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ENHERTU (fam-trastuzumab deruxtecan-nxki) Logo
For US Healthcare Professionals

About HER2-mutant Metastatic NSCLC

About HER2-mutant Metastatic NSCLC

Identify patients for treatment with ENHERTU based on
the presence of activating HER2 (ERBB2) mutations

Activating HER2 mutations are an actionable biomarker in mNSCLC1

An activating HER2 mutation is any mutation identified within the HER2 (ERBB2) gene that is known to play a role in the oncogenic process2

There are important differences between HER2 mutations and other HER2 alterations in NSCLC3,4

  • HER2 mutations occur in the HER2 (ERBB2) gene and are synonymous with ERBB2 mutations5
  • Other HER2 alterations4:
    • HER2 amplifications are distinct from HER2 mutations, in that they result in abnormally high HER2 (ERBB2) gene copies
    • HER2 overexpression is characterized by an overabundance of HER2 receptors on the surface of cancer cells

HER2 mutations have been observed in 2%-4% of patients with NSCLC4

  • HER2 mutations occur at a similar frequency to many other actionable biomarkers in NSCLC6
  • Other actionable biomarkers6:
    • ALK fusion ≈ 3.8%
    • MET splice (MET exon 14) ≈ 3%
    • ROS1 fusion ≈ 2.6%
    • BRAF V600E ≈ 2.1%

Testing and reporting

Testing eligible patients with mNSCLC for HER2 (ERBB2) mutations is recommended in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)7

Testing for HER2 (ERBB2) mutations Reporting HER2 (ERBB2) mutation status
  • HER2 mutations can be detected through broad molecular profiling, typically via NGS, which is recommended for the identification of biomarkers like HER2 mutations in mNSCLC1,3,4,7
  • Most NGS panels include HER2 (ERBB2) mutations8
  • Tissue or plasma specimens can be used to identify patients with activating HER2 (ERBB2) mutations1
  • If no mutation is detected with plasma, tumor tissue should be tested1
  • HER2 mutations are synonymous with and are often reported as mutations in the ERBB2 gene5
  • HER2 mutation results should be listed alongside other actionable biomarkers1,9,10
  • With the approval of ENHERTU in NSCLC, HER2 mutations can be classified as Tier 1A variants based on the criteria outlined in the joint consensus recommendation of the AMP, ASCO, and CAP1,9,10
  • Diagnostic labs may be able to run a report that can identify whether you have patients in your practice with a HER2 mutation
Testing for HER2 (ERBB2) mutations
  • HER2 mutations can be detected through broad molecular profiling, typically via NGS, which is recommended for the identification of biomarkers like HER2 mutations in mNSCLC1,3,4,7
  • Most NGS panels include HER2 (ERBB2) mutations8
  • Tissue or plasma specimens can be used to identify patients with activating HER2 (ERBB2) mutations1
  • If no mutation is detected with plasma, tumor tissue should be tested1
Reporting HER2 (ERBB2) mutation status
  • HER2 mutations are synonymous with and are often reported as mutations in the ERBB2 gene5
  • HER2 mutation results should be listed alongside other actionable biomarkers1,9,10
  • With the approval of ENHERTU in NSCLC, HER2 mutations can be classified as Tier 1A variants based on the criteria outlined in the joint consensus recommendation of the AMP, ASCO, and CAP1,9,10
  • Diagnostic labs may be able to run a report that can identify whether you have patients in your practice with a HER2 mutation

For patients with mNSCLC, refer to their NGS results to confirm the presence of activating HER2 (ERBB2) mutations

Information on FDA-approved tests for the detection of activating HER2 mutations is available at http://www.fda.gov/CompanionDiagnostics.

Learn to identify patients with actionable HER2 status

Download the HER2 Testing Guide for Pathologists  

ALK, anaplastic lymphoma kinase; AMP, Association for Molecular Pathology; ASCO, American Society of Clinical Oncology; BRAF, v-Raf murine sarcoma viral oncogene homolog B; CAP, College of American Pathologists; ERBB2, erb-b2 receptor tyrosine kinase 2; FDA, Food and Drug Administration; HER2, human epidermal growth factor receptor 2; MET, mesenchymal-epithelial transition; mNSCLC, metastatic non-small cell lung cancer; NCCN, National Comprehensive Cancer Network® (NCCN®); NGS, next-generation sequencing; NSCLC, non-small cell lung cancer; ROS1, ROS proto-oncogene 1, receptor tyrosine kinase.

IMPORTANT SAFETY INFORMATION, INCLUDING BOXED WARNINGS Expand

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.
INDICATION

ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy.

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.

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.

HER2-Mutant NSCLC and Other Solid Tumors (5.4 mg/kg)

In patients with HER2-mutant NSCLC and other solid tumors 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.

HER2-Mutant NSCLC and Other Solid Tumors (5.4 mg/kg)

In patients with HER2-mutant NSCLC and other solid tumors 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.

HER2-Mutant NSCLC and Other Solid Tumors (5.4 mg/kg)

In patients with HER2-mutant NSCLC and other solid tumors 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

HER2-Mutant NSCLC 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 DESTINY-Lung02 and other clinical trials. 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-Mutant Unresectable or Metastatic NSCLC (5.4 mg/kg)

DESTINY-Lung02 evaluated 2 dose levels (5.4 mg/kg [n=101] and 6.4 mg/kg [n=50]); however, only the results for the recommended dose of 5.4 mg/kg intravenously every 3 weeks are described below due to increased toxicity observed with the higher dose in patients with NSCLC, including ILD/pneumonitis.

The safety of ENHERTU was evaluated in 101 patients with HER2-mutant unresectable or metastatic NSCLC who received ENHERTU 5.4 mg/kg intravenously once every 3 weeks until disease progression or unacceptable toxicity in DESTINY-Lung02. Nineteen percent of patients were exposed for >6 months.

Serious adverse reactions occurred in 30% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, thrombocytopenia, dyspnea, nausea, pleural effusion, and increased troponin I. Fatality occurred in 1 patient with suspected ILD/pneumonitis (1%).

ENHERTU was permanently discontinued in 8% of patients. Adverse reactions which resulted in permanent discontinuation of ENHERTU were ILD/pneumonitis, diarrhea, decreased blood potassium, hypomagnesemia, myocarditis, and vomiting. Dose interruptions of ENHERTU due to adverse reactions occurred in 23% of patients. Adverse reactions which required dose interruption (>2%) included neutropenia and ILD/pneumonitis. Dose reductions due to an adverse reaction occurred in 11% of patients.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (61%), decreased white blood cell count (60%), decreased hemoglobin (58%), decreased neutrophil count (52%), decreased lymphocyte count (43%), decreased platelet count (40%), decreased albumin (39%), increased aspartate aminotransferase (35%), increased alanine aminotransferase (34%), fatigue (32%), constipation (31%), decreased appetite (30%), vomiting (26%), increased alkaline phosphatase (22%), and alopecia (21%).

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 101 patients with HER2-mutant unresectable or metastatic NSCLC treated with ENHERTU 5.4 mg/kg, 40% were ≥65 years and 8% 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 click here for full Prescribing Information, including Boxed WARNINGS, and click here for Medication Guide.

INDICATION

ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy.

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.

References
  • ENHERTU. Prescribing information. Daiichi Sankyo, Inc.; 2025.
  • Subramanian J, Katta A, Masood A, et al. Emergence of ERBB2 mutation as a biomarker and an actionable target in solid cancers. Oncologist. 2019;24(12):e1303-e1314. doi:10.1634/theoncologist.2018-0845
  • Jebbink M, de Langen AJ, Boelens MC, Monkhorst K, Smit EF. The force of HER2 - a druggable target in NSCLC? Cancer Treat Rev. 2020;86:101996. doi:10.1016/j.ctrv.2020.101996
  • Zhao J, Xia Y. Targeting HER2 alterations in non–small-cell lung cancer: a comprehensive review. JCO Precis Oncol. 2020;4:411-425. doi:10.1200/PO.19.00333
  • Li BT, Smit EF, Goto Y, et al; DESTINY-Lung01 Trial Investigators. Trastuzumab deruxtecan in HER2-mutant non–small-cell lung cancer. N Engl J Med. 2022;386(3):241-251. doi:10.1056/NEJMoa2112431
  • Jordan EJ, Kim HR, Arcila ME, et al. Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov. 2017;7(6):596-609. doi:10.1158/2159-8290.CD-16-1337
  • Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.3.2025. © National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed January 14, 2025. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
  • Sornkom J, Cirillo P, Hoefsmit M, et al. Real-world readiness of US laboratories to test metastatic NSCLC patients for rare actionable genomic variants by NGS. Presented at: WCLC 2021 Annual Meeting; September 8-14, 2021.
  • Li MM, Datto M, Duncavage EJ, et al. Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn. 2017;19(1):4-23. doi:10.1016/j.jmoldx.2016.10.002
  • Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol Lab Med. 2018;142(3):321-346. doi:10.5858/arpa.2017-0388-CP
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