T-DXd Displays Clinical Benefit in HER2-Overexpressed Metastatic NSCLC

James CH Yang, MD, PhD

Fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) monotherapy showed clinical benefit in patients with pretreated HER2-overexpressed (HER2-OE) metastatic non–small cell lung cancer, according to part 1 findings of the phase 1b DESTINY-Lung03 trial (NCT04686305) presented at the 2024 IASLC World Conference on Lung Cancer.¹

At a data cutoff date of April 1, 2024, results showed that the confirmed objective response rate (ORR) was 44.4% (n = 16; 95% CI, 27.9%-61.9%). All patients in the monotherapy arm (n = 36) had partial responses; there were no complete responses. Fifteen patients (41.7%) had stable disease for at least 5 weeks and 4 (11.1%) experienced disease progression. At 12 weeks, the disease control rate (DCR) was 77.8% (95% CI, 60.9%-89.9%) and the median duration of response (DOR) was 11.0 months (95% CI, 5.5-16.7 months).

“Currently, there are limited HER2-directed treatment options for HER2-overexpressed, non–small cell lung cancer. Trastuzumab deruxtecan, at 5.4 mg/kg, is approved in several regions, including the US and EU for previously treated HER2-mutant, unresectable, metastatic non–small cell lung cancer,” senior study author James CH Yang, MD, PhD, professor of medicine in the Department of Oncology at National Taiwan University Hospital and National Taiwan University Cancer Center in Taipei, Taiwan, said during an oral presentation of the data.

In August 2022, the FDA granted an accelerated approval to trastuzumab deruxtecan for adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 mutations, as detected by an FDA-approved test, and who have received previous systemic therapy.² The decision was based on findings from the phase 2 DESTINY-Lung02 trial (NCT04644237).

The phase 1b DESTINY-Lung03 trial is evaluating the safety and efficacy of T-DXd in HER2-OE NSCLC.¹ Part 1 of the trial focused on arm 1D, which included 36 patients who received T-DXd monotherapy at 5.4 mg/kg intravenously every 3 weeks. In 2 other arms, T-DXd is being combined with durvalumab (Imfinzi) and cisplatin (arm 1A) with durvalumab and carboplatin (arm 1B); enrollment in both arms is complete. Part 3 is a dose-confirmation and expansion-phase portion combining T-DXd plus volrustomig with or without carboplatin, and part 4 is a safety run-in and expansion portion of T-DXd combined with rilvegostomig with or without carboplatin; both part 3 and part 4 are currently recruiting.

To be eligible for enrollment, patients had to be aged at least 18 years old, have centrally assessed HER2-OE (immunohistochemistry [IHC] of 3+ or 2+) unresectable, locally advanced or metastatic nonsquamous NSCLC, measurable disease per RECIST v1.1 criteria, ECOG status of 0 or 1, and previously received 1 or 2 lines of therapy. Those with targetable alterations must have previously been treated with appropriate targeted therapy.

Prior lines of therapy included targeted therapy (n = 21; 58.3%), including an EGFR TKI (n = 19; 52.8%), platinum-based chemotherapy (n = 14; 38.9%), immunotherapy (n = 8; 22.2%), and taxane chemotherapy (n = 3; 8.3%).

“[Regarding] patient demographics, as you can see, [this is an] older population, [with a] median age of 66.5 [years] and two-thirds of them were female,” Yang explained. “A majority of patients come from Asia—88.9%—and a majority of them are also never smokers, [and for] staging, a majority of them have stage 4 [disease with an] ECOG performance status of 1.”

Key end points included investigator-assessed ORR, DCR, DOR, and progression-free survival (PFS); other end points included overall survival (OS), safety, and tolerability. Exploratory end points included efficacy end points by HER2 IHC status and prior exposure to EGFR TKIs.

At the data cutoff, 3 patients (8.3%) were still receiving T-DXd; 33 (91.7%) discontinued treatment due to objective disease progression per RECIST definition (n =16; 44.4%), subjective disease progression (n = 11; 30.6%), adverse events (AEs; n = 3; 8.3%), patient decision (n = 1; 2.8%), and other reasons (n = 2; 5.6%). The median duration of T-DXd treatment was 7.2 months (range, 0.7-23.3 months); the median duration of follow-up was 14.9 months (range, 0.7-25.3 months).

“As you can see, [of the] patients [included] in this analysis, most patients had already discontinued the treatment, therefore [it is] quite a mature study,” Yang noted during the presentation.

Additional findings showed that the median investigator-assessed PFS using RECIST v1.1 criteria was 8.2 months (95% CI, 6.7-11.1 months). The median OS was 17.1 months (95% CI, 11.6-23.8 months).

In an exploratory analysis, the confirmed ORR was 56.3% (95% CI, 29.9%-80.3%) in patients with HER2 IHC of 3+ (n = 9/16). In those with HER2 IHC of 2+ (n = 20), the confirmed ORR was 35.0% (n = 7; 95% CI, 15.4%-59.2%). In 19 patients who previously received EGFR TKIs, the confirmed ORR was 68.4% (n =13; 95% CI, 43.5%-87.4%); in patients who did not have prior EGFR TKI (n = 17) the confirmed ORR was 17.6% (n = 3; 95% CI, 3.8%-43.4%).

Furthermore, the 12-week DCR was 81.3% (95% CI, 54.4%-96.0%) in patients with HER2 IHC of 3+; and 75.0% (95% CI, 50.9%-91.3%) in patients with HER2 IHC of 2+. Additionally, the 12-week DCR for patients who did and did not previously receive EGFR TKI was 84.2% (95% CI, 60.4%-96.6%) and 70.6% (95% CI, 44.0%-89.7%), respectively.

The median DOR in patients with HER2 IHC of 3+ and IHC of 2+ was 12.5 months (95% CI, 5.5-not estimable [NE]) and 6.6 months (95% CI, 4.5-11.0), respectively. In those who had a prior EGFR TKI and those who did not, the median DOR was 11.7 months (95% CI, 5.5-NE) and 4.6 months (95% CI, 4.5-NE), respectively.

The median PFS in those with HER2 IHC of 3+ and IHC of 2+ was 6.9 months (95% CI, 5.3-17.9 months) and 8.2 months (95% CI, 5.4-10.0 months), respectively. The median OS was 16.4 months (95% CI, 6.8-NE) and 17.1 months (95% CI, 9.4-23.8) in patients with HER2 IHC of 3+ and IHC of 2+, respectively.

Median PFS in those with prior EGFR TKI and those without was 8.2 months (95% CI, 6.7-19.3) and 7.1 months (95% CI, 1.4-10.0), respectively. In patients with prior EGFR TKI and those without, the median OS was 19.6 months (95% CI, 13.5-NE) and 14.7 months (95% CI, 3.9-18.0), respectively.

Based on safety findings, treatment-related AEs (TRAEs) occurred in 94.4% of patients, of which 41.7% experienced grade 3 or higher TRAEs. TRAEs leading to discontinuations, dose reductions, and dose interruptions occurred in 8.3%, 19.4%, and 13.9% of patients, respectively. The most common any-grade TRAEs in at least 10% or more of patients included nausea (52.8%), vomiting (30.6%), fatigue (8.3%), anemia (25.0%), decreased appetite (19.4%), alopecia (13.9%), dyspepsia, (13.9%) thrombocytopenia (11.1%), and decreased neutrophil count (11.1%). No new safety signals were identified and the safety profile of T-DXd was consistent with the known profile.

“These data suggest that T-DXd is associated with improved outcomes over current second-line standard of care for metastatic HER2-overexpression non–small cell lung cancer,” Yang concluded. “These results reinforce HER2 expression as an actionable biomarker in non–small cell lung cancer and highlights the need for HER2 IHC testing in routine non–small cell lung cancer diagnostic tests.”

References

1. Planchard D, Kim HR, Suksombooncharoen T, et al. Trastuzumab deruxtecan monotherapy in pretreated HER2-overexpressing nonsquamous non-small cell lung cancer: DESTINY-Lung03 part 1. Presented at: IASLC 2024 World Conference on Lung Cancer; September 7-10, 2024; San Diego, CA. Abstract OA16.05.
2. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer. News release. FDA. August 11, 2022. Accessed August 11, 2022. https://bit.ly/3bVts9g