FDA approval summary: fam-trastuzumab deruxtecan-nxki for unresectable or metastatic non-small cell lung cancer with activating HER2 mutations

Abstract

On August 11, 2022, FDA granted accelerated approval to fam-trastuzumab deruxtecan-nxki (DS-8201a, T-DXd, ENHERTU, Daiichi Sankyo) for adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating human epidermal growth factor receptor 2 (HER2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. The approval was based on a prespecified interim analysis of DESTINY-Lung02 (Study U206), a multi-center, randomized, dose-optimization trial in patients with NSCLC harboring activating HER2-mutations. At the approved dose of 5.4 mg/kg given intravenously every 3 weeks, the overall response rate (ORR) was 58% (95% confidence interval [CI]: 43, 71). The median duration of response was 8.7 months (95% CI: 7.1, not estimable). These results were consistent with response rates observed at the 6.4 mg/kg dose level. The most common (≥ 20%) adverse reactions were nausea, constipation, decreased appetite, vomiting, fatigue, and alopecia. The rate of interstitial lung disease (ILD) or pneumonitis was 6% at the 5.4 mg/kg dose level and 14% at the 6.4 mg/kg dose level. In the setting of similar efficacy and reduced toxicity, approval was granted for the 5.4 mg/kg dose level. The applicant conducted a randomized, dose-optimization study with guidance from the FDA Oncology Center of Excellence’s Project Optimus. This is the first approval of a targeted therapy for HER2-mutated NSCLC.

The FDA granted accelerated approval to fam-trastuzumab deruxtecan-nxki for adult patients with unresectable or metastatic non-small cell lung cancer whose tumors have activating HER2 mutations. This article reports the review process that led to this approval.

Implications for Practice.

Fam-trastuzumab deruxtecan-nxki (T-DXd) is the first targeted therapy option approved for patients with unresectable or metastatic non-small cell lung cancer harboring HER2 mutations who have received a prior systemic therapy. A dose-randomized study of T-DXd allowed for identification of an optimized dosage in this population (5.4 mg/kg every 3 weeks), with similar efficacy and reduced toxicity compared when with a higher dosage. Interstitial lung disease and pneumonitis remain important toxicities for providers to monitor in patients receiving T-DXd.

Introduction

The erb-b2 receptor tyrosine kinase 2 (ERBB2) gene, commonly known as human epidermal growth factor receptor 2 (HER2), encodes for HER2 and is mutated in approximately 1.7% of patients with non-small cell lung cancer (NSCLC).¹ In the majority of these patients, HER2 (ERBB2) has been identified as the sole driver mutation. Aberrant HER2 signaling has been implicated in activation of the PI3K-Akt and MEK-ERK pathways driving oncogenesis.² Patients with HER2-mutant NSCLC tend to be relatively young (median age 60 years), female, and never-smokers.¹ Histologically these tumors are typically adenocarcinomas. Median survival in patients with metastatic HER2-mutated NSCLC is estimated to be 1.4 to 2.1 years, which is lower than the median survival for patients with NSCLC with other targetable mutations.³

Prior to the approval of fam-trastuzumab deruxtecan-nxki (DS-8201a, T-DXd, ENHERTU, Daiichi Sankyo), treatment options for patients with HER2-mutated NSCLC who had previously received systemic therapy included PD-(L)1 inhibitors for those who were immunotherapy-naïve and docetaxel as monotherapy or in combination with ramucirumab. In the post-platinum setting, these second-line options have had limited efficacy.⁴

T-DXd is the first FDA-approved drug for HER2-mutated NSCLC. FDA’s review of this marketing application for T-DXd for patients with unresectable or metastatic NSCLC whose tumors have activating HER2 mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy included assessment of late-breaking data received during the review period. This dynamic review process led to approval of a potentially safer, while similarly effective dosage of T-DXd for this patient population.

Regulatory history

T-DXd was first approved on December 20, 2019, for unresectable or metastatic HER2-positive breast cancer (5.4 mg/kg every 3 weeks). A subsequent approval was granted January 15, 2021, for locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma (6.4 mg/kg every 3 weeks). T-DXd received Breakthrough Therapy Designation for HER2-mutated NSCLC on May 14, 2020. The supplemental biologics license application (sBLA) for HER2-mutated NSCLC was submitted on February 16, 2022, and used the Assessment Aid to facilitate FDA’s review.⁵ Of note, during the review of T-DXd for HER2-mutated NSCLC, FDA contemporaneously reviewed and approved a marketing application for T-DXd for adults with unresectable or metastatic HER2-low breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. More recently, in April 2024, FDA approved T-Dxd for adult patients with unresectable or metastatic HER2-positive (IHC3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.

Nonclinical pharmacology and toxicology

T-DXd is an antibody-drug conjugate comprised of a humanized anti-HER2 IgG1 monoclonal antibody (MAAL-9001) covalently linked a topoisomerase I inhibitor (MAAA-118d, DXd) via a cleavable linker. T-DXd is believed to exert its pharmacological activity through antibody binding to HER2 resulting in internalization and lysosome trafficking of the HER2/antibody-drug conjugate complex in tumor cells. To support this pharmacological activity in an in vitro model of NSCLC, T-DXd was shown to have increased internalization in HER2-mutant expressing cells compared to HER2-wild type (WT) cells. The in vivo antitumor activity of T-DXd against NSCLC tumors with HER2-WT or HER2 mutations was assessed in a murine model. In general, a single administration of intravenous T-DXd to tumor-bearing mice demonstrated greater antitumor activity against HER2-WT and HER2-mutated NSCLC tumors compared to vehicle control. The antitumor activity was greater in HER2-mutant expressing tumors compared to HER2-WT expressing tumors. Primary pharmacology, pharmacokinetic, general toxicology studies of T-DXd, MAAA-1181a, and MAAL-9001 were performed in rats and monkeys, and have been previously described.⁶

Clinical Trials

The approval of T-DXd was based on the results of DESTINY-Lung01 and DESTINY-Lung02. DESTINY-Lung01 was a global, multi-center, multiple-cohort, open-label trial that enrolled 91 patients with unresectable or metastatic HER2-mutated NSCLC who had received prior systemic therapy.⁷ Patients were treated with T-DXd 6.4 mg/kg every 3 weeks. The primary efficacy endpoints in DESTINY-Lung01 were ORR and DOR, both determined by BICR per RECIST v1.1.

Emerging results from DESTINY-Lung02, a global, multi-center, randomized, dose-optimization trial that enrolled 152 patients with unresectable or metastatic HER2-mutated NSCLC who had received prior systemic therapy were received during review of the marketing application. In this trial, patients were randomized 2:1 to receive either T-DXd 5.4 mg/kg every 3 weeks or T-DXd 6.4 mg/kg every 3 weeks. Both DESTINY-Lung01 and DESTINY-Lung02 allowed patients with stable baseline brain metastases to enroll. Tumor imaging was obtained every 6 weeks. The primary efficacy endpoints to support marketing approval were ORR as determined by blinded independent central review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and duration of response (DOR). The key safety signal of ILD/pneumonitis was assessed by an independent ILD adjudication committee. A pre-specified interim analysis for efficacy took place after at least 75 patients had received at least one dose of study drug and had at least 4.5 months follow-up, allowing for 3 tumor imaging assessments. This interim analysis was performed without the intent to modify the study design or conduct.

Clinical pharmacology

The clinical pharmacology evaluation focused on appropriateness of the recommended dosage, 5.4 mg/kg every 3 weeks. This dosing regimen is supported by the efficacy and safety results of the DESTINY-Lung02 trial, which compared the recommended dosage of 5.4 mg/kg every 3 weeks to a higher dosage of 6.4 mg/kg every 3 weeks. Population pharmacokinetics (PK) showed linear PK of T-DXd over the dose range of 3.2 to 8 mg/kg (0.6 to 1.5 times the recommended dose in NSCLC), and generally comparable exposure at the same dosage (ie, 5.4 mg/kg every 3 weeks and 6.4 mg/kg every 3 weeks, respectively) for patients with NSCLC and patients with breast cancer (approved at 5.4 mg/kg every 3 weeks). Exposure-response analyses for efficacy based on data from the 5.4 and 6.4 mg/kg dosages suggest a lack of a clinically significant relationship for overall response rate (ORR). Exposure-response analyses for safety suggest a positive dose-exposure relationship for any grade interstitial lung disease (ILD), Grade ≥ 3 treatment-emergent adverse events (TEAEs), and serious TEAEs in all patients who received T-DXd. The totality of population PK data, safety and efficacy data, and exposure-response analyses from the DESTINY-Lung02 trial support a more favorable benefit-risk assessment for T-DXd in patients with HER2-mutant NSCLC at the 5.4 mg/kg every 3 weeks dosage versus the 6.4 mg/kg every 3 weeks dosage.

Efficacy results

Given the dose-optimization results, clinical trial data from patients enrolled on DESTINY-Lung02 and treated with T-DXd 5.4 mg/kg every 3 weeks were used to derive the primary efficacy results. Because of the need for mature efficacy data from DESTINY-Lung02, a pre-specified interim analysis was performed once 75 patients had been randomized to receive at least one dose of T-DXd and had at least 4.5 months of follow-up. The primary efficacy population was derived from this interim analysis of DESTINY-Lung02 and included 52 patients with HER2-mutated NSCLC who received T-DXd 5.4 mg/kg every 3 weeks. At the interim analysis data cutoff (DCO) date of March 24, 2022, the confirmed ORR in 52 patients treated at the 5.4 mg/kg dose level was 54% (95% CI: 40, 68). This efficacy result was consistent with the confirmed ORR among 28 patients treated at the 6.4 mg/kg dose level in DESTINY-Lung02 (43% [95% CI: 25, 63]), as well as in the 91 patients treated at the 6.4 mg/kg dose level in DESTINY-Lung01 (55% [95% CI: 44, 65]). Data after an additional 90 days of follow-up were provided for the primary efficacy population (5.4 mg/kg dose level in DESTINY-Lung02 interim analysis) demonstrating a confirmed ORR of 58% (95% CI: 43, 71) with a median DOR of 8.7 months (95% CI: 7.1, not estimable [NE])(Table 1).

Table 1.

Summary of primary efficacy results by blinded independent central review in DESTINY-Lung02.

Efficacy parameter	T-DXd 5.4 mg/kg (N = 52)
Overall response rate, n (%)	30 (58)
Clopper-Pearson 95% CI	(43, 71)
Complete response, n (%)	1 (1.9)
Duration of response
Median, months (95% CI) a	8.7 (7.1, NE)

^aEstimated using the Kaplan-Meier method.

^bBased on the observed number of patients with a response lasting > 6 months.

DCO: June 22, 2022.

Abbreviations: NE, not estimable; +, ongoing response.

Safety results

The safety of T-DXd in patients with HER2-mutated NSCLC was evaluated in 101 patients treated at the 5.4 mg/kg dose in DESTINY-Lung02 and was supported by experience in 152 patients at the 6.4 mg/kg dose in DESTINY-Lung01 and DESTINY-Lung02. Overall, the safety profile of T-DXd for patients with NSCLC was generally manageable and consistent with experience in patients with breast and gastric cancer. The most common (≥ 20%) adverse reactions, 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. The most common (≥ 2%) grade 3 or 4 adverse reactions were anemia (10%), fatigue (4%), nausea (3%), and vomiting (2%).

ILD/pneumonitis has been previously identified as an important risk of treatment with T-DXd in other tumor types. As patients with metastatic or unresectable NSCLC are likely to have received lung-directed local therapy (eg, surgery or radiation therapy) prior to treatment with T-DXd, special attention was paid to the risk of ILD/pneumonitis in this patient population who may be particularly vulnerable to pulmonary toxicity. The rates of ILD/pneumonitis at the 6.4 mg/kg dose, in both DESTINY-Lung01 (26%) with 13.1 months median duration of follow-up and DESTINY-Lung02 (14%) with 3.9 months median duration of follow-up, were greater in the NSCLC population than in the other previously-approved indications (5.4 mg/kg dose for metastatic breast cancer and 6.4 mg/kg dose for gastric cancer). However, the rate of ILD/pneumonitis with the 5.4 mg/kg dose in patients with HER2-mutant NSCLC (6%) was consistent with the risk identified across other tumor types (Table 2). This risk of ILD/pneumonitis is addressed through a boxed warning in the product label. Compared to the 6.4 mg/kg every 3 weeks dosage, patients treated with the 5.4 mg/kg every 3 weeks dosage experienced fewer grades 3-4 TEAEs, including neutropenia, and fewer dosage interruptions, dose reductions, and drug discontinuations.

Table 2.

Risk of interstitial lung disease/pneumonitis in FDA-approved indications.^*

	HER2-positive gastric cancer DESTINY-Gastric01 T-DXd 6.4 mg/kg N = 125	HER2-positive metastatic breast cancer DESTINY-Breast03 T-DXd 5.4 mg/kg N = 257	HER2-mutant NSCLC DESTINY-Lung02 T-DXd 5.4 mg/kg N = 101	HER2-mutant NSCLC DESTINY-Lung02* T-DXd 6.4 mg/kg N = 50
All grades, %	10	11	6	14
Grade ≥ 3, %	2.4	0.8	1.0	0

^*T-DXd is FDA-approved for HER2-mutant NSCLC at the 5.4 mg/kg dose but not the 6.4 mg/kg dose.

Source: ENHERTU (fam-trastuzumab deruxtecan-nxki) package insert (ref. ⁸).

Regulatory Insights

The accelerated approval of T-DXd provides the first targeted treatment option for patients with HER2-mutated NSCLC (Table 3). The review of this marketing application included several unique elements. T-DXd had been previously approved for breast and gastric cancer indications at different dosages (5.4 and 6.4 mg/kg every 3 weeks, respectively). Given the known risk of ILD/pneumonitis with this drug product and given anatomic location and risks associated with prior local therapy for NSCLC, the thoracic oncology team at FDA considered dose optimization of T-DXd for this indication to be a critical component of the marketing application and FDA’s review. FDA Oncology Center of Excellence’s Project Optimus is an initiative to reform the dose optimization and dose selection paradigm in oncology.⁹ Frequently, the dosages of oncology drugs are poorly characterized prior to seeking approval of a marketing application, which may expose patients to increased toxicity. Through Project Optimus, FDA aims for more comprehensive drug dosage assessment prior to approval such that patients receive a dosage optimized for benefit-risk at the time of approval. During development, Daiichi Sankyo used advice from Project Optimus to conduct the dose randomization study, DESTINY-Lung02, which was one of the first trials to be reported based on advice from Project Optimus. Emerging data from this trial demonstrated similar efficacy and reduced toxicity from ILD/pneumonitis at the 5.4 mg/kg dose level (6%) compared to the 6.4 mg/kg dose level (14%) and allowed the lower dose to be approved. This approval provides patients with a new targeted therapeutic with a dosage optimized for benefit-risk.

Table 3.

FDA benefit-risk analysis of T-DXd for HER2-mutant NSCLC.

Dimension	Evidence and uncertainties	Conclusions and reasons
Analysis of condition	HER2 mutations occur in 1.7% of NSCLC Median survival in patients with metastatic NSCLC with HER2 mutations is 1.4-2.1 years	Unresectable or metastatic NSCLC with a HER2 (ERBB2) mutation is a life-threatening disease with poor survival
Current treatment options	Second-line therapies for patients with metastatic NSCLC without a targetable mutation include immune checkpoint inhibitors and pemetrexed, if not already given, and docetaxel with or without ramucirumab	Prior to the approval of T-DXd, there were no approved targeted therapies for HER2-mutated NSCLC There is an unmet medical need for patients with previously treated NSCLC harboring HER2 mutations whose disease has progressed on or after prior systemic therapy
Benefit	The confirmed ORR by BICR in the primary efficacy population was 58% (95% CI: 43, 71) with a median DOR of 8.7 months (95% CI: 7.1, NE) The response rate at the 5.4 mg/kg dose level was consistent with the response rates observed with T-DXd 6.4 mg/kg.	The magnitude of the ORR observed at the 5.4 mg/kg dose level in DESTINY-Lung02 is likely to predict clinical benefit in patients with HER2-mutated NSCLC and meets the evidentiary standard for accelerated approval.
Risk and risk management	The most common (≥ 20%) adverse reactions, 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 The rate of ILD/pneumonitis was 6% in the 5.4 mg/kg arm of DESTINY-Lung02 compared with 14% in the 6.4 mg/kg arm. The rate of ILD in DESTINY-Lung01 (6.4 mg/kg) was 26%	The observed safety profile is manageable in the context of the treatment of a life-threatening disease and is overall consistent with the known adverse effects of T-DXd T-DXd is known to cause serious ILD/pneumonitis, which is currently addressed through a boxed warning in the product labeling. The rate of ILD/pneumonitis was lower in the 5.4 mg/kg dose cohort, supporting approval of this indication at a recommended dose of 5.4 mg/kg every 3 weeks

Abbreviations: ILD, interstitial lung disease; NSCLC, non-small cell lung cancer; NE, not estimable.

Accelerated approval of T-DXd allows for early marketing authorization based on an intermediate clinical endpoint that is reasonably likely to predict clinical benefit.¹⁰ For this approval, ORR and DOR in a limited subset of patients (n = 52) treated with the 5.4 mg/kg dose supported accelerated approval. These results were supported by safety and efficacy data in an additional 152 patients treated with the 6.4 mg/kg dose further demonstrating activity of the drug in this population. These clinical trial outcomes appear reasonably likely to predict clinical benefit, particularly in a setting where the existing standard of care had been limited to non-targeted therapies for relapsed or refractory NSCLC (ie, docetaxel or docetaxel and ramucirumab).⁴

A stipulation of accelerated approval is that clinical benefit should be verified by post-marketing trials, which are generally underway at the time of accelerated approval.¹⁰ The accelerated approval was part of a comprehensive drug development program, with post-marketing requirements (PMRs) issued for additional clinical data from DESTINY-Lung02 and the ongoing first-line trial, DESTINY-Lung04. With an additional 50 patients enrolled and treated with the 5.4 mg/kg dose, complete data from DESTINY-Lung02 are expected to provide additional precision around the point estimate for ORR and an improved estimation of DOR. DESTINY-Lung04 is an ongoing multicenter, randomized clinical trial of T-DXd (5.4 mg/kg every 3 weeks) compared to pembrolizumab, pemetrexed, and platinum chemotherapy in the first-line setting for patients with HER2-mutant NSCLC. Survival data from DESTINY-Lung04 may provide additional support to verify the clinical benefit of T-DXd in patients with HER2-mutant NSCLC. Given the results of DESTINY-Lung01 and DESTINY-Lung02 and FDA approval for patients with previously treated HER2-mutated NSCLC, design of a confirmatory trial in the same setting may be limited by lack of clinical equipoise and potentially compromised U.S. enrollment. Designing the confirmatory trial to study T-DXd in an earlier line of therapy potentially obviates these limitations. To date, the use of accelerated approval in precision oncology for targeted therapies such as T-DXd has been very successful with timely verification of clinical benefit.¹¹ This has allowed U.S. patients with cancer early access to a number of potentially life-saving therapies.

Conclusion

FDA approval of T-DXd for patients with NSCLC with activating HER2 mutations addresses a significant unmet medical need in a population without an existing targeted therapy. The response rate and duration of response observed with T-DXd in this setting represents a clinically meaningful improvement over available therapies for second- and later-line treatment. Evaluation of T-DXd in a randomized dose trial for patients with HER2-mutant NSCLC allowed for approval of a dosage which was optimized for benefit-risk. This development program and approval represent a significant advance for patients, providing a new treatment option for previously-treated HER2-mutant NSCLC.

Additional Information: Julia Beaver completed work on this publication while she was an employee at FDA. At the time of publishing, she is an employee at Treeline Biosciences.

Author contributions

Gautam U. Mehta (Conceptualization, Writing—original draft, Writing—review & editing), Paz J. Vellanki (Conceptualization, Writing—original draft, Writing—review & editing), Yi Ren (Conceptualization, Writing—original draft, Writing—review & editing), Anup K. Amatya (Conceptualization, Writing—original draft, Writing—review & editing), Pallavi S. Mishra-Kalyani (Conceptualization, Writing—original draft, Writing—review & editing), Lili Pan (Conceptualization, Writing—original draft, Writing—review & editing), Jeanne F. Zirkelbach (Conceptualization, Writing—original draft, Writing—review & editing), Yuzhuo Pan (Conceptualization, Writing—original draft, Writing—review & editing), Jiang Liu (Conceptualization, Writing—original draft, Writing—review & editing), Stephanie L. Aungst (Conceptualization, Writing—original draft, Writing—review & editing), Claudia P. Miller (Conceptualization, Writing—original draft, Writing—review & editing), Mirat Shah (Conceptualization, Writing—original draft, Writing—review & editing), Nam Atiqur Rahman (Conceptualization, Writing—original draft, Writing—review & editing), Marc Theoret (Conceptualization, Writing—original draft, Writing—review & editing), Paul Kluetz (Conceptualization, Writing—original draft, Writing—review & editing), Richard Pazdur (Conceptualization, Writing—original draft, Writing—review & editing), Julia A. Beaver (Conceptualization, Writing—original draft, Writing—review & editing), Harpreet Singh (Conceptualization, Writing—original draft, Writing—review & editing)

Funding

None declared.

Conflicts of Interest

The authors report no financial interests or relationships with the commercial sponsors of any products discussed in this report.

Data availability

No new data were generated or analyzed in support of this research.