The United States Food and Drug Administration (FDA) has approved trastuzumab deruxtecan* (Enhertu®; Daiichi Sankyo and AstraZeneca) 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 prior systemic therapy.

Trastuzumab deruxtecan is a HER2-directed antibody-drug conjugate (ADC) designed using Daiichi Sankyo’s proprietary DXd ADC technology. The drug consists of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

The new indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DoR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Trastuzumab deruxtecan is a specifically engineered HER2-directed antibody-drug conjugate (ADC). The accelerated approval by the FDA was based on the results from the DESTINY-Lung02 phase 2 trial.

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An interim efficacy analysis in a pre-specified patient cohort showed that trastuzumab deruxtecan (5.4 mg/kg) demonstrated a confirmed ORR of 57.7% (n=52; 95% confidence interval [CI]: 43.2-71.3) in patients with HER2 mutant unresectable or metastatic non-squamous NSCLC who had received one prior systemic therapy as assessed by blinded independent central review (BICR). Complete responses (CR) were seen in 1.9% of patients (n=1) and partial responses (PR) in 55.8% of patients (n=29) with a median duration of response of 8.7 months (95% CI: 7.1-NE).

Mutant metastatic NSCLC
Lung cancer is the second most common form of cancer globally, with more than two million patients diagnosed in 2020.[1] In the U.S., lung cancer is the second most commonly diagnosed cancer, with more than 236,000 patients expected to be diagnosed in 2022.[2] For patients with metastatic NSCLC, the prognosis is particularly poor, as only approximately 8% will live beyond five years after diagnosis.[3]

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors, including lung, breast, gastric and colorectal cancers. Certain HER2 gene alterations (called HER2 mutations) have been identified in patients with non-squamous NSCLC as a distinct molecular target, and occur in approximately 2 to 4% of patients with this type of lung cancer.[4][5]

Younger, female and non-smokers
While HER2 gene mutations can occur in a range of patients, they are more commonly found in patients with NSCLC who are younger, female, and have never smoked.[6] HER2 gene mutations have been independently associated with cancer cell growth and poor prognosis, with an increased incidence of brain metastases.[7]

Although the role of anti-HER2 treatment is well established in breast and gastric cancers, there were no approved HER2-directed therapies in NSCLC prior to the accelerated approval of trastuzumab deruxtecan in unresectable or metastatic NSCLC.[7][8] Next-generation sequencing has been utilized in the identification of HER2 (ERBB2) mutations.[9]

Trastuzumab deruxtecan is the first HER2-directed agent to be approved for the treatment of patients with HER2-mutant metastatic NSCLC. This is the third tumor type approved by the FDA for trastuzumab deruxtecan in three years.

The approval follows the recently received Priority Review, as well as the Breakthrough Therapy Designation, which was granted in 2020 by the FDA for this specific type of lung cancer based on the results of the DESTINY-Lung01. This trial was a global, open-label, two-cohort trial evaluating the efficacy and safety of trastuzumab deruxtecan (6.4 mg/kg and 5.4 mg/kg) in patients with HER2 mutant (cohort 2, n=91) or HER2 overexpressing (cohort 1 and 1a, n=90) (defined as IHC 3+ or IHC 2+) unresectable or metastatic non-squamous NSCLC who had progressed after one or more systemic therapies.

The primary endpoint of this study was confirmed ORR by independent central review (ICR). Key secondary endpoints include DoR, DCR, PFS, OS and safety. DESTINY-Lung01 enrolled 181 patients at multiple sites, including Asia, Europe and North America.

DESTINY-Lung02 is a global phase 2 trial evaluating the safety and efficacy of two doses (5.4 mg/kg or 6.4 mg/kg) of trastuzumab deruxtecan in patients with HER2 mutant metastatic NSCLC with disease recurrence or progression during or after at least one regimen of prior anticancer therapy that must have contained a platinum-based chemotherapy.

The primary endpoint of the study is ORR as assessed by BICR. Secondary endpoints include disease control rate (DCR), DoR, progression-free survival (PFS), investigator-assessed ORR, overall survival (OS) and safety. DESTINY-Lung02 enrolled 152 patients at multiple sites, including Asia, Europe and North America.

Companion diagnostic
Results from the DESTINY-Lung02 trial will be presented at an upcoming medical meeting. Concurrently with this approval, the FDA also approved companion diagnostic tests to
detect HER2 mutations in lung tumor tissue and plasma.

The FDA also approved the Life Technologies Corporation’s Oncomine™ Dx Target Test (tissue) and the Guardant Health Guardant360® CDx (plasma) as companion diagnostics for trastuzumab deruxtecan. The approval of the test based on mutations detected in a plasma specimen. However, if no mutations are detected in plasma, the tumor tissue should be tested.

Important milestone
“The approval of trastuzumab deruxtecan in non-small cell lung cancer is an important milestone for patients and the oncology community,” explained Bob T. Li, MD, Ph.D., MPH, Medical Oncologist, and Physician-Scientist, Memorial Sloan Kettering Cancer Center, New York.

“After two decades of research into the role of targeting HER2 in lung cancer, the approval of the first HER2-directed treatment option validates HER2 as an actionable target in lung cancer and marks an important step forward for treating this patient population with unmet medical needs.”

“The availability of trastuzumab deruxtecan as the first HER2 targeted treatment option for HER2 mutant non-small cell lung cancer is great news for patients,” said Upal Basu Roy, Ph.D., MPH, Executive Director of Research, LUNGevity.

“We are thrilled to see a novel treatment option available that targets this group of rare mutations in lung cancer. This approval is a great reminder that access to high-quality biomarker testing will be critical to ensuring that patients whose tumors have HER2 mutations have access to these new therapies.”

Trastuzumab deruxtecan is approved with Boxed WARNINGS for interstitial lung disease (ILD)/pneumonitis and Embryo-Fetal toxicity. In the DESTINY-Lung02 phase 2 trial, the safety of trastuzumab deruxtecan was further evaluated in an analysis of 101 patients with unresectable or metastatic HER2 mutant NSCLC who received at least one recommended dose of trastuzumab deruxtecan (5.4 mg/kg).

Adverse events
The most common adverse reactions (frequency ≥20%), including laboratory abnormalities, were nausea, decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, decreased lymphocyte count, decreased platelet count, decreased albumin, increased aspartate aminotransferase, increased alanine aminotransferase, fatigue, constipation, decreased appetite, vomiting, increased alkaline phosphatase, and alopecia.

“We are excited that the FDA has granted accelerated approval for trastuzumab deruxtecan for patients with HER2 mutant metastatic non-small cell lung cancer. trastuzumab deruxtecan has now been approved in three different tumor types, underscoring its significant potential across several HER2 targetable tumors,” noted Ken Keller, Global Head of Oncology Business, and President and Chief Executive Office, Daiichi Sankyo.

“We are continuing to evaluate the efficacy and safety of trastuzumab deruxtecan versus standard chemotherapy in our DESTINY clinical trials in lung cancer,” Keller added.

“HER2 mutant non-small cell lung cancer is an aggressive form of the disease which commonly affects young patients who have faced limited treatment options and a poor prognosis to date,” explained Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca.

“Today’s news provides these patients with the opportunity to benefit from a targeted therapy and highlights the importance of testing for predictive markers, including HER2 in lung cancer, at the time of diagnosis to ensure patients receive the most appropriate treatment for their specific disease,” Fredrickson concluded.

Note * In the United States: Fam-trastuzumab deruxtecan-nxki

Clinical trials
DS-8201a in Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing or -Mutated Non-Small Cell Lung Cancer (DESTINY-Lung01) – NCT03505710
Trastuzumab Deruxtecan in Participants With HER2-mutated Metastatic Non-small Cell Lung Cancer (NSCLC) (DESTINY-LUNG02) – NCT04644237
Phase Ib Study of the Safety of T-DXd and Durvalumab With Chemotherapy in Advanced or Metastatic HER2+ Non-squamous NSCLC (DL03) – NCT04686305

Highlights of prescribing information
Trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca) [Prescribing Information]

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Featured Image: Doctor explaining and younger patient. Courtesy: © 2019 – 2022. Fotolia/Adobe. Used with permission.

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