Skip to content

DESTINY-Lung02 Trial

DESTINY-Lung02 Trial

ENHERTU was granted accelerated approval based on DESTINY-Lung02

A Phase 2, multicenter, multicohort, randomized, blinded, dose-optimization trial1-3

Eligible adult patients were required to have:

  • Unresectable or metastatic non-squamous NSCLC
  • Presence of an activating HER2 (ERBB2) mutation in a tumor specimena
  • Disease progression after a prior systemic therapy

Randomized 2:1

ENHERTU 5.4 mg/kg IV Q3W (n=101)

  • Interim analysis from a prespecified patient cohort (n=52)

ENHERTU 6.4 mg/kg IV Q3W (n=50)

Treated until disease progression or unacceptable toxicityb

 

Major efficacy outcomes1

  • ORR (BICR based on RECIST v1.1)
  • DOR

Select exclusion criteria1

  • History of steroid-dependent ILD/pneumonitis
  • Clinically significant cardiac disease
  • Clinically active brain metastasesc
  • ECOG performance status >1

Only the results for the recommended dose of 5.4 mg/kg are described due to increased toxicity observed with the higher dose in patients with NSCLC, including ILD/pneumonitis1

aPatients were prospectively selected for treatment with ENHERTU based on the presence of activating HER2 (ERBB2) mutations by local testing using tissue. Samples from another study were retrospectively tested using Oncomine™ Dx Target Test (Life Technologies Corporation, Tissue-test) and Guardant360® CDx test (Guardant Health Inc., Plasma test).1

bRadiographic tumor assessments were obtained every 6 weeks.1

cPatients with clinically inactive brain metastases were included in DESTINY-Lung02. Clinically active brain metastases were defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms.2

 

Patient characteristics

ENHERTU was studied in a range of patients with activating HER2-mutant 2L mNSCLC1

Select patient demographics and clinical characteristics1

Patient characteristics ENHERTU
(n=52)
Median age (range) 58 (30-78)
Sex Female 69%
Race Asian 79%
White 12%
Other 10%
ECOG PS 0 29%
1 71%
Location of HER2 mutation Kinase domain 94%
Extracellular domain 6%
Histology Adenocarcinoma 96%
Median number of prior regimens (range) 2 (1-12)
Previous therapies Platinum-based therapy 100%
Immunotherapy 71%
Platinum therapy + immunotherapy 44%
Stable brain metastases at baseline 33%
Smoking history Former 50%
Never 50%

HER2 mutations are more commonly found in patients with NSCLC who are younger, female, and have never smoked4

2L, second line; BICR, blinded independent central review; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; ERBB2, erb-b2 receptor tyrosine kinase 2; HER2, human epidermal growth factor receptor 2; ILD, interstitial lung disease; IV, intravenous; mNSCLC, metastatic non-small cell lung cancer; NSCLC, non-small cell lung cancer; ORR, objective response rate; 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 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 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.

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. Fatal outcomes due to ILD and/or pneumonitis occurred in 1.0% of patients treated with ENHERTU. Median time to first onset was 6 months (range: 0.9 to 32).

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.

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. Sixteen 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 0.9% 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 3.9% of patients, of which 0.4% 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

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 1388 patients in DESTINY-Lung02 and other clinical trials. Among these patients, 68% were exposed for >6 months and 42% were exposed for >1 year. In this pooled safety population, the most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (75%), decreased white blood cell count (71%), decreased hemoglobin (67%), decreased neutrophil count (65%), decreased lymphocyte count (57%), fatigue (56%), decreased platelet count (48%), increased aspartate aminotransferase (45%), increased alanine aminotransferase (43%), vomiting (42%), increased blood alkaline phosphatase (39%), alopecia (39%), constipation (35%), decreased appetite (32%), hypokalemia (30%), diarrhea (28%), and musculoskeletal pain (26%).

Unresectable or Metastatic HER2-Mutant NSCLC (5.4 mg/kg)

DESTINY-Lung02 evaluated two 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 unresectable or metastatic HER2-mutant NSCLC who received ENHERTU 5.4 mg/kg intravenously every three 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, hypokalemia, 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 unresectable or metastatic HER2-mutant 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.; 2024.
  • Trastuzumab deruxtecan in participants with HER2-mutated metastatic non-small cell lung cancer (NSCLC) (DESTINY-LUNG02). ClinicalTrials.gov identifier: NCT04644237. Updated October 12, 2022. Accessed April 3, 2022. https://clinicaltrials.gov/ct2/show/NCT04644237
  • Smit EF, Li BT, Mazieres J, et al. Trastuzumab deruxtecan (T-DXd) in patients with HER2-mutated (HER2m) metastatic non–small cell lung cancer (NSCLC): a phase 2 study (DESTINY-Lung02). Poster presented at: ESMO Congress 2021; September 16-21, 2021.
  • 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
Back to top