The Clinical Use of HER2-Targeted Therapies in Gastric Cancer: The Current and Emerging Landscape

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Agenda:

This presentation consists of:

• Module 1: Therapeutic Targeting of HER2 in GEA and BTC
• Module 2: Biomarker Testing Best Practices: Testing for HER2 Overexpression 
• Module 3: Approved and Emerging HER2-Targeted Therapies in the Clinic: What You Need to Know

Module 1: Therapeutic Targeting of HER2 in GEA and BTC

INTRODUCTION
The epidermal growth factor receptor (EGFR) family, also known as the ErbB receptor family, plays a pivotal role in the regulation of cell growth, survival, and differentiation.¹ This family includes 4 related receptors¹:

• HER1 (also known as EGFR)
• HER2 (ErbB2/neu)
• HER3 (ErbB3)
• HER4 (ErbB4)

HER2 is unique among EGFR family members because it does not have a known natural ligand.² Instead, it dimerizes with other family members, acting as a coreceptor that amplifies the signal transduction pathways, leading to cellular proliferation and survival. This process is crucial for normal cell development and repair. However, overexpression of HER2, typically through gene amplification, leads to the aberrant activation of HER2 signaling, resulting in uncontrolled cell division and oncogenesis. In many tumor types, HER2 overexpression is associated with aggressive tumor behavior and poor prognostic outcomes.²

TARGETING HER2 IN GASTRIC CANCER
HER2 overexpression has been observed in various cancers, such as breast, prostate, and lung, and the use of HER2-targeted therapy has improved survival rates in patients with these conditions.¹ More recently, HER2 mutations have become increasingly recognized as frequent molecular abnormalities in GEA and BTC. ^1,3 The rationale for targeting HER2 is grounded in the oncogenic role of altered HER2 signaling.¹ Targeting HER2 with specific inhibitors can block the HER2-driven proliferative signals, thereby slowing cancer progression and potentially leading to tumor regression. HER2-targeting strategies include monoclonal antibodies, such as trastuzumab, and novel emerging therapies that block other mechanisms of aberrant HER2 signaling and resistance to anti-HER2 therapy. Importantly, appropriate and timely HER2 biomarker testing is critical in identifying patients with gastric cancer who may benefit from HER2-targeted therapy.¹

Module 2: Biomarker Testing Best Practices: Testing for HER2 Overexpression

CURRENT CHALLENGES IN BIOMARKER TESTING
As an actionable therapeutic target in gastric cancer, HER2 is often placed high on the priority list for biomarker testing.⁴ Because of the need to test for multiple biomarkers, however, several aspects regarding tissue analysis need to be considered. First, tissue acquisition, which typically occurs through endoscopic biopsy or surgical resection, must yield sufficient tissue to assess for multiple biomarkers, which increases the difficulty of obtaining specimens and sometimes requires multiple biopsies.⁴ Second, the biomarker analysis can involve a 2-step process of IHC followed by confirmatory in situ hybridization (ISH) testing in cases of equivocal results on the initial IHC testing.^4,5 In addition, intratumor heterogeneity of HER2 overexpression, a hallmark of gastric cancer, further complicates testing accuracy.⁴ Notably, longer specimen-processing time (> 120 minutes) after gastrectomy may be associated with higher likelihood of false-negative HER2 results.⁶

Despite their clinical utility, HER2 testing and biomarker-directed treatment are currently underused strategies in gastric cancer.⁷ Indeed, in an analysis of 3,291 patients diagnosed with advanced or metastatic GEA between 2011 and 2018, one-third (34%) did not undergo HER2 testing. Of those tested, 13% had HER2-positive tumors, indicating a potential benefit from HER2-directed therapy, yet only 58% of these patients received first-line anti-HER2 therapy.⁷ A more recent analysis of patients with advanced gastric cancer who started treatment between 2017 and 2020 found that 75% underwent HER2 testing, and two-thirds of those with positive HER2 results started first-line treatment with HER2-directed therapy.⁸ Although these findings suggest that HER2 testing rates are improving, it is important to highlight that approximately 1 in 4 patients with gastric cancer are currently missing opportunities for biomarker-directed care.^7,8

Fortunately, advances in techniques such as next-generation sequencing (NGS) may streamline biomarker testing, enabling healthcare professionals (HCPs) to select the most appropriate treatment for individual patients with gastric cancer.⁴

DEFINING HER2 OVEREXPRESSION
Approximately 10% to 20% of gastric cancers overexpress HER2, depending on histologic subtype and tumor grade.⁹ Testing for HER2 overexpression is recommended for all patients with locally advanced, recurrent, or metastatic gastric cancer who are being considered for HER2-directed therapy.^5,10

HER2 testing begins with IHC staining and scoring of tumor tissue collected as a surgical specimen or via biopsy (Table 1).^5,10 Scores indicating either negative (0 or 1+) or positive (3+) HER2 overexpression are sufficient to determine HER2 status. Equivocal results (2+) with IHC testing require additional evaluation with fluorescence in situ hybridization (FISH) or another ISH method to confirm results.^5,10

TABLE 1. Biomarker Testing for HER2 Overexpression in Gastric Cancer

Adapted from Bartley AN, Washington MK, Colasacco C, et al. HER2 testing and clinical decision making in gastroesophageal adenocarcinoma: guideline from the College of American Pathologists, American Society for Clinical Pathology, and the American Society of Clinical Oncology. J Clin Oncol. 2017;35(4):446-464.

HER2 assessment via IHC in gastric cancer involves criteria related to membrane staining that are distinct from those used in breast cancer evaluation¹¹:

1. An IHC score of 2+ or 3+ can be assigned with incomplete membrane staining, provided the staining is clearly visible under low (× 2.5 to 5 for IHC 3+) or medium (× 10 to 20 for IHC 2+) magnification
2. Membrane staining of sufficient intensity in ≥ 10% of tumor cells is restricted to full surgical resection samples only

The assessment of HER2 status by ISH, on the other hand, parallels that in breast cancer protocols, with a ratio of 2.0 or greater indicating HER2 gene amplification. Unlike breast cancer, however, gastric tumors frequently exhibit HER2 heterogeneity detectable by both IHC and ISH, which has led to a preference for bright-field ISH over FISH for these evaluations.¹¹

Initial tissue-based IHC testing should also include microsatellite instability mismatch repair status for all patients with newly diagnosed gastric cancer and programmed death ligand 1 (PD-L1) expression for patients with locally advanced, recurrent, or metastatic disease who are being considered for treatment with programmed death-1 (PD-1) inhibitors.⁵ When limited tissue is available or when the patient cannot undergo biopsy, ErbB2 copy number, derived from plasma-based NGS, can be used to evaluate the appropriateness of HER2-directed therapy.⁵

DEFINING LOW HER2 EXPRESSION
Low HER2 expression (defined as an IHC score of 1+ or as an IHC score of 2+ and negative results on ISH) has emerged in breast cancer research as a distinct molecular subtype responsive to some—but not all—HER2-targeted therapies.¹² In the phase 3 DESTINY-Breast04 trial, trastuzumab deruxtecan (T-DXd) improved survival outcomes in patients with HER2-low metastatic breast cancer. Compared with the physician’s choice of chemotherapy, T-DXd significantly improved progression-free survival (PFS) (5.4 vs 10.1 months, respectively; hazard ratio [HR], 0.51; P < .001) and overall survival (OS) (17.5 vs 23.9 months, respectively; HR, 0.64; P = .003).¹²

The role of T-DXd in other HER2-low cancers, however, remains unclear. The phase 2 DESTINY-PanTumor02 examined the efficacy of T-DXd across 7 types of HER2-overexpressing (IHC 3+/2+) cancers: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other. Although T-DXd yielded responses in all tumor subgroups, the greatest benefit was observed in patients with IHC 3+ disease, with the following objective response rates (ORR)¹³:

• 84.6% (95% CI, 54.6-98.1) for endometrial (n = 13)
• 75.0% (95% CI, 34.9-96.8) for cervical (n = 8)
• 63.6% (95% CI, 30.8-89.1) for ovarian (n = 11)
• 56.3% (95% CI, 29.9-80.2) for bladder (n = 16)
• 56.3% (95% CI, 29.9-80.2) for biliary tract (n = 16)
• 44.4% (95% CI, 13.7-78.8) for other tumors (n = 9)
• 0% for pancreatic cancer (n = 2)

Similarly, in the phase 2 DESTINY-CRC01, T-DXd was associated with an ORR of 45.3% (95% CI, 31.6-59.6; n = 24) in patients with HER2-positive metastatic colorectal cancer (mCRC), defined as IHC 3+ or IHC 2+/ISH+.¹⁴ By comparison, no responses to HER2-directed therapy were observed in patients with IHC 2+/ISH− or IHC 1+ mCRC.¹⁵ Results from a meta-analysis confirmed the benefit of HER2-targeted therapy in patients with HER2-positive mCRC, but most studies did not enroll patients with HER2-low variants.¹⁶

Emerging evidence suggests a potential role for T-DXd in HER2-low gastric cancer.¹⁷ ADCs such as T-DXd deliver toxins directly into HER2-positive cancer cells.¹ In a phenomenon termed “the bystander effect,” these ADC-delivered toxins also kill neighboring cells that do not overexpress HER2, thereby providing a clinical benefit for patients with low HER2 expression.¹ For instance, in the phase 2 DESTINY-Gastric01 trial, T-DXd was associated with an ORR of 26.3% (95% CI, 9.1-51.2; n = 5) and 9.5% (95% CI, 1.2-30.4; n = 2) in patients with IHC 2+/ISH− and IHC 1+ disease, respectively.¹⁷ These findings support the recognition of a new subgroup of patients with HER2-low gastric cancer who had previously been managed as having HER2-negative tumors, yet may benefit from HER2-directed therapies.¹⁷

COMMUNICATING BIOMARKER TEST RESULTS
Communicating biomarker test results to patients and their care partners is a critical aspect of individualized therapy.¹⁸ For patients with gastric cancer, the process begins with a detailed explanation of the significance of HER2 as a biomarker, highlighting its role in tumor growth and progression.¹⁹ HCPs can explain that HER2 testing involves obtaining tumor tissue through biopsy or surgery, then analyzing that tissue using techniques such as IHC and ISH. These tests help determine the presence and level of HER2 protein on cancer cells or the expression of HER2 genes within the tumor's DNA, respectively.¹⁹

Next, it is important to communicate that the results of HER2 biomarker testing help guide treatment decisions.¹⁹ Results showing HER2 overexpression (eg, IHC 3+) indicate that the tumor is likely to respond to HER2-targeted therapies such as trastuzumab. Conversely, a negative HER2 test result suggests that other treatment options may be more effective.¹⁹

Overall, HCPs should assure patients and their care partners that biomarker testing is a standard approach for selecting therapies tailored to the molecular characteristics of their tumor.¹⁹ Patients should understand that biomarker-directed therapy enhances the potential for effective treatment, reduces the likelihood of adverse effects from less-appropriate therapies, and aligns treatment choices with the patient's specific cancer profile.¹⁹

Module 3: Approved and Emerging HER2-Targeted Therapies in the Clinic: What You Need to Know

APPROVED HER2-TARGETED REGIMENS
Several trastuzumab-based regimens are currently available for the treatment of HER2-positive gastric cancer (Table 2). In the first-line setting, the combination of chemotherapy plus trastuzumab has been the standard of care for HER2-positive GEA for more than a decade.²⁰ Indeed, in the ToGA and HERXO trials, trastuzumab plus chemotherapy increased OS compared with chemotherapy alone.^20,21

More recently, pembrolizumab has been added to trastuzumab-based combination regimens for patients with HER2-positive gastric cancer.²² In the KEYNOTE-811 trial, adding pembrolizumab to standard first-line therapy with chemotherapy plus trastuzumab improved ORR and PFS in patients with advanced HER2-positive GEA. Notably, the improvement in PFS was limited to patients who had a PD-L1 combined positive score of at least 1; therefore, the use of pembrolizumab for HER2-positive GEA should be limited to patients whose tumors are also positive for PD-L1 expression.^22,23 Results for the coprimary endpoint of OS are forthcoming.

TABLE 2. First- and Subsequent-Line HER2-Directed Therapies for HER2-Positive Gastric Cancer

^aCoprimary endpoint: OS (analysis ongoing).
5-FU = 5-fluorouracil; CR = complete response; PR = partial response.
Data derived from Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010; 376(9742):687-97; HERCEPTIN (trastuzumab). Prescribing information. Genentech, Inc.; 2010; Rivera F, Romero C, Jimenez-Fonseca P, et al. Phase II study to evaluate the efficacy of trastuzumab in combination with capecitabine and oxaliplatin in first-line treatment of HER2-positive advanced gastric cancer: HERXO trial. Cancer Chemother Pharmacol. 2019;83(6):1175-1181; Janjigian YY, Kawazoe A, Bai Y, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. Lancet. 2023;402(10418):2197-2208; Shitara K, Bang YJ, Iwasa S, et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med. 2020;382(25):2419-2430; Shitara K. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer: a plain language summary of the DESTINY-Gastric01 study. Future Oncol. 2024;20(2):59-70, and ENHERTU® (fam-trastuzumab deruxtecan-nxki). Prescribing information. Daiichi Sankyo, Inc.; 2022.

After standard first-line trastuzumab-based treatment, the selection of subsequent therapies depends on the available options and patient’s HER2 status, which may change over time.¹ In the second-line setting, T-DXd is approved for the treatment of locally advanced or metastatic HER2-positive GEA in patients who have received prior trastuzumab.²⁴ T-DXd is an ADC consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor that delivers cytotoxic agents directly to HER2-expressing tumor cells.^24,25 In the phase 2 DESTINY-Gastric01 trial, T-DXd led to significant antitumor activity in patients with HER2-positive gastric cancer who experienced disease progression after 2 or more previous therapies, including trastuzumab.²⁴ Compared with physician’s choice of chemotherapy, T-DXd significantly improved ORR (14% vs 51%, respectively; P < .001) and OS (8.4 vs 12.5 months, respectively; P = .01).²⁴

INVESTIGATIONAL THERAPIES
HER2-Directed Therapies
Several novel HER2-directed therapies are currently in development and are being evaluated for their improved efficacy and ability to overcome resistance to trastuzumab, providing new options for treatment sequencing.¹ The following therapies are being examined in the first-line treatment of patients with advanced GEA. As these agents become available for clinical use, treatment for gastric cancer is expected to become more complex.

TABLE 3. Investigational HER2-Directed Therapies for HER2-Positive Gastric Cancer

Derived from Rugo HS, Im SA, Cardoso F, et al; SOPHIA Study Group. Margetuximab versus trastuzumab in patients with previously treated HER2-positive advanced breast cancer (SOPHIA): final overall survival results from a randomized phase 3 trial. J Clin Oncol. 2023;41(2):198-205; Harding JJ, Fan J, Oh DY, et al; HERIZON-BTC-01 study group. Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study. Lancet Oncol. 2023;24(7):772-782; Peng Z, Liu T, Wei J, et al. Efficacy and safety of a novel anti-HER2 therapeutic antibody RC48 in patients with HER2-overexpressing, locally advanced or metastatic gastric or gastroesophageal junction cancer: a single-arm phase II study. Cancer Commun (Lond). 2021;41(11):1173-1182; and Strickler JH, Cercek A, Siena S, et al; MOUNTAINEER investigators. Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): a multicentre, open-label, phase 2 study. Lancet Oncol. 2023;24(5):496-508.

Margetuximab (off-label use). Margetuximab is a monoclonal anti-HER2 antibody that is Fc optimized, indicating a greater induction of antibody-dependent cellular toxicity.^26,27 It has shown promising activity in combination with PD-1 inhibitors in patients with HER2-positive gastric cancer, including those with PD-L1–positive tumors. It is generally well tolerated with a toxicity profile similar to that of trastuzumab, but with a need to assess cardiac function every 3 months.^26-28

Zanidatamab. Zanidatamab is a bispecific antibody that targets 2 nonoverlapping domains of the HER2 receptor tyrosine kinase.^29,30 It has shown promising activity in GEA, BTC, and other HER2-overexpressing solid tumors, leading to fast-track designation from the Food and Drug Administration. ^29,30

Disitamab vedotin. Disitamab vedotin is an ADC that is approved in China for the second-line treatment of HER2-positive advanced GEA; it is currently undergoing evaluation in the phase 3 RC48-C007 trial (NCT04714190).^1,25

Tyrosine kinase inhibitors. Tyrosine kinase inhibitors, such as tucatinib and pyrotinib, target the intracellular kinase domain of HER2, thereby offering a different mechanism of action relative to antibody-based therapies.^31,32 Tucatinib, a next-generation tyrosine kinase inhibitor, blocks the phosphorylation of HER2 and HER3 upon heterodimerization, resulting in to the inhibition of downstream signaling with RAS-MAPK; it has demonstrated antitumor activity when combined with trastuzumab.³³ Notably, tucatinib may cause nausea, vomiting, abdominal pain, and diarrhea.³¹ Pyrotinib is an irreversible pan‐ErbB small‐molecule tyrosine kinase inhibitor that has been associated with diarrhea, anemia, neutropenia, and leukopenia.³² Both of these agents have demonstrated considerable activity in HER2-positive breast cancer, and tucatinib (in combination with trastuzumab) was recently approved in HER2-positive CRC.^31,32,34

Fibroblast Growth Factor Receptor Inhibitors
Beyond HER2-directed therapies, agents that inhibit fibroblast growth factor receptor (FGFR) provide additional options for targeted therapy. Two such agents are infigratinib (off-label use), an FGFR inhibitor available for the treatment of patients with BTC and an FGFR mutation, and pemigatinib (off-label use), a novel FGFR inhibitor currently undergoing evaluation in FGFR-altered BTC.^35,36

Potential Resistance Mechanisms of HER2-Targeted Therapy
Despite the advances in HER2-targeted gastric cancer treatment, most patients with advanced cancer experience disease progression or death due to treatment resistance. Notably, resistance to HER2-targeted therapy can arise through HER2 heterogeneity, loss of HER2-positive status, mutations in HER2 or downstream signaling pathways, and activation of alternative signaling pathways.¹ Strategies for overcoming resistance include combining HER2-targeted therapies with agents that block alternative pathways or using therapies with different mechanisms of action.¹ These approaches are expected to evolve as new therapies become available and offer novel options that may affect optimal sequencing​​.

PATIENT SELECTION FOR EMERGING HER2-TARGETED THERAPIES
As the gastric cancer therapeutic landscape evolves to include novel mechanisms of action and new options for treatment sequencing, patient selection for HER2-targeted therapies is becoming increasingly complex and nuanced.¹⁹ To date, no evidence-based algorithms are available to guide individualized therapy for HER2-positive gastric cancers across multiple lines of treatment.⁵ Therefore, shared decision making between patients and HCPs is critically important for treatment selection.¹⁹

Shared decision making aims to maximize treatment effectiveness, minimize toxicity, and improve overall patient outcomes by matching each patient with the most appropriate treatment regimen based on patient preferences, tumor HER2 status, treatment history, and other clinical details.¹⁹ This strategy involves considering patient preferences in the context of treatment goals, potential side effects, and quality-of-life expectations. When informed by the latest clinical evidence, shared decision making is critical in navigating the challenges of treatment selection and improving outcomes for patients with HER2-positive gastric cancer.¹⁹

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