HER2-positive Gastric Cancer Research Articles

Abstract P2-13-15: VRN101396, a brain-permeable HER2 inhibitor, shows the anti-tumor activity in preclinical HER2-positive cancer models

Abstract Breast cancer (BC) is the second most common cancer associated with brain metastasis (BM) and among patients with breast cancer brain metastasis (BCBM), human epidermal growth factor receptor 2 (HER2)-positive breast cancer is most likely to develop BM. The overall prognosis of HER2-positive BCBM remains dismal with median survival time after BM of less than a year. Drugs like T-DM1, T-DXd and Tucatinib are reported to deliver a progression-free survival benefit in HER2-positive BCBM patients, but there are still unmet needs for a drug that crosses the blood brain barrier more effectively. We develop VRN101396, a brain penetrant, orally available, and irreversible small molecule inhibitor targeting HER2 to offer a new therapeutic option for the treatment of HER2-positive BCBM. VRN101396 potently inhibits catalytic activity of HER2 but spares wild-type EGFR. In HER2-positive breast cancer cell lines BT474 and SK-BR3 and gastric cancer cell line NCI-N87, VRN101396 inhibited the cell proliferation and phosphorylation of HER2 with single- or double-digit nanomolar IC50 values while inhibiting wild type EGFR with an IC50 value of >100 nM. In both subcutaneous and intracranial efficacy mouse models, once-daily oral dose of VRN101396 significantly inhibited tumor growth and achieved tumor regression. In N87 subcutaneous xenograft model, VRN101396 alone showed superior efficacy to the combination of Tucatinib and Trastuzumab. Additionally, in intracranial xenograft model, VRN101396 showed superior efficacy to Tucatinib. Pharmacokinetics of VRN101396 displayed higher brain exposure than tucatinib and lapatinib, indicating better target engagement in the brain. Pharmacodynamic analysis revealed that VRN101396 reduced phosphorylation of HER2, HER3, AKT, and ERK compared to vehicle group after administration up to 24 hours. In conclusion, VRN101396 is a therapeutic candidate for the treatment of HER2-positive BC, BCBM and gastric cancer. Citation Format: Hong-ryul Jung, Sunghwan Kim, Jihye Yoo, Chan mi Park, Somi Lee, Hyoju Lee, Youngyi Lee, Jinhee Park, Kyungah Seo, Dong-Hyuk Seo, Eunhwa Ko, Jung Beom Son, Deakwon Kim, Hwan Geun Choi, Nam Doo Kim. VRN101396, a brain-permeable HER2 inhibitor, shows the anti-tumor activity in preclinical HER2-positive cancer models [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-15.

A randomized phase II trial of preoperative chemotherapy of S-1/CDDP with or without trastuzumab followed by surgery in HER2 positive advanced gastric or esophagogastric junction adenocarcinoma with extensive lymph node metastasis: Japan Clinical Oncology Group study JCOG1301C (Trigger Study).

285 Background: The efficacy of trastuzumab has been established for HER2-positive advanced gastric cancer patients with metastatic disease. However, it remains unclear if the addition of trastuzumab to preoperative chemotherapy is effective for treatment of HER2-positive locally advanced gastric cancer. Methods: Eligible patients with HER2-positive gastric cancer with extensive lymph node metastasis were randomized to preoperative S-1/cisplatin (SP) (group A) or SP plus trastuzumab (group B). In both groups, patients received S-1, 80–120 mg/body, on days 1–14 and cisplatin, 60 mg/m2, on day 1, q21, 3-4 courses. Additionally, in group B, patients received infusions of trastuzumab (first course 8 mg/kg followed by 6 mg/kg, day 1). After gastrectomy, adjuvant chemotherapy with S-1 was performed for 1 year in both groups. The primary endpoint was overall survival, and the sample size was planned to be 130 patients in total, expecting a 10% increase in the 3-year overall survival (70% vs 80%) with a 1-sided alpha of 0.2, a power of 0.75. Results: The study was terminated in March 2021 due to slow patient accrual. In total, 46 patients were randomized to either group A (22 patients) or group B (24 patients). Patient characteristics were well balanced between the groups. Planned preoperative chemotherapy was completed in 20 patients (90.9%) in group A and in 23 patients (95.8%) in group B, and R0 resection was achieved in 20 patients (90.9%) in group A and 22 patients (91.7%) in group B. The incidences of grade 3 or 4 hematological/non-hematological adverse events during preoperative chemotherapy were 27.3/18.2% in group A and 4.2/8.3% in group B. Objective response rate (CR/PR) tended to be higher in group B (66.7% [16/24]) than in group A (36.4% [8/22], p = 0.08). Pathological response rate (> grade 1b in Japanese classification, 22.7% [5/22] vs. 50.0% [12/24], p = 0.07) and the proportion of patients achieving downstage to ypStage 0/I/II (22.7% [5/22] vs. 50.0% [12/24], p = 0.07) were also higher in group B than in group A. Conclusions: Preoperative chemotherapy with SP plus trastuzumab was feasible, and tended to show better radiological and pathological response rates. Better survival outcomes are expected by adding trastuzumab to preoperative chemotherapy with SP for locally advanced gastric cancer with extensive nodal metastasis. Clinical trial information: UMIN000016920.

Multicenter phase Ib/II study of second-line trastuzumab, ramucirumab, and paclitaxel in patients with HER2-positive advanced gastric or gastroesophageal junction cancer: Updated HER-RAM study with biomarker analysis.

330 Background: HER-RAM study is the phase Ib/II multicenter study to evaluate the safety and efficacy of adding trastuzumab to ramucirumab and paclitaxel as a second-line treatment in HER2-positive advanced gastric or gastroesophageal junction (G/GEJ) cancer progressed from trastuzumab containing chemotherapy. We report survival follow up and exploratory biomarker results. Methods: Patients with HER2-positive advanced G/GEJ cancer who progressed after first-line trastuzumab containing chemotherapy were enrolled. Trastuzumab 4mg/kg on day 1 followed by 2mg/kg on days 8, 15, and 22, ramucirumab 8mg/kg on days 1 and 15, and paclitaxel (dose level 1: 80mg/m2, dose level -1: 70 mg/m2) on days 1, 8, and 15 of a 28-day cycle was tested. After safety analysis of lead-in safety cohort (phase 1b), phase 2 part was conducted to evaluate the primary endpoint of progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Results: No dose limiting toxicity at the dose level 1 was observed at the phase Ib part, the dose level 1 with full dose combination was determined as recommended phase 2 dose. At the time of data lock on September 7th, 2021, 50 patients including 3 patients from the phase 1b part were evaluable for response and safety. Median age was 60 years old (range 29-82) and most patients were male (40/50). At baseline, 39 patients had tumors with HER-2 3+ by immunohistochemistry (IHC) and 11 had those with HER-2 2+ by IHC with ERBB2 amplification by in situ hybridization. With median follow-up duration of 18.8 months, median PFS and OS were 7.0 months (95% confidence interval [CI]: 4.9-9.2 months) and 13.6 months (95% CI: 9.5-17.6 months), respectively. ORR was 54% (27/50, complete response = 1, partial response = 26) and DCR was 96% (48/50), respectively. On the exploratory analysis, HER-2 positivity of tumor tissue was lost after fist-line chemotherapy in 8 of 23 patients (34.7%) without any definite association between loss of HER-2 and outcomes. Most common hematologic adverse event (AE) was neutropenia (all grade: 64%, grade 3/4: 52%) with 1 case of febrile neutropenia (2%). Most common non-hematologic AE was peripheral sensory neuropathy and anorexia (all grade: 32%, grade 3: 2%, respectively). Gastrointestinal (GI) bleeding occurred in 6 cases (grade 3 upper GI bleeding: 3 patients, grade 1/2 lower GI bleeding: 3 patients), whereas GI perforation was not observed. Hypertension occurred in 3 patients (grade 1/2: 1 patient, grade 3: 2 patients). No new or unexpected AEs were observed. Conclusions: The continuous use of trastuzumab in combination with ramucirumab and paclitaxel showed promising activity and manageable safety profile in HER2-positive G/GEJ cancer patients who progressed after trastuzumab containing chemotherapy. Clinical trial information: NCT04888663.

Safety and early efficacy results of a phase Ib study of nivolumab plus trastuzumab with S-1/capecitabine plus oxaliplatin for HER2-positive advanced gastric cancer (Ni-HIGH study).

276 Background: Addition of an anti-PD-1 antibody to trastuzumab reportedly enhances ADCC activity of trastuzumab, leading to an additive antitumor effect. In the KEYNOTE-811 study, pembrolizumab in combination with trastuzumab plus chemotherapy resulted in a durable response. We investigated the safety and tolerability of nivolumab plus trastuzumab combined with S-1 or capecitabine (Cape) and oxaliplatin (Ox) for patients (pts) with HER2-positive advanced gastric cancer (AGC). The safety parts of this study have already shown that there are no safety concerns (Takahari, et al. ASCO-GI 2021). Methods: This study is an open-label, non-randomized phase 1b study conducted at four centers in Japan to confirm the tolerability of addition of nivolumab to chemotherapies with trastuzumab in safety part (n = 12) followed by assessing their efficacy in expansion part (n = 30). Chemotherapy-naïve adult pts with histologically confirmed HER2-positive AGC who had measurable lesions were eligible. Pts received nivolumab (360 mg/body, day 1) and trastuzumab (cycle 1: 8 mg/kg; cycle 2–: 6 mg/kg, day 1), Ox (130 mg/m2, day 1) in combination with either S-1 (40 mg/m2 bid, days 1–14; cohort 1) or Cape (1000 mg/m2 bid, days 1–14; cohort 2) every 3 weeks until disease progression or unacceptable toxicity. Initial eligible 12 pts for safety part were enrolled alternatively to cohort 1 or 2, and patients for expansion part were allocated to either cohort by investigators’ choice up to 21 patients in each cohort. Safety and short-term efficacy data during 8 cycles (6 months) were assessed for this presentation. Results: Between November 2018 and January 2021, a total of 42 pts with HER2-positive AGC were enrolled (21 pts in each cohort). As of July 31, 2021, 29 pts discontinued protocol treatment and the rest 13 pts are still on treatment. Of the 29 pts, only 3 pts (10.3%)discontinued the treatment due to adverse event (AE). AE (≥ G3) occurred in 25 pts (59.5%) including neutropenia in 8 pts (19.0%) and diarrhea in 4 pts (9.5%). Immune-related AEs (≥ G3) occurred in 7 pts (16.6%) including diarrhea/colitis in 4 pts (9.5%). Median relative dose intensity was 100%, 78%, 73%, 75%, and 75% for nivolumab, trastuzumab, Ox, S-1, and Cape, and the percentage of dose reduction or discontinuation within initial 8 cycles were 33%, 33%, 79%, 81%, and 81%, respectively. The ORR was 76.2% (95% CI 60.6-86.9, CR 4.8%, PR 71.4%), and the DCR was 97.6%. Conversion surgery was performed in 2 pts (4.8%). 6-month PFS rate was 68.7% (95% CI 51.7-81.3). Subset results by the cohorts will be presented at the conference. Conclusions: Nivolumab, trastuzumab and either S-1 or Cape plus Ox was tolerable and showed acceptable safety and promising early efficacy results in pts with HER2-positive AGC. Clinical trial information: UMIN000034222.

Trastuzumab combined with irinotecan in patients with HER2-positive metastatic colorectal cancer: A phase II multicenter single-arm study and exploratory biomarker analysis.

301 Background: HER2 overexpression has proven to be an effective treatment target in several malignancies. Trastuzumab plus chemotherapy showed favorable clinical efficacy and safety in HER2-positive gastric cancer and breast cancers. In this study, we aimed to evaluate the antitumor activity of trastuzumab plus irinotecan in pretreated patients with HER2-postive unresectable metastatic CRC and explore biomarkers for response and resistance to this treatment. Methods: mCRC patients with confirmed HER2 positivity (defined as IHC3+ or IHC2+/FISH+ on archival tissue) and wild-type RAS gene that progressed after ≥ 1 prior systemic treatment were enrolled in this phase II clinical trial. Patients received trastuzumab (6mg/kg q3w) plus irinotecan (120mg/m2, d1,8 q3w) for the first six cycles and trastuzumab (6mg/kg q3w) as maintenance treatment sequentially. Primary end point is objective response rate (ORR) and secondary endpoints are progression-free survival (PFS) and safety. Pretreatment tumor tissue, plasma at baseline and after disease progression were collected and analysed using a customized NGS panel covering 733 cancer-related genes in a CAP/CLIA-approved laboratory (3DMed). Results: Between June 2019 and December 2020, 21 HER2 positive patients were enrolled, with median age 55(30-67). At data cutoff (August 1, 2021), six (28.6%) of 21 patients achieved a partial response, and 12 (57.1%) patients had stable disease. The median progression-free survival was 4.3 months (95% CI, 2.65 to 5.95 months). Treatment-related adverse events of grade 3 or 4 occurred in 9.5% of patients, with the most common being neutropenia. No treatment-related death was reported. HER2 3+ expression and higher tumor tissue HER2 copy number were associated with durable response (p for PFS = 0.09 and 0.019, respectively). Two patients with KRAS amplification and one patient with BRAF amplification and fusion mutation at baseline all experienced primary resistance. In the after-progression plasma samples, heterogeneous and complicated genomic alterations potentially contribute to the acquired resistance were observed, with RAS/MAPK pathway (n = 4), cyclin/CDK-RB-E2F pathway (n = 4), PI3K/AKT/mTOR pathway (n = 3), and HER2 gene (n = 1) involved. Intriguingly, except for the SNV, copy number variation and gene fusion may represent an important resistance mechanism of HER2 targeted therapy. Conclusions: Trastuzumab plus irinotecan showed promising efficacy and well tolerated safety profile in HER2-positive mCRC. This combination therapy might present a feasible option for patients with HER2-positive unresectable metastatic colorectal adenocarcinoma. ctDNA sequencing provides novel insights into genomic alteration underlying HER2 targeted therapy in HER2-positive mCRC. Clinical trial information: NCT03185988.

Effectiveness of third- or later-line therapy in patients with HER2-positive advanced gastric cancer: Results from an observational retrospective study in Japan.

277 Background: The real-world effectiveness of third- or later-line (3L+) therapies in patients (pts) with HER2-positive gastric cancer remains unknown. We report a multicenter, retrospective, observational study at 20 centers in Japan to investigate the outcomes of 3L+ therapy in pts with HER2-positive advanced gastric/gastroesophageal junction (G/GEJ) cancer previously receiving trastuzumab (UMIN000040853). Methods: Pts aged ≥20 years with HER2-positive advanced G/GEJ cancer who were previously treated with trastuzumab and newly initiated on nivolumab, irinotecan, or trifluridine/tipiracil monotherapy as 3L+ therapy (Sep 2017 to Mar 2020) were evaluated for overall survival (OS), progression-free survival (PFS), duration of response (DOR), time to treatment failure (TTF), objective response rate (ORR), and disease control rate (DCR). An exploratory analysis for factors affecting OS was conducted using a multivariate Cox regression model, with HER2 status as a covariate. Results: The overall analysis population was 117 pts (median: age, 71 years; number of prior treatment lines, 2; days since the initiation of first-line treatment, 431 days). Median (95% confidence interval) OS, PFS, and TTF were 6.2 months (4.5–8.0), 1.9 months (1.5–2.3), and 1.8 months (1.5–2.2), respectively, at a median follow-up of 150 days. Outcomes by treatment groups are shown in the Table. ORR and DCR in 100 pts with evaluable target lesions were 9.0% and 32.0%, respectively, and median DOR was 8.4 months. A higher neutrophil-lymphocyte ratio (≥2.540), Glasgow prognostic score (≥1), ECOG PS (≥2), and hepatic metastasis significantly impacted OS. Conclusions: The real-world effectiveness of 3L+ therapies was limited in this study. New HER2 treatment agent is expected to improve outcomes in pts with HER2-positive G/GEJ cancer.[Table: see text]

Phase II study of SHR1210 and trastuzumab in combination with CAPOX for neoadjuvant treatment of HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.

296 Background: Perioperative treatments have significantly improved survival in patients with resectable gastric cancer. PANTHERA study had showed a significant tumor shrinkage for HER2 positive advanced gastric cancer treated with anti-PD-1 agent, transtuzumab and chemotherapy. SHR1210, a human IgG4 monoclonal antibody that binds to PD-1, has shown remarkable clinical efficacy in various cancers. We aimed to assess the activity and safety profile of the addition of SHR1210 and trastuzumab to CAPOX for neoadjuvant treatment of HER2-positive gastric or GEJ adenocarcinoma. Methods: In this ongoing, single-arm, phase II study, we recruited patients from Henan Cancer Hospital in China with histopathologically diagnosed resectable HER2-positive gastric or GEJ adenocarcinoma who had clinical T3/N+ or higher stage. Patients were given 4 cycles of transtuzumab (loading dose of 8mg/kg, with subsequent doses of 6 mg/kg, q3w) and CAPOX (oxaliplatin 130 mg/m2 day 1, capecitabine 1000 mg/ m2 bid po day 1-14, q3w) in combination with 3 cycles of SHR1210 (200mg, iv, d1, q3w), followed by surgery and 4 postoperative cycles of CAPOX. The primary endpoint was pathological complete response (pCR). The secondary endpoints included major pathological remission (MPR) and objective response rate (ORR). This trial is registered with ClinicalTrials.gov, number NCT03950271. Results: Between Jan 20, 2020, and Sept 15, 2021, 22 patients were enrolled and commenced treatment. Four patients had not completed neoadjuvant treatment. Twopatitents refused surgery. Sixteen patients who experienced D2 resection, 9 (56.3%) achieved MPR, including 5 (31.3%) with pCR (ypT0N0M0). The R0 rese-ction rate was 100%. The ORR was 77.3%. The main grade 3 or 4 treatment-related adverse events (TRAEs) included lymphocytopenia (22.7%), neutropenia(13.6%), thrombocytopenia (13.6%) and anaemia (5%). Most frequent grade 1 or 2 TRAEs were Nausea (68.2%), lymphocytopenia (63.6%), leukopenia (59.1%), Anaemia (59.1%), Thrombocytopenia (50%), Serum aspartate aminotransfe-rase increased (45.5%) and hypothyroidism (31.8%). There was no surgical del-ays or unexpected surgical complications related to drug toxicity. Conclusions: Neoadjuvant combination of SHR1210, transtuzumab and CAPOX is a safe and efficacious treatment option for patients with HER2-positive gastric or GEJ adenocarcinoma. More importantly, 31.3% pCR rate is encouraging. Our clinical study is still enrolling, and the survival effects are under follow up. Clinical trial information: NCT03950271.

Trastuzumab deruxtecan in patients with HER2-overexpressing locally advanced, unresectable, or metastatic colorectal cancer (mCRC): A randomized, multicenter, phase 2 study (DESTINY-CRC02).

TPS224 Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate comprising an anti-HER2 antibody (trastuzumab) linked to a potent topoisomerase I inhibitor (DXd). T-DXd has been approved to treat HER2-positive metastatic breast cancer (United States [US], Japan, Europe, Israel) and advanced gastric cancer (US, Japan, Israel). It is currently being evaluated in other solid tumor types including colorectal cancer. The phase 2 DESTINY-CRC01 study included patients with RAS wild-type mCRC, with a median 4 (range, 2-11) prior lines of therapy. Preliminary results in patients with HER2-overexpressing (IHC 3+ or IHC 2+/ISH+) mCRC showed T-DXd treatment (6.4-mg/kg intravenously [IV] every 3 weeks [Q3W]) resulted in a confirmed objective response rate (ORR) of 45.3% (24/53; 95% CI, 31.6-59.6%) and a median progression-free survival (PFS) of 6.9 months (95% CI, 4.1-not estimable; Siena J Clin Oncol. 2020). Activity was also seen in patients treated with prior anti-HER2 therapy. Although 5.4-mg/kg and 6.4-mg/kg doses of T-DXd have shown clinical efficacy in multiple cancer indications, the lower dose has not yet been tested in patients with HER2-overexpressing mCRC. Preliminary data also suggest T-DXd may be active in RAS mutant mCRC, unlike other anti-HER2 therapies. The DESTINY-CRC02 study aims to determine efficacy and safety of T-DXd in patients with HER2-overexpressing, RAS wild-type or mutant mCRC at 5.4-mg/kg and 6.4-mg/kg doses. Methods: DESTINY-CRC02 (NCT04744831) is a multicenter, randomized, double-blind, 2-arm, parallel phase 2 study that will be conducted in 2 stages. Eligible patients (≥18 years; ≥20 years in Japan, Taiwan, and Korea) will have HER2-overexpressing (IHC 3+ or IHC 2+/ISH+) locally advanced, unresectable or metastatic CRC and have previously received chemotherapy, anti-EGFR therapy, anti-VEGF treatment, and/or anti–PD-1/PD-L1 therapy, as clinically indicated. Prior anti-HER2 therapy will be allowed. In stage 1, patients will be randomly assigned 1:1 to receive T-DXd IV Q3W at a dose of 5.4-mg/kg (n = 40; arm 1) or 6.4-mg/kg (n = 40; arm 2). Randomization will be stratified by ECOG PS (0 or 1), HER2 status (IHC 3+ or IHC 2+/ISH+), and RAS status (wild-type or mutant). After stage 1 enrollment is complete, eligible patients in stage 2 (n = 40) will receive T-DXd 5.4 mg/kg until disease progression or other treatment discontinuation criteria are met. The study is actively enrolling and aims to enroll 120 patients across 60 sites. The primary objective is to assess efficacy of T-DXd at the 5.4-mg/kg and 6.4-mg/kg doses, with a primary endpoint of confirmed ORR by blinded independent central review. Secondary endpoints include investigator-assessed ORR, PFS, duration of response, disease control rate, clinical benefit rate, overall survival, pharmacokinetics, and safety. Clinical trial information: NCT04744831.

Concordance of HER2 status tested by IHC and FISH in biopsy and surgical resection specimens and comparison with clinicopathological features in gastric carcinoma.

HER2-targeted therapy has been shown to benefit HER2-positive gastric cancer. It is very important to determine the HER2 expression level correctly to select the appropriate test and sampling method. In this study, we investigated the frequency of overexpression of HER2 and intratumoral heterogeneity of HER2-positive cases, comparison of HER2 used immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) performance in biopsy and resection specimens, the correlation of HER2 status between biopsy and resection specimens, and its relationship with clinicopathological findings. Formalin-fixed, paraffin-embedded specimens of a total of 40 surgically resected and biopsy specimens of gastric cancer were analyzed. HER2 status was examined using both IHC and FISH techniques, and the findings and their association with different clinicopathological parameters were evaluated. The concordance rate between the results of IHC and FISH in biopsy and resection specimens was 96.6% and 86.6%, respectively. In paired 20 cases, the overall concordance rate of HER2-IHC and HER2-FISH status between biopsy and resection specimens was 90% and 100%, respectively. HER2-IHC analysis revealed that 5/40 cases were IHC 2+ and only 1 of 5 IHC 2+ cases demonstrated HER2-FISH amplification. Our results showed that HER2-IHC was well concordant with FISH in cases with a score of 0/1+ or 3+ and demonstrates strong concordance between biopsy and resection specimens. FISH should be performed when the IHC result is equivocal. In our study, no statistically significant correlation was observed between HER2 positivity and clinicopathological parameters. Overall, both biopsy and resection specimens are appropriate for HER2 testing.

Current status and future perspectives in HER2 positive advanced gastric cancer.

Gastric cancer is one of the most common malignancy worldwide with a prognosis less than 1 year in unresectable or metastatic disease. HER2 expression is the main biomarker to lead the addition of trastuzumab to first line systemic chemotherapy improving the overall survival in advanced HER2-positivegastric adenocarcinoma. The inevitable development of resistance to trastuzumab remains a great problem inasmuch several treatment strategies that have proven effective in breast cancer failed to show clinical benefit in advanced gastric cancer. In this review, we summarize the available data on the mechanisms underlying primary and secondary resistance toHER2-targeted therapy and current challenges in the treatment of HER2-positive advanced gastric cancer refractory to trastuzumab. Further, we describe the prognostic value of new non-invasive screening techniques, the current development of novel agents such us HER2 antibody-drug conjugates and bispecific antibodies, and the strategies with antitumor activity on going.

HER-2 Status and Heterogeneity in Gastric Cancer: An Experience at a Community Hospital

Background: The efficacy of the trastuzumab therapy in breast cancer patients prompted studies to evaluate potential clinical benefit of the drug in patients with HER2 positive gastric cancer. Unlike in breast cancer, the studies, in gastric cancer to date have yielded inconsistent findings regarding the frequency of HER-2 status. Furthermore, few studies have shown that intratumoral heterogeneity can lead to false negative results. All studies were done at the large medical centers. At the community hospital, we wish to assay HER-2 status intratumoral heterogeneity in patients with gastric cancer, and compare the results with that of large medical centers. Materials and Methods: We investigated 185 cases of gastric cancer specimens using immunohistochemistry (IHC) for HER2 status. The matched biopsy and resection specimen of 30 patients were also investigated for their correlation and the presence of intratumoral heterogeneity. Results: The positive HRE2 status was 29.7% (n=55), falling between the published data .One of two neuroendocrine tumors was HER2 positive, which was never reported before. We found the concordance rate of 83% in 30 matched biopsy and gastrectomy specimens; 57% of the gastrectomy specimens showed intratumoral heterogeneity. Conclusion: Anti-HER2 targeted therapy has been approved by FDA, Japan, and European Medicine Agency, as a standard initial treatment in HER2 positive gastric cancer. Overall, both biopsy and resection specimens are appropriate for HER-2 testing. The wide range of HER-2 frequency giving in the literature indicated that some problems exist. We are hoping that future study will clarify those confusing problems and standardized HER-2 assay method will become available. It is crucial for accurate selection of patients who could really benefit from a targeted therapy.

Ramucirumab plus paclitaxel as a second-line treatment in HER2-positive gastric cancer: subgroup analysis of a nationwide, real-world study in Korea (KCSG-ST19-16).

A subgroup analysis of data from a nationwide study (KCSG-ST19-16) was performed to evaluate the efficacy and safety of second-line ramucirumab plus paclitaxel treatment in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric or gastro-esophageal junction (GEJ) adenocarcinoma. The KCSG-ST19-16 study enrolled a total of 1063 patients from 56 hospitals in South Korea with advanced gastric or GEJ adenocarcinoma, who had received second-line treatment with ramucirumab plus paclitaxel. HER2 status was known for 994 (93.5%) of these patients, who were thus included in the subgroup analysis. In total, 163 of 994 patients (16.4%), had HER2-positive gastric or GEJ adenocarcinoma. The objective response rate to ramucirumab plus paclitaxel treatment was significantly higher in patients with HER2-positive disease compared to those with HER2-negative disease (23.0% [95% confidence interval (CI), 15.9-30.1] vs. 15.1% [95% CI, 12.3-17.9], p = 0.025). The median progression-free survival was longer in patients with HER2-positive versus HER2-negative disease, but the difference was not statistically significant (4.3months [95% CI, 3.7-5.3] vs 3.7months [95% CI, 3.4-4.0], p = 0.054). There was no statistically significant difference in median overall survival (OS) between the groups (9.8months [95% CI, 8.9-12.3] vs 10.1months [95% CI, 9.2-10.9], p = 0.564). In patients with HER2-positive gastric or GEJ adenocarcinoma, the objective response rate to second-line treatment with ramucirumab plus paclitaxel was significantly higher compared to patients with HER2-negative disease. However, an increased response to treatment was not associated with an improvement in OS.

The Efficacy and Plasma ctDNA as a Biomarker of Dual PD-1 and HER2 Blockade in HER2-Positive Gastric or Gastroesophageal Junction Cancers

The Efficacy and Plasma ctDNA as a Biomarker of Dual PD-1 and HER2 Blockade in HER2-Positive Gastric or Gastroesophageal Junction Cancers

Apatinib as a Third-Line Treatment for HER2-Positive Metastatic Gastric Cancer: A Multi-Center Single-Arm Cohort Study.

Treatment options are limited after the failure of first-and second-line treatments in patients with HER2+ metastatic gastric cancer (mGC). The present study aimed to explore the efficacy, safety, and prognostic factors of apatinib efficacy as a third-line therapy for patients with human epithelial growth factor receptor 2-positive (HER2+) mGC. A total of 59 HER2+ mGC patients who received apatinib as third-line therapy were retrospectively enrolled in this two-center, single-arm, cohort study; the clinical response, survival data, and adverse events were retrieved. The median progression-free survival (PFS) was 5.2 months (95% confidence interval [CI], 3.9-6.5), and the median overall survival (OS) was 8.2 months (95% CI, 6.6-9.8) Furthermore, forward stepwise multivariate Cox regression analysis showed that a higher Eastern Cooperative Oncology Group performance status score and multiple metastases were independently correlated with decreased PFS and OS (both P<0.05). The main adverse events were leukopenia (45.8%), hypertension (44.1%), thrombocytopenia (39.0%), hand-foot syndrome (37.3%), and elevated transaminase (33.9%). Grade 3 adverse events mainly included hypertension (5.1%) and neutropenia (5.1%); grade 4 adverse events did not occur. Apatinib is efficient and well tolerated in patients with HER2+ mGC as a third-line treatment, suggesting that it may be a candidate of choice for these patients.

Ultrasound Microbubbles Mediated Sonosensitizer and Antibody Co-delivery for Highly Efficient Synergistic Therapy on HER2-Positive Gastric Cancer.

Trastuzumab combined with chemotherapy is the first-line treatment for advanced HER2-positive gastric cancer, but it still suffers from limited therapeutic efficiency and serious side effects, which are usually due to the poor delivery efficiency and the drug resistance of tumor cells to the chemotherapeutic drugs. Herein, a type of ultrasound microbubble for simultaneous delivery of sonosensitizers and therapeutic antibodies to achieve targeting combination of sonodynamic therapy and antibody therapy of HER2-positive gastric cancer was constructed from pyropheophorbide-lipid followed by trastuzumab conjugation (TP MBs). In vitro and in vivo studies showed that TP MBs had good biological safety, and their in vivo delivery can be monitored by ultrasound/fluorescence bimodal imaging. With ultrasound (US) located at the tumor area, TP MBs can be converted into nanoparticles (TP NPs) in situ by US-targeted microbubble destruction; plus the enhanced permeability and retention effects and the targeting effects of trastuzumab, the enrichment of sonosensitizers and antibodies in the tumor tissue can be greatly enhanced (∼2.1 times). When combined with ultrasound, TP MBs can not only increase the uptake of sonosensitizers in HER2-positive gastric cancer NCI-N87 cells but also efficiently generate singlet oxygen to greatly increase the killing effect on cells, obviously inhibiting the tumor growth in HER2-positive gastric cancer NCI-N87 cell models with a tumor inhibition rate up to 79.3%. Overall, TP MBs combined with US provided an efficient way for co-delivery of sonosensitizers and antibodies, greatly enhancing the synergistic therapeutic effect on HER2-positive gastric cancer while effectively reducing the side effects.

The Impact of Tumor Mutation Burden on the Effect of Frontline Trastuzumab Plus Chemotherapy in Human Epidermal Growth Factor Receptor 2-Positive Advanced Gastric Cancers.

BackgroundTrastuzumab is a HER2-trargeted humanized monoclonal antibody that has been studied as a first-line treatment for patients with HER2-positive advanced gastric cancer (AGC). The effect of anti-HER2 therapy according to tumor mutational burden (TMB) in HER2-positive AGC remains unclear.MethodsWe performed next-generation sequencing (NGS), including TMB analysis, in 31 HER2-positive AGC patients with trastuzumab plus chemotherapy as first-line therapy for recurrent (n=8) or metastatic (n=23) tumors. The TruSight Oncology 500 Assay from Illumina (San Diego, CA, USA) was used to evaluate TMB.ResultsAmong 31 patients, 30 had tumors with immunohistochemistry (IHC) 3+, and one was IHC 2+ and silver in situ hybridization (SISH) positive. The median age was 57.0 years old (range, 35-76), and the majority had tumors with low TMB (87.1%, n=27/31). Only four (12.9%) had tumors with high TMB. Of these four, three achieved complete response (CR) or partial response (PR) to treatment, and the remaining patient was not evaluable for tumor response. Objective response rate (ORR) to trastuzumab plus chemotherapy showed a favorable trend in patients with high TMB (75.0%, n=3/4) compared to patients with low TMB (59.3%, n=16/27) (P=0.546). The median progression-free survival (PFS) was not reached in the TMB-high group but was 8.0 months (95% CI, 7.6-8.5) in the TMB-low group (P=0.019)ConclusionThe status of TMB could be a novel biomarker in predicting the efficacy of trastuzumab plus chemotherapy in HER2-positive AGCs.

Comparative effectiveness and tolerability of targeted agents combined with chemotherapy in patients with HER2-positive gastroesophageal cancer: A network meta-analysis.

Background:Gastric cancer (GC) or gastroesophageal junction (GEJ) cancer with HER2 overexpression is highly invasive, with a poor prognosis. With the development of new targeted agents, which agents have ideal therapeutic effects must be determined. This network meta-analysis analyzed the effectiveness and tolerability of targeted agents combined with chemotherapy in HER2-positive GC/GEJ cancer.Methods:Public databases were searched from the date of inception to October 22, 2020. Randomized controlled trials (RCTs) on targeted agent-related regimens for HER2-positive advanced GC or GEJ cancer were included. Subgroup analyses based on publication language, first-line treatment, second/third-line treatment, and HER2 staining intensity were performed.Results:In total, 13 articles were included. The trastuzumabderuxtecan (TraD) and pertuzumab plus trastuzumab and chemotherapy (PerTraChemo) regimens were considered to have high effectiveness but low tolerability. In the subgroup analysis, PerTraChemo still had high effectiveness with low tolerability as the first-line therapy. As the second- or third-line therapy, TraD and lapatinib plus chemotherapy (LapChemo) had high effectiveness and moderate tolerability. In terms of overall survival (OS) time, PerTraChemo had a relative advantage in the immunohistochemistry (IHC) 2+/in situ hybridization (ISH)+ population, whereas TraD, PerTraChemo, and trastuzumab plus chemotherapy (TraChemo) had a relative advantage in the IHC3+ population.Conclusion:TraD had relative advantages as the second- or third-line therapy and in the IHC3 + population. PerTraChemo is a potential first-line therapy, but it requires further confirmation because the JACOB phase III clinical trial failed to confirm the superiority of PerTraChemo over TraChemo with regard to OS.

Drug-induced thrombocytopenia associated with trastuzumab in a patient with HER2-positive recurrent gastric cancer

Here, we report a 57-year-old female patient with HER2-positive recurrent gastric cancer who experienced drug-induced thrombocytopenia associated with trastuzumab, a humanized anti-HER2 monoclonal antibody. Shortly after the initiation of S-1, oxaliplatin, and trastuzumab chemotherapy, the patient experienced severe thrombocytopenia and did not respond to platelet transfusions. Based on the findings of increased numbers of polynuclear megakaryocytes in the bone marrow and an elevated level of platelet-associated IgG (PA-IgG), the patient was diagnosed with drug-induced thrombocytopenia (DITP). The platelet count recovered rapidly with oral prednisolone (1 mg/kg). Since we initially suspected oxaliplatin as the causal agent, S-1 was restarted as a monotherapy, followed by trastuzumab after a 3-week interval, without oxaliplatin. On the second day after the addition of trastuzumab, severe thrombocytopenia occurred again, which suggests that trastuzumab was responsible for the DITP. The patient no longer experienced severe thrombocytopenia during the subsequent S-1 and oxaliplatin chemotherapy, which supports this hypothesis.

HER2 promotes epithelial-mesenchymal transition through regulating osteopontin in gastric cancer

AimsHER2 and osteopontin (OPN) are both important biomarkers in gastric cancer (GC). The relationships between them remain to be revealed. The purpose of this study is to explore the role of OPN in epithelial-mesenchymal transition (EMT) in HER2 positive GCs. MethodsNanostring analysis was used to compare the mRNA levels of 730 cancer related genes between paired HER2 3+ and non-3+ areas in GC patients. Immunohistochemistry (IHC) staining was performed to analyze the expression levels of OPN, as well as EMT markers including E-cad, N-cad, twist and vimentin in both areas. To further verify the role of OPN in EMT, the expression levels of OPN and EMT markers, tumor invasion/migration were analyzed after down-regulating HER2 and OPN in GC cell lines MKN-45 and N-87. ResultsNanostring analysis identified 8 differential expression genes between HER2 3+ and non-3+ areas. Among them, the expression level of OPN was positively correlated with that of HER2. In GC specimens, OPN showed higher expression level in HER2 3+ areas where higher E-cad expression levels and lower N-cad and twist levels were also found. After knocking down OPN and HER2 by siRNA, both cell lines show decreased invasion/migration abilities, along with the down-regulation of the EMT phenotype, supporting by the decrease of E-cad, and the increase of N-cad and twist at both mRNA and protein levels. In addition, HER2 knock-down lead to a dramatic decrease of OPN expression. ConclusionsThese findings indicate that HER2 may promote EMT via the regulation of OPN in GCs.

Trastuzumab deruxtecan and other HER2-targeting agents for the treatment of HER2-positive gastric cancer

ABSTRACT Introduction Although various new drugs have been developed, the prognosis of therapeutic advances for metastatic gastric cancer is insufficient. Trastuzumab deruxtecan (T-DXd), a new human epidermal growth factor receptor 2 (HER2)-targeting antibody–drug conjugate (ADC), has demonstrated promising results in clinical trials. Areas covered In this article, we review the history of anti-HER2 ADCs and focus on the efficacy and safety of T-DXd and describe the development of new anti-HER2 drugs. Expert opinion So far, no other anti-HER2 ADCs have demonstrated efficacy in patients with HER2-positive advanced gastric cancer with two or more previous lines of chemotherapy, including trastuzumab. However, a new drug, T-DXd, has shown a significantly higher objective response rate and a longer overall survival and, thus, was approved in Japan. In the future, new anti-HER2 drugs and/or treatment strategies including T-DXd along with cytotoxic chemotherapy or immune checkpoint inhibitors will be developed.