HER2 positive gastric cancer represents a distinct form of stomach cancer that affects approximately 15 to 30 percent of people diagnosed with this disease, characterized by tumors producing high levels of a protein called HER2 that causes cancer cells to grow more rapidly than normal.

How Treatment Approaches Target HER2 Positive Stomach Cancer

When someone receives a diagnosis of HER2 positive gastric cancer, understanding the available treatment options becomes essential for making informed decisions about care. The goal of treatment in this disease involves controlling symptoms, slowing down how fast the cancer spreads, and extending survival time as much as possible. Treatment decisions depend heavily on the stage of the cancer at diagnosis and the individual characteristics of each patient, including their overall health and how well they can tolerate different therapies.^[1]

Medical societies have established standard treatments that doctors follow based on years of research and clinical experience. At the same time, research teams around the world continue investigating new therapies through clinical trials. These trials test innovative drugs and treatment combinations that might work better than current options or cause fewer side effects. The landscape of HER2 positive gastric cancer treatment has evolved significantly, particularly since 2010 when the first targeted therapy became available.^[2]

The presence of HER2 protein in cancer cells creates both a challenge and an opportunity. These cells grow faster because of the extra HER2 protein on their surface. However, this same protein serves as a clear target that specialized drugs can attack. This targeting approach differs from traditional chemotherapy, which affects all rapidly dividing cells in the body. By focusing specifically on HER2, targeted therapies aim to destroy cancer cells while potentially causing less harm to healthy tissue.^[6]

Standard Medical Treatment Using HER2 Targeted Drugs

The cornerstone of standard treatment for HER2 positive gastric cancer combines chemotherapy (drugs that kill rapidly dividing cells) with targeted therapy (drugs that attack specific proteins on cancer cells). This combination approach has become the established first-line treatment for people with advanced or metastatic disease who have not received prior treatment for their cancer that has spread.^[7]

The most important targeted drug in this setting is trastuzumab, which is sold under the brand name Herceptin. Trastuzumab is a monoclonal antibody, meaning it is an immune system protein created in a laboratory that specifically recognizes and attaches to HER2 receptors on cancer cell surfaces. When trastuzumab binds to these receptors, it blocks signals that tell cancer cells to grow and multiply. Additionally, it marks the cancer cells so that the body’s immune system can recognize and destroy them more effectively.^[1]

Trastuzumab is given together with chemotherapy drugs, specifically cisplatin combined with either capecitabine or 5-fluorouracil. A landmark clinical trial in 2010 showed that adding trastuzumab to chemotherapy substantially improved how long people with HER2 positive gastric cancer lived compared to chemotherapy alone. This study showed that people receiving trastuzumab lived a median of 13.5 months compared to 11 months for those receiving only chemotherapy. This represented the first major survival improvement in decades for this type of cancer and quickly became the standard treatment approach worldwide.^[7]

The duration of treatment varies depending on how well the cancer responds and how well a person tolerates the therapy. Doctors typically continue treatment until the cancer starts growing again or until side effects become too difficult to manage. Throughout treatment, medical teams monitor patients closely with regular scans and blood tests to assess whether the therapy is working and to catch any complications early.^[13]

Side effects from trastuzumab can vary from person to person. Common side effects include feeling tired or weak, nausea, persistent cough, headaches, and diarrhea. These effects often improve over time as the body adjusts to the medication. A more serious but rare complication involves damage to the heart muscle, which can affect how well the heart pumps blood. Because of this risk, doctors typically perform tests to check heart function before starting treatment and monitor it regularly throughout therapy. People with existing heart problems may need special consideration when deciding whether trastuzumab is appropriate for them.^[15]

Adding Immunotherapy to Standard Treatment

Recent advances have introduced immunotherapy drugs into the treatment of HER2 positive gastric cancer. Immunotherapy works by helping the body’s own immune system recognize and attack cancer cells more effectively. One such drug, pembrolizumab, has been combined with trastuzumab and chemotherapy in certain patients.^[2]

Pembrolizumab targets a protein called PD-L1 that some cancer cells use to hide from the immune system. However, this drug only benefits patients whose tumors have elevated levels of PD-L1. To determine PD-L1 levels, doctors use a measurement called a combined positive score or CPS. Patients whose tumors have a PD-L1 CPS of 1 or greater may receive pembrolizumab along with trastuzumab and chemotherapy as their initial treatment.^[7]

A large clinical trial called KEYNOTE-811 showed that adding pembrolizumab to standard therapy improved how long patients lived without their disease worsening, but only in those with elevated PD-L1 levels. About 85 percent of participants in this trial had PD-L1 positive tumors. Interestingly, patients whose tumors had little or no PD-L1 actually appeared to have worse outcomes when pembrolizumab was added, highlighting the importance of testing tumor characteristics before choosing treatment.^[2]

Treatment When Cancer Progresses After Initial Therapy

When HER2 positive gastric cancer continues growing despite initial treatment with trastuzumab, patients need different therapeutic options. The most important advancement in this setting is trastuzumab deruxtecan, also known by its brand name Enhertu. This medication represents a newer type of targeted therapy called an antibody-drug conjugate or ADC.^[6]

Trastuzumab deruxtecan combines trastuzumab with a powerful chemotherapy drug called deruxtecan. Think of it as a guided missile: the trastuzumab part acts like a homing device that finds cancer cells with HER2 on their surface, while the chemotherapy part acts as the weapon that destroys those cells once the drug attaches. This approach delivers chemotherapy directly to cancer cells while potentially sparing more healthy tissue than traditional chemotherapy that circulates throughout the entire body.^[13]

A major clinical trial called DESTINY-Gastric04 compared trastuzumab deruxtecan to standard second-line treatment (paclitaxel chemotherapy combined with ramucirumab, a drug that blocks blood vessel formation in tumors). The study included 494 patients whose cancer had grown during or after trastuzumab-based treatment. Results showed that trastuzumab deruxtecan improved median overall survival to 14.7 months compared to 11.4 months with standard therapy. The drug also slowed cancer growth for longer, with median progression-free survival of 6.7 months versus 5.6 months. Additionally, more patients responded to treatment with trastuzumab deruxtecan, as 44.3 percent saw their tumors shrink compared to the standard treatment group.^[20]

Based on these results, trastuzumab deruxtecan received approval in more than 65 countries as a treatment option for people with advanced HER2 positive gastric cancer who have previously received trastuzumab-based therapy. The drug is given intravenously at a dose of 5.4 milligrams per kilogram of body weight.^[10]

Side effects from trastuzumab deruxtecan can include low blood cell counts, which may increase the risk of infections and bleeding. Other common side effects vary among individuals but can include nausea, diarrhea, constipation, hair loss, and persistent fatigue. A serious but uncommon side effect involves lung inflammation, which requires immediate medical attention if breathing problems develop. Doctors monitor patients carefully throughout treatment for any signs of these complications.^[15]

Innovative Therapies Being Tested in Clinical Trials

Research teams worldwide continue investigating new drugs and treatment combinations for HER2 positive gastric cancer through clinical trials. These studies happen in phases, each designed to answer specific questions about a new therapy.

Phase I trials focus primarily on safety. Researchers determine what doses of a new drug people can tolerate and identify potential side effects. These studies usually involve small numbers of participants. Phase II trials expand to larger groups and test whether the drug actually works against the cancer, measuring responses like tumor shrinkage. Phase III trials are the largest and most rigorous, comparing the new treatment directly against current standard therapies to determine if it works better, has fewer side effects, or offers other advantages.^[26]

Several promising approaches are currently under investigation for HER2 positive gastric cancer:

Combining Multiple HER2 Targeted Drugs

Scientists are exploring whether using two HER2 targeted drugs together might work better than one alone. One such combination under study involves pertuzumab plus trastuzumab. Pertuzumab is another monoclonal antibody that targets HER2, but it works slightly differently than trastuzumab by blocking HER2 from pairing with other proteins that help cancer cells grow. The theory is that attacking HER2 through multiple mechanisms simultaneously might overcome resistance that develops to single-drug treatment. Studies testing this dual HER2 blockade approach in gastric cancer are ongoing, following the success this strategy has shown in breast cancer.^[5]

New Antibody-Drug Conjugates

Following the success of trastuzumab deruxtecan, researchers are developing other antibody-drug conjugates that link HER2 targeting antibodies to different chemotherapy drugs. These newer ADCs aim to deliver even more powerful cancer-killing drugs directly to tumor cells while causing fewer side effects to healthy tissues. Early-phase clinical trials are testing several of these experimental compounds.^[6]

Combining Targeted Therapy with Immunotherapy

The DESTINY-Gastric05 trial represents an important ongoing study investigating whether trastuzumab deruxtecan works as a first-line treatment. This phase III trial is comparing trastuzumab deruxtecan combined with fluoropyrimidine chemotherapy and pembrolizumab immunotherapy against the current standard of trastuzumab with platinum-based chemotherapy and pembrolizumab. The study includes patients who have not yet received treatment for their advanced HER2 positive gastric cancer and whose tumors have PD-L1 levels of 1 or greater. If successful, this combination could replace current standard treatment by potentially working better and avoiding the need for platinum chemotherapy drugs like cisplatin, which can cause significant side effects.^[10]

This trial recruited its first patient in early 2025 and is being conducted at multiple medical centers around the world, including sites in the United States, Europe, and Asia. Researchers hope this platinum-free regimen might improve survival while being easier for patients to tolerate. The trial also includes an exploratory group of patients with lower PD-L1 levels to help understand how these treatments work in different patient populations.^[10]

Tyrosine Kinase Inhibitors

Another approach involves drugs called tyrosine kinase inhibitors or TKIs, which are small molecules that can enter cells and block HER2 signaling from inside the cell rather than from the surface. Lapatinib is one such drug that has been tested in gastric cancer. Unlike antibodies like trastuzumab that must be given intravenously, TKIs can be taken as pills. However, studies testing lapatinib in HER2 positive gastric cancer in the second-line setting showed disappointing results and did not lead to approval for this indication. Researchers continue investigating whether newer TKIs or different combinations might prove more effective.^[6]

Understanding Resistance Mechanisms

An important area of research focuses on understanding why HER2 positive gastric cancers eventually stop responding to targeted therapies. Scientists have discovered that cancer cells can develop various mechanisms to evade treatment. Some tumors have uneven distribution of HER2, a characteristic called heterogeneity, where some cancer cells have high HER2 levels while others have low or no HER2. As treatment kills the HER2 positive cells, the HER2 negative cells can continue growing unchecked. Other resistance mechanisms involve cancer cells finding alternative growth pathways that bypass the blocked HER2 signaling.^[6]

Researchers are using advanced genetic and molecular analysis techniques to map these resistance pathways. This knowledge helps them design new treatment strategies that can overcome or prevent resistance. Some trials are investigating sequential treatment approaches, where patients receive one therapy until resistance develops, then switch to a different drug that attacks a different pathway. Others are testing combinations that block multiple pathways simultaneously to prevent resistance from developing in the first place.^[5]

Testing for HER2 Status

Accurate testing to determine HER2 status is absolutely essential because it determines which treatments a person can receive. Not all gastric cancers are HER2 positive, so testing must be performed before starting HER2 targeted therapy. The testing process involves examining tumor tissue obtained through biopsy (removing a small sample of tissue) or surgery.^[4]

Laboratories use two main methods to test for HER2. Immunohistochemistry or IHC measures how much HER2 protein appears on the surface of cancer cells. Results are scored from 0 to 3 plus, with 3 plus indicating strong HER2 overexpression. In situ hybridization or ISH testing looks directly at the cancer cell DNA to see if there are extra copies of the HER2 gene, a condition called gene amplification. Often, laboratories perform IHC first, and if results are uncertain (typically a 2 plus score), they confirm with ISH testing.^[4]

Testing standards for gastric cancer differ somewhat from those used for breast cancer, even though both cancers can be HER2 positive. Gastric cancers often show more heterogeneity in their HER2 expression, meaning HER2 levels can vary within different parts of the same tumor. Guidelines from organizations like the College of American Pathologists provide detailed criteria for accurate HER2 testing and interpretation in gastric cancer to ensure patients receive appropriate treatment recommendations.^[4]

Most common treatment methods

• Targeted therapy with trastuzumab
  • Monoclonal antibody that binds to HER2 receptors on cancer cells
  • Combined with cisplatin and either capecitabine or 5-fluorouracil chemotherapy
  • Standard first-line treatment for HER2 positive metastatic gastric cancer
  • Improved median survival to 13.5 months compared to 11 months with chemotherapy alone
  • Given intravenously throughout treatment until disease progression
• Targeted therapy with trastuzumab deruxtecan
  • Antibody-drug conjugate combining trastuzumab with deruxtecan chemotherapy
  • Used after HER2 positive gastric cancer has grown despite trastuzumab treatment
  • Approved in over 65 countries as second-line or later treatment
  • Improved median survival to 14.7 months compared to 11.4 months with standard second-line therapy
  • Given intravenously at dose of 5.4 mg/kg body weight
• Immunotherapy with pembrolizumab
  • Anti-PD-1 antibody that helps immune system recognize cancer cells
  • Combined with trastuzumab and chemotherapy for first-line treatment
  • Only for patients whose tumors have PD-L1 CPS of 1 or greater
  • Improved progression-free survival in PD-L1 positive patients
  • Not effective in patients with low or no PD-L1 expression
• Platinum-based chemotherapy
  • Cisplatin or oxaliplatin combined with fluoropyrimidine drugs
  • Used together with targeted therapies as backbone of treatment
  • Works by damaging DNA in rapidly dividing cancer cells
  • Standard component of first-line treatment regimens
• Second-line chemotherapy with ramucirumab
  • Paclitaxel chemotherapy combined with ramucirumab
  • Ramucirumab targets VEGF to block new blood vessel formation in tumors
  • Standard second-line option when HER2 targeted therapy is not available or appropriate
  • Used as comparison arm in trastuzumab deruxtecan clinical trials