And the conclusions needed to be confirmed in subsequent trials. Clinical trial information: ChiCTR2400089133 .

Phase I/II study of cabozantinib alone or in combination with panitumumab in patients with MET -amplified metastatic colorectal cancer.

146 Background: Despite the introduction of anti-EGFR therapies, resistance remains a significant challenge in metastatic colorectal cancer (mCRC). MET amplification is a recognized resistance mechanism. Cabozantinib, a multi-kinase inhibitor targeting MET, has shown promise in overcoming resistance to anti-EGFR therapy. This study aimed to evaluate the efficacy and safety of cabozantinib alone (Cabo) or in combination with panitumumab (Cabo+Pmab) in patients with MET-amplified mCRC. Patients and Methods: The study population included patients with RAS and BRAF wild-type mCRC who had progressed on anti-EGFR therapy and subsequently confirmed MET amplification by circulating tumor DNA. The phase I part aimed to establish the recommended cabozantinib dose in combination with panitumumab by assessing dose-limiting toxicity (DLT) within the first four weeks. The primary endpoint of phase II part was objective response rate (ORR) in patients receiving the study treatment as third-line therapy or later. In phase II part, patients were randomized to Cabo or Cabo+Pmab group. Based on a threshold ORR of 1.6% response rate and an expected efficacy of 30%, the planned sample size was 14 patients with one-sided alpha of 1.25% and power of 80% in each arm, Cabo and Cabo+Pmab. A tumor response of at least 3 out of 14 patients would warrant further investigation of these treatments. Results: A total of 35 patients were enrolled (6 in phase I and 29 in phase II, 28 for the primary analysis; 13 in Cabo and 15 in Cabo+Pmab). In phase I, no DLTs were observed. This allowed researchers to set the maximum tolerated dose and recommend a dosage of 60 mg/day of cabozantinib in combination with panitumumab for phase II. Of 28 pts for the primary analysis, ORR was 7.7% (1/13; 95%CI 0.2-36%) in Cabo group and 0% (0/15; 95%CI 0-21.8%) in Cabo+Pmab group, median progression-free survival was 3.1 months in both groups, and cumulative proportion of pts with grade ≥3 treatment-related adverse events was 38.5% (including hypertension [23.1%]) in Cabo and 60% (including hypomagnesaemia [20%]) in Cabo+Pmab group. Conclusions: The combination of cabozantinib 60 mg plus panitumumab had manageable safety profile. However, this treatment did not demonstrate significant clinical benefit in patients with MET-amplified mCRC. Further investigation is warranted to explore alternative therapeutic strategies for this patient population. Clinical trial information: jRCT1080224637 .

FG-M108 plus capecitabine and oxaliplatin (CAPOX) for first-line treatment of CLDN18.2+/HER2- advanced gastric/gastroesophageal junction adenocarcinoma (GC): Update results of a phase I/II trial to determine RP2D.

431 Background: There exists unmet need for previously untreated pts with CLDN18.2+/HER2- advanced GC. FG-M108, an mAb specifically targeting CLDN18.2 and exhibiting enhanced ADCC activity, has the potential to benefit these pts. Methods: This phase I/II trial evaluated safety, pharmacokinetics and preliminary antitumor activity of FG-M108 plus CAPOX in previously untreated pts with CLDN18.2+/HER2- advanced GC, where FG-M108 was administered intravenously at 300 mg/m 2 or 600 mg/m 2 Q3W. Here we compare results of FG-M108 at 300mg/m 2 (Cohort A) with 600mg/m 2 (Cohort B) to establish RP2D. Results: As of August 28, 2024, 63 pts with CLDN18.2+ (IHC 1/2/3+≥10%) GC were treated, 70% of whom had CLDN18.2 Medium-High expression (CMH, IHC 2/3+≥40%). Baseline characteristics were comparable between Cohorts A & B. Increasing the FG-M108 dosage did not result in a higher incidence or severity of treatment-related adverse events (TRAE) overall. However, nausea and vomiting, identified as CLDN18.2 on-target toxicities, were significantly more frequent and severe in Cohort B compared to Cohort A.When 300 or 600 mg/m² of FG-M108 was administered intravenously Q3W, serum trough concentration exceeded the target drug concentration predicted by in vitro ADCC activity. The 300 mg/m² dose is expected to provide sufficient drug exposure as the effective dose.Moreover, in Cohort A, pts with CMH expression had a confirmed ORR of 78% (unconfirmed ORR=81%) and a median PFS of 11.0 months（95%CI 6.9-12.7）, significantly better than those in Cohort B. Based on safety, PK and efficacy trends, the RP2D was determined to be FG-M108 at 300mg/m 2 plus CAPOX. Conclusions: FG-M108 plus CAPOX had a manageable safety profile and promising antitumor activity in GC, with RP2D at 300mg/m 2 . A phase III trial is ongoing to confirm the efficacy of FG-M108 at 300mg/m 2 plus CAPOX as first-line treatment (NCT06177041). Clinical trial information: NCT04894825 . Cohort A n=52 Cohort B n=11 CMH % 71 64 Primary lesion-Stomach % 92 100 Metastatic organs ≥3 % 27 9 ORR/DCR with CMH % 81/97 57/86 PFS/DOR with CMH months 11.0/9.9 5.5/4.2 ≥G3 TRAE % 37 18 TRAE-Nausea % / ≥G3 Nausea % 38/2 64/9 TRAE-Vomiting % / ≥G3 Vomiting % 23/2 73/9

Phase 1b portion of the ACTION-1 phase 1b/3 trial of RYZ101 in gastroenteropancreatic neuroendocrine tumors (GEP-NET) progressing after 177 Lu somatostatin analogue (SSA) therapy: Safety and efficacy findings.

661 Background: RYZ101 ( 225 Ac-DOTATATE) is an alpha-emitting radiopharmaceutical in development for SSTR2+ solid tumors. Alpha-particles have a shorter path length/higher linear energy transfer than beta-particles, causing more frequent double-strand DNA breaks and potentially improving the therapeutic index. ACTION-1 (NCT05477576) is a two-part, global, randomized, controlled, open-label, phase 1b/3 trial of RYZ101 in advanced, well-differentiated SSTR+ GEP-NETs progressing after 177 Lu-SSA therapy. Herein, we report updated results from the phase 1b portion of the trial. Methods: The phase 1b portion of the ACTION-1 trial had a dose de-escalation/Bayesian optimal interval design with boundaries based on a dose-limiting toxicity (DLT) rate of 25%. Patients received RYZ101 IV every 8 weeks for 4 cycles. Planned dose levels (n=6/level): Level 0 (starting dose) 120 kBq/kg; Level 1 90 kBq/kg; Level 2 60 kBq/kg. DLTs were assessed for 56 days after the first RYZ101 dose. Treatment-emergent adverse events (TEAEs) were graded by NCI-CTCAE v5.0. A Data Review Committee oversaw dose de-escalation decisions/safety data. Tumor response was assessed locally by RECIST v1.1. Results: Seventeen patients received at least one dose of RYZ101 at 120 kBq/kg (4 doses: 15 patients; 2 doses: 2 patients; median 8.3 MBq). Baseline patient characteristics: median age 63 years; male (n=11); ECOG PS 0/1 (n=10/7); primary tumor site GI/pancreas (n=12/5). As of 14 December 2023, the most frequent TEAEs were anemia (58.8%), nausea (58.8%), and fatigue (52.9%). Serious adverse events (SAEs) were observed in 6 patients (35.3%, none were treatment-related); grade ≥3 TEAEs occurred in 9 patients (5 were treatment-related, 29.4%). No TEAEs led to treatment discontinuation. Four patients had TEAEs leading to dose modification, dose hold, and/or dose delays. There was one grade 5 TEAE of hepatic failure that was deemed unrelated to the study drug. The confirmed objective response rate was 29.4% (n=5; 1 complete response, 4 partial responses). One additional patient had an unconfirmed partial response at the time of data cutoff, which was subsequently confirmed. Seven patients (41.2%) had stable disease and 3 (17.6%) had progressive disease. The median duration of response was not estimable (95% CI 9.26 months, not estimable), and the median progression-free survival was not estimable (95% CI 12.16 months, not estimable). Conclusions: RYZ101 was well tolerated, and a fixed dose of 10.2 MBq was declared the recommended phase 3 dose. Initial data suggest promising efficacy and a manageable safety profile. Part 2 (phase 3) of the ACTION-1 trial is enrolling and will compare RYZ101 at 10.2 MBq every 8 weeks for 4 cycles with standard of care in patients with advanced SSTR2+ GEP-NETs progressing after 177 Lu-labeled SSAs. Clinical trial information: NCT05477576 .

Transarterial chemoembolization (TACE) combined with camrelizumab and apatinib versus TACE alone in the treatment of unresectable hepatocellular carcinoma eligible for embolization: A multicenter, open-label, randomized, phase 2 study (CAP-ACE).

LBA522 Background: Transarterial chemoembolization (TACE) has been established as a standard treatment for hepatocellular carcinoma (HCC) eligible for embolization. Combining immunotherapy and tyrosine kinase inhibitors (TKIs) with TACE can potentially enhance antitumor activity by activating the immune system and inhibiting tumor neovascularization. This study investigated whether the addition of camrelizumab and apatinib to TACE could bring better survival benefits. Methods: This open-label, randomized phase 2 study (NCT04559607) was conducted at 23 sites in China. Patients with unresectable HCC eligible for embolization were randomly assigned to receive either TACE combined with camrelizumab (200 mg once every 3 weeks) and apatinib (250 mg once daily; TACE-CA) or TACE alone. The stratification factors for randomization included vascular invasion (yes vs. no), prior use of TKIs (yes vs. no), and number of prior TACE (0 vs. 1-2). Prior immunotherapy was not allowed. The primary endpoint was progression-free survival (PFS) assessed by investigators according to the Response Evaluation Criteria In Cancer of the Liver (RECICL), analyzed in intention-to-treat population. Results: Between Dec 28, 2020 and Oct 29, 2023, 200 patients were randomized (100 in each group). Median age was 58.5 years (IQR, 51.5-65) and 57.0 years (IQR, 51-65.5) in the TACE-CA and TACE groups, respectively; most patients had Barcelona Clinic liver cancer (BCLC) stage B-C disease (86.0% and 86.0%). As of October 16, 2024, the median follow-up duration was 13.6 months (IQR, 8.2-20.5). Median PFS per RECICL was significantly longer in the TACE-CA group compared with the TACE group (11.0 months [95% CI, 8.8-13.8] vs. 3.1 months [95% CI, 2.0-4.1]; hazard ratio, 0.3, P<0.0001). The objective response and disease control rates were 65.0% (95% CI, 54.8-74.3) and 87.0% (95% CI, 78.8-92.9) in the TACE-CA group and 30.0% (95% CI, 21.2-40.0) and 63.0% (95% CI, 52.8-72.4) in the TACE group, respectively. Overall survival data are immature. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 76.6% (72/94) of patients with TACE-CA and 24.3% (25/103) of patients with TACE. The most common grade ≥3 TRAEs were increased aspartate aminotransferase (AST; 29 [30.9%]), increased alanine aminotransferase (ALT; 23 [24.5%]), hypertension (13 [13.8%]), and decreased platelet count (11 [11.7%]) in the TACE-CA group, and increased ALT (16 [15.5%]) and increased AST (15 [14.6%]) in the TACE group. Conclusions: The addition of camrelizumab and apatinib to TACE can significantly prolong progression-free survival in patients with unresectable HCC eligible for embolization, with a manageable safety profile. Clinical trial information: NCT04559607 .

Fruquintinib combined with FOLFIRI/mFOLFOX6 as second-line treatment in patients with RAS-mutant metastatic colorectal cancer (mCRC): A multicenter, open-label, phase II study.

151 Background: Anti-angiogenic drugs combined with chemotherapy could bring good clinical benefit to patients (pts) with mCRC, but the efficacy in pts with RAS mutant mCRC was limited. Fruquintinib is a highly selective oral inhibitor of vascular endothelial growth factor receptors (VEGFRs -1, -2, and -3) and was approved for previously treated mCRC. Our study was to explore the efficacy and safety of fruquintinib combined with FOLFIRI/mFOLFOX6 in the second line treatment of RAS-mutant mCRC (NCT05634590). Methods: Eligible pts with histologically confirmed RAS-mutant mCRC who had received first-line standard chemotherapy regimens were included in the study, and pts received Fru (4 mg, p.o. qd, 3 weeks on/1 week off, q4w) plus FOLFIRI/mFOLFOX6 (d1-15, q4w) until disease progression, unacceptable toxicities, or withdrew consent. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS)and safety. Results: As of Aug 30, 2024, 25 eligible pts were enrolled and received at least one time treatment. Baseline characteristics included median age (66.0 [range: 35-73]), female/male (56.0% / 44.0%), ECOG PS 1(68.0%), left-sided and right-sided colon (72.0% / 28.0%), liver metastasis (64.0%), prior anti-VEGF therapies (76.0%). 14 pts had received at least one tumor assessment. Five pts achieved partial response (PR), 9 pts achieved stable disease (SD), and the ORR was 35.7% (5/14) (95% confidence interval [CI]: 12.8-64.9), the DCR was 100.0% (14/14) (95% CI: 76.8-100.0). Compared to liver metastases, the ORR was higher without liver metastases (42.9% [95%CI 9.9-81.6]). The median PFS was 6.41 months (95% CI: 6.37 - NA), and median OS was not reached yet. In the subgroup analysis, Median PFS was also longer without liver metastases pts than with liver metastases (8.84 mo vs 6.41 mo; HR=1.230; 95%CI 0.2462-6.148; p=0.7775). Additionally, Grade ≥3 treatment-emergent adverse events (TEAEs) included platelet count decreased (18.2%), hypertension (9.1%) and neutrophil count decreased (9.1%). Conclusions: Fruquintinib combined with FOLFIRI/mFOLFOX6 as second-line in patients with RAS-mutant mCRC achieved a promising clinical benefit, with a manageable safety profile. This trial is ongoing and more updated clinical data will be presented in the future. Clinical trial information: NCT05634590 .

Efficacy and safety of surufatinib in unresectable or metastatic grade 3 pancreatic neuroendocrine tumors (NET G3): Real-world analysis.

657 Background: Currently, there is limited exploration regarding the treatment of NET G3, resulting in restricted treatment options. Therapeutics for NET G1/2 may serve as an alternative. Surufatinib, with its potent targeting of VEGFRs, FGFR1, and CSF-1R, not only exerts inhibitory effects on tumor angiogenesis but also modulates the immune microenvironment. Due to its demonstrated efficacy and manageable safety profile, it has secured approval for the treatment of G1/2 NETs. Methods: This is a multi-center real-world study that retrospectively analyzes the clinical data of pts with NET G3 who received surufatinib-based treatment from December 2021 to February 2024, aiming to assess its efficacy and safety. Eligible pts were unresectable or metastatic p-NET with ki-67>20%. The primary endpoint was PFS, with secondary endpoints were ORR, DCR, and safety. Results: As of September 2024, data from 37 pts were analyzed. The median age was 54 years (range: 32-80), with 59.5% male. The median Ki-67 index was 30% (range: 25-70%), and 94.6% of the cases were non-functional p-NETs, with 89.2% having liver metastases and 35.1% having bone metastases. In terms of prior treatments, 18.9%, 40.5%, and 40.5% of pts had received 0, 1, and ≥2 systemic therapies, respectively. Among them, 81.1% had previously undergone chemotherapy, 35.1% had received interventional therapy of liver metastases, and 13.5% with everolimus or anti-angiogenic agents. 48.6% pts had surufatinib-based combination treatment. The median PFS was 9.30 months (mo, 95% CI: 8.02–13.02), with an ORR of 21.6% and a DCR of 81.1%. First-line (1L) treatment showed a higher ORR (42.9% vs. 16.7%) and a trend of better PFS (9.67 vs. 9.04 mo, p=0.7) compared to ≥2L treatment. Combination therapy improved ORR (33.3% vs. 10.5%) with a similar PFS (9.30 vs. 9.44 mo, p=0.93) compared to surufatinib monotherapy. Liver metastases had limited impact on PFS (9.93 vs 9.30 mo, p=0.55). Common grade ≥3 adverse events included hypertension (8.1%), proteinuria (5.4%), and elevated bilirubin (5.4%). Conclusions: Surufatinib has demonstrated initial efficacy and manageable safety in pts with NET G3, providing a new treatment option for these pts. First-line therapy may be a favorable factor for improving PFS. To delve deeper into these findings, additional subgroup analyses, with a particular emphasis on pts with ep-NET G3 will be conducted in the future.

HERIZON-BTC-302: A phase 3 study of zanidatamab with standard-of-care (SOC) therapy vs SOC alone for first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced/metastatic biliary tract cancer (BTC).

TPS648 Background: Zanidatamab is a humanized, IgG1-like, HER2-targeted bispecific antibody that simultaneously binds to 2 non-overlapping domains on HER2. Zanidatamab is being investigated for the treatment of HER2-expressing solid tumors, including BTC. In the phase 2 HERIZON-BTC-01 trial, zanidatamab monotherapy demonstrated promising antitumor activity in 80 patients with previously treated HER2-positive BTC. Confirmed objective response rate (cORR) was 41.3% with rapid and durable responses and a manageable safety profile. This phase 3 trial is assessing zanidatamab + SOC therapy vs SOC alone for first-line treatment of HER2-positive advanced/metastatic BTC. Methods: This ongoing, global, phase 3, randomized, open-label trial (NCT06282575) is investigating the efficacy and safety of zanidatamab with cisplatin and gemcitabine (CisGem) vs CisGem alone ± a programmed cell death protein-1/ligand 1 (PD-1/L1) inhibitor (pembrolizumab or durvalumab at physician’s discretion if locally approved) as first-line treatment for patients with advanced HER2-positive BTC. Eligibility criteria include ≥18 years of age; locally advanced, unresectable, or metastatic HER2-positive BTC by immunohistochemistry and in situ hybridization assay (IHC 3+ or IHC 2+/ISH+); and Eastern Cooperative Oncology Group performance status ≤1. Patients may have received ≤2 cycles of a gemcitabine-based regimen ± pembrolizumab or durvalumab. Prior HER2-targeted therapy is not allowed except for patients who completed it for breast cancer >5 years prior to BTC diagnosis. Eligible patients will be randomized to receive zanidatamab (flat 2-tiered dosing: 1800 mg intravenous [IV; body weight <70 kg] or 2400 mg IV [body weight ≥70 kg] every 3 weeks) + a standard dose of CisGem ± a PD1/L1 inhibitor or CisGem alone ± a PD1/L1 inhibitor (≤8 cycles). The primary endpoint is progression-free survival (PFS) in patients with IHC 3+ tumors. Secondary/exploratory endpoints include overall survival (IHC 3+ subgroup; overall population), PFS (overall population), cORR, incidence and severity of adverse events, and patient-reported outcomes. The study is currently recruiting patients. Clinical trial information: NCT06282575 .

Zimberelimab platform study: Safety and efficacy of zimberelimab in combination with futibatinib and chemotherapy in patients with first-line advanced or metastatic esophageal carcinoma.

409 Background: Zimberelimab: AB122 (Zim) platform study is a Phase 1 a/b study with multiple cohorts designed to evaluate the safety and efficacy of Zim, an anti-PD-1 antibody. Futibatinib (Futi) is an FGFR inhibitor that covalently binds FGFR1–4; FGFR inhibitors have been reported to modulate the tumor immune microenvironment, including reducing MDSCs and inhibiting CAFs. These immunomodulatory effects are expected to enhance the efficacy of the anti-PD-1 antibodies. The safety and efficacy of the combination of Zim, Futi, and chemotherapy were evaluated in patients (pts) with first-line advanced or metastatic esophageal cancer (EC) in Japan. Methods: Key eligibility criteria included age ≥ 18 years, histologically confirmed advanced or metastatic EC with measurable lesions by RECIST v1.1 regardless of FGFR and PD-L1 status, previously untreated, adenocarcinoma or squamous cell carcinoma, and ECOG PS 0 or 1. Patients received Zim 360 mg on day 1, Futi 20 mg QD, fluorouracil 800 mg/m2 on days 1–5, and cisplatin 80 mg/m2 on day-1 of a three-week cycle. The primary endpoint was dose-limiting toxicity (DLT). The secondary endpoints included adverse events, antitumor activity, pharmacokinetics, pharmacodynamics, and pharmacogenomics. Results: As of May 10, 2024, 43 pts were enrolled. At the data cutoff date for this analysis (July 15, 2024), treatment was ongoing in 23 pts. Safety and efficacy were evaluated in 43 and 41 pts, respectively. The median age of the pts was 61 years (53–70). An ECOG PS score of 0 was observed in 31 pts. DLTs were evaluated in the first three pts, and none were reported. Common treatment-emergent adverse events (TEAEs)were hyperphosphatemia (81.4%), diarrhea (67.4%), nausea (62.8%), decreased appetite (62.8%), constipation (55.8%), anemia (53.5%), stomatitis (51.2%), neutrophil count decreased (37.2%), alanine aminotransferase increased (34.9%), and palmar-plantar erythrodysaesthesia syndrome (30.2%). Grade ≥ 3 TEAEs occurred in 31 pts (72.1%), and common events (≥ 30%) were anaemia (30.2%) and neutrophil count decreased (30.2%). The objective response rate was 70.7% (95% CI: 54.5–83.9), and the confirmed overall response rate was 58.5% (95% CI: 42.1–73.7). The disease control rate was 92.7% (95% CI: 80.1–98.5). Median duration of response was 5.6 months (95% CI: 4.1–5.6), and median progression-free survival was 4.9 months (95% CI: 3.4–6.7). Conclusions: The combination of Zim, Futi, and chemotherapy has a manageable safety profile without new safety signals and shows promising antitumor activity in pts with advanced or metastatic EC. As more than half of the enrolled pts are still undergoing treatment, these are preliminary data; follow-up is needed to evaluate the viability of this combination appropriately. Clinical trial information: NCT04999761 .

First results of nivolumab (NIVO) plus ipilimumab (IPI) vs NIVO monotherapy for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) from CheckMate 8HW.

LBA143 Background: The CheckMate 8HW study met its dual primary endpoint with NIVO + IPI demonstrating superior progression-free survival (PFS) by blinded independent central review (BICR) vs chemotherapy (chemo) in patients (pts) with centrally confirmed MSI-H/dMMR mCRC in the first-line (1L) setting (HR 0.21; 95% CI 0.14–0.32; P < 0.0001). We report first results from the other dual primary endpoint of PFS for NIVO + IPI vs NIVO across all lines of therapy in pts with centrally confirmed MSI-H/dMMR mCRC. Methods: Immunotherapy-naive pts with unresectable or mCRC and MSI-H/dMMR status by local testing who had received 0 or 1 prior line of therapy were randomized 2:2:1 to (i) NIVO (240 mg) Q2W (6 doses, then NIVO 480 mg Q4W), (ii) NIVO (240 mg) + IPI (1 mg/kg) Q3W (4 doses, then NIVO 480 mg Q4W), or (iii) chemo ± targeted therapies. Pts who had received ≥ 2 prior lines of therapy were randomized 1:1 to the NIVO + IPI or NIVO arms. Treatments continued until disease progression or unacceptable toxicity (all arms), or a maximum of 2 years (NIVO ± IPI arms). Results: Across all lines of therapy,707 pts were randomized to NIVO + IPI (n = 354) or NIVO (n = 353); 55% and 52% received study treatment in the 1L setting, respectively. Of all randomized pts, 296 in the NIVO + IPI arm and 286 in the NIVO arm had centrally confirmed MSI-H/dMMR status. With 47.0 months (mo) of median follow-up (range, 16.7–60.5), NIVO + IPI demonstrated clinically meaningful and statistically significant improvement in PFS by BICR vs NIVO (HR 0.62; 95% CI 0.48–0.81; P = 0.0003) and higher 12-, 24-, and 36-mo PFS rates vs NIVO (Table). Objective response rate (ORR) by BICR was significantly higher with NIVO + IPI vs NIVO (71% vs 58%; P = 0.0011; Table); best overall response of progressive disease was reported in 10% and 19% of pts, respectively. No new safety concerns were identified (Table). Conclusions: In the first randomized study to compare dual- vs single-agent immunotherapy in MSI-H/dMMR mCRC, NIVO + IPI demonstrated superior PFS vs NIVO across all lines of therapy, with a manageable safety profile. These results establish NIVO + IPI as the potential new standard-of-care treatment for MSI-H/dMMR mCRC. Clinical trial information: NCT04008030 . Efficacy by BICR (all lines; centrally confirmed MSI-H/dMMR by IHC and/or PCR test) NIVO + IPI(n = 296) NIVO(n = 286) Median PFS (95% CI), mo NR (53.8–NE) 39.3 (22.1–NE) HR (95% CI); P value 0.62 (0.48–0.81); 0.0003 PFS rate (12/24/36-mo), % 76/71/68 63/56/51 ORR, n (%); 95% CI, % 209 (71); 65–76 165 (58); 52–64 P value 0.0011 Safety (all lines; all treated), n (%) NIVO + IPI (n = 352) NIVO (n = 351) Any-grade/grade 3–4 TRAEs 285 (81)/78 (22) 249 (71)/50 (14) Any-grade/grade 3–4 TRAEs leading to discontinuation 48 (14)/33 (9) 21 (6)/14 (4) Treatment-related deaths 2 (< 1) 1 (< 1) IHC, immunohistochemistry; NE, not estimable; NR, not reached; PCR, polymerase chain reaction; TRAE, treatment-related adverse event.

PD-1 inhibitor (sintilimab) and fruquintinib plus SOX as conversion therapy for initially unresectable gastric/gastroesophageal junction adenocarcinoma (GC/GEJC): Updated results from a single-arm, phase 2 clinical trial.

406 Background: The evidence of conversion therapy for unresectable GC/GEJC is limited. Previously, preliminary results of the ongoing open-label, phase 2 study (NCT05177068) have showed promising R0 surgical conversion rate (62.1%), R0 resection rate (100%) and acceptable tolerability in unresectable GC/GEJC with sintilimab and fruquintinib plus SOX (ASCO 2024). Here we present updated results with longer follow-up duration, including more enrolled patients. Methods: Eligible patients were administered fruquintinib (4mg/d, po, qd, d1-14), sintilimab (200mg, iv, d1), oxaliplatin (130 mg/m 2 , iv, d1) and S-1 (40-60mg based on BSA, po, bid, d1-14) every 3 weeks for 3 or 6 cycles. One more cycle of sintilimab plus SOX was given before resection. Patients were assessed for tumor response and surgical feasibility by radiologic imaging & MDT every 3 cycles. Primary endpoint was R0 resection rate. Secondary endpoints included pathological response, ORR, PFS, OS, and safety. Results: As of July 30, 2024, 42 pts (37 males/5 females) with a median age of 64 years (range: 43–76), 71% ECOG PS1, 55% GEJC were enrolled. Nine (21.4%) of the 42 pts had distant metastasis and five (11.9%) pts had more than one unresectable factors. The most common unresectable factors were extensive or bulky lymph nodes 54.8% (23), liver metastasis 11.9% (5), peritoneal metastasis 4.8% (2), para-aortic lymph node metastasis 2.4% (1), and local progression 38.1% (16). Of 35 evaluable pts, ORR was 68.6% and DCR was 97.1%. Among the 29 pts who had completed surgical conversion, the R0 resection rate was 100% (29/29) and R0 surgical conversion rate was 82.9% (29/35). 10.3% (3/29) pts achieved pathological complete response (pCR), and 20.7% (6/29) pts reached tumor regression grade (TRG) 0-1. Additionally, the pathological response rate (pRR) according to JCGC (≥ Grade 1b) was 93.1% (27/29). Seven pts (16.7%) had grade 3 treatment-emergent adverse events, including 4 cases of anemia, 2 cases of neutrophil count decreased, and 1 case of each (lymphocyte count decreased, gastrointestinal hemorrhage, diarrhea, and immune-related pneumonitis). No severe surgery-related complication was observed. Conclusions: Fruquintinib combined with sintilimab and SOX yielded very high R0 conversion rate and R0 resection rate with a manageable safety profile in unresectable GC/GEJC, representing a potential and feasible conversion therapy regimen for this population. Survival data will continue to be followed up. Clinical trial information: NCT05177068 .

Preliminary safety and efficacy of upfront FOLFOXIRI and bevacizumab with cadonilimab in patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) metastatic colorectal cancer: A multicenter phase II study (SYLT-026).

198 Background: The AtezoTRIBE phase II trial reported that adding Atezolizumab to upfront FOLFOXIRI plus Bevacizumab significantly improved overall survival (OS) in patients with metastatic colorectal cancer (mCRC). However, the improvement in OS was modest within the pMMR/MSS subgroup (HR, 0.80 [80% CI, 0.63–1.02]; P = 0.117) [1]. Cadonilimab, a humanized bispecific antibody targeting both PD-1 and CTLA-4, may offer enhanced therapeutic benefits. Therefore, this study aims to investigate whether the addition of Cadonilimab to upfront FOLFOXIRI plus Bevacizumab improves efficacy while maintaining safety in patients with pMMR/MSS mCRC. Methods: This multicenter, single-arm phase II study enrolled treatment-naive patients with pMMR/MSS mCRC, aged 18–75, who had at least one measurable lesion according to RECIST 1.1, an ECOG performance status (PS) of 0–2, and adequate organ function. Patients with dMMR/MSI-H tumors or prior immunotherapy were excluded. Eligible participants received FOLFOXIRI (irinotecan 165 mg/m², oxaliplatin 85 mg/m², leucovorin 200 mg/m², and fluorouracil 2400 mg/m² as a 48-hour infusion), along with Bevacizumab (5 mg/kg), and Cadonilimab (6 mg/kg). Treatment was administered for up to twelve 14-day cycles, followed by maintenance therapy with fluoropyrimidine and Bevacizumab plus Cadonilimab for up to 52 weeks, or until disease progression, unacceptable toxicity, or withdrawal of consent. Patients were equally enrolled, with 10 having liver metastases and 10 without. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Results: As of August 30, 2024, 20 patients were enrolled, with a median age of 65.5 years (range: 33–74). Of these, 40% had an ECOG PS of 1 or 2, 55% had three or more metastatic organs, and 7 patients (35%) had RAS or BRAF mutations. The median follow-up was 5.0 months. Fifteen patients underwent at least two imaging assessments, revealing a confirmed ORR of 100% (15/15) and a disease control rate (DCR) of 100%. The median progression-free survival (PFS) and OS data were not yet mature. All 20 patients experienced treatment-emergent adverse events, most of which were grade 1 or 2. One patient (5%) discontinued treatment due to immune-mediated colitis. The most common grade 3/4 adverse events included neutropenia (55%), leukopenia (15%), infusion reactions (5%), dermatitis (5%), colitis (5%), anemia (5%), elevated ALT (5%), and diarrhea (5%). No new safety signals were identified. Conclusions: In conclusion, Cadonilimab in combination with FOLFOXIRI and Bevacizumab demonstrated promising efficacy and a manageable safety profile as a first-line treatment for patients with pMMR/MSS mCRC. Further investigation in larger trials is warranted. 1. Antoniotti, et al, J Clin Oncol, 2024. Clinical trial information: NCT05839470 .

HLX22 plus trastuzumab and XELOX for first-line treatment of HER2-positive locally advanced or metastatic gastric/gastroesophageal junction cancer (G/GEJC): Updated results with additional patients.

440 Background: Approximately 12–23% G/GEJC patients have human epidermal growth factor receptor 2 (HER2)-positive disease. Despite survival benefit from combination therapy with trastuzumab and chemotherapy, the prognosis remains unsatisfactory; more effective treatments are needed. This phase 2 study is evaluating the combination of HLX22 (an anti-HER2 monoclonal antibody targeting a different epitope than trastuzumab), trastuzumab, and XELOX chemotherapy as first-line treatment for patients with advanced/metastatic G/GEJC. Following the most recent report of 17 to 18 patients in each group at ASCO 2024 Annual Meeting, herein we present the updated efficacy and safety results with 31 patients in each group. Methods: Patients with locally advanced or metastatic HER2-positive G/GEJC and no prior systemic antitumor therapy were enrolled. Herein reported are results from Stage 2 of the study. Eligible patients were randomized to receive either HLX22 + trastuzumab + XELOX or placebo + trastuzumab + XELOX in 3-week cycles. Primary endpoints were independent radiology review committee (IRRC)-assessed progression-free survival (PFS) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints included other efficacy and safety endpoints. Results: As of June 30, 2024, 62 patients were randomized to the respective groups (31 vs 31), of whom 51 (82.3%) patients were male. Median follow-up duration was 20.3 and 24.0 months for the respective groups. The efficacy results are shown in the table. Treatment-emergent adverse events (TEAEs) were reported in 30 (96.8%) and 31 (100%) patients, and HLX22- or placebo-related TEAEs of grade 3 or higher were reported in 9 (29.0%) and 6 (19.4%) patients in the respective groups. One patient (3.2%) in the placebo + trastuzumab + XELOX group had a grade 5 HLX22-/placebo-related TEAE. Conclusions: With a manageable safety profile, the addition of HLX22 to first-line treatment with trastuzumab plus XELOX conferred survival benefit for HER2-positive G/GEJC patients. Clinical trial information: NCT04908813 . Updated efficacy, IRRC-assessed. HLX22 + trastuzumab + XELOX (n=31) placebo + trastuzumab + XELOX (n=31) Median PFS, months (95% CI) NR (23.49, NE) 8.3 (5.7, 12.7) HR (95% CI) 0.2 (0.06, 0.45) - 12-month PFS rate (95% CI) 73.8 (50.3, 87.4) 34.2 (12.0, 58.1) 24-month PFS rate (95% CI) 61.5 (30.4, 82.0) 24.0 (10.3, 27.3) Confirmed ORR, % (95% CI) 87.1 (70.2, 96.4) 80.6 (62.5, 92.5) Week 48 ORR, % (95% CI) 38.7 (21.8, 57.8) 9.7 (2.0, 25.8) Median OS, months (95% CI) NR (17.6, NE) 22.0 (10.6, NE) HR (95% CI) 0.5 (0.20, 1.21) - Median DOR, months (95% CI) NR (22.1, NE) 9.7 (4.6, 20.0) HR (95% CI) 0.1 (0.04, 0.41) - CI, confidence interval. NE, not evaluable. NR, not reached.

Paclitaxel oral solution versus paclitaxel injection as a second-line therapy in advanced gastric cancer: A randomized, open-label, non-inferiority phase 3 trial.

442 Background: Paclitaxel injection (paclitaxel IV) is category 1 preferred regimen in the second-line therapy of gastric cancer, while it has shortcomings including vehicle-led safety risk, long time injection, premedication or frequent hospital visit. Paclitaxel oral solution (Liporaxel), the world's first successfully developed oral formulation, is an alternative. This study aimed to establish non-inferiority in efficacy and comparable safety profile of paclitaxel oral solution versus paclitaxel IV, as a second-line monotherapy in gastric cancer. Methods: This is a randomized, open-label, non-inferiority phase 3 trial conducted at 53 centers in China. Patients with unresectable or recurrent or metastatic gastric cancer progressed after fluoropyrimidine- or fluoropyrimidine plus platinum-based first-line therapy were randomly assigned at 1:1 ratio (stratified by gastrectomy, ECOG PS and prior chemotherapy) to receive paclitaxel oral solution (200mg/m 2 twice daily on days 1, 8, 15 of a 28-day cycle) or paclitaxel IV (175mg/m 2 on day 1 of a 21-day cycle). Co-primary endpoints were progression-free survival (PFS) assessed by blind independent review committee (BIRC) and overall survival (OS), with non-inferiority margin of hazard ratio (HR) of 1.18 for PFS and 1.16 for OS. Results: From April 22, 2019, to January 31, 2022 (data cut-off), 536 patients were randomized to receive either paclitaxel oral solution (n=268) or paclitaxel IV (n=268), with a median follow-up of 13.4 vs. 12.6 months. PFS met non-inferiority criteria, with BIRC-assessed median PFS of 3.02 months (95% confidence interval [CI]: 2.69, 3.71) in the oral group vs. 2.89 months (95% CI: 2.53, 3.48) in the IV group (HR=0.894, 95% CI: 0.719, 1.112, p =0.311). OS (cut-off on February 15, 2023, for OS primary analysis) demonstrated superiority for paclitaxel oral solution, with median OS of 9.13 months (95% CI: 7.72, 10.97) vs. 6.54 months (95% CI: 5.75, 7.26), showing 2.59-month improvement (HR=0.770, 95.5% CI: 0.635, 0.934, p =0.006). For the treatment-related adverse events (TRAEs), the oral group showed lower incidences of neuropathy (22.3% vs. 38.7% all grade), alopecia, fatigue, musculoskeletal and connective tissue disorders, and no hypersensitivity occurred without premedication. The most common ≥Grade 3 TRAEs were neutrophil count decreased (47.9% in oral vs. 54.5% in IV), white blood cell count decreased (41.5% vs. 35.3%) and anemia (16.6% vs. 10.9%). Grade 5 TRAEs were rare with comparable rates across two groups (four [1.5%] vs. three [1.1%]). Conclusions: Paclitaxel oral solution demonstrated non-inferiority in PFS and superiority in OS compared to paclitaxel IV, with clinically manageable and favorable safety profile, supporting paclitaxel oral solution as a second-line treatment option for gastric cancer. Clinical trial information: CTR20190050.

Results from a phase 2 study of triplet blockade of the IL-27, PD-(L)1, and VEGF pathways with casdozokitug (casdozo, CHS-388) in combination with atezolizumab and bevacizumab in patients with unresectable, locally advanced or metastatic hepatocellular carcinoma (uHCC).

605 Background: Casdozo is the first in class and only clinical-stage IL-27 targeting antibody, which induces increased serum IFN-γ and NK cell gene activation, leading to reversal of IL-27-mediated immune suppression. A phase (Ph) 1 study demonstrated a favorable safety profile and antitumor activity of casdozo alone and in combination with PD-1 blockade in indications with known high levels of IL-27 pathway activation, including HCC (NCT04374877). This open-label Ph 2 trial examined the potential antitumor activity and safety of casdozo with PD-L1 and VEGF blockade in uHCC (NCT05359861). Updated clinical and biomarker data are presented. Methods: Patients (Pts) with untreated uHCC received casdozo 10 mg/kg, atezolizumab (atezo) 1200 mg, and bevacizumab (bev) 15 mg/kg IV Q3W. Primary endpoints were safety and tolerability, with key secondary endpoints of investigator-assessed ORR by RECIST1.1 and mRECIST, PFS, and OS. Results: As of Sept 4, 2024, 30 pts received casdozo/atezo/bev. Most pts were male (77%), Asian (67%), had viral etiology (53% HBV, 17% HCV), and poor-prognosis disease assessed by metastatic spread (67%) and/or macrovascular invasion (13%). Median follow-up was 15 months (mo). Median time on therapy was 8 mo. The most common (>20%) adverse events related to any study drug were proteinuria (43%), hypertension (27%), fatigue (23%), and diarrhea (20%); Grade ≥3 events occurred in 67%, with only hypertension (20%), arising in >10% of pts. Treatment-emergent adverse events (TEAEs) resulting in any study drug discontinuation occurred in 30% of pts. No treatment-related deaths were reported. In the 29 RECIST1.1 response-evaluable pts, ORR was 38% with 17% of pts achieving a CR (5 CRs, 6 PRs); mPFS (95% CI) was 8.1 mo (1.9, 13.6); landmark PFS rates at 6, 12 and 18 mo were 58.6%, 36.1% and 27.1%, respectively; mDoR (95% CI) was NR (6.1, -). In the 28 pts evaluable for mRECIST, ORR was 43% (5 CRs, 7 PRs); mPFS (95% CI) was 8.4 mo (2.0, 14.5); mDoR was NR (12.7, -). mOS (95% CI) was 19.9 mo (14.2, -); the 12-mo survival rate (95% CI) was 85% (65, 94). More than 40% of pts remain on study, and 16.7% remain on study treatment. Available archival tissue of responders expressed IL-27+ TAMs by IHC, including tumors of viral and nonviral etiologies. Conclusions: Triplet blockade of IL-27, PD-(L)1, and VEGF pathways with casdozo/atezo/bev continues to show a manageable safety profile with promising antitumor activity in uHCC that warrants continued exploration. Toxicity was consistent with the known profiles of the agents, with no new safety signals identified. Biomarker analysis to evaluate immune response and associations of IL-27 pathway and clinical outcomes is ongoing. Additional clinical studies of casdozo in combination with toripalimab are planned. Clinical trial information: NCT05359861 .

Updated efficacy and subgroup analysis of first-line serplulimab plus bevacizumab and XELOX versus placebo plus bevacizumab and XELOX in metastatic colorectal cancer: A phase 2/3 study.

170 Background: This is a randomized, double-blind, multicenter phase 2/3 study comparing the efficacy and safety of serplulimab (a novel anti-PD-1 antibody) plus bevacizumab and XELOX chemotherapy vs. placebo plus bevacizumab and XELOX as first-line treatment for metastatic colorectal cancer (mCRC). Our previous presentation at the 2024 ASCO Meeting showed the progression-free survival results. Here we present the updated efficacy and safety findings together with subgroup analysis results after a median follow-up of 31.0 months. Methods: A total of 114 patients with mCRC and no prior systemic therapy were randomized 1:1 (serplulimab arm, n = 57; placebo arm, n = 57) to receive intravenous (IV) serplulimab (300 mg) plus bevacizumab (7.5 mg/kg) and XELOX (IV oxaliplatin [130 mg/m 2 ] and oral capecitabine [1000 mg/m 2 ]) (group A) or placebo plus bevacizumab and XELOX (group B) once every 3 weeks. Stratification factors were PD-L1 expression level, ECOG PS score, and primary tumor site. The primary endpoint was independent radiological review committee (IRRC)-assessed PFS per RECIST 1.1. Secondary endpoints included other efficacy endpoints, safety, pharmacokinetics, biomarker explorations, and quality-of-life assessments. Results: In the phase 2 part, by the data cutoff of June 30, 2024, sustained improvements in PFS (16.6 vs. 10.7 months, stratified HR 0.66, 95% CI 0.37–1.19) and DOR (17.7 vs. 11.3 months, stratified HR 0.45, 95% CI 0.20–0.98) were observed for patients in group A compared to group B in the modified intent-to-treat population (n = 112; two patients in group A did not receive any intended study treatment). 32/55 (58.2%) patients in group A and 35/57 (61.4%) in group B have died. Median overall survival (OS) was 25.6 months in group A and 21.2 months in group B (stratified HR 0.86, 95% CI 0.53–1.42). A trend of PFS and OS benefits was similarly observed for the patients with a microsatellite stable (MSS) status (PFS: 16.8 vs. 10.1 months, stratified HR 0.65, 95% CI 0.33–1.29; OS: 23.5 vs. 20.2 months, stratified HR 0.79, 95% CI 0.45–1.38). 39 (70.9%) patients in group A and 34 (59.6%) in group B had grade ≥3 treatment-related adverse events. Serplulimab/placebo-related serious TRAEs occurred in 13 (23.6%) patients in group A and 14 (24.6%) patients in group B. Conclusions: With a follow-up duration of 31.0 months, improved survival benefits demonstrated with the addition of serplulimab were maintained in the first-line treatment of mCRC patients including those with MSS status alongside a manageable safety profile. The phase 3 part of this study is currently ongoing to further evaluate serplulimab plus bevacizumab and XELOX as a first-line treatment option in mCRC. Clinical trial information: NCT04547166 .

Targeted antibody therapy as a treatment strategy for aggressive adult T-cell leukemia/lymphoma.

The standard treatment for aggressive adult T-cell leukemia/lymphoma (ATL) is multi-agent chemotherapy, but the use of more intense cytotoxic anticancer agents is becoming more difficult with the aging of patients at the time of diagnosis. As a means of overcoming this hurdle, antibody drugs, which are supposed to be less toxic, have been developed for ATL. The advent of the anti-CC chemokine receptor 4 (CCR4) antibody mogamulizumab has significantly advanced ATL treatment. Real-world data and a phase 2 clinical trial suggest the efficacy and manageable safety profile of mogamulizumab with combination chemotherapy in elderly patients. Interestingly, mogamulizumab has performed well in cases with CCR4 mutations and cutaneous adverse events. In addition, emerging immunotherapies, including Tax peptide dendritic cell vaccines, immune checkpoint inhibitors, and Chimeric Antigen Receptor-T cell therapy, are under investigation. These innovative approaches aim to enhance immunogenic responses and offer hope for better outcomes in this challenging malignancy.

Safety and preliminary efficacy of ATG-022 in patients with advanced/metastatic gastric cancer (CLINCH).

456 Background: ATG-022 is an antibody-drug conjugate (ADC) targeting Claudin 18.2 (CLDN 18.2) tumor antigen broadly expressed in gastric and other solid tumors. ATG-022 consists of a humanized monoclonal antibody that binds to CLDN 18.2 with high affinity of sub-nM grade and a conjugated linker-payload VC-MMAE, demonstrating activity across a wide range of CLDN18.2 expression levels, including both high and low/ultra-low expression levels. Methods: The CLINCH study included dose escalation phase and dose expansion phase. In the dose escalation, patients(pts) with advanced solid tumors regardless of CLDN 18.2 expression received ATG-022 once every three weeks (0.3-3.0 mg/kg Q3W) to evaluate the safety, tolerability, and pharmacokinetics. CLDN 18.2-positive patients were enrolled in dose expansion to receive ATG-022 at recommended phase 2 doses (RP2D) to evaluate the efficacy and safety. The primary endpoints included dose-limiting toxicity (DLT) and adverse events (AEs). The efficacy endpoints included objective response rate (ORR) and disease control rate (DCR), evaluated per RECIST1.1 criteria. Results: As of Aug 21, 2024, 16 pts with advanced solid tumors, including 7 gastric cancer (GC), were treated with ATG-022 from 0.3 to 3.0 mg/kg in dose escalation, with 1 DLT of grade 3 nausea found at 3 mg/kg among 6 pts, and 21 GC pts were enrolled in dose expansion to receive RP2D of 2.4 mg/kg Q3W. Among all 37 pts, median age was 61 years. Baseline ECOG were 0 (9 pts) and 1 (28 pts); 33 (89.2%) pts had stage IV disease; 26 (70.3%) pts had received ≥ 2 prior lines of systemic therapy and 14 (37.8%) pts had prior anti-PD-1/L1 therapy. At 2.4 mg/kg in expansion, 3 (14.3%) pts had ≥ 1 Serious TRAEs; 8 (38.1%) pts had grade ≥ 3 TRAEs; the most common TRAEs included neutrophil count decreased (47.6%), nausea (38.1%) and white blood cell count decreased (33.3 %). In dose escalation, 7 GC pts were enrolled, including 3 CLDN 18.2-positive pts. One PR and 1 CR was observed in pts with GC at the dosage of 1.8 mg/kg and 2.4 mg/kg, respectively. Among 12 GC pts who had at least 1 tumor evaluation in dose expansion, 5 PR and 7 SD were observed, resulting in an ORR of 41.7%, and a DCR of 100%. One CR and 1 PR were observed among 3 GC pts receiving 2.4 mg/kg and with CLDN 18.2 expression < 2+, 5%. The Cmax of both total antibody and ADC drug is increased as dose increased from dose 0.3 – 3.0 mg/kg. No pronounced exposure accumulation was found after multiple dose treatment. Preliminary data showed Dose-Normalized AUC of MMAE for ATG-022 is comparable with other vcMMAE ADC drugs. Conclusions: ATG-022 demonstrated a manageable safety profile, comparable PK properties in current dosing levels, and encouraging preliminary antitumor effects in GC pts from high CLDN 18.2 expression to low CLDN 18.2 expression, suggesting further clinical investigation in pts with variable CLDN 18.2 expression. The enrollment of GC and other solid tumors are ongoing. Clinical trial information: NCT05718895 .