Antibody Drug Conjugate Shows Favorable Clinical Activity in Phase 2 DESTINY-Lung01 Study

Fam-trastuzumab deruxtecan-nxki (Enhertu) showed favorable clinical activity with a high objective response rate (ORR) and durable responses in patients with HER2-mutated non-small cell lung cancer (NSCLC), according to cohort findings from an interim analysis of the phase 2 DESTINY-Lung01 study.¹

The open-label, multicenter, multicohort phase 2 study, presented at the 2020 ASCO Virtual Scientific Meeting, enrolled patients with unresectable or metastatic, relapsed or refractory non-squamous NSCLC whose tumors harbor a HER2-expressing or HER2-activating mutation. To be eligible for enrollment, patients could not have received prior HER2-targeted therapy with the exception of pan-HER TKIs.

The primary endpoint of the trial was confirmed ORR by independent central review (ICR).

“Trastuzumab deruxtecan demonstrated clinical activity in this interim analysis, with a high ORR and durable response rate in a heavily pretreated population of patients with HER2-mutated NSCLC,” lead study author Egbert F. Smit, MD, professor of pulmonary medicine at the Netherlands Cancer Institute, and professor in the Department of Pulmonary Diseases of the Vrje Universiteit Medical Centre in Amsterdam, The Netherlands, said in a virtual presentation during the meeting. “These data demonstrate the potential of this agent as a new treatment option for these patients.”

Patients were enrolled into 2 cohorts. The first enrolled patients with HER2-expressing tumors as defined by immunohistochemistry (IHC) 3+ or IHC 2+ (n = 42). The second cohort took patients whose tumors harbored a HER2 mutation as determined by a local laboratory test (n = 42). These patients were treated with 4.6 mg/kg of trastuzumab deruxtecan every 3 weeks via intravenous infusion.

At the data cutoff of November 25, 2019, 45% of patients (n = 19) in cohort 2 were still on treatment; 54.8% of patients discontinued treatment primarily due to disease progression or adverse events (AEs; 21.4% each).

In the 42 patients enrolled in cohort 2 of the analysis, treatment with the novel antibody-drug conjugate (ADC) led to a confirmed ORR of 61.9% (95% CI, 45.6%-76.4%) by ICR, and the median duration of response had not yet been reached (95% CI, 5.3 months—not evaluable [NE]). The estimated median progression-free survival (PFS) with the agent was 14.0 months.

Even further, more than half, or 59.5%, of patients experienced a partial response with the ADC and 28.6% had stable disease as their best outcome. Furthermore, 2 patients experienced disease progression and 2 patients were not evaluable. The disease control rate was 90.5% (95% CI, 77.4%-97.3%).

In the 39 patients who were evaluable for response, investigators reported that all patients experienced a decrease in tumor size. “One may note that responses were observed at an early time, most frequently at the time of the first tumor assessment after initiation of treatment, and these responses were for the majority of patients long lasting,” said Smit.

Moreover, at a median follow-up of 8.0 months (range, 1.4-14.2), the median overall survival (OS) had not yet been reached (95% CI, 11.8—NE). Notably, patients were censored if they discontinued treatment.

Treatment-emergent AEs (TEAEs) that occurred in 15% or more of patients were mainly nausea, alopecia, anemia, decreased appetite, a decrease in neutrophil count, vomiting, and diarrhea. The majority of these events were grade 1 or 2 in severity. Notably, the median duration exposure of patients to trastuzumab deruxtecan was 7.76 months (range, 0.7-14.3).

“Only a few patients experienced grade 3 or higher TEAEs,” said Smit. “In particular, [they experienced] anemia, neutrophil count decrease, and a minority [of patients] experienced gastrointestinal events, such as nausea, vomiting, diarrhea, and decrease of weight.”

Interstitial lung disease (ILD) was an AE of special interest, according to Smit. In this analysis, 5 patients (11.9%) experienced grade 2 ILD; however, no patients reported ILD of higher grades. The median time to ILD onset was 86 days (range, 41-255). Four patients who experienced this AE had the drug withdrawn and 1 had the drug interrupted. All of these patients received steroid treatment, and 2 patients recovered, 1 recovered with sequelae, 1 was recovering, and 1 had not recovered by data cutoff. No grade 5 ILD was reported in the cohort.

“The safety profile in the HER2-mutated cohort was generally consistent with what was previously reported. Low grade gastrointestinal and hematologic AEs were most common,” Smit explained. “Drug-related ILD events observed in this patient population were low grade and there were no deaths. However, ILD remains an important identified risk for patients treated with trastuzumab deruxtecan and requires careful monitoring and management.”

Importantly, enrollment in this HER2-mutated cohort has been expanded with an additional 50 patients in an effort to better characterize the risk-benefit ratio of trastuzumab deruxtecan in patients with HER2-mutated NSCLC.

In May 2020, the FDA granted trastuzumab deruxtecan a breakthrough therapy designation for the treatment of patients with metastatic NSCLC whose tumors have a HER2 mutation and with disease progression on or after platinum-based therapy. The decision was based on data from DESTINY-Lung01 and will accelerate the development and review of the ADC in this setting.²

References:

1. Smit EF, Nakagawa K, Nagasaka M, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): interim results of DESTINY-Lung 01. J Clin Oncol. 2020;38(suppl; abstr 9504).

2. Enhertu granted breakthrough therapy designation in the US for HER2-mutant metastatic non-small cell lung cancer. AstraZeneca. May 18, 2020. Accessed May 29, 2020. bit.ly/2TOHcqa.