376 Background: Paclitaxel combined with cisplatin regimen has been the standard of care as first-line therapy in advanced ESCC for almost two decades. PD-1 blockades combined with chemotherapy as first line setting exhibited superior efficacy for patients with ESCC recently. Anlotinib was a potential second-line monotherapy for patients with ESCC in China. Therefore, this study was designed to explore the efficacy and safety of paclitaxel and cisplatin combined with anlotinib as first-line therapy in advanced ESCC. The study had been reported in 2020 ESMO (Abs 1448), 2021 ASCO-GI Symposium (Abs 181), 2021 ASCO (e16013), 2021 ESMO (Abs 1805) and 2022 ASCO-GI Symposium (Abs 315) consecutively and the update results were reported here. Methods: Patients with previously untreated metastatic or locally advanced ESCC were recruited and were given paclitaxel (135mg/m 2 , iv, q3w) and cisplatin (60~75mg/m 2 , iv, d1~3, q3w) plus anlotinib (10mg, po, d1~14, q3w) for 4~6 cycles as initial therapy. For those who did not have PD, maintenance treatment was adopted with anlotinib monotherapy (10mg, po, d1~14, q3w) until PD or unacceptable toxicity. The tumor response was assessed according to RECIST 1.1 using CT scans every two cycles. The predefined sample size was 47. Primary endpoint was PFS and secondary endpoints included safety, ORR, DCR and DOR. Results: From Oct 2019 to Mar 2021, a total of 47 patients were enrolled, 46 patients included in per-protocol set analysis. The best overall response indicated that there were 4 CR (8.7%), 31 PR (67.4%), 7 SD (15.2%) and 4 NE (8.7%). Consequently, ORR was 76.1% (95%CI: 61.2%-87.4%) and DCR was 91.3% (95%CI: 79.2%-97.6%). At the data cut-off date on Jan 2022, The median PFS and median OS were 8.38 months (95% CI, 6.59-10.17) and 18.53 months (95% CI, 13.11-23.95), respectively. Additionally, safety profile exhibited that the regimen was tolerable. Common grade ≥3 adverse reactions were neutropenia (17.0%), bone marrow suppression (12.8%), nausea (10.6%), and vomiting (10.6%). Conclusions: Regimen of paclitaxel and cisplatin combined with anlotinib as first-line therapy for advanced ESCC exhibited encouraging efficacy and tolerable safety profile. And the conclusions needed to be confirmed in phase III clinical trials. Clinical trial information: NCT04063683 .
Importance Gastric and gastroesophageal junction cancers are diagnosed in more than 1 million people worldwide annually, and few effective treatments are available. Sintilimab, a recombinant human IgG4 monoclonal antibody that binds to programmed cell death 1 (PD-1), in combination with chemotherapy, has demonstrated promising efficacy. Objective To compare overall survival of patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancers who were treated with sintilimab with chemotherapy vs placebo with chemotherapy. Also compared were a subset of patients with a PD ligand 1 (PD-L1) combined positive score (CPS) of 5 or more (range, 1-100). Design, Setting, and Participants Randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 62 hospitals in China that enrolled 650 patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma between January 3, 2019, and August 5, 2020. Final follow-up occurred on June 20, 2021. Interventions Patients were randomized 1:1 to either sintilimab (n = 327) or placebo (n = 323) combined with capecitabine and oxaliplatin (the XELOX regimen) every 3 weeks for a maximum of 6 cycles. Maintenance therapy with sintilimab or placebo plus capecitabine continued for up to 2 years. Main Outcomes and Measures The primary end point was overall survival time from randomization. Results Of the 650 patients (mean age, 59 years; 483 [74.3%] men), 327 were randomized to sintilimab plus chemotherapy and 323 to placebo plus chemotherapy. Among the randomized patients, 397 (61.1%) had tumors with a PD-L1 CPS of 5 or more; 563 (86.6%) discontinued study treatment and 388 (59.7%) died; 1 patient (<0.1%) was lost to follow-up. Among all randomized patients, sintilimab improved overall survival compared with placebo (median, 15.2 vs 12.3 months; stratified hazard ratio [HR], 0.77 [95% CI, 0.63-0.94]; P = .009). Among patients with a CPS of 5 or more, sintilimab improved overall survival compared with placebo (median, 18.4 vs 12.9 months; HR, 0.66 [95% CI, 0.50-0.86]; P = .002). The most common grade 3 or higher treatment-related adverse events were decreased platelet count (sintilimab, 24.7% vs placebo, 21.3%), decreased neutrophil count (sintilimab, 20.1% vs placebo, 18.8%), and anemia (sintilimab, 12.5% vs placebo, 8.8%). Conclusions and Relevance Among patients with unresectable locally advanced or metastatic gastric and gastroesophageal junction adenocarcinoma treated with first-line chemotherapy, sintilimab significantly improved overall survival for all patients and for patients with a CPS of 5 or more compared with placebo. Trial Registration ClinicalTrials.gov Identifier: NCT03745170
Abstract Background PAX8 was not only a mitotic factor, but identified as a transcription factor involved in the prognosis of human tumor patients. Elucidating the function of PAX8 on the pathology of stomach cancer was meaningful. Results: PAX8 was found to be upregulated in primary stomach cancer tissue and the TCGA stomach cancer dataset. Interestingly, SOX13 and PAX8 showed consistent expression patterns, and the combined high PAX8 and SOX18 expression induced a worse prognosis of stomach cancer patients. SOX13 was further identified as a transcription factor of PAX8, and further affect Aurora B and Cyclin B1 expression, two cell cycle related factors of the downstream of PAX8, including. Furthermore, PAX8 depletion inducted G1-phase arrest and the decrease of EdU incorporation, cell viability and colony formation can be rescued by SOX13 overexpression. Conclusions: SOX13 participated in the elevated expression of PAX8, which promote the proliferation of stomach cancer cells. Therefore, SOX13 mediated PAX8 expression was recognized as a tumor-promoting role in stomach cancer.
367 Background: Efficacy and prognosis of chemotherapy in first-line setting for patients (pts) with advanced HER2-negative G/GEJ adenocarcinoma was dismal currently. PD-1 blockades combined with chemotherapy as first-line regimen exhibited superior efficacy for pts with G/GEJ adenocarcinoma recently, and the efficacy of tumor regression still needs to be improved. Anlotinib was a novel oral multi-targeted tyrosine kinase inhibitor for tumor angiogenesis and proliferation, which had been approved for treatment of considerable malignancies in China. We aimed to investigate the efficacy and safety of TQB2450 (PD-L1 blockade) plus anlotinib combined with CAPEOX (oxaliplatin and capecitabine) as first-line regimen for advanced G/GEJ adenocarcinoma and report the preliminary results timely. Methods: Pts with HER2-negative unresectable locally advanced or metastatic G/GEJ adenocarcinoma who did not expose to previous systemic treatment were recruited in this study. Eligible pts received TQB2450 (1200mg, iv, d1, q3w) plus anlotinib (10mg, po, d1~14, q3w) combined with oxaliplatin (130mg/m 2 , d1, iv, q3w) and capecitabine (1000mg/m 2 , po, bid, d1~14, q3w) for 6 cycles as initial therapy. For those without disease progression (PD), maintenance therapy was adopted with TQB2450 (1200mg, iv, d1, q3w) plus anlotinib (10mg, po, d1~14, q3w) until PD or unacceptable toxicity. Tumor response was assessed by investigator according to RECIST version 1.1 using CT scans. The calculated sample size was 25. The primary endpoint was ORR, secondary endpoints were DoR, PFS, OS, DCR and safety. Results: From Apr 2021 to Jul 2022, a total of 20 pts were enrolled and available for efficacy evaluation. In best overall response assessment, there were 15 PR (75.0%), 4 SD (20.0%) and 1 NE (5.0%). In consequence, the preliminary ORR was 75.0% (95%CI: 50.9%~91.3%), DCR was 95.0% (95%CI: 75.1%~99.9%). Median PFS of the 20 pts was not yet reached. Furthermore, the most common treatment-emergent adverse events with the incidence >40% were thrombocytopenia (80%), anemia (75%), leukopenia (65%), decreased total protein (45%) and decreased total protein (45%). The common grade ≥3 treatment-emergent adverse events were neutropenia (15%), lymphocyte count decreased (10%), anemia (5%), leukopenia (5%), elevated aspartate aminotransferase (5%) and elevated alkaline phosphatase (5%). Conclusions: Preliminary results suggested that TQB2450 plus anlotinib combined with CAPEOX in first-line setting for advanced G/GEJ adenocarcinoma exhibited encouraging efficacy and manageable adverse events. The conclusion should be validated in more pts consecutively. Clinical trial information: NCT04891900 .
190 Background: Panitumumab plus FOLFOX or FOLFIRI has been approved as the first-line therapy for RAS wild-type mCRC. QL1203 is a panitumumab biosimilar showing similarity to the originator panitumumab (Vectibix, Amgen) in preclinical studies and phase 1 clinical pharmacokinetic study. Here we present results from interim analysis of a phase 3 trial (NCT04233151) investigating QL1203 vs placebo plus mFOLFOX6 as first-line therapy in Chinese patients (pts) with RAS wild-type mCRC. Methods: Pts with treatment-naïve, RAS and BRAF wild-type, mCRC unsuitable for radical resection and local therapy were enrolled and randomly assigned (2:1) to receive QL1203 (6 mg/kg) plus mFOLFOX6 once every 2 weeks (Q2W) or placebo plus mFOLFOX6 Q2W, stratified by primary tumor site, liver metastases, and previous neoadjuvant/adjuvant therapy. The primary endpoint was PFS assessed by a Blinded Independ Review Committee (BICR) per RECIST v1.1. Key secondary endpoints include PFS by investigator (INV), OS, ORR, DoR, and safety. This planned IA was conducted at 338 (81.25%) of 416 PFS events occurred. Results: From Jan 8, 2020 to Jun 12, 2023, 641 pts were randomized (QL1203/placebo, n=426/215). 551 (86.0%) pts had left-sided tumors (QL1203/placebo, 85.9%/86.0%). 433 (67.6%) pts had liver metastases (QL1203/placebo, 68.1%/66.5%). As of data cutoff of this IA (Mar 22, 2024), median follow-up was 23.8 months. Median PFS by BIRC was 11.20 months for QL1203 and 8.34 months for placebo (hazard ratio [HR], 0.61 [97.42% confidence interval [CI], 0.47-0.79]; stratified one-sided log-rank p<0.0001). Other efficacy results are presented (Table). Incidence of grade≥ 3 adverse events (AEs) related to study drug was 59.9% for QL1203 and 32.9% for placebo. The most common grade≥3 AE related to QL1203 was neutrophil count decreased (20.3%). Conclusions: QL1203 demonstrated significantly improved PFS versus placebo and higher ORR. Clinical trial information: NCT04233151 . QL1203 (n=426) Placebo (n=215) PFS by BIRC mPFS, months (95% CI) 11.20 (9.89-13.11) 8.34 (7.26-8.54) HR (97.42% CI) 0.61 (0.47-0.79) PFS by INV mPFS, months (95% CI) 10.91 (9.69-11.30) 8.41 (7.39-9.07) HR (95% CI) 0.74 (0.60-0.91) mOS, months (95% CI) 27.66 (24.74-32.79) 24.54 (20.17-27.79) HR (95% CI) 0.82 (0.64-1.06) ORR by BIRC, n (%) 68.31% 47.91% 95% CI 63.66-72.70 41.07-54.81 ORR by INV, n (%) 64.08% 49.30% 95% CI 59.33-68.65 42.44-56.19
AbstractBackgroundBreakthrough cancer pain (BTcP) has a negative impact on patients’ quality of life, general activities, and is related to worse clinical outcomes. Fentanyl inhalant is a hand-held combination drug-device delivery system providing rapid, multi-dose (25μg/dose) administration of fentanyl via inhalation of a thermally generated aerosol. This multicenter, randomized, placebo-controlled, multiple-crossover, double-blind study evaluated the efficacy, safety, and tolerability of fentanyl inhalant in treating BTcP in opioid-tolerant patients. Methods Each patient was treated and observed for 6 episodes of BTcP (4 with fentanyl inhalant, 2 with placebo). During each episode of targeted BTcP, patients were allowed up to six inhalations. Primary outcome was the time-weighted sum of PID (pain intensity difference) scores at 30 minutes (SPID30). Results A total of 335 BTcP episodes in 59 patients were treated. The mean SPID30 was -97.4 ± 48.43 for fentanyl inhalant-treated episodes, and -64.6 ± 40.25 for placebo-treated episodes (p<0.001). Significant differences in PID for episodes treated with fentanyl inhalant versus placebo was seen as early as 4 minutes and maintained for up to 60 minutes. The percentage of episodes reported PI (pain intensity) scores ≤ 3, a ≥ 33% or ≥ 50% reduction in PI scores at 30 minutes, PR30 (pain relief scores at 30 minutes) and SPID60 favored fentanyl inhalant over placebo. Only 4.4% of BTcP episodes required rescue medication in fentanyl inhalant group. Most AEs were of mild or moderate severity and typical of opioid drugs. Conclusion Fentanyl inhalant was efficacious, safe, and well tolerated in the management of BTcP. Trial registration ClinicalTrials.gov: NCT05531422
3000 Background: Folate receptor α (FRα) and vanilloid subfamily member 6 of transient receptor potential channels (TRPV6) are overexpressed in many solid tumors hence could be promising therapeutic targets. CBP-1008 is a first-in-class bi-specific ligand drug targeting FRα and TRPV6 carrying monomethyl auristatin E (MMAE) as payload. Here we report the first-in-human, multicenter, phase Ia/Ib study designed to explore the safety, pharmacokinetics and efficacy of CBP-1008 in advanced solid tumors. Methods: CBP-1008 was administered by intravenous infusion. Phase Ia study included a dose-escalation period initiated by accelerated titration (0.015, 0.03mg/kg d1,15; q28d) and then switched to 3+3 scheme (0.12, 0.15, 0.17, 0.18mg/kg d1,15; q28d) and a dose expansion period. Phase Ib clinical expansion study included 3 cohorts, platinum-resistant ovarian cancer (OC), metastatic triple negative breast cancer (TNBC) and other solid tumors. The primary objective was to assess the safety and preliminary efficacy. Results: As of January 13, 2022, 106 patients received at least one dose of study drug were enrolled (phase Ia: n = 30; phase Ib: n = 76) and received median 3 prior regimens. Included tumor species were OC (n = 52), TNBC (n = 20), ER+/Her2+ breast cancer (BC) (n = 16), lung cancer (n = 3), pancreatic cancer (n = 2) and others (n = 13). In phase Ia study, DLTs were observed in 3 patients (0.12, 0.15, 0.18mg/kg, n = 1 each), including grade 4 hypophosphatemia, neutropenia, febrile neutropenia, and grade 3 hyperglycemia, alanine aminotransferase (ALT). MTD was not yet reached. Majority of adverse events were mild to moderate. The most common grade 3/4 treatment-emerging adverse events (TEAEs) were neutropenia (37.7%), AST elevation (6.6%), ALT elevation (5.7%), hyperglycemia (2.8%), hypohemoglobinemia (2.8%) and nausea (1.9%). Drug-related death was not observed. A total of 69 patients at dose of 0.15mg/kg or above were evaluable for efficacy assessment. There were 11 patients achieved partial response (PR) (OC n = 8, ER+/Her2+ BC n = 2, TNBC n = 1) and 30 patients achieved stable disease (SD). In 32 advanced platinum-resistant OC patients with FRα and/or TRPV6-positive expression, 6 PR and 16 SD were observed. Moreover, 6/18 PR (33.3%) and 8/18 SD (44.4%) were observed in enriched OC patients who showed high score of FRα/TRPV6 receptor. Conclusions: The preliminary results showed that CBP-1008 has manageable safety profile. Antitumor activity was observed in patients with FRα/TRPV6 receptor expression, especially in platinum-resistant OC cohort with high score of the two receptors. Clinical trial information: NCT04740398.
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 .
2641 Background: HBM4003 is a fully human heavy chain only monoclonal antibody (HCAb) to CTLA-4, which has been engineered to deplete Treg cells by enhanced antibody-dependent cellular cytotoxicity (ADCC) activity. In the Phase 1 dose escalation part, HBM4003 showed favorable safety and efficacy profile in patients (pts) with advanced solid tumors. Here, we present the updated data from the dose escalation part and most recent safety and clinical activity data from three expansion cohorts of pts with advanced hepatocellular carcinoma (HCC), melanoma, and renal cell carcinoma (RCC). Methods: In the dose-escalation part, pts were enrolled into 3 dose levels (DL): 0.3mg/kg QW (28-day cycle), 0.45mg/kg Q3W (21-day cycle), and 0.6mg/kg Q3W (21-day cycle). In the dose-expansion part, pts with advanced HCC, melanoma, and RCC received 0.45 mg/kg Q3W (21-day cycle). Tumor measurements were performed every 6 weeks for up to 12 months and subsequently every 12 weeks per RECIST v1.1. Results: In total 60 pts were included for this analysis, including 24 pts with advanced solid tumors in the dose escalation part and 36 pts in the dose expansion part: 18 pts with HCC, 4 pts with melanoma, and 14 pts with RCC, from 12 sites in mainland China, 5 sites in Australia, and 1 site in Hong Kong. 46 pts (77%) received ≥ 2 lines of previous systemic therapies and 37 pts (62%) received previous PD-1/PD-L1 treatment. For the HCC cohort, 19 pts were treated in dose-escalation (1 pt, 0.45 mg/kg Q3W) and dose-expansion parts. All 19 pts received previous PD-1/PD-L1 therapy. 12 pts were evaluable for efficacy. Two had stable disease (SD), 2 pts had partial response (PR) as best response. For 12 evaluable pts, ORR was 16.7% and disease control rate (DCR) was 33.3%. For the RCC cohort, 19 pts were treated in dose-escalation and dose-expansion parts; 18 pts were evaluable for efficacy. Eight had SD as best response; the DCR was 44.4%. Overall, the most common treatment-related adverse event (TRAE) (incidence ≥ 10%) of all grades was rash (16 [26.7%] pts). At the 0.45 mg/kg Q3W DL, the most common TRAE of all grades was hepatic function abnormalities (12 [27.9%] pts) and rash (12 [27.9%] pts). 30 (69.8%) pts reported Gr 1 or 2 TRAEs. Gr ≥3 TRAEs occurred in 4 (9.3%) pts. 1 pt reported Gr 4 TRAE: blood creatine phosphokinase increased. No Gr 5 TRAE was reported. TRAE leading to discontinuation occurred in 4 pts. In mouse model, only tumor infiltrating lymphocytes Treg was depleted upon HBM4003 treatment while no Treg change in blood and spleen. In pts, Treg depletion was observed only in tumor tissue on day 21 post dosing. Overall, HBM4003 demonstrated dose proportional pharmacokinetics and low immunogenicity. Conclusions: HBM4003 showed a favorable safety profile, promising antitumor activity and intratumoral Treg depletion in pts with advanced solid tumors at the 0.45 mg/kg Q3W DL. Clinical trial information: NCT04135261.
3574 Background: CPGJ602 is a recombinant anti-EGFR human-mouse chimeric monoclonal antibody. CPGJ602 plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) may have efficacy in KRAS/NRAS/BRAF wild-type metastatic colorectal cancer. Methods: In this open-label, randomized trial, patients who had received no previous treatment were randomly assigned (2:2:1) to receive CPGJ60（325mg/m 2 , q2w) plus mFOLFOX6 (biweekly group), CPGJ602 (400 mg/m 2 initial dose followed by 250 mg/m 2 /week thereafter) plus mFOLFOX6 (weekly group) or cetuximab (400 mg/m 2 initial dose followed by 250 mg/m 2 /week thereafter) plus mFOLFOX6 (cetuximab group). All subjects received treatment up to 16 weeks. The primary endpoint was the best overall response (BOR) at 16 weeks. The second endpoints were DCR, DOR, PFS, safety. Results: As of Dec 30, 2021, 76 patients were enrolled (30 in biweekly group, 32 in weekly group and 14 in control group). The best overall response achieved at 16 weeks was 76.7% (23/30, 95% CI 60.3% - 92.0%),78.1% (25/32, 95% CI 62.5% - 92.5%) and 78.6% (11/14, 95% CI 49.2% - 95.3%) in the biweekly group, weekly group and cetuximab group, respectively. The confirmed overall response rate at 16 weeks was 60%(18/30), 71.9%(23/32) and 57.1%(8/14) in the biweekly group, weekly group and cetuximab group, respectively. The PFS rates at 16 weeks were 81.5% (95% CI 57.7% -92.6%), 96.8% (95% CI 79.2%-99.5%), 81.3% (95% CI 41.5%- 95.2%) in the biweekly group, weekly group and cetuximab group, respectively. The most common adverse events were a decreased neutrophil count (60%，78.1% and 71.4% in the biweekly group, weekly group and cetuximab group respectively), decreased white-cell count (53.3%, 78.1% and 71.4% respectively), decreased platelet count (40.0%, 40.6% and 42.9% respectively), and elevated serum aspartate aminotransferase (43.3%, 37.5% and 35.7% respectively). Conclusions: CPGJ602 plus mFOLFOX6 could be an option for KRAS/NRAS/BRAF wild-type metastatic colorectal cancer. Clinical trial information: NCT04466254.
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