Inetetamab combined with S-1 and oxaliplatin as first-line treatment for human epidermal growth factor receptor 2-positive gastric cancer.

e16028 Background: Patients with HER2-positive advanced gastric cancer have a poor prognosis. Trastuzumab combined with chemotherapy is the first-line standard treatment. Inetetamab is a novel anti-HER2 drug, and its efficacy and safety in gastric cancer have not been reported yet. Methods: Thirty-eight patients with HER2-positive advanced gastric cancer or gastroesophageal junction adenocarcinoma were randomly divided into two groups: one group received inetetamab combined with the SOX regimen, and the other group received trastuzumab combined with the SOX regimen. After 4-6 cycles, patients with stable disease received maintenance therapy. The primary endpoints were progression-free survival (PFS) and overall survival (OS), and the secondary endpoints were the objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Results: Thirty-seven patients completed the trial, with 18 patients in the inetetamab group and 19 patients in the trastuzumab group. In the inetetamab group, the median PFS was 8.5 months, compared to 7.3 months in the trastuzumab group (P = 0.046), indicating a significant difference. The median OS was 15.3 months vs. 14.3 months (P = 0.46), and the ORR was 50% vs. 42% (P = 0.63), with no significant differences between groups. Common AEs included leukopenia, thrombocytopenia, nausea, and vomiting. The incidence rates of grade ≥ 3 AEs were 56% in the inetetamab group and 47% in the trastuzumab group (P = 0.63), with no significant difference. Conclusions: In the first-line treatment of HER2-positive advanced gastric cancer, the efficacy of inetetamab and trastuzumab was comparable. The inetetamab group had superior PFS benefits, and both groups had good safety.

BackgroundThe ToGA study showed that trastuzumab plus chemotherapy prolonged median survival in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer. Among chemotherapy options, oxaliplatin might be as effective as cisplatin but has shown to be more tolerable. To further improve treatment options for patients with advanced gastric cancer, we initiated a study to evaluate the efficacy and safety of trastuzumab plus oxaliplatin/capecitabine in patients with HER2-positive advanced gastric cancer.MethodsCGOG1001 was an open-label, multicenter, prospective phase II study. Patients with chemotherapy-naive HER2-positive advanced gastric cancer were eligible. Trastuzumab was administered at a loading dose of 8 mg/kg followed by 6 mg/kg infusion every 3 weeks (q3w). Oxaliplatin was administrated as a 130 mg/m2 infusion, q3w, for up to 6 cycles. Capecitabine 1000 mg/m2 was given orally twice daily on days 1–14 followed by a 7-day rest interval. Trastuzumab and capecitabine were continued until disease progression or intolerable toxicity. The primary endpoint was objective response rate. Simon two-stage design (H0 = 40 %, H1 = 60 %, α = 0.05, β = 0.2) by Response Evaluation Criteria In Solid Tumors 1.0 was applied.ResultsFifty-one patients were enrolled. Confirmed response was recorded in 46 patients. One patient achieved complete response and 33 patients achieved partial response (response rate 34/51 [66.7 %] in the intent-to-treat population). Median follow-up time was 28.6 months, with a median progression-free survival of 9.2 months (95 % confidence interval [CI]: 6.5–11.6) and a median overall survival (OS) of 19.5 months (95 % CI: 15.5–26.0). Patients with a HER2/CEP17 ratio of greater than five achieved improved OS (20.9 vs 19.5 months, p = 0.001). The most common adverse events of grade 3 or above were thrombocytopenia (21.6 %), neutropenia (13.7 %), anemia (5.9 %) and leucopenia (3.9 %).ConclusionThe addition of trastuzumab to oxaliplatin/capecitabine was well tolerated and the results demonstrated encouraging efficacy.Trial registrationClinicalTrials.gov NCT01364493.

Claudin 18.2—a FAST-moving target in gastric cancer?

PurposeThe phase III ToGA trial established cisplatin, fluoropyrimidine and trastuzumab as the standard treatment in HER2-positive advanced gastric cancer (AGC). However, as demonstrated in HER2-negative AGC, oxaliplatin-based regimens could improve tolerance remaining effective. The aim of this trial was to explore the potential activity and safety of capecitabine, oxaliplatin (XELOX) and trastuzumab in patients with HER-2 positive advanced gastric cancer.MethodsWe conducted a multicentre, prospective, non-randomised, non-controlled, open-label and national (Spanish) phase II study. Patients with HER2-positive advanced gastric or gastro-oesophageal junction (EGJ) cancer received XELOX and trastuzumab as first-line treatment. Primary endpoint was objective tumour response rate (ORR).Results45 patients from ten hospitals in Spain were included from September 2011 to December 2013. Median age was 65 years, 82.2% were male, 69% had gastric cancer and 31% had EGJ tumours. At a median follow-up of 13.7 months (7.1–20.9), the estimated median progression-free survival and overall survival were 7.1 (95% CI 5.5–8.7) and 13.8 months (95% CI 10.1–17.4), respectively, with 8.9%, 37.8% and 31.1% of patients achieving complete response, partial response and stable disease. Regarding safety, 44.4% of the patients had grade 3 or greater adverse events, being the most frequent diarrhoea (26.6%), fatigue (15.5%), nausea (20%) and vomiting (13.3%). Only two patients (4.4%) developed asymptomatic grade 2 left ventricle ejection fraction reduction.ConclusionsXELOX-trastuzumab is a promising and effective therapy as first-line treatment for patients with HER2-positive AGC, with comparable results to the ones obtained with other “platinum-based” regimens. This scheme is feasible and tolerable with a low incidence of cardiac toxicity.

Human epidermal growth-factor receptor 2 (HER2) was an important therapeutic target in gastric cancer. Through the last decade, strategy with trastuzumab-based chemotherapy remains the first-line standard of treatment in advanced HER2-positive gastric cancer. Based on the Trastuzumab for Gastric Cancer trial, trastuzumab plus systemic chemotherapy of cisplatin and fluoropyrimidine as the backbone was established as the first-line therapy in advanced HER2-positive gastric cancer. Since then, studies have explored the optimization of the front-line strategy, including the dose of trastuzumab, chemotherapy regimen and maintenance therapy. A large number of clinical trials were conducted to explore the optimal front-line therapy regimens, such as lapatinib and pertuzumab. Safe and effective first-line regimens are still lacking. Recently, two phase II studies of combining immune checkpoint inhibitor in first-line treatment of advanced HER2-positive gastric cancer showed promising results. The progress of immunotherapy has gradually promoted the development of front-line treatment of advanced HER2-positive gastric cancer to potential chemotherapy-free strategies. Therefore, this article reviewed these significant clinical trials and focus on the front-line treatment strategies for HER2-positive gastric cancer.

SY10-4 - First-Line Treatment in HER2-Positive Advanced or Metastatic Gastric Cancer

BackgroundUnresectable advanced or recurrent gastric cancer patients have a poor prognosis. PD-1 monotherapy regimen and PD-1 combined chemotherapy regimen have become the standard third- and first-line treatment for advanced gastric cancer, respectively. However, the status of immune checkpoint inhibitors in the second-line treatment for advanced gastric cancer has not been established. The combination of chemotherapy and anti-PD-1 antibody has been demonstrated to have a synergistic effect. In this study, we aimed to evaluate the efficacy and safety of sintilimab combined with nab-paclitaxel in the second-line treatment for advanced gastric cancer (GC)/gastroesophageal junction (GEJ) cancer patients.Patients and MethodsWe retrospectively analyzed patients with advanced GC/GEJ cancer that progressed after first-line systemic therapies with sintilimab combined with nab-paclitaxel from April 1, 2019 to December 31, 2021. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety.ResultsThirty-nine patients were enrolled and eligible for response assessment. Complete response (CR) was not observed, 15 patients achieved partial response (PR), 16 patients had stable disease (SD) and 9 patients had progressive disease (PD). The ORR and DCR were 15 (38.5%) and 31 (79.5%), respectively. Median PFS was 5.4 months (95%CI: 3.072-7.728). PFSs between different subgroups were analyzed. The results showed that gender, age, Human epidermal growth factor receptors 2 (HER2) status, PD-L1 expression, primary tumor site and chemotherapy cycles had no significant effect on PFS. Most of the adverse events (AEs) were of grade 1-2 and manageable. The common treatment-related adverse events of grade 3 or 4 included anemia (12.8%), neutropenia (12.8%), leukopenia (10.3%), hand-foot syndrome (7.7%), thrombocytopenia (7.7%). The potential immune-related adverse events (irAEs) were grade 1 pneumonia (1 pts [2.6%]) and grade 4 hepatitis (1 pts [2.6%]). There were no treatment-related deaths.ConclusionThese results indicate that sintilimab combined with nab-paclitaxel exhibits good anti-tumor activity and an acceptable safety profile as a second-line treatment for advanced or metastatic gastric cancer. These results warrant further investigation and evaluation to identify patients who can benefit more from the combined treatment strategy.

Trastuzumab plus chemotherapy is the standard-of-care (SoC) first-line therapy for HER2-positive advanced gastric cancer. Combining PD-1 antibody with SoC first-line therapy showed encouraging results in the KEYNOTE-811 study. The retrospective study aims to evaluate the efficacy and safety of SoC vs. SoC plus camrelizumab (PD-1 antibody) as a first-line treatment for HER2-positive advanced gastric cancer in a real-world setting. This study included 41 patients with HER2-positive advanced gastric cancer who received SoC or SoC plus camrelizumab from June 2017 to December 2020. The endpoints were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Thirteen patients received SoC (SoC group) and 28 patients received SoC plus camrelizumab (camrelizumab group). As of December 2020, the median follow-up time was 10.0 months. In the camrelizumab and SoC groups, the ORRs were 75.0% and 46.2% (P=0.032), respectively. The DCR was 96.4% in the camrelizumab group and 69.2% in the SoC group (P=0.003). The median OS was 18.4 in the camrelizumab group and 13.2 months in the SoC group [hazard ratio (HR) =0.343; 95% confidence interval (CI): 0.151-0.783; P=0.008]. The median PFS was 3.78 in the camrelizumab group and 1.74 months in the SoC group (HR =0.416; 95% CI: 0.186-0.932; P=0.027). In the HER2 subgroups in the camrelizumab group, the median PFS of immunohistochemistry (IHC) 3+ vs. IHC 2+ fluorescence in situ hybridization (FISH) was 11.3 vs. 9.0 months (HR =1.684; 95% CI: 0.710-3.994; P=0.047). The incidence rates of reactive cutaneous capillary endothelial proliferation (RCCEP) (P<0.001), abnormal liver function (P=0.040), and hypothyroidism (P=0.039) between the two groups were significantly different. RCCEP and hypothyroidism were considered to be related to camrelizumab. First-line treatment with camrelizumab combined with SoC showed significant clinical benefits and good tolerance compared with SoC for HER2-positive advanced gastric cancer.

Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study

Encouraging results for PD-1 inhibition in gastric cancer

For patients with human epidermal growth factor receptor-2 (HER2)-positive advanced or metastatic gastric cancer who have progressed on first-line trastuzumab therapy, the clinical value of the continuous use of trastuzumab beyond progression (TBP) is controversial. The present study was conducted to evaluate the efficacy and explore new treatment strategies of TBP for patients with trastuzumab-resistant HER2-positive advanced or metastatic gastric cancer in the era of cancer immunotherapy. Retrospective analysis. Patients with HER2-positive advanced or metastatic gastric cancer who have failed first-line treatment based on trastuzumab-targeted therapy from June 2019 to December 2020 were retrospectively analyzed. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Survival curves of patients were estimated by the Kaplan-Meier method and compared using the log-rank test. In all, 30 patients received TBP with chemotherapy, immunotherapy, or anti-angiogenic therapy, and the other 26 patients received treatment of physician's choice without trastuzumab. The median PFS in the TBP and non-TBP population was 6.0 [95% confidence interval (CI) = 3.8-8.2] and 3.5 (95% CI = 2.2-4.8) months, respectively (p = 0.038), and the median OS was 12.3 (95% CI = 10.4-14.2) and 9.0 (95% CI = 6.6-11.4) months (p = 0.008). The patients who received TBP treatment had more favorable PFS and OS than the non-TBP population. In the TBP group, patients who received trastuzumab plus chemotherapy and immunotherapy had higher ORR (40.0% versus 16.7%), DCR (90.0% versus 50.0%), and showed a significant improvement in PFS (7.0 versus 1.9 m) compared to TBP with chemotherapy alone. Subgroup analysis suggested that patients with male, HER2 positive with immunohistochemistry score 3+ and PFS of first-line treatment less than 6 months had a greater benefit from TBP. The incidence of Grade 3-4 adverse events in the TBP and non-TBP groups was 43.3% and 38.5%. The continuous use of TBP improves PFS and OS in patients with trastuzumab-resistant HER2-positive advanced or metastatic gastric cancer with well-tolerated toxicity. In the era of immunotherapy, TBP combined with chemotherapy and immunotherapy may further enhance the clinical benefit and provide a new treatment strategy. This study is a retrospective study, which does not require clinical registration.

Significant effect of posterior line treatment of HER2 positive advanced gastric cancer: A case report

IntroductionCT-P6, the first trastuzumab biosimilar, was approved on the basis of data limited to human epidermal growth factor receptor-2 (HER2)-positive early breast cancer. Usage for other indications was granted by extrapolation, and post-approval clinical studies were conducted to confirm the effect of CT-P6 in HER2-positive gastric cancer.MethodsAfter approval in Japan in 2018, a prospective post-marketing surveillance was conducted in 171 patients (130 male, 41 female) with HER2-positive unresectable advanced or recurrent gastric cancer. The safety and efficacy of CT-P6 were evaluated over 1 year.ResultsCT-P6 was primarily combined with fluoropyrimidine and/or platinum agents. Adverse events occurred in 151 patients (88.3%), with 55 patients (32.2%) experiencing grade 3 or higher. Infusion reactions occurred in 12.3%. Four cardiac disorders were reported: two of grade 1 cardiac dysfunction and two of severe ischemic heart disease. Interstitial lung disease was reported in four patients (2.3%). The objective response rate was 34.4%, and the disease control rate was 82.4%. The progression-free survival (PFS) was 7.4 months. Significant risk factors for PFS included gastroesophageal junction, ≥ 3 metastases, no gastrectomy, prior chemotherapy, and no platinum agent.ConclusionsIn this cohort study, CT-P6 demonstrated sufficient efficacy and no new safety concerns in HER2-positive advanced gastric cancer, serving as a cost-effective alternative to originator trastuzumab.Trial RegistrationJapan Registry of Clinical Trials, Trial ID: jRCT2071230094 (November 2023)Supplementary InformationThe online version contains supplementary material available at 10.1007/s40487-025-00341-7.

282 Background: Albumin-bound paclitaxel has been proven to be an active agent in advanced gastric cancer, and was approved by PMDA Japan for use as a second-line treatment of advanced gastric cancer. The aim of this study was to evaluated the efficacy and safety of AS and SOX in the first-line treatment of advanced gastric cancer. Methods: Patients diagnosed with unresectable locally advanced, recurrent or metastatic human epidermal growth factor receptor type 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma were randomized (1:1) to either AS group (albumin-bound paclitaxel 260mg/m2 d1 or 130mg/m2 d1, 8; S-1 40 mg [BSA &lt; 1.25 m2], 50 mg [1.25 ≤ BSA &lt; 1.50 m2] and 60 mg [BSA ≥1.50 m2] b.i.d. d1-14, every 3wks) or SOX group (oxaliplatin 130mg/m2 d1; S-1 40 mg [BSA &lt; 1.25 m2], 50 mg [1.25 ≤ BSA &lt; 1.50 m2] and 60 mg [BSA ≥1.50 m2] b.i.d. d1-14, every 3wks). Primary endpoint was progression-free survival (PFS), secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. Results: Between March 2019 and March 2021, 96 patients were enrolled and 85 patients (AS group, n = 43; SOX group, n = 42) who received at least one dose of study drug and had at least one postbaseline efficacy evaluation were included in the final analysis. 34 (79.0%) patients in the AS group and 35 (83.3%) in the SOX group had discontinued treatment. Of these 85 patients, 78.8% had two or more organs involved, 61.2% had peritoneal dissemination, and more than 1/4 had massive ascites. Patient demographics and disease characteristics were generally balanced between arms. With median follow-up 15.4 months (95% CI, 8.8-21.9), the median PFS of AS group vs. SOX group was 9.2 vs.5.1 months (HR = 0.58 [95% CI 0.36-0.96], p = 0.034); and the median OS was 14.4 vs. 15.4 months (HR = 0.73 [95%CI 0.40-1.34], p = 0.375). Tumor response was assessable in 33 patients according to RECIST V1.1 in both cohorts, the ORR and DCR were similar in AS vs. SOX arm (ORR: 54.5% vs. 51.5%, P = 0.805; DCR: 78.8% vs. 78.8%, P = 1.000). The main grade 3 or worse treatment-related adverse events were neutropenia (30.2% vs 23.8%), Leucopenia (11.6% vs 11.9%) and peripheral sensory neuropathy (4.7% vs 7.1%) in AS and SOX group. The study was planned to be adjusted, due to the widespread use of immunotherapy in first-line treatment of gastric cancer. Conclusions: The results of this study indicated that in previously untreated patients with unresectable locally advanced, recurrent or metastatic HER2-negative gastric or GEJ adenocarcinoma, AS achieved better PFS than SOX, with an inadequate power. The toxicities were controllable and consistent with previously reported. Clinical trial information: NCT03801668.

BackgroundImage texture analysis is a noninvasive technique for quantifying intratumoral heterogeneity, with derived texture features reported to be closely related to the treatment outcome of tumors. Gastric cancer is one of the most common tumors and the third leading cause of cancer-related deaths worldwide. Although trastuzumab is associated with a survival gain among patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer, optimal patient selection is challenging. The purpose of this study was to determine whether CT texture features of HER2-positive gastric cancer were related to the survival rate after trastuzumab treatment.Methods and FindingsPatients diagnosed with HER2-positive advanced gastric cancer from February 2007 to August 2014 were retrospectively selected. Using in-house built software, histogram features (kurtosis and skewness) and gray-level co-occurrence matrices (GLCM) features (angular second moment [ASM], contrast, entropy, variance, and correlation) were derived from the CT images of HER2-positive advanced gastric cancer in 26 patients. All the patients were followed up for more than 6 months, with no confirmed deaths. The patients were dichotomized into a good and poor survival group based on cutoff points of overall survival of 12 months. A receiver-operating characteristics (ROC) analysis was performed to test the ability of each texture parameter to identify the good survival group. Kaplan–Meier curves for patients above and below each threshold were constructed. Using a threshold of >265.8480 for contrast, >488.3150 for variance, and ≤0.1319×10−3. for correlation, all of the area under the ROC curves showed fair accuracy (>0.7). Kaplan–Meier analysis showed statistically significant survival difference between two groups according to optimal cutoff values of contrast, variance, correlation and ASM. However, as this study had a small number of patients, a further study with a larger population will be needed to validate the results.ConclusionsHeterogeneous texture features on CT images were associated with better survival in patients with HER2-positive advanced gastric cancer who received trastuzumab-based treatment. Therefore, texture analysis shows potential to be a clinically useful imaging biomarker providing additional prognostic information for patient selection.