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Clinical Trials

ENHERTU was granted accelerated approval for a tumor-agnostic indication based on the combined evidence from 3 separate clinical trials in HER2+ (IHC 3+) metastatic solid tumors

DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02 were all multicenter clinical trials1

DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02 were all
                                    multicenter clinical trials DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02 were all
                                    multicenter clinical trials

Major efficacy outcome1

  • Confirmed objective response rate (ICR based on RECIST v1.1)

Additional select efficacy outcome1

  • Duration of response (ICR based on RECIST v1.1)

Select exclusion criteria1

  • History of ILD/pneumonitis requiring steroids or ILD/pneumonitis at screening
  • Clinically significant cardiac disease
  • Clinically active brain metastasese
  • ECOG performance status >1

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.

aDESTINY-PanTumor02 included 111 adult patients with locally advanced, unresectable, or metastatic HER2+ (IHC 3+) solid tumors who have progressed following at least 1 prior systemic regimen in the advanced/metastatic setting or who have no satisfactory alternative treatment option, with the exception of breast cancer, non-small cell lung cancer, gastric cancer, and colorectal cancer. Efficacy was assessed in patients with HER2+ (IHC 3+) solid tumors (by either local or central assessment) according to the ASCO-CAP gastric HER2 scoring method (BTC [n=22]; bladder cancer [n=27]; endometrial cancer [n=16]; ovarian cancer [n=15]; pancreatic cancer [n=5]; cervical cancer [n=10]; salivary gland cancer [n=9]; oropharyngeal neoplasm [n=1]; vulvar cancer [n=1]; extramammary Paget's disease [n=1]; lacrimal gland cancer [n=1]; lip and/or oral cavity cancer [n=1]; esophageal adenocarcinoma [n=1]; esophageal squamous cell carcinoma [n=1]).1,2

bDESTINY-Lung01 included 17 patients with previously treated, unresectable or metastatic HER2+ (IHC 3+) NSCLC. Patients must have relapsed from or be refractory to standard treatment or have no available standard treatment. Efficacy was assessed in patients with centrally confirmed HER2+ (IHC 3+) NSCLC according to the ASCO-CAP gastric HER2 scoring method.1,3

cDESTINY-CRC02 included 64 patients with previously treated, unresectable or metastatic HER2+ (IHC 3+) CRC. Unless contraindicated, patients must have received fluoropyrimidine, oxaliplatin, and irinotecan. If clinically indicated, patients must have received anti-EGFR treatment, anti-VEGF treatment, and anti-PD-L1 therapy. Efficacy was assessed in patients with centrally confirmed HER2+ (IHC 3+) CRC according to the ASCO-CAP gastric HER2 scoring method.1

dTumor assessments were conducted every 6 weeks. In DESTINY-PanTumor02, they were conducted every 6 weeks for the first 48 weeks and then every 12 weeks thereafter.4-6

ePatients with clinically inactive brain metastases were included. Patients with treated brain metastases that were no longer symptomatic and who required no treatment with corticosteroids or anticonvulsants were allowed in the study if they recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks was required to have elapsed between the end of whole brain radiotherapy and study enrollment.4-6

A range of patients with HER2+ (IHC 3+) solid tumors were studied in 3 clinical trials

Select patient characteristics ENHERTU
(n=192)
Metastatic
solid tumors1
(n=111)
mNSCLC1,7
(n=17)
mCRC1,7
(n=64)
Age, median (range) 64 years
(23-85)
59 years
(31-74)
58 years
(25-78)
Sex, % Female 59% 41% 47%
Male 41% 59% 53%
Race, % White 58% 65% 41%
Black or African American 4% 12% 0%
Asian 34% 18% 55%
Hispanic/Latino 3% 0% 1.6%
ECOG performance status, % 0 49% 12% 58%
1 51% 88% 42%
Median number of prior regimens in any treatment setting 2 3 4
Select patient characteristics ENHERTU (n=192)
Metastatic solid
tumors1 (n=111)
Age, median (range) 64 years
(23-85)
Sex, % Female 59%
Male 41%
Race, % White 58%
Black or African American 4%
Asian 34%
Hispanic/
Latino
3%
ECOG
performance
status, %
0 49%
1 51%
Median number of prior regimens in any treatment setting 2
Select patient characteristics ENHERTU (n=192)
mNSCLC1,7
(n=17)
Age, median (range) 59 years
(31-74)
Sex, % Female 41%
Male 59%
Race, % White 65%
Black or African American 12%
Asian 18%
Hispanic/
Latino
0%
ECOG
performance
status, %
0 12%
1 88%
Median number of prior regimens in any treatment setting 3
Select patient characteristics ENHERTU (n=192)
mCRC1,7
(n=64)
Age, median (range) 58 years
(25-78)
Sex, % Female 47%
Male 53%
Race, % White 41%
Black or African American 0%
Asian 55%
Hispanic/
Latino
1.6%
ECOG
performance
status, %
0 58%
1 42%
Median number of prior regimens in any treatment setting 4

All patients treated with ENHERTU had received prior treatment, regardless of tumor type1

ASCO-CAP, American Society of Clinical Oncology–College of American Pathologists; BTC, biliary tract cancer; CRC, colorectal cancer; ECOG, Eastern Cooperative Oncology Group; HER2, human epidermal growth factor receptor 2; ICR, independent central review; IHC, immunohistochemistry; ILD, interstitial lung disease; IV, intravenous; mCRC, metastatic colorectal cancer; mNSCLC, metastatic non-small cell lung cancer; NSCLC, non-small cell lung cancer; Q3W, every 3 weeks; RECIST, Response Evaluation Criteria in Solid Tumors.

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 HER2-positive (IHC3+) 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.

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 one 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 (IHC3+) and Other Solid Tumors (5.4 mg/kg)

In patients with 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 1.0% 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 one 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 one level.

Solid Tumors (IHC3+) and Other Solid Tumors (5.4 mg/kg)

In patients with solid tumors treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 63% of patients. Seventeen 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% 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 (IHC3+) and Other Solid Tumors (5.4 mg/kg)

In patients with solid tumors treated with ENHERTU 5.4 mg/kg, LVEF decrease was reported in 3.8% of patients, of which 0.6% were Grade 3.

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 one level.

Adverse Reactions

Solid Tumors (IHC3+) 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 1799 patients in Study DS8201-A-J101 (NCT02564900), DESTINY-Breast01, DESTINY-Breast02, DESTINY-Breast03, DESTINY-Breast04, DESTINY-Lung01, DESTINY-Lung02, DESTINY-CRC02, and DESTINY-PanTumor02. Among these patients, 65% 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 nausea (73%), decreased white blood cell count (70%), decreased hemoglobin (66%), decreased neutrophil count (63%), decreased lymphocyte count (58%), fatigue (56%), decreased platelet count (48%), increased aspartate aminotransferase (47%), increased alanine aminotransferase (43%), vomiting (40%), increased blood alkaline phosphatase (38%), alopecia (34%), constipation (33%), decreased appetite (32%), decreased blood potassium (31%), diarrhea (29%), musculoskeletal pain (24%), and abdominal pain (20%).

HER2-Positive (IHC3+) Unresectable or Metastatic Solid Tumors

The safety of ENHERTU was evaluated in 347 adult patients with unresectable or metastatic HER2-positive (IHC3+) 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 one 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 or older and 9% were 75 years or older. 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.

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 HER2-positive (IHC3+) 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.

References
  • ENHERTU. Prescribing information. Daiichi Sankyo, Inc.; 2024.
  • Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: primary results from the DESTINY-PanTumor02 phase II trial. J Clin Oncol. 2024;42(1):47-58.
  • Li BT, Smit EF, Goto Y, et al. Trastuzumab deruxtecan in HER2-mutant non–small-cell lung cancer. N Engl J Med. 2022;386(3):241-251.
  • Meric-Bernstam F, Makker V, Oaknin A, et al. Protocol for: Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: primary results from the DESTINY-PanTumor02 phase II trial. J Clin Oncol. 2024;42(1):47-58.
  • Li BT, Smit EF, Goto Y, et al. Protocol for: Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. N Engl J Med. 2022;386(3):241-251.
  • Protocol for: Trastuzumab deruxtecan in participants with HER2-overexpressing advanced or metastatic colorectal cancer (DESTINY-CRC02). ClinicalTrials.gov identifier: NCT04744831. Updated January 22, 2024. Accessed January 24, 2024. https://clinicaltrials.gov/study/NCT04744831
  • Data on file. Daiichi Sankyo, Inc. Basking Ridge, NJ.
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