Encouraging Activity Shown With Trastuzumab Deruxtecan in HER2-Overexpressing NSCLC

Antitumor activity was demonstrated with trastuzumab deruxtecan (Enhertu) treatment in patients with HER2-overexpressing non–small cell lung cancer (NSCLC), regardless of HER2 expression levels, according to interim findings from a cohort of the phase 2 DESTINY Lung-01 trial (NCT03505710).¹ 

“The encouraging early efficacies support the continued exploration of [trastuzumab deruxtecan] in patients with HER2-overexpressing non–small cell lung cancer,” said Kazuhiko Nakagawa, MD, PhD, in a presentation during the International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer (WCLC) Singapore.

Trastuzumab deruxtecan is an antibody–drug conjugate (ADC) composed of an anti-HER2 antibody, a tetrapeptide-based linker, and a topoisomerase I inhibitor payload. The ADC earlier demonstrated promising activity in patients with HER2-expressing or -mutant nonbreast and nongastric solid tumors in an open-label, multi-dose, 2-part phase 1 trial (NCT02564900).2 In the NSCLC cohort of 18 patients, the objective response rate (ORR) was 55.6% (95% CI, 30.8%-78.5%) with responses lasting for a median of 10.7 months (95% CI, 6.9-11.5), and the median progression-free survival (PFS) was 11.3 months (95% CI, 7.2-14.3). These results led to the FDA granting a breakthrough designation in the previously treated HER2-mutant metastatic NSCLC setting in May 2020.^2,3

DESTINY-Lung 01 is an open-label, multicenter, multicohort phase 2 study of trastuzumab deruxtecan in patients with HER2-overexpressing or HER2-mutant metastatic NSCLC. Patients with unresectable or metastatic nonsquamous NSCLC who had relapsed from or who are refractory to standard treatment and an ECOG performance status of 0 or 1 were eligible for enrollment into one of the cohorts.

Cohort 1 consists of 49 patients with HER2-overexpressing (immunohistochemistry [IHC] 3+ or 2+) NSCLC who received 6.4 mg/kg of trastuzumab deruxtecan every 3 weeks and an additional cohort (1a) of the same patient population (n = 41) received the 5.4-mg/kg dose every 3 weeks. Cohort 2 comprised patients with HER2-mutated NSCLC (n = 42) who received the 6.4-mg/kg dose.

The primary end point of the study was ORR and secondary end points included PFS, overall survival (OS), duration of response (DOR), disease control rate (DCR), and safety and tolerability. The data cutoff date for the interim analysis of cohort 1 was May 31, 2020. As of this date, 11 patients in cohort 1 remained on treatment. The remainder had discontinued treatment, primarily due to progressive disease (n = 22) or adverse events (AEs; n = 9). The median treatment duration was 18.0 weeks (range, 3.0-57.1).

In cohort 1, the focus of Nakagawa’s WCLC presentation, patients had a median age of 63.0 years (range, 37-85), and most were male (61.2%) with an ECOG performance status of 1 (71.4%). The majority of patients (79.6%) had IHC 2+ HER2 expression and 3+ in 20.4%. Other gene abnormalities were not reported in 65.3% of patients, but 6.1% had an EGFR, ALK, ROS1, or BRAF alteration. Central nervous system (CNS) metastases were reported in 34.7% of patients at baseline.

The median number of prior lines of therapy was 3 (range, 1-8) with prior therapies consisting of platinum-based chemotherapy in 91.8%, anti–PD-1/PD-L1 antibodies in 73.5%, and docetaxel in 24.5%).

The confirmed ORR was 24.5% (95% CI, 13.3%-38.9%) in all patients and included 1 complete response; an additional 22 patients (44.9%) had stable disease (SD), resulting in a DCR of 69.4% (95% CI, 54.6%-81.8%). The median DOR was 6.0 months (95% CI, 3.2-not evaluable [NE]).

Among patients with IHC 3+ overexpression, confirmed responses were observed in 20% (95% CI, 2.5-55.6%) and SD was achieved in 60.0%; the DCR was 80.0% (95% CI, 44.4%-97.5%). DOR reached a median of 6.0 months (95% CI, NE-NE).

In patients with IHC 2+, responses were observed in 25.6% (95% CI, 13.0%-42.1%) and 41.0% had SD, for a DCR of 66.7% (95% CI, 49.8%-80.9%). The median DOR was 5.8 months (95% CI, 3.2-NE).

“Overall, the size of most tumors were reduced in this [phase 2 study],” said Nakagawa, professor in the Department of Medical Oncology, Faculty of Medicine, Kindai University. “Progressive reduction in tumor volume was found in some patients.”

The median PFS was 5.4 months (95% CI, 2.8-7.0) and the median OS was 11.3 months (95% CI, 7.8-NE).

Treatment-emergent AEs (TEAEs) were observed in all patients and were considered drug related in 89.8%. Drug-related TEAEs were grade ≥3 in 55.1%, serious in 16.3%, associated with dose discontinuation in 22.4%, associated with dose reduction in 32.7%, and associated with dose interruption in 34.7%).

Nakagawa noted that the safety profile was generally consistent with that of previous trials with gastrointestinal and hematologic TEAEs being the most common.

The most common grade ≥3 event was decreased neutrophil count in 20.4% of patients. Decreased neutrophil count also led to dose reduction in 10.2% and dose interruption in 10.2%. Nausea led to dose reduction and dose interruption in 6.1%, fatigue was associated with dose reduction in 8.2%, and pneumonitis was associated with treatment discontinuation in 10.2%. Grade 5 TEAEs were reported in 7 patients, including disease progression in 4, and hydrocephalus, pneumonitis, and bronchospasm in 1 patient each; 1 such event was considered drug related.

Drug-related interstitial lung disease (ILD), as determined by an independent adjudication committee, was reported in a total of 8 patients, with 2 being grade 1, 3 of grade 2, and 3 of grade 5. The median time to onset for all cases was 64.5 days (range, 2-126). Trastuzumab deruxtecan was withdrawn for all of these patients and steroids were given for all of the patients with grade ≥2 ILD.

Three of the patients with mild to moderate ILD recovered and 2 others had not yet recovered by the time of data cutoff. Four of the 8 patients had previously received immune checkpoint inhibitors.

In the 3 patients with grade 5 events, steroid treatment was given within 5 days of the reporting of the event and all of these patients had previously received immune checkpoint inhibition. The primary cause of death in these patients was progressive disease for 2 and pneumonitis for 1.

ILD continues to be closely monitored and proactively managed, Nakagawa said, with further investigation planned as more follow-up data become available.

_References:

_{1. Nakagawa K, Nagasaka M, Felip E, et al. Trastuzumab deruxtecan in HER2-overexpressing metastatic non-small cell lung cancer: Interim Results of DESTINY-Lung01. Presented at: 2020 World Conference on Lung Cancer Singapore; January 28-31; Virtual. Abstract OA04.05.}

_{2. Tsurutani J, Iwata H, Krop I, et al. Targeting her2 with trastuzumab deruxtecan: a dose-expansion, phase I study in multiple advanced solid tumors. Cancer Discov. 2020;10(5):688-701. doi:10.1158/2159-8290.CD-19-1014}

_{3. ENHERTU Granted Breakthrough Therapy Designation in the US for HER2-Mutant Metastatic Non-Small Cell Lung Cancer. News release. AstraZeneca and Daiichi Sankyo Company. May 18, 2020. Accessed January 29, 2021. https://bwnews.pr/2X5scoU}