Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance

Abstract

Trastuzumab, a monoclonal antibody to human epidermal growth factor receptor 2 (HER2), has improved survival in patients with HER2-positive advanced gastric or gastroesophageal junction cancer (AGC). The inevitable development of resistance to trastuzumab remains a problem, however, with several treatment strategies that have proven effective in breast cancer having failed to show clinical benefit in AGC. In this review, we summarize the mechanisms underlying resistance to HER2-targeted therapy and outline past and current challenges in the treatment of HER2-positive AGC refractory to trastuzumab. We further describe novel agents such as HER2 antibody-drug conjugates that are under development and have shown promising antitumor activity in early studies. basis of these results, trastuzumab was approved for AGC with a high HER2 expression level, and trastuzumab-containing regimens are now a standard option for the first-line treatment of such patients, who accounted for 7% to 17% of all individuals with gastric cancer [3-5]. Derivatives of the ToGA Regimen in the First-Line SettingThe ToGA trial adopted a regimen of cisplatin combined with either 5-fluorouracil (5-FU) or capecitabine, whereas subsequent prospective studies found similar treatment outcomes with regimens containing oxaliplatin or tegafur-gimeracil-oteracil (S-1). In a single-arm, nonrandomized phase II trial (HER2-based strategy in stomach cancer (HERBIS)-1) performed in Japan [6], trastuzumab in combination with S-1 plus cisplatin yielded a confirmed ORR of 68%, with a median OS and a median PFS of 16.0 and 7.8 months, respectively, in HER2-positive AGC patients with measurable lesions, with these results being similar to those of the ToGA trial [2]. Similar efficacy was also apparent in AGC patients without measurable lesions (HERBIS-1B study) [7]. Three phase II studies that assessed the combination of trastuzumab with capecitabine plus oxaliplatin reported a median OS, a median PFS, and an ORR of 13.8 to 21.0 months, 7.1 to 9.8 months, and 46.7% to 67.3%, respectively [8][9][10]. Trastuzumab in combination with S-1 plus oxaliplatin was also shown to provide a similar treatment outcome in a phase II study, with a median OS, a median PFS, and an ORR of 18.1 months, 8.8 months, and 70.7%, respectively [11]. A meta-analysis of data from these trials revealed that S-1 or oxaliplatin can substitute effectively for capecitabine or 5-FU or for cisplatin, respectively [12].Immune checkpoint inhibitors such as antibodies to programmed cell death-1 (PD-1) have recently revolutionized treatment strategies for advanced cancer. Given that trastuzumab was found to stimulate T cell responses [13], the combination of trastuzumab-containing regimens with antibodies to PD-1 is receiving attention. A phase II study including 37 patients with HER2-positive AGC treated in the first-line setting with capecitabine, oxaliplatin, and trastuzumab in combination with the anti-PD-1 antibody pembrolizumab reported an ORR of 83%, with a median PFS of 11.4 months and a median ...

Gastric cancer: a comprehensive review of current and future treatment strategies

“…AZD4547, a compound that inhibits FGFR2 activity, was found to elicit anti-tumor response in gastric cancer cell lines, cell line xenograph, and PGDGX models [64]. Tucatinib, an oral HER2 inhibitor, was found to sensitize gastric cancer cells that were resistant to HER2 inhibition via trastuzumab and has improved patient survival with advanced gastric cancer [65].…”

PET and SPECT Imaging of the EGFR Family (RTK Class I) in Oncology

“…HER2 is probably the most explored target for molecular imaging among the EGFR-family receptors. Targeted treatment of HER2-positive breast and gastric cancers substantially improves the survival of patients [ 163 , 164 ]. However, only in situ hybridization (ISH) positive patients or patients with HER2 expression of 3+ according to IHC are considered to be clinically HER2-positive and eligible for HER2 targeted treatment.…”

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“…This shows that trastuzumab deruxtecan can overcome trastuzumab resistance, likely due to less reliance on the homogeneity of HER2 positivity and the ability to kill neighboring HER2 negative cells (known as the "bystander effect"). 50,51 No responses were observed in cohorts B or C. 50 Adverse effects included neutropenia, anemia, and interstitial lung disease. 50 Overall, there are many challenges but steady progress is being made to refine our understanding of the best therapeutic application of medications to inhibit the VEGF, EGFR, and HER2 pathways to improve outcomes in mCRC patients.…”

“…This shows that trastuzumab deruxtecan can overcome trastuzumab resistance, likely due to less reliance on the homogeneity of HER2 positivity and the ability to kill neighboring HER2 negative cells (known as the “bystander effect”). 50 , 51 No responses were observed in cohorts B or C. 50 Adverse effects included neutropenia, anemia, and interstitial lung disease. 50 …”