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Development of HER2-targeted Therapies for Gastrointestinal Cancer

Human epidermal growth factor receptor 2 (HER2) amplification is an important molecular mechanism underlying carcinogenesis and is associated with various types of cancer. Although the advancement of HER2-targeted therapy has been the most pronounced in breast cancer, interest has emerged in exploring the efficacy of HER2-targeted therapies in gastrointestinal (GI) cancers. In particular, the addition of trastuzumab to first-line chemotherapy has improved the overall survival of patients with HER2-positive gastric or oesophagogastric junction cancer. Although subsequent trials involving lapatinib, ado-trastuzumab emtansine (T-DM1), and pertuzumab have failed to show significant survival benefits for HER2-positive gastric or oesophagogastric junction cancer, several trials are currently ongoing. HER2-targeted therapy has also been tested in patients with other GI cancers. Some combination therapies, such as trastuzumab plus pertuzumab, have shown promising results in single-arm phase II studies. Moreover, trials of novel anti-HER2 agents, including trastuzumab deruxtecan (T-DXd), tucatinib and margetuximab – which demonstrated improvement of clinical outcomes in breast cancer – are ongoing for GI cancers. In this review, we provide an overview of the current status of HER2-targeted therapies and focus on future perspectives for overcoming issues in the treatment of HER2-positive GI cancer.

A distinct characteristic of HER2-positive gastric cancer, including GEJ cancer, that differentiates it from HER2-positive breast cancer is intra-tumoural heterogeneity, [14][15] which is characterised as the presence of areas with different HER2 immunohistochemistry (IHC) scores within the same tumour. Moreover, the criteria for HER2 positivity differ slightly between gastric cancer and breast cancer. In the ToGA trial, which was the first randomised phase III study of HER2-positive gastric or GEJ cancer, HER2 positivity was defined as either: (1) IHC 3+ (defined as moderate to strong, complete or basolateral membrane staining in >10% of tumour cells); or (2) in situ hybridisation (ISH)-positive (defined as a HER2:CEP17 ratio of >2). 16 Based on these criteria, 22.1% of tumours were classified as HER2 positive. However, because the IHC 1+/0 and the ISH-positive subgroup did not show a clinical benefit in this trial, HER2 positivity has since been redefined as IHC 3+ or IHC 2+ and ISH-positive tumours in clinical settings. 17 In the ToGA trial (A study of herceptin [trastuzumab] in combination with chemotherapy compared with chemotherapy alone in patients with HER2-positive advanced gastric cancer; ClinicalTrials.gov identifier: NCT01041404), 584 patients with HER2-positive gastric or GEJ cancer were recruited according to the above criteria and were randomised to receive fluoropyrimidine and cisplatin with trastuzumab (monoclonal antibody targeting HER2) or placebo. 16,18 In the trastuzumab group, median overall survival (OS) was 13.8 months and median progression-free survival (PFS) was 6.7 months. These durations were significantly longer than those in the placebo group (i.e., 11.1 and 5.5 months, respectively) ( Table 1). 16,[18][19][20][21][22][23][24][25][26][27][28][29] In particular, in patients who first-line chemotherapy plus trastuzumab, were assigned to groups treated with paclitaxel with or without trastuzumab. 19 The median OS and PFS were 10.0 and 3.2 months in the trastuzumab combination group and 10.2 and 3.7 months in the paclitaxel monotherapy group (OS: HR 1.23, p=0.20; PFS 0.91, p=0.33), which was not significant ( Table 1). On exploratory analyses, HER2 expression was lost after first-line chemotherapy in 11 of 16 (69%) patients whose tumour tissues were available, which might cause no clinical benefit by trastuzumab beyond disease progression.
Lapatinib, a tyrosine kinase inhibitor (TKI) that binds to the intracellular tyrosine kinase domains of epidermal growth factor receptor (EGFR) and HER2, blocking autophosphorylation and downstream signalling, has been investigated for gastric cancer. In the TRIO-013/LOGiC trial Enrolled patients were randomised to receive paclitaxel with or without  Table 1). 28 Based on these promising results, the phase II DESTINY-Gastric01 trial (DS-8201a in human epidermal growth factor receptor 2 (HER2)-expressing gastric cancer; ClinicalTrials.gov identifier: NCT03329690), for patients with previously treated HER2-positive (IHC 3+ or 2+ and FISH-positive) metastatic gastric or GEJ cancer, was performed. 28,29 The results were reported recently; OS was longer with T-DXd than with the physician's choice of chemotherapy (median, 12.5 versus 8.4 months; p=0.01) and ORR in T-DXd was higher than that of chemotherapy (51 versus 14%, p<0.001). 28 Accordingly, the approval of this drug for clinical use is anticipated in Japan, where the SAKIGAKE designation system to promote driving early practical application for innovative pharmaceutical products has been granted for this indication.

Colorectal cancer
The incidence of HER2 amplification is 1-5% in unselected colorectal cancer (CRC). 34 Table 3). 43,49,50,[67][68][69][70] In the SUMMIT basket study, 11 patients with mBTC harbouring HER2 mutations received treatment with neratinib, and partial responses were observed in 22% of the patients. 39 In addition, the MOSCATO study, a prospective molecular profiling study for advanced cancers, reported that a complete response with trastuzumab plus chemotherapy was achieved in one patient with HER2-positive mBTC. 71,72 Although sample size of these trials was small, these results suggest that HER2-targeted therapy may also be effective in patients with mBTC harbouring HER2 amplification and HER2-activated alterations.
A single-arm, phase II trial of T-DXd for HER2-positive BTC, the HERB study, is ongoing in Japan (JMA-IIA00423). 73 In the main cohort, IHC 3+ or IHC 2+ and ISH-positive patients determined by central imaging review are eligible. In an additional exploratory cohort, IHC 2+ and ISH-negative  patients and IHC 1+ patients are eligible. The primary endpoint of this trial is ORR in the main cohort and the key secondary endpoints are PFS, OS, and ORR in patients with low HER2 expression (Table 4). 54,55, Pancreatic cancer The frequency of HER2 overexpression has been reported to be 17-45% pancreatic cancer, 113,114 with the frequency of HER2 amplification approximately 3%. 113 In both pancreatic-cancer cell lines and a xenograft mouse model, HER2-targeted therapy with trastuzumab showed favourite results. 115  These results were not an improvement over those of standard chemotherapy ( Table 3).
In another phase II study of trastuzumab and gemcitabine among 34 patients with metastatic pancreatic cancer, four (12%) had IHC 3+ and 30 (88%) had IHC 2+. 69 Confirmed partial responses were observed in two patients (6%) and 13 (41%) had either an unconfirmed partial response or a >50% reduction in CA 19-9. The median OS for all 34 patients was 7 months, with a 1-year survival rate of 19% ( Table 3). As these results were similar to those for gemcitabine alone, the addition of the anti-HER2 agent does not improve clinical outcomes in pancreatic cancer.

Future perspectives
The first ToGA trials demonstrated the survival benefit of anti-HER2 antibody conjugated to an immunostimulatory agent. 136 A phase I trial designed to determine safety and dose of NJH395 is currently recruiting patients with non-breast HER2-positive advanced-stage cancer (ClinicalTrials.gov identifier: NCT03696771). 104 4-1BB (CD137) is a key costimulatory immunoreceptor and promising therapeutic target in cancer. PRS-343, which is a 4-1BB/HER2 bispecific molecule, is designed to facilitate T-cell costimulation by tumour-localized, HER2-dependent 4-1BB clustering and activation. 137 In a phase I, dose-escalation study, PRS-343 monotherapy was well-tolerated in all doses and demonstrated objective response in two of 18 evaluable patients (11%) in heavily pre-treated patient with HER2-positive solid tumours. 138 Currently, another phase I trial with PRS-343 in combination with atezolizumab in HER2-positive solid tumours, is ongoing (ClinicalTrials.gov identifier: NCT03650348). 137

Conclusion
In GI cancers, HER2-targeted therapy is an area of active investigation. Although trastuzumab in advanced gastric or GEJ cancer is the only anti-HER2 agent in GI cancer so far, other novel HER2-targeted agents have emerged and shown promising efficacy in gastric and other GI cancers. Although several issues, including more precise selection of patients to receive HER2-targeted therapies, still need to be addressed for progress in the development of HER2-targeted therapy in GI cancer, novel methods such as screening using ctDNA, basket trials, and an establishment of international diagnostic criteria will likely enable continued advances in HER2-targeted therapy in the future. q