Fam-trastuzumab Deruxtecan-nxki (Enhertu)

Number: 0966

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses fam-trastuzumab deruxtecan-nxki (Enhertu) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of fam-trastuzumab deruxtecan-nxki (Enhertu) is required of all Aetna participating providers and members in applicable plan designs. For precertification of fam-trastuzumab deruxtecan-nxki (Enhertu), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

1. Criteria for Initial Approval

   Aetna considers fam-trastuzumab deruxtecan-nxki (Enhertu) medically necessary for the following indications when criteria are met:

   1. Breast Cancer

      For treatment of breast cancer when either of the following criteria are met:

      1. Member has HER2-positive breast cancer and meets all of the following criteria:

         1. The disease had no response to preoperative systemic therapy, or the disease is recurrent, metastatic, or unresectable; and
         2. The requested drug will be used as a single agent; or

      2. Member has HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer and meets all of the following criteria:

         1. The disease had no response to preoperative systemic therapy, or the disease is recurrent, metastatic, or unresectable; and
         2. The member has tried at least one prior chemotherapy in the metastatic setting or developed recurrence during or within 6 months of completing adjuvant chemotherapy; and
         3. The requested medication will be used as a single agent.

   2. Cervical Cancer

      For subsequent treatment of recurrent or metastatic HER2-positive (IHC 3+ or 2+) cervical cancer when used as a single agent.

   3. Colorectal Cancer

      For treatment of colorectal cancer (including appendiceal and anal adenocarcinoma) with HER2-amplified and RAS and BRAF wild-type disease as a single agent when the requested medication will be used as subsequent therapy for progression of advanced or metastatic disease.

   4. Endometrial Carcinoma

      For subsequent treatment of recurrent HER2-positive (IHC 3+ or 2+) endometrial carcinoma when used as a single agent.

   5. Esophageal, Gastric or Gastroesophageal Junction Adenocarcinoma

      For subsequent treatment of HER2-positive locally advanced, recurrent or metastatic esophageal, gastric or gastroesophageal junction adenocarcinoma as a single agent.

   6. Non-small cell lung cancer (NSCLC) 

      For subsequent treatment of non-small cell lung cancer with HER2 (ERBB2) mutations when both of the following criteria are met:

      1. The disease is recurrent, advanced, metastatic, or unresectable; and
      2. The requested medication will be used as a single agent.

   7. Salivary Gland Tumor

      For treatment of recurrent HER2-positive salivary gland tumor when used as a single agent.

   Aetna considers fam-trastuzumab deruxtecan-nxki experimental and investigational for all other indications.

2. Continuation of Therapy

   Aetna considers continuation of fam-trastuzumab deruxtecan-nxki (Enhertu) therapy medically necessary in members requesting reauthorization for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Dosage and Administration

Enhertu (fam-trastuzumab deruxtecan-nxki) is available for injection as 100 mg lyophilized powder in a single-dose vial for intravenous infusion only. Enhertu is not to be not substituted for or with trastuzumab or ado-trastuzumab emtansine.

• First infusion is administered over 90 minutes with subsequent infusions administered over 30 minutes if prior infusions were well tolerated.
• Permanently discontinue Enhertu in case of severe infusion reactions.

Unresectable or metastatic HER2-low breast cancer:

• The recommended dosage of Enhertu is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

Locally advanced or metastatic gastric cancer:

• The recommended dosage of Enhertu for gastric cancer is 6.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity. 

Unresectable or metastatic HER2-mutant non-small cell lung cancer (NSCLC):

• The recommended dosage of Enhertu is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

Source: Daiichi Sankyo, 2022

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
HCPCS codes covered if selection criteria are met:
J9358	Injection, fam-trastuzumab deruxtecan-nxki, 1 mg
ICD-10 codes covered if selection criteria are met:
C07	Malignant neoplasm of parotid gland
C08.0 - C08.9	Malignant neoplasm of other and unspecified major salivary glands
C15.3 - C15.9	Malignant neoplasm of esophagus
C16.0 – C16.9	Malignant neoplasm of cardia [including locally advanced metastatic gastric or gastroesophageal junction adenocarcinoma]
C18.0 – C20	Malignant neoplasm of colon and rectum [HER2-amplified and RAS and BRAF wild-type disease]
C21.0- C21.8	Malignant neoplasm of anus and anal canal
C34.00 - C34.92	Malignant neoplasm of bronchus and lung [non-small cell lung cancer with HER2 mutations]
C50.011 - C50.929	Malignant neoplasm of breast
C53.0 - C53.9	Malignant neoplasm of cervix uteri [Cervical cancer]
C54.0 – C54.9	Malignant neoplasm of corpus uteri

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• HER2-positive Breast Cancer

  Enhertu is indicated for the treatment of adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive, 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 six months of completing therapy.

• HER2-low Breast Cancer

  Enhertu is indicated for the treatment of adult patients with unresectable or metastatic HER2-low [immunohistochemistry score (IHC) 1+ or IHC 2+/ in situ hybridization test (ISH) negative] 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.

• Gastric or Gastroesophageal Junction Adenocarcinoma

  Enhertu is indicated for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.

• Non-Small Cell Lung Cancer (NSCLC)

  Enhertu is 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.

Compendial Uses

• HER2-positive breast cancer, treatment of recurrent disease
• HER2-low breast cancer, treatment of recurrent disease
• Non-small cell lung cancer with HER2 mutations, treatment of recurrent and advanced disease
• HER2-amplified and RAS and BRAF wild-type colorectal cancer (including appendiceal and anal adenocarcinoma)
• HER2-positive esophageal cancer
• HER2-positive cervical cancer
• HER2-positive endometrial carcinoma
• HER2-positive salivary gland tumor

Enhertu is a HER2-directed antibody and topoisomerase inhibitor conjugate, which targets the changes in HER2 that can potentiate cancer growth and metastases. Topoisomerise inhibitor is a chemical compound that is toxic to cancer cells. Following binding to HER2 on tumor cells, fam-trastuzumab deruxtecan-nxki undergoes internalization and intracellular linker cleavage by lysosomal enzymes. Upon release, the membranepermeable DXd causes DNA damage and apoptotic cell death (Daiichi Sankyo, 2021).

Enhertu carries a black box warning for interstitial lung disease and embryo-fetal toxicity. Interstitial lung disease (ILD) and pneumonitis, including fatal cases, have been reported with use of Enhertu. It is advised to monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms, and permanently discontinue Enhertu in all patients with Grade 2 or higher ILD/pneumonitis. The patients are to be advised of the risk and to immediately report symptoms. In addition,  exposure to Enhertu during pregnancy can cause embryo-fetal harm.The patients are to be advised of these risks and the need for effective contraception (Daiichi Sankyo, 2021). 

Warnings and precautions include neutropenia and left ventricular dysfunction (LVD). For risk of neutropenia, it is recommended to monitor complete blood counts prior to initiation of Enhertu and prior to each dose, and as clinically indicated. Manage through treatment interruption or dose reduction. For risk of LVD, it is recommended to assess LVEF prior to initiation of Enhertu and at regular intervals during treatment as clinically indicated. Manage through treatment interruption or discontinuation. Permanently discontinue Enhertu in patients with symptomatic congestive heart failure (CHF) (Daiichi Sankyo, 2021).

The most common adverse reactions (≥20%) in patients with breast cancer were nausea, white blood cell count decreased, hemoglobin decreased, neutrophil count decreased, fatigue, vomiting, alopecia, aspartate aminotransferase increased, alanine aminotransferase increased, platelet count decreased, constipation, decreased appetite, anemia, diarrhea, hypokalemia, and cough. In gastric cancer were hemoglobin decreased, white blood cell count decreased, neutrophil count decreased, lymphocyte count decreased, platelet count decreased, nausea, decreased appetite, anemia, aspartate  minotransferase increased, fatigue, blood alkaline phosphatase increased, alanine aminotransferase increased, diarrhea, hypokalemia, vomiting, constipation, blood bilirubin increased, pyrexia, and alopecia (Daiichi Sankyo, 2021).

Breast Cancer

HER2-positive breast cancer is a type of breast cancer that tests positive for a protein called human epidermal growth factor receptor 2 (HER2), which promotes the growth of cancer cells. HER2 proteins are receptors on breast cells which normally help control how a healthy breast cell grows, divides, and repairs itself. However, in some individuals the HER2 gene that makes the HER2 proteins results in HER2 protein overexpression, called HER2-positive. HER2-positive breast cancers tend to grow faster and are more likely to metastasize and recur compared to HER2-negative breast cancers. There are now treatments available that specifically target HER2-positive breast cancers; however, some HER2 breast cancer patients do not respond or have built a resistance to current treatment.

On December 23, 2019, the U.S. Food and Drug Administration (FDA) granted accelerated approval to Enhertu (fam-trastuzumab deruxtecan-nxki) for the treatment of adults with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.

FDA approval for Enhertu was based on the results of a multicenter, single-arm, clinical trial, DESTINY-Breast01 (NCT03248492), that enrolled 184 female patients with HER2-positive, unresectable and/or metastatic breast cancer who had received two or more prior anti-HER2 therapies in the metastatic setting. Patients were excluded for a history of treated ILD or current ILD at screening, or history of clinically significant cardiac disease, active brain metastases, and ECOG performance status greater than 1. Patients received Enhertu 5.4 mg/kg by intravenous infusion every 3 weeks until unacceptable toxicity or disease progression. All patients received prior trastuzumab, ado-trastuzumab emtansine, and 66% had prior pertuzumab. Tumor imaging was obtained every 6 weeks and CT/MRI of the brain was mandatory for patients with brain metastases at baseline. The overall response rate was 60.3%, which reflects the percentage of patients that had a certain amount of tumor shrinkage with a median duration of response of 14.8 months.

On August 5, 2022, the U.S. Food and Drug Administration (FDA) granted accelerated approval and breakthrough designation to Enhertu (fam-trastuzumab-deruxtecan-nxki) for treatment of patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-low breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy. About 60% of HER2-negative metastatice breast cancers express low levels of HER2 which is defined by a score of 1+ on immunohistochemical (IHC) analysis or as an IHC score of 2+ and negative results on in situ hybridization (ISH). This HER2-low subtype make up a heterogenous population inclusive of both hormone receptor-positive (HR+) and hormone receptor-negative (HR-) breast cancers that are wide ranging in prognosis and sensitivity to systemic treatments. The FDA approval of Enhertu for this indication was based on supporting data from the DESTINY-Breast04 study (FDA, 2022a and 2022b; Modi, et al., 2022).

In the DESTINY-Breast04 study, a randomized, multicenter, open-label, phase 3 clinical trial, Modi and colleagues (2022) evaluated the safety and efficacy of Enhertu (fam-trastuzumab-deruxtecan-nxki) involving patients with HER2-low metastatic breast cancer who received one or two previous lines of chemotherapy. Low expression of HER2 was established as a score of 1+ on immunohistochemical (IHC) analysis or as an IHC score of 2+ and negative results on in situ hybridization. Patient (n=557) randomization occurred in a 2:1 ratio to receive Enhertu or the physician's selection of chemotherapy. The two cohorts in this trial were represented by 494 hormone receptor positive (HR+) patients and 63 hormone receptor negative (HR-) patients. Three hundred and seventy-three patients received Enhertu 5.4 mg/kg via intravenous infusion every 3 weeks and 184 patients received physician's chemotherapy selection (eribulin, capecitabine, gemcitabine, nab-paclitaxel, or paclitaxel). The primary efficacy endpoint was progression-free survival (PFS) in patients with hormone receptor-positive (HR+) breast cancer. Notable secondary efficacy endpoints were PFS among all patients (all randomized HR+ and HR-negative and overall survival (OS) in HR+ patients, and OS in among all patients. The median progression-free survival was 10.1 months in the Enhertu group and 5.4 months in the physician's selection group (hazard ratio for disease progression or death, 0.51; p<0.001), and overall survival was 23.9 months and 17.5 months, respectively (hazard ratio for death,0.64; p = 0.003). For overall patients, the median progression-free survival was 9.9 months in the Enhertu group and 5.1 months in the physician's selection group (hazard ratio for disease progression or death, 0.50; p<0.001), and overall survival was 23.4 months and 16.8 months, respectively (hazard ratio for death, 0.64; p = 0.001). Grade 3 or greater adverse events were noted in 52.6% of the patients who received Enhertu and 67.4% of those who received the physician's selection of chemotherapy. Adjudicated, drug associated interstitial lung disease was noted in 12.1% of the patients who received Enhertu; 0.8% had grade 5 events. The investigators concluded that patients with HER2-low metastatic breast cancer receiving Enhertu resulted in significantly longer progression-free and overall survival compared to physician's selection of chemotherapy.

Gastric or Gastroesophageal Junction Adenocarcinoma

In January 2021, the FDA approved the use of Enhertu (trastuzumab deruxtecan) for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen. Approximately 60% of 

FDA approval was based on the results of the multicenter, open-label, randomized trial conducted in Japan and South Korea [DESTINY-Gastric01 (NCT03329690)]. The trial evaluated the efficacy of fam-trastuzumab deruxtecan-nxki (Enhertu) in adult patients (median age 66 years; 100% Asian) with HER2-positive (IHC 3+ or IHC 2+/ISH positive), locally advanced or metastatic gastric or GEJ adenocarcinoma who had progressed on at least two prior regimens including trastuzumab, a fluoropyrimidine- and a platinum-containing chemotherapy. HER2 expression was determined by a central lab on tissue obtained either before or after prior trastuzumab treatment. Patients were excluded for a history of treated or current ILD, a history of clinically significant cardiac disease, active brain metastases, or ECOG performance status >1. The study enrolled 188 patients who were randomized 2:1 to receive Enhertu (n=126) 6.4 mg/kg intravenously every 3 weeks or physician’s choice of chemotherapy: irinotecan monotherapy (n=55) 150 mg/m2 intravenously every 2 weeks or paclitaxel monotherapy (n=7) 80 mg/m2 intravenously weekly. Randomization was stratified by HER2 status (IHC 3+ or IHC 2+/ISH+), ECOG performance status (0 or 1), and region (Japan or South Korea). Tumor imaging assessments were performed at screening and every 6 weeks from the first treatment dose. Treatment was administered until unacceptable toxicity or disease progression. The major efficacy outcomes were objective response rate (ORR) assessed by ICR according to RECIST v1.1 and overall survival (OS) in the intent-to-treat population. Additional efficacy outcomes were progression-free survival (PFS) and duration of response (DOR). In the study, Enhertu-treated patients had a 41% reduction in the risk of death versus chemotherapy-treated patients. At a pre-specified interim analysis, those patients treated with Enhertu demonstrated a median OS of 12.5 months compared to 8.4 months with chemotherapy (i.e., irinotecan or paclitaxel). Trial results also showed a confirmed ORR of 40.5% with Enhertu compared to 11.3% with chemotherapy. Patients treated with Enhertu had a 7.9% complete response rate (CRR) and a 32.5% partial response rate compared to a CRR of 0% and a partial response rate of 11.3% for patients treated with chemotherapy (AstraZeneca, 2021; BioSpace, 2021; Daiichi Sankyo, 2021).

Non-small Cell Lung Cancer

On August 12, 2022, the U.S. Food and Drug Administration (FDA) granted accelerated approval to Enhertu (fam-trastuzumab-deruxtecan-nxki) 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. The FDA approval of Enhertu for this indication was based on supporting data from the DESTINY-Lung02 Phase II trial. Upon interim efficacy analysis in a pre-specified patient cohort, the administration of Enhertu 5.4 mg/kg via intravenous infusion every 3 weeks demonstrated a confirmed objective response rate (ORR) of 57.7% (n=52; 95% confidence interval [CI] 43.2-71.3) in patients with previously treated unresectable or metastatic non-squamous HER2-mutant (HERm) NSCLC. Complete responses (CR) were noted in 1.9% of patients and partial responses (PR) in 55.8% of patients with a median duration of response (DoR) of 8.7 months (95% CI 7.1-NE). A safety analysis of Enhertu was conducted in 101 patients with unresectable or metastatic HER2m NSCLC who received at least one dose of Enhertu 5.4 mg/kg in the DESTINY-Lung02 study. The analysis revealed Enhertu's safety profile to be consistent with prior clinicals with no new safety concerns raised (AstraZeneca, 2022).

Li et al (2022) stated that HER2-targeted therapies have not been approved for patients with non-small-cell lung cancer (NSCLC). The safety and effectiveness of trastuzumab deruxtecan, a HER2 antibody-drug conjugate, in patients with HER2-mutant NSCLC have not been examined extensively. In an international, multi-center, phase-II clinical trial, trastuzumab deruxtecan (6.4 mg/kg body weight) was administered to patients who had metastatic HER2-mutant NSCLC that was refractory to standard treatment. The primary outcome was objective response as assessed by independent central review. Secondary outcomes included the duration of response, PFS, OS, and safety. Biomarkers of HER2 alterations were assessed. A total of 91 patients were enrolled. The median duration of follow-up was 13.1 months (range of 0.7 to 29.1). Centrally confirmed objective response occurred in 55 % of the patients (95 % CI: 44 to 65). The median duration of response was 9.3 months (95 % CI: 5.7 to 14.7). Median PFS was 8.2 months (95 % CI: 6.0 to 11.9), and median OS was 17.8 months (95 % CI: 13.8 to 22.1). The safety profile was generally consistent with those from previous studies; grade-3 or higher drug-related adverse events (AEs) occurred in 46 % of patients, the most common event being neutropenia (in 19 %). Adjudicated drug-related interstitial lung disease (ILD) occurred in 26 % of patients and resulted in death in 2 patients. Responses were observed across different HER2 mutation subtypes, as well as in patients with no detectable HER2 expression or HER2 amplification. The authors concluded that this study provided clinical evidence of anti-tumor activity from a HER2-targeted therapy for patients with previously treated HER2-mutant NSCLC. The safety profile included ILD that was fatal in 2 cases. Observed toxic effects were generally consistent with those in previously reported studies.

Salivary Gland Cancer

Shukla et al (2022) stated that HER2 mutations have been shown to be targetable in select cases of salivary gland cancers with over-expression or amplification of the HER2 oncogene.  Fam-trastuzumab deruxtecan, a novel antibody-drug conjugate that combines trastuzumab with a topoisomerase I inhibitor, has recently demonstrated effectiveness as a 3rd-line agent in HER2-over-expressing breast cancer after trastuzumab failure.  These promising results in breast cancer suggested a potential paradigm for use in other tumors with known HER2 alterations, including salivary gland cancer.  These researchers reported on the case of a 67-year-old man with HER2-positive metastatic parotid gland carcinoma who experienced disease progression after parotidectomy with adjuvant cisplatin-based chemoradiation, neratinib, and ado-trastuzumab emtansine.  After disease progression on the latter HER2-directed therapy, his malignancy demonstrated CR to fam-trastuzumab deruxtecan, which has been sustained for the past 7 months.  The authors concluded that fam-trastuzumab deruxtecan appeared to be a well-tolerated therapeutic option in patients with HER2-positive salivary gland carcinoma, with activity demonstrated after progression on ado-trastuzumab emtansine and HER2-directed kinase inhibition.  Moreover, these researchers stated that further studies are needed to examine the use of this agent in HER2-positive salivary gland cancers.

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References