HER2-Directed Therapy: The New Frontier in Gastric Cancer

The global incidence of gastric cancer (GC) is on the rise, with risk factors ranging from the corporeal (obesity) to the minuscule (Helicobacter pylori infection) to the unseen-by-the-naked-eye—the overexpression and/or amplification of HER2 (ERBB2).

While there is the standard treatment for HER2-positive GC in the form of trastuzumab-chemotherapy, "other HER2-targeted therapies have not demonstrated survival benefits in patients with GC, despite showing efficacy in patients with HER2-positive breast cancer. This indicates that there are unique challenges to the use of currently available HER2-targeted therapies for the treatment of HER2-positive GC," stated Kohei Shitara, MD, of the National Cancer Center Hospital East in Kashiwa, Japan, and co-authors in a 2021 Gastric Cancer review.

Shitara would know, as a leader in the effort to put HER-targeting therapies in a better position as GC treatment, most notably the antibody-drug conjugate trastuzumab deruxtecan (T-DXd), which is "the first HER2-targeting ADC that has demonstrated a superior response rate and survival benefit over standard chemotherapy." (A previous BreakingMED article highlighted T-DXd outcomes in other solid tumors).

DESTINYgastric Data

The year 2020 saw the release of findings from the DESTINYgastric-01 trial conducted by Shitara and co-authors. They reported in the New England Journal of Medicine that the phase III trial evaluated T-DXd in comparison with chemo in pre-treated patients with HER2-positive advanced GC or gastroesophageal junction adenocarcinoma (GEJ).

Among 187 patients, those who got T-DXd benefited from a longer overall survival (OS) versus those who received chemo (median 12.5 vs 8.4 months; hazard ratio [HR], 0.59 for death), while median progression-free survival (PFS) came in at 5.6 months versus 3.5 months, respectively (HR, 0.47 for progression or death). Shitara’s group also reported that in the T-DXd group, patients with a HER2 score 3+ achieved a higher objective response (OR) versus the percentage of patients with an objective response was higher among those with a HER2 score of 3+ (HER2-positive) on immunohistochemical analysis than among those with a score of 2+ (equivocal HER2 status that needs more testing).

On the less positive side, more patients on T-DXd stopped treatment due to adverse events (AEs), such as interstitial lung disease (ILD), versus chemo patients; the authors said it was appropriately managed via active monitoring, dose modification or discontinuation, glucocorticoid therapy, and supportive care.

A related 2023 Journal of Clinical Oncology exploratory analysis investigated T-DXd’s efficacy and safety in patients with HER2-low (IHC 2+/ISH– or IHC 1+) GC/GEJ patients who did not get anti-HER2 treatment in Gastric01. It was a small phase II trial of 21 patients who had received at least two prior, non-HER2-targeting therapies, explained Kensei Yamaguchi, MD, of the the Cancer Institute Hospital of JFCR in Tokyo, and co-authors including Shitara. Still, T-DXd’s impact was impressive, with an OR rate ranging from 9.5% to 26.3%, depending on the specifics of the patient’s HER2-low status. Median OS was around 8 months. There were a couple of drug-related cases of ILD but no drug-related deaths, the authors said.

So, the stage was set for DESTINYgastric-02, reported at the 2022 European Society for Medical Oncology (ESMO) meeting and in 2023 in The Lancet Oncology. Eric Van Cutsem, MD, PhD, of the University of Leuven in Belgium, and co-authors noted that Gastric01 focused on East Asian patients, while Gastric-02 had patients from the U.S. and Europe. Once again, OR and survival outcomes were "clinically meaningful," per the authors, although co-investigator Geoffrey Ku, MD, Memorial Sloan Kettering Cancer Center in New York City, noted in a 2022 VJOncology interview, that there were some fatal ILD events, which "truly reinforces the fact that…physicians have to be very familiar with identifying and treating these events when they occur."

Thanks to these results, T-DXd was FDA approved for HER2+ advanced/metastatic GC/GEJ after a prior trastuzumab-based regimen in 2021. T-DXd also made the cut in a 2022 American Society of Clinical Oncology (ASCO) guideline as recommended second-line therapy for GC/GEJ. Manish A. Shah, MD, of Weill Cornell Medicine in New York City, and co-authors stressed that "[s]hared decision making is recommended when considering this treatment option, taking into account patient experience, tolerance, and performance status."

On the Horizon

What might be next for T-DXd in this disease state? Shitara’s group suggested that "[a]s has been the case with the treatment of HER2-positive breast cancer, it may be necessary to modify the treatment of HER2-positive GC based on subtype (e.g., Epstein-Barr virus-positive, microsatellite instability, genomically stable, or chromosomal instability from the first treatment to the second- and third-line treatments."

Of course, there are other agents available for GC/GEJ, including pembrolizumab, which gained FDA approval in 2023 in GC/GEJ in combination with fluoropyrimidine-platinum chemo based on the KEYNOTE-859 findings. This was a win for pembrolizumab, as its developer voluntarily withdrew the agent’s accelerated approval as third-line treatment for PD-L1-expression GC/GEJ after other treatments such as chemo and HER2-targeting therapy. The problem? No significant long-term OS in the phase III setting.

Shitara’s group highlighted that T-DXd "novel treatment combinations" need to be looked at, and some of those studies are underway, such as:

• DESTINYGastric-03: Phase I/II trial of T-DXd in combination with cytotoxic chemotherapy and/or immunotherapy in the second-line, including oral capecitabine and pembrolizumab. Estimated study completion date of September 2025.
• DESTINYGastric-04: Phase III trial of HER2+ metastatic and/or unresectable GC or GEJ of T-DXd in combination with paclitaxel and ramucirumab. Estimated study completion date of November 2024.
• DESTINYGastric-06: Phase II trial in China looking at T-DXd in patients who received at least two prior regimens including a fluoropyrimidine and a platinum agent. Estimated study completion date of February 2024.
• VKTORY-2: Phase I/II trial of T-DXd-afatinib in HER2-low advanced gastric cancer

Lastly, there is the matter of treatment resistance. A 2023 Science Reports study evaluated trastuzumab-resistant (TR) cell lines in GC/GEJ. Sun Young Rha, MD, PhD, of Yonsei University in Seoul, and co-authors reported that "T-DXd showed promising antitumor activity in both parental and TR cell lines, suggesting that it is a potential candidate for overcoming trastuzumab resistance…Moreover, the efficacy of T-DXd correlated with HER2 expression levels…HER2-targeted therapies are potent therapeutics to overcome resistance in GC patients, given that the established TR cell lines retain high HER2 expression."

The DESTINYgastric trials are supported by Daiichi Sankyo or Daiichi Sankyo and AstraZeneca. Some co-authors are employees of Daiichi Sankyo or AstraZeneca.

Shitara and Yamaguchi reported relationships with, and/or support from, multiple entities including Daiichi Sankyo.

The Gastric Cancer review by Shitara’s group was funded by Daiichi Sankyo.

van Cutsem reported relationships with, and/or support from, multiple entities including Daiichi Sankyo and AstraZeneca.

Shah reported support from Merck, Oncolys BioPharma, and Bristol Myers Squibb.

Shitara K, et al "Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer" N Engl J Med 2020; 382: 2419-2430 DOI: 10.1056/NEJMoa2004413.

Van Cutsem E, et al "Trastuzumab deruxtecan in patients in the USA and Europe with HER2-positive advanced gastric or gastroesophageal junction cancer with disease progression on or after a trastuzumab-containing regimen (DESTINY-Gastric02): Primary and updated analyses from a single-arm, phase 2 study" Lancet Oncol 2023; 24(7): 744-756 DOI: 10.1016/S1470-2045(23)00215-2.

Shitara K, et al "Discovery and development of trastuzumab deruxtecan and safety management for patients with HER2-positive gastric cancer" Gastric Cancer 2021; 24: 780-789 DOI: 10.1007/s10120-021-01196-3.

Yamaguchi K, et al "Trastuzumab deruxtecan in anti–human epidermal growth factor receptor 2 treatment-naive patients with human epidermal growth factor receptor 2–low gastric or gastroesophageal junction adenocarcinoma: Exploratory cohort results in a phase II trial" J Clin Oncol 2023; 41: 816-825 DOI: 10.1200/JCO.22.00575.

Shah MA, et al "Immunotherapy and targeted therapy for advanced gastroesophageal cancer: ASCO Guideline" J Clin Oncol 2023; 41: 1470-1491 DOI: 10.1200/JCO.22.02331.