Fam-trastuzumab deruxtecan, an anti-human epidermal growth factor receptor type 2 (anti- HER2 ) antibody-drug conjugate consisting of a humanized IgG1 monoclonal antibody (trastuzumab) covalently linked to a type I DNA topoisomerase inhibitor DXd (an exatecan derivative), is an antineoplastic agent.1, 2, 3, 4, 6, 7
Fam-trastuzumab deruxtecan-nxki is used in combination with pertuzumab for the first-line treatment of adults with unresectable or metastatic human epidermal growth factor receptor type 2 (HER2)-positive (immunohistochemistry [IHC] 3+ or in situ hybridization [ISH] positive) breast cancer, as determined by an FDA-approved test.1, 14
Fam-trastuzumab deruxtecan-nxki is used as monotherapy for the treatment of adults with unresectable or metastatic HER2-positive (IHC 3+ or ISH+) breast cancer who have received a prior anti-HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy.1, 2, 15, 16
Fam-trastuzumab deruxtecan-nxki is also used as monotherapy for the treatment of adults with unresectable or metastatic hormone receptor-positive (HR+) HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer, as determined by an FDA-approved test, that has progressed on one or more endocrine therapies in the metastatic setting.1, 17
Fam-trastuzumab deruxtecan-nxki is also used for the treatment of adults with HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-approved test, who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy.1, 18
HER2-Positive Metastatic Breast Cancer
Combination Therapy with Pertuzumab
Efficacy of fam-trastuzumab deruxtecan-nxki in combination with pertuzumab for the first-line treatment of HER2-positive metastatic breast cancer was evaluated in a phase 3, randomized, multicenter study (DESTINY-Breast09) in 1157 adults with HER2-positive (defined as HER2 IHC 3+ or ISH positive) advanced or metastatic breast cancer.1, 14 Patients received no prior chemotherapy or HER2-directed therapy for metastatic disease; if they had received neoadjuvant or adjuvant HER2-targeted therapy, a disease-free interval of more than 6 months between completion of systemic therapy and the diagnosis of advanced or metastatic disease was required for eligibility.1, 14 Patients were excluded if they had a history of interstitial lung disease (ILD)/pneumonitis requiring treatment with steroids, ILD/pneumonitis at screening, symptomatic brain metastases, or a history of clinically significant cardiac disease.1 Patients were stratified by prior treatment status (de novo vs recurrent), hormone receptor status, and PIK3CA mutation status, and then randomized to receive trastuzumab deruxtecan 5.4 mg/kg plus pertuzumab, THP (taxane [docetaxel or paclitaxel], trastuzumab, and pertuzumab), or an investigational therapy by IV infusion every 3 weeks until unacceptable toxicity or disease progression.1 Patients with HR+ disease were allowed to receive concurrent endocrine therapy after 6 cycles of trastuzumab deruxtecan or after discontinuation of the taxane in the THP arm.1 The median age of patients was 54 years (range: 20-88).1 All patients were female; 50% were Asian, 37% were White, 52% had de novo disease, 48% had recurrent disease, 53% were HR-positive, 47% were HR-negative, and 31% of patients had a PIK3CA mutation.1 The primary efficacy outcome was progression-free survival (as assessed by blinded independent central review [BICR]) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1).1, 14 Overall survival and confirmed objective response rate were also assessed.1 At the prespecified interim analysis, patients receiving fam-trastuzumab deruxtecan-nxki and pertuzumab had substantially prolonged progression-free survival compared with those receiving THP (median progression-free survival of 40.7 versus 26.9 months, respectively).1, 14 The objective response rate was 87% in the trastuzumab deruxtecan and pertuzumab group and 81% in the THP group.1 Overall survival data were not mature at the time of data analysis, with 16% of deaths occurring across both groups in the overall population.1
Efficacy of fam-trastuzumab deruxtecan-nxki as monotherapy for the treatment of HER2-positive metastatic breast cancer was evaluated in 3 multicenter, open-label studies (DESTINY-Breast03, DESTINY-Breast02, and DESTINY-Breast01) in adults with HER2-positive (IHC 3+ or ISH positive) unresectable and/or metastatic breast cancer.1, 2, 15, 16
The DESTINY-Breast03 study evaluated efficacy and safety of trastuzumab deruxtecan versus trastuzumab emtansine in 524 patients with HER2-positive, unresectable or metastatic breast cancer who were previously treated with trastuzumab and taxane therapy for metastatic disease or who developed disease recurrence during or within 6 months after neoadjuvant or adjuvant therapy.1, 15 Patients were excluded if they had a history of ILD/pneumonitis requiring treatment with steroids, ILD/pneumonitis at screening, clinically significant cardiac disease, or untreated and symptomatic brain metastases.1, 15 Patients were stratified by hormone receptor status, prior treatment with pertuzumab, and visceral versus non-visceral disease, and then were randomized to receive trastuzumab deruxtecan 5.4 mg/kg or trastuzumab emtansine 3.6 mg/kg by IV infusion every 3 weeks; treatment was continued until unacceptable toxicity or disease progression.1, 15 The primary efficacy outcomes were progression-free survival (as assessed by BICR) according to RECIST 1.1 and overall survival; confirmed objective response rate was assessed as an additional outcome measure.1, 15 The median age of patients enrolled in the study was 54 years; 60% were Asian, 27% were White, and all patients had an ECOG performance status of 0 or 1 at baseline.1 Most patients (73%) had visceral disease, 16% had brain metastases at baseline, 52% had HR+ disease, and 48% had received one line of prior systemic therapy in the metastatic setting.1 At the time of analysis, median progression-free survival was 6.8 months in the trastuzumab emtansine group and had not been reached in the trastuzumab deruxtecan group; median overall survival had not been reached in both treatment groups, with 72 (28%) overall survival events in the trastuzumab deruxtecan group and 97 (37%) overall survival events in the trastuzumab emtansine group.1 The confirmed objective response rate was 82.7% in the trastuzumab deruxtecan group and 36.1% in the trastuzumab emtansine group.1 The overall survival benefit with trastuzumab deruxtecan was consistent across subgroups analyzed, including presence of baseline brain metastases, previous treatment with pertuzumab, presence of baseline visceral disease, and hormone receptor status.15
In the DESTINY-Breast02 study,608 patients with HER2-positive, unresectable and/or metastatic breast cancer previously treated with trastuzumab emtansine were randomized 2:1 to receive trastuzumab deruxtecan 5.4 mg/kg by IV infusion every 3 weeks or treatment of physician's choice (trastuzumab plus capecitabine or lapatinib plus capecitabine); treatment was continued until unacceptable toxicity or disease progression.1, 16 Randomization was stratified by hormone receptor status, prior treatment with pertuzumab, and visceral versus non-visceral disease.1, 16 The primary efficacy outcomes were progression-free survival (as assessed by BICR) according to RECIST 1.1 and overall survival.1 The median age of patients was 54 years (range: 22-88); 63% were White, 29% were Asian, and 99% had an ECOG performance status of 0 or 1 at baseline.1 Most patients (78%) had visceral disease, 18% had brain metastases at baseline, 59% were HR+, and 5% had received one prior systemic therapy in the metastatic setting.1 The median follow-up was 21.5 months in the trastuzumab deruxtecan group and 18.6 months in the treatment of physician's choice group.16 Median progression-free survival was substantially prolonged in patients receiving trastuzumab deruxtecan compared with those receiving treatment of physician's choice (17.8 versus 6.9 months, respectively).1, 16 Overall survival was also improved with trastuzumab deruxtecan compared with treatment of physician's choice (median of 39.2 versus 26.5 months).1 The confirmed objective response rate was 69.7% in the fam-trastuzumab deruxtecan-nxki group and 29.2% in the group receiving treatment of physician's choice.1
In the DESTINY-Breast01 study, 184 patients with HER2-positive, unresectable and/or metastatic breast cancer who were previously treated with at least 2 prior anti-HER2-based regimens received trastuzumab deruxtecan 5.4 mg/kg by IV infusion every 3 weeks.1, 2 Treatment was continued until disease progression or unacceptable toxicity occurred or the patient withdrew from the study.1, 2 The study excluded patients with active brain metastases, ILD or history of ILD requiring treatment, or history of clinically significant cardiac disease.1 The primary efficacy end points were objective response rate (as evaluated by an independent central review) according to RECIST 1.1 and duration of response.1, 2, 8 The median age of patients was 55 years (range: 28-96 years); 99% had a baseline ECOG performance status of 0 or 1, 55% were White, 38% were Asian, and 53% had HR+ tumors.1 Most patients (92%) had visceral disease, 29% had bone metastases, and 13% had brain metastases.1 Patients enrolled in the study received a median of 5 prior systemic therapies for locally advanced or metastatic disease; all patients had received trastuzumab or ado-trastuzumab emtansine, and 66% had received pertuzumab.1, 2 At a median follow-up of 11.1 months, the objective response rate was 60.3%; complete response was achieved in 4.3% of patients.1 The median duration of response was 14.8 months.1, 2
HER2-Low and HER2-Ultralow Metastatic Breast Cancer
Efficacy of fam-trastuzumab deruxtecan-nxki in the treatment of HER2-low and HER2-ultralow metastatic breast cancer was evaluated in 2 multicenter, randomized, open-label studies (DESTINY-Breast06 and DESTINY-Breast04).1
The DESTINY-Breast06 study included 866 adults with HR+, HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) metastatic breast cancer.1, 17 Patients were eligible for the study if they had disease progression after receiving at least 2 previous lines of endocrine therapy for metastatic disease; patients who had received one prior line of endocrine therapy in the metastatic setting were also eligible if they had disease recurrence within 24 months after initiation of adjuvant endocrine therapy, or if they had disease progression within 6 months after initiating first-line endocrine therapy in combination with a CDK 4/6 inhibitor in the metastatic setting.1, 17 Patients who were previously treated with chemotherapy in the neoadjuvant or adjuvant setting were also eligible if they had a disease-free interval greater than 12 months.1, 17 The study excluded patients who received prior chemotherapy for advanced or metastatic disease, and those with a history of ILD/pneumonitis requiring treatment with steroids or ILD/pneumonitis at screening, uncontrolled or significant cardiovascular disease, or untreated and symptomatic brain metastases.1, 17 Patients were stratified by prior CDK4/6 inhibitor use, prior taxane use in the non-metastatic setting, and HER2 IHC status, and then randomized to receive trastuzumab deruxtecan 5.4 mg/kg by IV infusion every 3 weeks or physician's choice of single agent chemotherapy (capecitabine, nab-paclitaxel, or paclitaxel); treatment was continued until disease progression or unacceptable toxicity.1, 17 The primary outcome measure was progression-free survival in the HER2-low population (assessed by BICR) according to RECIST 1.1.1, 17 Additional outcomes were progression-free survival in the intention-to-treat population, which included all patients who underwent randomization (both HER2-low and HER-2 ultralow patients), overall survival in HER2-low patients, and overall survival in the overall population.1, 17 The median age of patients was 57 years (range: 28-87); 53% were White and 35% were Asian.1 Most (98%) of the patients had an ECOG performance status of 0 or 1 at baseline; 18% were IHC 0 with membrane staining, 55% were IHC 1+, and 27% were IHC 2+/ISH-; 67% had liver metastases, 32% had lung metastases, 8% had brain metastases, and 3% had bone-only metastases.1 Patients received a median of 2 prior lines of endocrine therapy in the metastatic setting; 89% of patients had prior endocrine therapy in combination with CDK4/6 inhibitor treatment in the metastatic setting, and 41% had prior taxane use in the non-metastatic setting.1 Median progression-free survival in patients with HER2-low metastatic breast cancer was substantially prolonged with trastuzumab deruxtecan therapy compared with chemotherapy (13.2 versus 8.1 months, respectively); median progression-free survival in the overall population was also prolonged with trastuzumab deruxtecan (13.2 months) versus chemotherapy (8.1 months).1 Among HER2-low patients, the confirmed objective response rate was 62% in the trastuzumab deruxtecan group and 35.2% in the chemotherapy group, and in the overall population, the objective response rate was 62.6% in the trastuzumab deruxtecan group and 34.4% in the chemotherapy group.1 The analysis in patients with HER2-ultralow expression was exploratory; median progression-free survival in this prespecified exploratory population was 15.1 months in the trastuzumab deruxtecan group and 8.3 months in the chemotherapy group.1 Confirmed objective response rate was 65.7% and 30.8% in patients treated with trastuzumab deruxtecan or chemotherapy and with measurable disease at baseline, respectively.1 Median duration of response was 14.3 and 14.1 months in the trastuzumab deruxtecan and chemotherapy groups, respectively.1
The DESTINY-Breast04 study included 557 adult patients with HER2-low (IHC 1+ or IHC 2+/ISH-) unresectable or metastatic breast cancer; 494 of the patients had HR+ disease and 63 patients had hormone receptor negative (HR-) disease.1, 18 Patients were eligible for the study if they received chemotherapy for metastatic disease or had disease recurrence during or within 6 months of completing adjuvant chemotherapy.1, 18 The study excluded patients with a history of ILD/pneumonitis requiring treatment with steroids or ILD/pneumonitis at screening, clinically significant cardiac disease, or untreated or symptomatic brain metastases.1, 18 Patients with HR+ disease were required to have received at least one line of endocrine therapy or be ineligible for endocrine therapy.1 Patients were stratified by HER2 IHC status, number of previous lines of chemotherapy for metastatic disease, and HR status/prior CDK4/6 inhibitor treatment, and then randomized 2:1 to receive either trastuzumab deruxtecan 5.4 mg/kg by IV infusion every 3 weeks or physician's choice of chemotherapy (eribulin, capecitabine, gemcitabine, nab-paclitaxel, or paclitaxel).1, 18 Treatment was continued until disease progression, death, withdrawal of consent, or unacceptable toxicity.1 The primary efficacy outcome was progression-free survival in patients with HR+ breast cancer (assessed by BICR) according to RECIST 1.1.1, 18 Additional efficacy outcome measures were progression-free survival in the overall population (all randomized HR+ and HR- patients), overall survival in HR+ patients, and overall survival in the overall population.1, 18 The median age of patients was 57 years (range: 28-81); 48% were White and 40% were Asian.1 All patients had an ECOG performance status of 0 or 1 at baseline; 58% of patients were IHC 1+, 42% were IHC 2+/ISH-, 70% had liver metastases, 33% had lung metastases, and 6% had brain metastases.1 Patients in both treatment groups had a median of 3 lines of systemic treatment for metastatic disease.18 Therapy with trastuzumab deruxtecan was associated with significantly longer progression-free survival and overall survival than physician's choice of chemotherapy, regardless of the patient's hormone-receptor status.1, 18 Median progression-free survival in the HR+ cohort was 10.1 months with trastuzumab deruxtecan compared with 5.4 months with chemotherapy.1 In the overall population, median progression-free survival was 9.9 months with trastuzumab deruxtecan compared with 5.1 months with chemotherapy.1 Median overall survival in the HR+ cohort was 23.9 months in the trastuzumab deruxtecan group and 17.5 months in the chemotherapy group.18 The median overall survival among all patients was 23.4 months in the trastuzumab deruxtecan group and 16.8 months in the chemotherapy group.1 Among HR+ patients, the confirmed objective response rate was 52.9% in the trastuzumab deruxtecan group and 16.6% in the chemotherapy group, and in the overall population, the objective response rate was 52.3% in the trastuzumab deruxtecan group and 16.3% in the chemotherapy group.1 Duration of response was 10.7 months with trastuzumab deruxtecan treatment and 6.8 months with chemotherapy treatment in both the HR+ group and the overall population.1
Fam-trastuzumab deruxtecan-nxki is used as monotherapy for the treatment of adults 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.1 This indication is approved under accelerated approval based on objective response rate and duration of response.1 Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.1
Efficacy of fam-trastuzumab deruxtecan-nxki in the treatment of NSCLC was evaluated in a multicenter, multicohort, randomized, blinded, phase 2 study (DESTINY-Lung02) in patients with unresectable or metastatic HER2-mutant non-squamous NSCLC with disease progression after one prior systemic therapy.1, 11, 12 In the majority of patients, HER2 mutations were exon20 insertions in the tyrosine kinase domain.11 Patients were excluded from the study if they had a history of steroid dependent ILD/pneumonitis, clinically significant cardiac disease, or clinically active brain metastases.1, 11, 13 The study evaluated 2 dosages of fam-trastuzumab deruxtecan-nxki (5.4 mg/kg and 6.4 mg/kg by IV infusion every 3 weeks until disease progression or unacceptable toxicity).1 The primary efficacy outcomes were confirmed objective response rate (as assessed by BICR) according to RECIST 1.1 and duration of response.1 The median age of patients was 58 years (range 30-78); 69% were female; 79% were Asian, 12% were White, and 10% were other races.1 All patients had an ECOG performance status of 0 or 1; 33% had stable brain metastases, 94% had a mutation in the ERBB2 kinase domain, 6% had a mutation in the extracellular domain, and 96% had adenocarcinoma histology.1 Patients received a median of 2 prior lines of therapy; all patients received prior platinum therapy, 71% received prior immunotherapy, and 44% received both in combination.1 While the objective response rate was comparable between the 2 dosage groups, the lower dose of 5.4 mg/kg was associated with a favorable toxicity profile including a lower incidence of ILD.1 Based on results of an interim analysis conducted in 52 patients, the confirmed objective response rate was 57.7% and the median duration of response was 8.7 months in patients receiving fam-trastuzumab deruxtecan-nxki 5.4 mg/kg once every 3 weeks.1 Responses were observed across treatment arms regardless of prior systemic anticancer therapy and baseline CNS metastases.11, 12
In a previously conducted open-label, phase 2 study (DESTINY-Lung01), a trastuzumab deruxtecan dosage of 6.4 mg/kg once every 3 weeks was evaluated in 91 patients with previously treated HER2 mutation-positive metastatic NSCLC.10 At a median duration of follow-up of 13.1 months, the confirmed objective response rate (as assessed by independent central review) was 55%.10 Median duration of response was 9.3 months, median progression-free survival was 8.2 months, and median overall survival was 17.8 months.10 Despite evidence of clinical benefit, ILD occurred in 26% of patients in this study and resulted in death in 2 patients, warranting evaluation of the lower 5.4 mg/kg dose in the DESTINY-Lung02 study and subsequent FDA approval of this dose.10, 12
The American Society of Clinical Oncology (ASCO) guidelines on management of stage IV NSCLC with driver alterations addresses treatment decisions based on HER2 overexpression.13 Trastuzumab deruxtecan is one of several treatment options recommended for the treatment of patients with stage IV NSCLC with HER2 exon20 mutations.13
Fam-trastuzumab deruxtecan-nxki is used as monotherapy for the treatment of adults with locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH+) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen.1 The drug has been designated an orphan drug by FDA for the treatment of gastric cancer, including gastroesophageal junction cancer.22
Efficacy of fam-trastuzumab deruxtecan-nxki in the treatment of gastric cancer was evaluated in a multicenter, open-label, randomized phase 2 study (DESTINY-Gastric01) conducted in Japan and South Korea; the study included patients with HER2 positive (IHC 3+ or IHC 2+/ISH+), locally advanced or metastatic gastric or GEJ adenocarcinoma that had progressed on at least two prior regimens including trastuzumab, a fluoropyrimidine, and a platinum agent.1, 19 The study excluded patients with a history of treated or current ILD, history of clinically significant cardiac disease, or active brain metastases.1, 19 Patients were stratified by HER2 status, ECOG performance status, and region (Japan or South Korea), and then randomized 2:1 to receive trastuzumab deruxtecan 6.4 mg/kg by IV infusion every 3 weeks or physician's choice of chemotherapy (irinotecan 150 mg/m2 IV every 2 weeks or paclitaxel 80 mg/m2 IV weekly).1, 19 Treatment was administered until unacceptable toxicity or disease progression.1, 19 The primary efficacy outcomes were objective response rate (assessed by independent central review) according to RECIST 1.1 and overall survival in the intent-to-treat population.1, 19 Additional efficacy outcomes were progression-free survival and duration of response.1, 19 The median age of patients was 66 years (range 28-82); 76% were male and 100% were Asian.1 All patients had previously received a trastuzumab-based regimen and had an ECOG performance status of 0 or 1; 87% had gastric adenocarcinoma, 13% had GEJ adenocarcinoma, 76% were IHC 3+, 23% were IHC 2+/ISH+, 65% had inoperable advanced cancer, 35% had postoperative recurrent cancer, 54% had liver metastases, 29% had lung metastases, and 45% had received at least 3 previous therapies for locally advanced or metastatic disease.1 Confirmed objective response rate was 40.5% in patients receiving trastuzumab deruxtecan and 11.3% in patients receiving physician's choice of chemotherapy.1 Overall survival was substantially prolonged with trastuzumab deruxtecan treatment (12.5 months) compared with treatment with irinotecan or paclitaxel (8.4 months).1, 19 The median duration of response was 11.3 months in the trastuzumab deruxtecan group and 3.9 months in the group receiving physician's choice of chemotherapy.1
Fam-trastuzumab deruxtecan-nxki is used as monotherapy for the treatment of adults with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.1 This indication is approved under accelerated approval based on objective response rate and duration of response.1 Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.1
Efficacy of fam-trastuzumab deruxtecan-nxki for this indication was evaluated in 192 adult patients with previously treated unresectable or metastatic HER2-positive (IHC 3+) solid tumors who were enrolled in one of the following multicenter trials: DESTINY-PanTumor02, DESTINY-Lung01, or DESTINY-CRC02.1, 10, 20, 21 Patients in these studies had an ECOG performance status of 0 or 1 at baseline.1 Patients were excluded if they had a history of ILD/pneumonitis requiring treatment with steroids or had ILD/pneumonitis, active brain metastases, or clinically significant cardiac disease at screening.1, 20, 21 Patients received trastuzumab deruxtecan 5.4 mg/kg by IV infusion every 3 weeks; treatment was continued until disease progression, death, withdrawal of consent, or unacceptable toxicity.1 In all 3 studies, the primary efficacy outcome measure was confirmed objective response rate (as assessed by independent central review) according to RECIST 1.1; duration of response was also assessed.1
DESTINY-PanTumor02 was a multicenter, multicohort, open-label, phase 2 study that included 111 adults with locally advanced, unresectable, or metastatic HER2-positive (IHC 3+) solid tumors that progressed following at least one prior systemic regimen in the advanced/metastatic setting or that had no satisfactory alternative treatment option.1 The median age of patients was 64 years (range 23-85); 59% were female, 58% were White, and 34% were Asian.1 The median number of prior regimens in any treatment setting was 2.1
DESTINY-Lung01 was a multicenter, open-label trial that included 17 adults with previously treated, unresectable, or metastatic HER2-positive (IHC 3+) NSCLC.1, 10 The median age of patients was 59 years (range 31-74); 59% were male, 65% were White, 18% were Asian, and 12% were Black or African American.1 The median number of prior regimens in any treatment setting was 3.1
DESTINY-CRC02 was a multicenter, randomized, 2-arm, phase 2 study that included 64 patients with previously treated, unresectable or metastatic HER2-positive (IHC 3+) colorectal cancer.1, 21 To be eligible for inclusion, patients were required to have previously received fluoropyrimidine, oxaliplatin, and irinotecan, unless contraindicated.1 If clinically indicated, patients also were required to have received anti-EGFR treatment, anti-VEGF treatment, and anti-PDL1 therapy.1 The median age of patients was 58 years (range 25-78); 53% were male, 55% were Asian, and 41% were White.1 The median number of prior regimens in any treatment setting was 4.1
In patients with HER2-positive (IHC 3+) solid tumors who were assessed in these studies, the confirmed objective response rates were 51.4% in DESTINY-PanTumor02, 52.9% in DESTINY-Lung01, and 46.9% in DESTINY-CRC02.1 Median duration of response was 19.4 months in the DESTINY-PanTumor02 study, 6.9 months in the DESTINY-Lung01 study, and 5.5 months in the DESTINY-CRC02 study.1
Dispensing and Administration Precautions
Fam-trastuzumab deruxtecan-nxki is administered by IV infusion through polyolefin or polybutadiene administration sets with a 0.2 or 0.22-µm polyethersulfone (PES) or polysulfone filter.1 The drug is commercially available as a lyophilized powder that must be reconstituted and further diluted prior to IV infusion.1
Fam-trastuzumab deruxtecan-nxki should not be mixed with or administered simultaneously through the same IV line with other drugs.1
Unopened vials of fam-trastuzumab deruxtecan-nxki lyophilized powder for injection should be stored at 2-8°C in the original carton for protection from light; vials should not be frozen.1
Prior to administration, fam-trastuzumab deruxtecan-nxki lyophilized powder for injection must be reconstituted and diluted using proper aseptic technique.1 The powder for injection is reconstituted by adding 5 mL of sterile water for injection to a vial labeled as containing 100 mg of the drug to provide a solution containing 20 mg/mL.1 The vial should be gently swirled until complete dissolution of the powder occurs; the vial should not be shaken.1 The reconstituted solution should be inspected visually for particulate matter and discoloration prior to dilution and administration.1 The reconstituted solution should be clear and colorless to light yellow, and free of visible particulates.1 Reconstituted solutions of the drug should be diluted immediately since the powder for injection contains no preservative.1 If reconstituted solutions are not diluted immediately, the solution may be stored for up to 24 hours at 2-8°C.1 The reconstituted solution should be protected from light and should not be frozen.1 Any unused portions in the vial should be discarded after 24 hours.1
For preparation of the final diluted fam-trastuzumab deruxtecan-nxki solution for IV infusion, the required amount of reconstituted fam-trastuzumab deruxtecan-nxki solution should be withdrawn from the vial(s) and added to a polyvinyl chloride (PVC) or polyolefin infusion bag containing 100 mL of 5% dextrose injection; do not use sodium chloride injection.1 The final diluted fam-trastuzumab deruxtecan-nxki solution for infusion should be mixed by gentle inversion and should not be shaken.1 If diluted solutions of fam-trastuzumab deruxtecan-nxki are not administered immediately, they may be stored at room temperature for up to 4 hours (including preparation and infusion time) or at 2-8°C for up to 24 hours; diluted solutions of the drug should be allowed to reach room temperature prior to administration.1 Diluted solutions of the drug should be protected from light and should not be frozen.1
The initial dose of fam-trastuzumab deruxtecan-nxki should be administered by IV infusion over 90 minutes; subsequent doses may be administered by IV infusion over 30 minutes if prior infusions were well tolerated.1 Fam-trastuzumab deruxtecan-nxki solutions should not be administered by rapid IV injection, such as IV push or bolus. 1
If infusion-related reactions occur, slow or interrupt fam-trastuzumab deruxtecan infusion.1 If severe infusion-related reactions occur, fam-trastuzumab deruxtecan should be permanently discontinued.1
The recommended adult dosage of fam-trastuzumab deruxtecan-nxki for the treatment of HER2-positive, HER2-low, or HER2-ultralow metastatic breast cancer is 5.4 mg/kg administered as an IV infusion every 3 weeks.1 Treatment should be continued until disease progression or unacceptable toxicity.1
The recommended adult dosage of fam-trastuzumab deruxtecan-nxki in combination with pertuzumab for the treatment of HER2-positive metastatic breast cancer is 5.4 mg/kg administered as an IV infusion every 3 weeks.1 In cycle 1, the fam-trastuzumab deruxtecan-nxki dose should be followed 30 minutes later by pertuzumab 840 mg.1 In subsequent cycles, the fam-trastuzumab deruxtecan-nxki dose should be followed 30 minutes later by pertuzumab 420 mg.1 Treatment should be continued until disease progression or unacceptable toxicity.1
If a dose is missed or delayed, the dose should be administered as soon as possible; do not wait until the next planned cycle.1 The schedule of administration should be adjusted to maintain a 3-week interval between doses.1
The recommended adult dosage of fam-trastuzumab deruxtecan-nxki for the treatment of HER2-mutant unresectable or metastatic NSCLC is 5.4 mg/kg administered as an IV infusion every 3 weeks.1 Treatment should be continued until disease progression or unacceptable toxicity.1
If a dose is missed or delayed, the dose should be administered as soon as possible; do not wait until the next planned cycle.1 The schedule of administration should be adjusted to maintain a 3-week interval between doses.1
The recommended adult dosage of fam-trastuzumab deruxtecan-nxki for the treatment of HER2-positive locally advanced or metastatic gastric cancer as monotherapy is 6.4 mg/kg administered as an IV infusion once every 3 weeks.1 Treatment should be continued until disease progression or unacceptable toxicity1 .
If a dose is missed or delayed, the dose should be administered as soon as possible; do not wait until the next planned cycle.1 The schedule of administration should be adjusted to maintain a 3-week interval between doses.1
The recommended adult dosage of fam-trastuzumab deruxtecan-nxki for the treatment of HER2-positive (IHC 3+) unresectable or metastatic solid tumors is 5.4 mg/kg administered as an IV infusion once every 3 weeks.1 Treatment should be continued until disease progression or unacceptable toxicity.1
If a dose is missed or delayed, the dose should be administered as soon as possible; do not wait until the next planned cycle.1 The schedule of administration should be adjusted to maintain a 3-week interval between doses.1
Dosage Modification for Toxicity
If dosage reduction is required, the dosage of fam-trastuzumab deruxtecan should be reduced as described in Table 1.1 Dosage of fam-trastuzumab deruxtecan should not be re-escalated following a dosage reduction.1
Dosage Reduction Level | Breast Cancer, NSCLC, and IHC3+ Solid Tumors | Gastric Cancer |
|---|---|---|
Recommended starting dose | 5.4 mg/kg | 6.4 mg/kg |
First dose reduction | 4.4 mg/kg | 5.4 mg/kg |
Second dose reduction | 3.2 mg/kg | 4.4 mg/kg |
Requirement for further dose reduction | Discontinue treatment | Discontinue treatment |
The following recommended dosage modification for fam-trastuzumab deruxtecan toxicity table (Table 2) indicates the recommended dosage modification (i.e., temporary interruption of therapy, dosage reduction, discontinuance of therapy) for adverse effects according to severity.1
Adverse Reaction and Severity | Dosage Modification |
|---|---|
Asymptomatic interstitial lung disease (ILD) or pneumonitis (Grade 1) | Withhold therapy and consider initiating corticosteroid therapy If ILD or pneumonitis resolves in ≤28 days of onset, resume therapy at same dosage If ILD or pneumonitis does not resolve within 28 days of onset, resume therapy at a reduced dosage by one dose level (see Table 1) |
Symptomatic ILD or pneumonitis (Grade 2 or greater) | Permanently discontinue therapy and promptly initiate corticosteroid therapy |
Neutropenia Grade 3 (absolute neutrophil count [ANC] 500-1000/mm3) | Withhold therapy; when neutropenia improves to grade 2 or less, resume therapy at same dose |
Neutropenia Grade 4 (ANC <500/mm3) | Withhold therapy; when neutropenia improves to grade 2 or less, resume therapy at reduced dosage by one dose level (see Table 1) |
Febrile neutropenia (ANC <1000/mm3 with fever >38.3ºC or ≥38ºC for >1 hour) | Withhold therapy; when febrile neutropenia resolves, resume therapy at reduced dosage by one dose level (see Table 1) |
Thrombocytopenia Grade 3 (platelets 25 to <50 × 109/L) | Withhold therapy; when thrombocytopenia resolves to grade 1 or less, resume therapy at same dosage |
Thrombocytopenia Grade 4 (platelets <25 × 109/L) | Withhold therapy; when thrombocytopenia resolves to grade 1 or less, resume therapy at reduced dosage by one dose level (see Table 1) |
Left ventricular ejection fraction (LVEF) >45% with an absolute decrease from baseline of 10-20% | Continue therapy at same dosage |
LVEF decreases to 40-45% with an absolute decrease from baseline of <10% | Continue therapy at same dosage and reassess LVEF within 3 weeks. |
LVEF decreases to 40-45% with an absolute decrease from baseline of 10-20% | Withhold therapy and reassess LVEF within 3 weeks If LVEF improves to within 10% of baseline, resume therapy at same dosage If LVEF does not improve to within 10% of baseline, permanently discontinue therapy |
LVEF decreases to <40% or absolute decrease from baseline of >20% | Withhold therapy and reassess LVEF within 3 weeks If LVEF <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue therapy |
Symptomatic congestive heart failure | Permanently discontinue therapy |
Dosage adjustment is not necessary in patients with mild (total bilirubin concentration not exceeding the upper limit of normal [ULN] with AST concentration exceeding the ULN, or total bilirubin concentration exceeding the ULN, but no more than 1.5 times the ULN, with any AST concentration) or moderate (total bilirubin concentration exceeding 1.5 times the ULN, but no more than 3 times the ULN, with any AST concentration) hepatic impairment; however, patients with moderate hepatic impairment should be closely monitored for signs of toxicity from the type I DNA topoisomerase inhibitor component of the antibody-drug conjugate.1
The manufacturer states that the recommended dosage in patients with severe hepatic impairment (total bilirubin concentration exceeding 3 times the ULN with any AST concentration) has not been established.1
Dosage adjustment is not necessary in patients with mild (creatinine clearance of 60-89 mL/minute) or moderate (creatinine clearance of 30-59 mL/minute) renal impairment.1
The manufacturer states that the recommended dosage in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) has not been established.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, has been reported in patients receiving fam-trastuzumab deruxtecan-nxki and a boxed warning about this risk has been included in the prescribing information for the drug.1 In clinical trials evaluating fam-trastuzumab deruxtecan-nxki 5.4 mg/kg monotherapy in patients with HER2-positive, HER2-low, and HER2-ultralow metastatic breast cancer, HER2-mutant NSCLC, and solid tumors (including IHC 3+), ILD or pneumonitis occurred in 12% of patients receiving the drug and was fatal in 0.9% of patients.1 The median time to onset of ILD or pneumonitis was 5.5 months (range 0.9-31.5 months).1 In clinical trials evaluating fam-trastuzumab deruxtecan-nxki 5.4 mg/kg in combination with pertuzumab in patients with HER2-positive breast cancer, ILD occurred in 12% of patients and was fatal in 0.5% of patients.1 The median time to onset was 8 months (range 0.6-33.8 months).1 In patients with HER2-positive locally advanced or metastatic gastric cancer receiving fam-trastuzumab deruxtecan-nxki 6.4 mg/kg, ILD was reported in 10% of patients; median time to onset was 2.8 months (range: 1.2-21 months).
Patients receiving fam-trastuzumab deruxtecan should be monitored for manifestations of ILD.1 If ILD is suspected, patients should be evaluated for ILD using radiographic imaging; consultation with a pulmonologist should be considered.1
In patients who develop asymptomatic (grade 1) ILD, systemic corticosteroid therapy should be considered (at least 0.5 mg/kg of prednisolone daily [or equivalent])9 followed by gradual tapering (e.g., over 4 weeks) of the corticosteroid dosage once symptoms improve.1 In patients who develop symptomatic (grade 2 or greater) ILD, systemic corticosteroid therapy should be initiated (at least 1 mg/kg of prednisolone daily [or equivalent])9 and continued for at least 14 days followed by gradual tapering (e.g., over at least 4 weeks) once symptoms improve.1 Temporary interruption, dosage reduction, or discontinuance of fam-trastuzumab deruxtecan may be necessary if ILD occurs.1
Fetal/Neonatal Morbidity and Mortality
Fam-trastuzumab deruxtecan may cause fetal harm if administered to pregnant women based on its mechanism of action and a boxed warning about this risk has been included in the prescribing information for the drug.1 There are no adequate and well-controlled studies to date in pregnant women; however, oligohydramnios, fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death have been reported in women receiving an anti-human epidermal growth factor receptor type 2 (anti- HER2 ) antibody during pregnancy in postmarketing experience.1 Based on the mechanism of action of the type I DNA topoisomerase inhibitor DXd (derivative of exatecan), embryotoxic and fetotoxic effects may occur.1
Pregnancy should be avoided during fam-trastuzumab deruxtecan therapy.1 The manufacturer states that a pregnancy test should be performed prior to initiation of fam-trastuzumab deruxtecan in women of reproductive potential and that such women should be advised to use effective contraceptive methods while receiving the drug and for at least 7 months after the last dose.1 In addition, men with such female partners should use effective contraceptive methods while receiving the drug and for at least 4 months after the last dose.1 If fam-trastuzumab deruxtecan is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.1
Women who received fam-trastuzumab deruxtecan during pregnancy or within 7 months prior to conception should be monitored for oligohydramnios.1 If oligohydramnios occurs, fetal testing appropriate for gestational age and according to standards of care should be performed.1
Other Warnings and Precautions
Severe neutropenia, including febrile neutropenia, has been reported in patients receiving fam-trastuzumab deruxtecan.1 In clinical trials evaluating fam-trastuzumab deruxtecan-nxki 5.4 mg/kg in patients with metastatic breast cancer, NSCLC, and solid tumors, decreased neutrophil count was reported in 65% of patients and febrile neutropenia was reported in 1.2% of patients; 19% had grade 3 or 4 decreased neutrophil count.1 Median time to first onset of decreased neutrophil count was 22 days (range: 2-939 days).1 In patients receiving fam-trastuzumab deruxtecan-nxki 5.4 mg/kg in combination with pertuzumab, decreased neutrophil count occurred in 79% of patients and febrile neutropenia was reported in 2.6% of patients; 29% had grade 3 or 4 decreased neutrophil count.1 Median time to first onset of decreased neutrophil count was 22 days (range: 5-994 days).1 In patients with locally advanced or metastatic HER2-positive gastric cancer treated with fam-trastuzumab deruxtecan-nxki 6.4 mg/kg, decreased neutrophil count was reported in 72% of patients; 51% of cases were grade 3 or 4.1 Median time to first onset of decreased neutrophil count was 16 days (range: 4-187 days).1 Febrile neutropenia was reported in 4.8% of patients.1
Complete blood cell counts (CBCs) should be monitored at baseline and prior to each dose of fam-trastuzumab deruxtecan and as clinically indicated.1 Temporary interruption of fam-trastuzumab deruxtecan therapy or dosage reduction may be necessary if neutropenia occurs.1
Patients receiving fam-trastuzumab deruxtecan are at increased risk of developing left ventricular dysfunction.1 Decreases in left ventricular ejection fraction (LVEF) have been reported in patients receiving anti- HER2 antibody therapy, including fam-trastuzumab deruxtecan.1 In clinical trials evaluating fam-trastuzumab deruxtecan-nxki 5.4 mg/kg in patients with metastatic breast cancer, NSCLC, and solid tumors, decreased LVEF occurred in 4.6% of patients, of which 0.6% were grade 3 or 4.1 In patients who received fam-trastuzumab deruxtecan-nxki 5.4 mg/kg in combination with pertuzumab, decreased LVEF was reported in 11% of patients, of which 2.1% were grade 3 or 4.1 In clinical trials of patients with HER2-positive locally advanced or metastatic gastric cancer receiving fam-trastuzumab deruxtecan-nxki 6.4 mg/kg, clinically important heart failure was not reported; however, 8% of patients were found to have an asymptomatic grade 2 decrease in LVEF.1
Fam-trastuzumab deruxtecan has not been studied in patients with a history of clinically significant cardiac disease or LVEF less than 50% prior to initiation of treatment.1, 8
LVEF should be assessed prior to initiation of fam-trastuzumab deruxtecan, regularly during therapy, and as clinically indicated.1 If left ventricular dysfunction occurs, reassessment of left ventricular function within 3 weeks may be necessary.1 Temporary interruption or discontinuance of fam-trastuzumab deruxtecan may be necessary if left ventricular dysfunction occurs.1
There is potential for immunogenicity with fam-trastuzumab deruxtecan therapy.1 Among patients who received fam-trastuzumab deruxtecan as a single agent over a 6 to 9 month treatment period in clinical trials, anti-drug antibodies developed in 2.2% of patients who received a dosage of 5.4 mg/kg every 3 weeks and in 2.6% of patients who received a dosage of 6.4 mg/kg every 3 weeks.1 Among patients who received fam-trastuzumab deruxtecan (5.4 mg/kg every 3 weeks) in combination with pertuzumab in clinical trials, anti-drug antibodies were detected in 7.7% of patients.1 Among patients who developed anti-drug antibodies, neutralizing antibodies were detected in 6% of patients who received fam-trastuzumab deruxtecan as a single agent and in 18% of patients who received the drug in combination with pertuzumab.1 No clinically important effects on the pharmacokinetics or safety of fam-trastuzumab deruxtecan-nxki have been observed; because of the low incidence of antibody development, the effects of antibodies on the effectiveness of the drug is not known.1
Fam-trastuzumab deruxtecan may cause fetal harm if administered to pregnant women based on its mechanism of action.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Women who received fam-trastuzumab deruxtecan during pregnancy or within 7 months prior to conception should be monitored for oligohydramnios.1 If oligohydramnios occurs, fetal testing appropriate for gestational age and according to standards of care should be performed.1
It is not known whether fam-trastuzumab deruxtecan is distributed into human milk.1 The effects of the drug on nursing infants or on milk production also are unknown.1
Because of the potential for adverse reactions to fam-trastuzumab deruxtecan in nursing infants, women should be advised to discontinue breast-feeding while receiving the drug and for 7 months after the last dose.1
Females and Males of Reproductive Potential
Because of the potential for fetal harm, verify pregnancy status of females of reproductive potential prior to initiation of fam-trastuzumab deruxtecan.1 Advise females of reproductive potential to use effective contraception during treatment with fam-trastuzumab deruxtecan and for 7 months after the last dose.1 Because of the potential for genotoxicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment with fam-trastuzumab deruxtecan and for 4 months after the last dose.1
Based on findings from animal studies, fam-trastuzumab deruxtecan may impair male fertility.1 In repeat-dose toxicity studies, spermatid retention, reduced reproductive organ weights, tubular atrophy/degeneration in testes, and hypospermia were observed in animals receiving fam-trastuzumab deruxtecan-nxki at exposure levels above human exposure at the recommended dosa the effects of fam-trastuzumab deruxtecan on fertility appeared to be reversible 3 months after discontinuance of the drug.1
Safety and efficacy of fam-trastuzumab deruxtecan-nxki have not been established in pediatric patients.1
Juvenile animal studies have not been conducted with fam-trastuzumab deruxtecan-nxki.1 In a 6-week toxicity study in rats, IV administration of fam-trastuzumab deruxtecan-nxki at doses higher than the human recommended doses resulted in dental toxicities (e.g., incisor tooth toxicity, including necrosis and degeneration of enamel, abnormal dentin formation, hemorrhage in the subenamel organ tissue, root fracture).1
In clinical trials evaluating fam-trastuzumab deruxtecan-nxki in patients with HER2-positive, HER2-low, or HER2-ultralow breast cancer, no difference in efficacy was observed between patients ≥65 years of age and younger adult patients; however, grade 3-4 adverse reactions occurred more frequently in patients ≥65 years of age than younger patients.1 In studies evaluating fam-trastuzumab deruxtecan-nxki and pertuzumab combination therapy in patients with HER2-positive unresectable or metastatic breast cancer, no overall differences in efficacy or safety were observed between patients ≥65 years of age and younger adults.1 In clinical trials of fam-trastuzumab deruxtecan-nxki for the treatment of NSCLC, gastric cancers, or solid cancers, no overall differences in efficacy or safety were observed between patients ≥65 years of age and younger adult patients..1
Population pharmacokinetic analysis suggests that the pharmacokinetics of the antibody-drug conjugate and the type I DNA topoisomerase inhibitor DXd are not substantially altered in patients with mild hepatic impairment (total bilirubin concentration not exceeding the upper limit of normal [ULN] with AST concentration exceeding the ULN, or total bilirubin concentration exceeding the ULN, but no more than 1.5 times the ULN, with any AST concentration).1
The effect of moderate (total bilirubin concentration exceeding 1.5 times the ULN, but no more than 3 times the ULN, with any AST concentration) or severe (total bilirubin concentration exceeding 3 times the ULN, but no more than 10 times the ULN, with any AST concentration) hepatic impairment on the pharmacokinetics of the antibody-drug conjugate or DXd has not been established; however, systemic exposure may be increased in patients with moderate hepatic impairment.1
Population pharmacokinetic analysis suggests that the pharmacokinetics of the antibody-drug conjugate and the type I DNA topoisomerase inhibitor DXd are not substantially altered in patients with mild (creatinine clearance of 60-89 mL/minute) or moderate (creatinine clearance of 30-59 mL/minute) renal impairment.1 The effect of severe renal impairment (creatinine clearance less than 30 mL/minute) on the pharmacokinetics of the antibody-drug conjugate or DXd has not been established.1
A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment; monitor these patients more closely.1
The most common adverse effects in patients with HER2-positive, HER2-low, and HER2-ultralow metastatic breast cancer, HER2-mutant NSCLC, and HER2-positive (including IHC 3+) solid tumors receiving fam-trastuzumab deruxtecan-nxki were decreased white blood cell count, nausea, decreased hemoglobin, decreased neutrophil count, decreased lymphocyte count, fatigue, decreased platelet count, increased aspartate aminotransferase, increased alanine aminotransferase, increased alkaline phosphatase, vomiting, alopecia, constipation, decreased potassium, decreased appetite, diarrhea, and musculoskeletal pain.1
The most common adverse effects in patients with HER2-positive metastatic breast cancer receiving fam-trastuzumab deruxtecan-nxki in combination with pertuzumab were decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, nausea, increased alanine aminotransferase, diarrhea, increased aspartate aminotransferase, decreased lymphocyte count, decreased platelet count, increased alkaline phosphatase, decreased potassium, fatigue, alopecia, vomiting, upper respiratory tract infection, constipation, decreased appetite, decreased weight, COVID-19, musculoskeletal pain, increased bilirubin, and abdominal pain.1
The most common adverse effects in patients with HER2-positive gastric cancer receiving fam-trastuzumab deruxtecan-nxki are were decreased hemoglobin, decreased white blood cell count, decreased neutrophil count, decreased lymphocyte count, decreased platelet count, nausea, decreased appetite, increased aspartate aminotransferase, fatigue, increased alkaline phosphatase, increased alanine aminotransferase, diarrhea, decreased potassium, vomiting, constipation, increased bilirubin, pyrexia, and alopecia.1
In vitro studies indicate that DXd, the type I DNA topoisomerase inhibitor component of fam-trastuzumab deruxtecan-nxki, is primarily metabolized by cytochrome P-450 (CYP) isoenzyme 3A4.1 In vitro, DXd does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A or induce CYP isoenzymes 1A2, 2B6, or 3A.1
In vitro studies indicate that DXd is not expected to inhibit organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, organic anion transport protein (OATP) 1B1, OATP1B3, multidrug and toxin extrusion (MATE) transporter 1, MATE2K, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), or bile salt export pump (BSEP) at clinically relevant concentrations.1 DXd is a substrate of OATP1B1, OATP1B3, MATE2K, P-gp, multidrug resistance protein (MRP) 1, and BCRP.1
Drugs Affecting Hepatic Microsomal Enzymes and Transport Systems
When the strong CYP3A inhibitor itraconazole (200 mg twice daily) was administered concomitantly with fam-trastuzumab deruxtecan-nxki (5.4 mg/kg every 3 weeks), AUC of fam-trastuzumab deruxtecan and DXd increased by 11 and 18%, respectively; these changes are not considered clinically meaningful.1, 8
Inhibitors of CYP3A and OATP1B
When the combined CYP3A and OATP1B inhibitor ritonavir (200 mg twice daily) was administered concomitantly with fam-trastuzumab deruxtecan-nxki (5.4 mg/kg every 3 weeks), AUC of fam-trastuzumab deruxtecan and DXd increased by 19 and 22%, respectively; these changes are not considered clinically meaningful.1, 8
Fam-trastuzumab deruxtecan, an anti-human epidermal growth factor receptor type 2 (anti- HER2 ) antibody-drug conjugate, is an antineoplastic agent.1, 2, 3, 4, 6, 7 The anti- HER2 antibody, a humanized IgG1 monoclonal antibody, is conjugated with the type I DNA topoisomerase inhibitor DXd (an exatecan derivative).1, 2, 7 A protease-cleavable maleimide tetrapeptide linker covalently binds DXd to the antibody component; the resultant complex is referred to as deruxtecan.1, 2, 4, 6 Fam-trastuzumab deruxtecan has a higher drug-to-antibody ratio (approximately 8 molecules of deruxtecan are attached to each molecule of antibody) compared with ado-trastuzumab emtansine (approximately 3-4 molecules of emtansine are attached to each molecule of antibody).1, 2, 4, 7 The antibody portion of fam-trastuzumab deruxtecan binds specifically to the extracellular domain of the HER2 receptor.1, 4 Following binding of the antibody portion of fam-trastuzumab deruxtecan to the HER2 receptor on tumor cells, the resultant complex is internalized by the cell.1, 2, 4, 6 DXd is released following cleavage of the linker by lyososomal enzymes and binds to and stabilizes DNA topoisomerase I cleavable complexes, resulting in double-stranded breaks in DNA and apoptosis.1, 4, 6
Following administration of fam-trastuzumab deruxtecan, systemic exposure to the antibody-drug conjugate and free DXd increases in a dose-proportional manner over a dose range of 3.2-8 mg/kg.1 Steady-state concentrations of the antibody-drug conjugate are achieved after 3 treatment cycles; systemic accumulation of the antibody-drug conjugate is approximately 35%.1 The anti- HER2 antibody is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.1 In vitro, DXd is metabolized by the cytochrome P-450 (CYP) 3A4 isoenzyme.1 In vitro, DXd is approximately 97% bound to plasma proteins.1 The median elimination half-life of the antibody-drug conjugate is 5.4 to 5.7 days, and the median elimination half-life of DXd is 5.4 to 6.1 days.1
The pharmacokinetics of the antibody-drug conjugate or DXd do not appear to be affected substantially by age (range: 20-96 years), race, sex, and body weight (range: 27-125 kg).1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Fam-trastuzumab deruxtecan-nxki is available only from designated specialty pharmacies and distributors.5 Contact manufacturer for additional information.5
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For Injection, for IV Infusion only | 100 mg | Daiichi Sankyo (comarketed with AstraZeneca) |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions April 10, 2026. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Daiichi Sankyo Inc. Enhertu® (fam-trastuzumab deruxtecan-nxki) injection for intravenous use prescribing information. Basking Ridge, NJ; 2025 Dec.
2. Modi S, Saura C, Yamashita T et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med. . 2020; 382:610-21. [PubMed 31825192]
3. Tamura K, Tsurutani J, Takahashi S et al. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study. Lancet Oncol . 2019; 20:816-26. [PubMed 31047803]
4. Rinnerthaler G, Gampenrieder SP, Greil R. HER2 Directed Antibody-Drug-Conjugates Beyond T-DM1 in Breast Cancer. Int J Mol Sci . 20(5):111 . 2019; 20:1-17. [PubMed 31047803]
5. Daiichi Sankyo Inc. Enhertu® Distribution. From Enhertu®4U for US Health Care Professionals website.. [Web]
6. Nakada T, Sugihara K, Jikoh T et al. The Latest Research and Development into the Antibody-Drug Conjugate, [fam-] Trastuzumab Deruxtecan (DS-8201a), for HER2 Cancer Therapy. Chem. Pharm. Bull . 2019; 67:173-85. [PubMed 31047803]
7. Sharma P. Major Strides in HER2 Blockade for Metastatic Breast Cancer. N Engl J Med. . 2020; 382:669-71.
8. US Food and Drug Administration. Center for Drug Evaluation and Research: Application number 761139Orig1s000: Multi-discipline review. 2019 Jun 11. From FDA website. [Web]
9. Daiichi Sankyo Inc. Basking Ridge, NJ: Personal communication.
10. Li BT, Smit EF, Goto Y et al. Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell Lung Cancer. N Engl J Med. 2022 Jan 20;386(3):241-251. doi: 10.1056/NEJMoa2112431. Epub 2021 Sep 18. PMID: 34534430; PMCID: PMC9066448.
11. Goto K, Goto Y, Kubo T et al. Trastuzumab Deruxtecan in Patients With HER2-Mutant Metastatic Non-Small-Cell Lung Cancer: Primary Results From the Randomized, Phase II DESTINY-Lung02 Trial. J Clin Oncol. 2023 Nov 1;41(31):4852-4863. doi: 10.1200/JCO.23.01361. Epub 2023 Sep 11. Erratum in: J Clin Oncol. 2024 Feb 1;42(4):485. doi: 10.1200/JCO.23.02574. Erratum in: J Clin Oncol. 2024 Oct 20;42(30):3635. doi: 10.1200/JCO-24-01883. PMID: 37694347; PMCID: PMC10617843.
12. Jänne PA, Goto Y, Kubo T et al. Final Analysis Results and Patient-Reported Outcomes From DESTINY-Lung02-A Dose-Blinded, Randomized, Phase 2 Study of Trastuzumab Deruxtecan in Patients With HER2-Mutant Metastatic NSCLC. J Thorac Oncol. 2025 Dec;20(12):1814-1828. doi: 10.1016/j.jtho.2025.07.129. Epub 2025 Jul 30. Erratum in: J Thorac Oncol. 2026 Feb 23:103557. doi: 10.1016/j.jtho.2026.103557. PMID: 40749900.
13. Puri S, Leighl NB, Ismaila N et al. Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, 2026.3.0. J Clin Oncol. 2026 Feb 3:JCO2502822. doi: 10.1200/JCO-25-02822. Epub ahead of print. PMID: 41632926.
14. Tolaney SM, Jiang Z, Zhang Q et al. Trastuzumab Deruxtecan plus Pertuzumab for HER2-Positive Metastatic Breast Cancer. N Engl J Med. 2025 Oct 29. doi: 10.1056/NEJMoa2508668. Epub ahead of print. PMID: 41160818.
15. Hurvitz SA, Hegg R, Chung WP et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet. 2023 Jan 14;401(10371):105-117. doi: 10.1016/S0140-6736(22)02420-5. Epub 2022 Dec 7. Erratum in: Lancet. 2023 Feb 18;401(10376):556. doi: 10.1016/S0140-6736(22)00045-9. PMID: 36495879.
16. André F, Hee Park Y, Kim SB et al. Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023 May 27;401(10390):1773-1785. doi: 10.1016/S0140-6736(23)00725-0. Epub 2023 Apr 20. Erratum in: Lancet. 2023 Dec 9;402(10418):2196. doi: 10.1016/S0140-6736(23)02709-5. Erratum in: Lancet. 2024 Mar 9;403(10430):912. doi: 10.1016/S0140-6736(24)00420-3. PMID: 37086745.
17. Bardia A, Hu X, Dent R et al. Trastuzumab Deruxtecan after Endocrine Therapy in Metastatic Breast Cancer. N Engl J Med. 2024 Dec 5;391(22):2110-2122. doi: 10.1056/NEJMoa2407086. Epub 2024 Sep 15. PMID: 39282896.
18. Modi S, Jacot W, Yamashita T et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. doi: 10.1056/NEJMoa2203690. Epub 2022 Jun 5. PMID: 35665782; PMCID: PMC10561652.
19. Shitara K, Bang YJ, Iwasa S et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N Engl J Med. 2020 Jun 18;382(25):2419-2430. doi: 10.1056/NEJMoa2004413. Epub 2020 May 29. PMID: 32469182.
20. Meric-Bernstam F, Makker V 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 Jan 1;42(1):47-58. doi: 10.1200/JCO.23.02005. Epub 2023 Oct 23. PMID: 37870536; PMCID: PMC10730032.
21. Raghav K, Siena S, Takashima A et al. Trastuzumab deruxtecan in patients with HER2-positive advanced colorectal cancer (DESTINY-CRC02): primary results from a multicentre, randomised, phase 2 trial. Lancet Oncol. 2024 Sep;25(9):1147-1162. doi: 10.1016/S1470-2045(24)00380-2. Epub 2024 Aug 5. PMID: 39116902.
22. Food and Drug Administration. Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website. [Web]