Promising Treatments for HER2-Positive Stage 4 Stomach Cancer

Stomach and gastroesophageal junction cancers overexpress human epidermal growth factor receptor 2 (HER2) on the cancer cell surface in 15% to 20 percent of cases; these are called HER2-positive stomach cancers. For patients with advanced HER2-positive stomach cancer, standard 1st-line treatment combines chemotherapy with the anti-HER2 antibody we have used for many years, trastuzumab. However, testing other anti-HER2 drugs in later lines had not shown meaningful efficacy before the study discussed in this article.

For treatments after first-line therapy, irinotecan, taxanes, trifluridine-tipiracil and immunotherapies are additional options. Placebo comparisons show an overall survival benefit of approximately 2 months with nivolumab and trifluridine-tipiracil.

Trastuzumab deruxtecan (known in the United States as fam-trastuzumab deruxtecan-nxki [Enhertu]) is an anti-HER2 monoclonal antibody linked to a chemotherapy agent in the "topoisomerase I inhibitor" class. Trastuzumab deruxtecan has been approved in Japan and the United States for patients with metastatic HER2-positive breast cancer who have received multiple previous treatment lines (see the related FDA approval).

The antibody in this drug binds to HER2 on the cancer cell surface and kills cancer cells. The chemotherapy/antibody ratio in the drug is 8/1, also making it an effective option for cancer cells that are not strongly HER2-positive.

In patients with HER2-positive stomach and gastroesophageal junction cancers who had received multiple previous treatment lines, trastuzumab deruxtekan was investigated in an open-label, multicenter, phase II clinical trial whose results we present here.

Study details and results

• The study's primary endpoint was objective response rate, and secondary endpoints were overall survival, response duration, progression-free survival, confirmed response, and safety.
• Of the 187 patients enrolled, 125 received trastuzumab deruxtecan and 62 received chemotherapy (55 irinotecan and 7 paclitaxel).
• The objective response rate was 51% with trastuzumab deruxtecan and 14% with chemotherapy.
• Median overall survival was markedly longer in the trastuzumab deruxtecan arm: 12.5 versus 8.4 months (hazard ratio [HR] for death 0.59; 95% confidence interval 0.39 - 0.88; P=0.01).
• The most common serious side effects (grade 3 or higher) were more frequent in the trastuzumab deruxtecan arm: neutropenia (51% versus 24%); anemia (38% versus 28%); leukopenia (21% versus 11%).
• Interstitial lung disease or pneumonitis developed in 12 patients receiving trastuzumab deruxtecan (9 mild, 3 severe); 1 week died from pneumonia.

In conclusion, trastuzumab deruxtecan produced, in previously multiply treated advanced HER2-positive stomach cancers, the best survival and response data reported to date. However, side effects are not infrequent; many are manageable, and patients should be monitored carefully for them.

Other innovative treatments for HER2-positive stomach cancers

HER2 is a key element in controlling cell growth and proliferation, and in cancers with HER2 genetic changes, this target can be seen as an Achilles tendon.

Below, HER2-positive stomach cancers can be seen being targeted by many different agents (monoclonal antibodies, immunotherapies, cellular immunotherapies, chemotherapy-antibody conjugates, and tyrosine kinase inhibitors).

Among the approaches above, besides familiar drugs, 2 cellular immunotherapy (living drug) methods are particularly noteworthy. They are not yet approved for HER2-positive stomach cancer, but are being tested in many clinical trials.

• The innate immune system's natural killer cells are NK (natural killer) cells, whose Fc receptors (FcR) are linked to anti-HER2 antibodies through genetic engineering techniques, triggering an anticancer immune response through antibody-dependent cellular cytotoxicity (ADCC).
• Another cellular immunotherapy involves an element of the adaptive (acquired) immune system: T cells, into which chimeric antigen receptors are engineered to recognize HER2-positive cells (CAR) using genetic engineering techniques. With HER2-specific chimeric antigen receptors, CAR T cells may be an option for HER2-positive stomach cancer.