Trastuzumab Deruxtecan Induces Durable Responses in HER2-Mutant NSCLC

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

Egbert F. Smit, MD

Fam-trastuzumab deruxtecan-nxki (Enhertu) demonstrated 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 trial reported at the 2020 ASCO Virtual Scientific Meeting.¹

In the 42 patients enrolled in cohort 2 of the analysis, treatment with the novel antibody-drug conjugate led to a confirmed ORR of 61.9% (95% CI, 45.6%-76.4%) by independent central review (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.

“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.”

In the open-label, multicenter, multicohort phase 2 trial, investigators enrolled patients with unresectable or metastatic nonsquamous NSCLC who were determined to be relapsed or refractory to standard treatments and 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.

Patients were enrolled into 2 cohorts. The first cohort 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 trastuzumab deruxtecan at a dose of 4.6 mg/kg 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 because of disease progression or adverse events (AEs; 21.4% each).

Of the 42 patients included in the second cohort, the median age was 63 years (range, 34-83), and 59.5% of patients were younger than 65 years of age. Additionally, 64.3% of patients were female. Divided by region, 35.7% were from Asia, 31.0% were from North America, and 33.3% were from Europe. The majority of the patients had an ECOG performance status of 1 (76.2%) at baseline, and 23.8% of patients had a performance status of 0. For the majority of patients (90.5%), their HER2 mutation was located in the kinase domain. Only 1 patient had a mutation present in the extracellular domain, and in 1 patient this information was not reported. Just less than half of patients (45.2%) had evidence of central nervous system metastases.

Additionally, patients enrolled on the study received 2 median prior lines of treatment (range, 1-6), with a range of 1 to 6. Ninety percent of patients had received platinum-based therapy prior to the study, while 54.8% and 19.0% received prior anti—PD-1 or –PD-L1 therapy or docetaxel, respectively. Notably, 3 patients received prior poziotinib, 2 received afatinib (Gilotrif), and 1 received mobocertinib (TAK-788).

The primary end point of the trial was confirmed ORR by ICR, and trastuzumab deruxtecan induced an ORR of 61.9% in this patient population. One patient (2.4%) achieved a complete remission with the treatment. 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,” noted Smit.

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

The safety profile of the treatment in the HER2-mutated cohort was generally consistent with what has been previously reported with the agent, according to Smit. The 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.

“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.”

Notably, the median duration exposure of patients to trastuzumab deruxtecan was 7.76 months (range, 0.7-14.3). The most common TEAEs associated with dose reduction were fatigue, which occurred in 11.9% of patients, and nausea, which was reported in 9.5% of patients. Additionally, the most common TEAEs linked with dose interruption included neutrophil count decrease (19.0%) and lung infection (7.1%). Five patients experienced TEAEs that were associated with death, but none of them were determined to be related to the study treatment.

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,” said Smit. “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.”

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.

Earlier this month, 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.

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