Understanding Treatment Strategies for HER2 Positive IHC3+ Metastatic Solid Tumors

The expert interviewed for this article is an internationally recognized specialist in the management of solid tumors and served as a paid consultant to Daiichi Sankyo and AstraZeneca on this article’s content.

Solid tumors make up approximately 90% of adult cancers, and with rising rates of certain metastatic solid cancers, targeted treatments are available to help patients.^1,2,3,4,5

Providing these medicines to eligible patients often involves developing personalized treatment plans, implementing disease management strategies, and identifying biomarkers to understand a tumor’s characteristics.^6,7,8,9 This approach is crucial for managing certain aggressive metastatic solid tumors, such as those with human epidermal growth factor receptor 2 (HER2) overexpression.^3,10

Why HER2 Biomarker Testing Matters

While HER2 overexpression is well-established across breast and gastric cancers, it is also observed in other solid tumors, such as biliary tract, non-small cell lung cancers (NSCLC), colorectal, bladder, ovarian, endometrial, and cervical cancers.^11,12

HER2 overexpression can be assessed through immunohistochemistry (IHC) testing at initial diagnosis and upon disease progression.^13,14,15,16 While archival tissue may be used if a new biopsy is not feasible, it’s important to consider that HER2 expression may change over time.^13,14,15,17

“Despite growing evidence, IHC testing for HER2 overexpression in certain metastatic solid tumors is not widely performed,” explained Dr. Ronan Kelly, Director of Oncology at the Charles A. Sammons Cancer Center at Baylor University Medical Center in Dallas. “As a result, we are missing opportunities to identify patients who could potentially benefit from HER2-directed therapies.”

While next-generation sequencing (NGS) can be used to detect HER2 mutations, IHC testing identifies protein overexpression.^13,14 Without IHC testing for metastatic solid tumors, there’s risk of missing eligible patients who may benefit from HER2-directed therapies.^13,14,18,19

IHC testing may have been historically underutilized in identifying certain HER2 positive metastatic solid tumors due to limited treatment options.^3,20 However, the advent of antibody-drug conjugates (ADCs), which target overexpressed proteins like HER2, offer additional treatment options to eligible patients.²¹ ADCs underscore the importance of prioritizing IHC testing to identify biomarkers that drive disease progression, especially in aggressive HER2-expressing cancers.^13,22,23

ADCs are composed of a monoclonal antibody, which is designed to target proteins such as HER2 on cancer cell surfaces, attached to a cytotoxic chemotherapy drug via a chemical linker.^21,24,25 Upon binding, the ADC is internalized by the cancer cell, releasing the drug to destroy it.²⁵

“Emerging clinical evidence suggests HER2-directed ADCs could potentially address critical unmet needs and also potentially offer an additional treatment option to eligible patients,” explained Dr. Kelly.

Exploring ENHERTU^® (fam-trastuzumab deruxtecan-nxki) as a Potential Treatment Option

In 2024, ENHERTU was granted U.S. Food and Drug Administration (FDA) approval for the treatment of adult patients with unresectable or metastatic HER2 positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options. ENHERTU was granted accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.⁴

ENHERTU carries Boxed WARNINGS for Interstitial Lung Disease/Pneumonitis and Embryo-Fetal Toxicity, with risks of lung problems, low white blood cell counts, and heart problems. In patients with HER2 positive (IHC 3+) metastatic solid tumors who received ENHERTU, the most common adverse reactions (frequency greater than or equal to 20%), including laboratory abnormalities, were decreased white blood cell count, nausea, decreased hemoglobin, decreased neutrophil count, fatigue, decreased lymphocyte count, decreased platelet count, increased aspartate aminotransferase, increased alanine aminotransferase, increased blood alkaline phosphatase, vomiting, decreased appetite, alopecia, diarrhea, decreased blood potassium, constipation, decreased sodium, stomatitis, and upper respiratory tract infection. Please see Important Safety Information below.

This accelerated approval marks another indication for ENHERTU for the treatment of previously treated patients with HER2 positive (IHC 3+) metastatic solid tumors.⁴

The clinical trials DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02 supported the accelerated approval, for ENHERTU. The major efficacy outcome was confirmed objective response rate (ORR) evaluated by ICR based on RECIST v1.1 and additional select efficacy outcome was duration of response (DOR) evaluated by ICR based on RECIST v1.1.⁴

• In DESTINY-PanTumor02, the confirmed objective response rate was 51.4% (n=57/111; 95% CI; 41.7, 61.0) for ENHERTU, and the median DOR was 19.4 months (n=57; range: 1.3, 27.9+).
• In DESTINY-Lung01, the confirmed objective response rate was 52.9% (n=9/17; 95% CI; 27.8, 77.0) for ENHERTU, and the median DOR was 6.9 months (n=9; range: 4.0, 11.7+).
• In DESTINY-CRC02, the confirmed objective response rate was 46.9% (n=30/64; 95% CI; 34.3, 59.8) for T-DXd, and the median DOR was 5.5 months (n=30; range: 1.3+, 9.7+).

Dr. Kelly has observed the impact of ENHERTU firsthand: “The approval of ENHERTU has reshaped approaches to later-line treatment for patients with HER2 positive (IHC 3+) metastatic disease who have no satisfactory alternative treatment options, working to address a critical treatment gap,” said Dr. Kelly.

Considerations for Clinical Practice

Addressing HER2 positive (IHC 3+) metastatic solid tumors presents challenges and opportunities in the complex oncology landscape. Accurate diagnosis hinges on timely biomarker testing, which is helpful for guiding treatment strategies and improving outcomes.^26,27,28

“Broadening IHC testing across multiple metastatic solid tumor types can potentially identify more patients who could be eligible for HER2-directed therapies like ENHERTU, which is supported by efficacy and safety data in patients with HER2 positive (IHC 3+) metastatic solid tumors who have no satisfactory alternative treatment options,” Dr. Kelly reiterated. “As our understanding of metastatic solid tumors evolves, HER2 biomarker testing will be important to optimize patient care and ensure access to targeted treatments.”

Visit www.ENHERTUHCP.com for more information on ENHERTU.

Indication and Important Safety Information

Indication

ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated:

• HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors: as monotherapy for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

IMPORTANT SAFETY INFORMATION

WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY

• Interstitial lung disease (ILD) and pneumonitis, including fatal cases, have been reported with ENHERTU. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue ENHERTU in all patients with Grade 2 or higher ILD/pneumonitis. Advise patients of the risk and to immediately report symptoms.
• Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception.

Contraindications

None.

Warnings and Precautions

Interstitial Lung Disease / Pneumonitis

Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU. A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to Grade 0, then if resolved in ≤28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose 1 level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥0.5 mg/kg/day prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate systemic corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks.

Solid Tumors (IHC 3+) and Other Solid Tumors (5.4 mg/kg)

In patients treated with ENHERTU 5.4 mg/kg, ILD occurred in 12% of patients. Median time to first onset was 5.5 months (range: 0.9 to 31.5). Fatal outcomes due to ILD and/or pneumonitis occurred in 0.9% of patients treated with ENHERTU.

Neutropenia

Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 10⁹/L), interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 10⁹/L), interrupt ENHERTU until resolved to Grade 2 or less, then reduce dose by 1 level. For febrile neutropenia (ANC <1.0 x 10⁹/L and temperature >38.3º C or a sustained temperature of ≥38º C for more than 1 hour), interrupt ENHERTU until resolved, then reduce dose by 1 level.

Solid Tumors (IHC 3+) and Other Solid Tumors (5.4 mg/kg)

In patients treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 65% of patients. Nineteen percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 22 days (range: 2 to 939). Febrile neutropenia was reported in 1.2% of patients.

Left Ventricular Dysfunction

Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including ENHERTU. Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage LVEF decrease through treatment interruption. When LVEF is >45% and absolute decrease from baseline is 10-20%, continue treatment with ENHERTU. When LVEF is 40-45% and absolute decrease from baseline is <10%, continue treatment with ENHERTU and repeat LVEF assessment within 3 weeks. When LVEF is 40-45% and absolute decrease from baseline is 10-20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU. If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose. When LVEF is <40% or absolute decrease from baseline is >20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF of <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue ENHERTU. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure. Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiation of treatment.

Solid Tumors (IHC 3+) and Other Solid Tumors (5.4 mg/kg)

In patients treated with ENHERTU 5.4 mg/kg, LVEF decrease was reported in 4.6% of patients, of which 0.6% were Grade 3 or 4.

Embryo-Fetal Toxicity

ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. Verify the pregnancy status of females of reproductive potential prior to the initiation of ENHERTU. Advise females of reproductive potential to use effective contraception during treatment and for 7 months after the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 4 months after the last dose of ENHERTU.

Additional Dose Modifications

Thrombocytopenia

For Grade 3 thrombocytopenia (platelets <50 to 25 x 109/L), interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose. For Grade 4 thrombocytopenia (platelets <25 x 109/L), interrupt ENHERTU until resolved to Grade 1 or less, then reduce dose by 1 level.

Adverse Reactions

Solid Tumors (IHC 3+) and Other Solid Tumors (5.4 mg/kg)

The pooled safety population reflects exposure to ENHERTU 5.4 mg/kg intravenously every 3 weeks in 2233 patients in Study DS8201-A-J101 (NCT02564900), DESTINY-Breast01, DESTINY-Breast02, DESTINY-Breast03, DESTINY-Breast04, DESTINY-Breast06, DESTINY-Lung01, DESTINY-Lung02, DESTINY-CRC02, and DESTINY-PanTumor02. Among these patients, 67% were exposed for >6 months and 38% were exposed for >1 year. In this pooled safety population, the most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count (73%), nausea (72%), decreased hemoglobin (67%), decreased neutrophil count (65%), decreased lymphocyte count (60%), fatigue (55%), decreased platelet count (48%), increased aspartate aminotransferase (46%), increased alanine aminotransferase (44%), increased blood alkaline phosphatase (39%), vomiting (38%), alopecia (37%), constipation (32%), decreased blood potassium (32%), decreased appetite (31%), diarrhea (30%), and musculoskeletal pain (24%).

HER2-Positive (IHC 3+) Unresectable or Metastatic Solid Tumors

The safety of ENHERTU was evaluated in 347 adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who received ENHERTU 5.4 mg/kg intravenously once every 3 weeks in DESTINY-Breast01, DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02. The median duration of treatment was 8.3 months (range 0.7 to 30.2).

Serious adverse reactions occurred in 34% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were sepsis, pneumonia, vomiting, urinary tract infection, abdominal pain, nausea, pneumonitis, pleural effusion, hemorrhage, COVID-19, fatigue, acute kidney injury, anemia, cellulitis, and dyspnea. Fatalities due to adverse reactions occurred in 6.3% of patients including ILD/pneumonitis (2.3%), cardiac arrest (0.6%), COVID-19 (0.6%), and sepsis (0.6%). The following events occurred in 1 patient each (0.3%): acute kidney injury, cerebrovascular accident, general physical health deterioration, pneumonia, and hemorrhagic shock.

ENHERTU was permanently discontinued in 15% of patients, of which ILD/pneumonitis accounted for 10%. Dose interruptions due to adverse reactions occurred in 48% of patients. The most frequent adverse reactions (>2%) associated with dose interruption were decreased neutrophil count, anemia, COVID-19, fatigue, decreased white blood cell count, and ILD/pneumonitis. Dose reductions occurred in 27% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, decreased neutrophil count, ILD/pneumonitis, and diarrhea.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count (75%), nausea (69%), decreased hemoglobin (67%), decreased neutrophil count (66%), fatigue (59%), decreased lymphocyte count (58%), decreased platelet count (51%), increased aspartate aminotransferase (45%), increased alanine aminotransferase (44%), increased blood alkaline phosphatase (36%), vomiting (35%), decreased appetite (34%), alopecia (34%), diarrhea (31%), decreased blood potassium (29%), constipation (28%), decreased sodium (22%), stomatitis (20%), and upper respiratory tract infection (20%).

Use in Specific Populations

• Pregnancy: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. There are clinical considerations if ENHERTU is used in pregnant women, or if a patient becomes pregnant within 7 months after the last dose of ENHERTU.
• Lactation: There are no data regarding the presence of ENHERTU in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ENHERTU and for 7 months after the last dose.
• Females and Males of Reproductive Potential: Pregnancy testing: Verify pregnancy status of females of reproductive potential prior to initiation of ENHERTU. Contraception: Females: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for 7 months after the last dose. Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 4 months after the last dose. Infertility: ENHERTU may impair male reproductive function and fertility.
• Pediatric Use: Safety and effectiveness of ENHERTU have not been established in pediatric patients.
• Geriatric Use: Of the 192 patients with HER2-positive (IHC 3+) unresectable or metastatic solid tumors treated with ENHERTU 5.4 mg/kg in DESTINY-PanTumor02, DESTINY-Lung01, or DESTINY-CRC02, 39% were ≥65 years and 9% were ≥75 years. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients.
• Renal Impairment: A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Monitor patients with moderate renal impairment more frequently. The recommended dosage of ENHERTU has not been established for patients with severe renal impairment (CLcr <30 mL/min).
• Hepatic Impairment: In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor, DXd. The recommended dosage of ENHERTU has not been established for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST).

To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch.

Please see full Prescribing Information, including Boxed WARNINGS, and Medication Guide.

ENHERTU^® is a registered trademark of Daiichi Sankyo Company, Limited.

^©2026 Daiichi Sankyo, Inc. and AstraZeneca.

PP-US-ENTA-0352 04/26

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