Trastuzumab Deruxtecan Elicits Durable Response in HER2+ Gastric/GEJ Cancer

Fam-trastuzumab deruxtecan-nxki (Enhertu) elicited clinically meaningful response in patients with HER2-positive gastric or gastroesophageal junction (GEJ) cancer, according to findings from the phase 2 DESTINY-Gastric02 trial (NCT04014075).¹

Results from the primary and updated analysis of the study published concurrently in Lancet Oncology. Among patients who had disaese progression after treatment with trastuzumab (Herceptin), patients treated with the antibody-drug conjugate (n = 79) achieved a confirmed objective response rate (ORR) by independent central review was 38% (95% CI, 27.3%-49.6%), including 3 patients with a complete response (CR). The median follow-up for the primary analysis was 5.9 months (range, 4.6-8.6).¹

Additionally, at a median follow-up of 10.2 months (range, 5.6-12.9), findings from the updated analysis showed that the confirmed ORR was 42% (95% CI, 30.8%-53.4%), with 4 patients achieving a CR. The data cutoff for the updated analysis was November 8, 2021.¹

Trastuzumab deruxtecan previously gained approval from the FDA on January 25, 2021, for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or GEJ cancer who underwent prior treatment with a trastuzumab-based regimen. The indication was supported by findings from the phase 2 DESTINY-Gastric01 trial (NCT03329690), which showed that patients who received the agent (n = 126) achieved a confirmed ORR of 40.5% (95% CI, 31.8%-49.6%) compared with 11.3% (95% CI, 4.7%-21.9%) among patients treated with irinotecan or paclitaxel (n = 62; P < .0001). Additionally, the median overall survival (OS) was 12.5 months (95% CI, 9.6-14.3) vs 8.4 months (95% CI, 6.9-10.7), respectively (HR, 0.59; 95% CI, 0.39-0.88; P = .0097).²

In the multicenter, single-arm DESTINY-Gastric02 trial, investigators enrolled adult patients with unresectable or metastatic gastric/GEJ cancer that had progressed on or after frontline treatment with a trastuzumab-containing regimen. Patients needed to have HER2-positive disease, defined as immunohistochemistry (IHC) 3+ or IHC 2+ with HER2 amplification, an ECOG performance status of 1 or less, and a minimum left ventricular ejection fraction of 50% to be included in the study. Those who received an anticancer therapy following first-line treatment with a trastuzumab-based regimen, had spinal cord compression or active central nervous system metastases, cardiovascular disease, or clinically severe pulmonary disease were not eligible.¹

The median age of patients included in the trial was 60.7 years (range, 52.0-68.3), with most patients being aged less than 65 years (58%). Most patients were men (72%), White (87%), had an ECOG performance status of 1 (63%), had HER2 expression of IHC 3+ (86%), had GEJ cancer (66%), and had at least 2 metastatic sites (94%). The median time from diagnosis was 14.2 months (range, 10.2-25.9).¹

Most patients had previously received 1 systemic therapy for locally advanced or metastatic cancer (92%). All patients underwent prior platinum-based treatment, prior trastuzumab therapy, and had not undergone a total gastrectomy. Previous treatment with an immune checkpoint inhibitor was reported in 9% of patients, including 1 patient who received avelumab (Bavencio) and 6 who were treated with pembrolizumab (Keytruda).¹

Trastuzumab deruxtecan was administered intravenously at a dose of 6.4 mg/kg every 3 weeks until disease progression, clinical progression, withdrawal, or death. Dose reductions were permitted, from 6.4 mg/kg to 5.4 mg/kg then to 4.4 mg/kg; dose delays up to 28 days were also allowed. Study withdrawal occurred for patients after exceeding 2 dose reductions if further adverse effects (AEs) requiring dose reduction were present.¹

The primary end point of the study was confirmed ORR by RECIST 1.1 criteria as assessed by independent central review. Progression-free survival (PFS) represented the key secondary end point; other secondary end points included OS, duration of response (DOR), and safety.¹

Additional findings from the primary analysis showed that the median PFS was 5.5 months (95% CI, 4.2-7.2), the median OS was 12.1 months (95% CI, 8.6-not estimable [NE]), and the median DOR was 8.1 months (95% CI, 4.1-NE). At the time of the updated analysis, which was requested as part of a health authority review, these figures were 5.6 months (95% CI, 4.2-8.3), 12.1 months (95% CI, 9.4-15.4), and 8.1 months (95% CI, 5.9-NE), respectively.¹

The confirmed disease control rate remained the same from the primary to the updated analysis, at 81% (95% CI, 70.6%-89.0%). Similarly, the median time to response was 1.4 months in both analyses. At the time of the updated analysis, 13% of patients remained on study treatment and 39 had received subsequent anticancer therapy following study completion.¹

According to results from the updated analysis, treatment with trastuzumab deruxtecan produced a response across all prespecified subgroups. High ORRs were seen among patients 75 years or older (n = 4; 100%; 95% CI, 39.8%-100%), among a patient with diffuse histological subtype (n = 1; 100%; 95% CI, 2.5%-100%), and those with moderate renal impairment at baseline (n = 8; 62.5%; 95% CI, 24.5%-91.5%).¹

In terms of safety, the median duration of treatment was 4.3 months (range, 2.7-10.1) at the later data cutoff. All patients experienced a treatment-emergent AE (TEAE), including 56% who had a TEAE of grade 3 or higher severity and 42% of patients reported a serious AE. Drug-related TEAEs were reported in most patients (95%), of which 30% were grade 3 or greater and 13% were serious.¹

The most common grade 1 or 2 TEAEs included nausea (59%), vomiting (42%), fatigue (38%), and diarrhea (35%). Common grade 3 TEAEs included anemia (14%), nausea (8%), and decreased white blood cell count (6%). Grade 4 events consisted of decreased neutrophil count (5%), pneumonia (3%), bacterial sepsis (1%), interstitial lung disease (ILD; 1%), febrile neutropenia (1%), and hypokalemia (1%).¹

There were 11 grade 5 events: disease progression (n = 2), COVID-19 (n = 2), malignant neoplasm progression (n = 2), pneumonitis (n = 1), ILD (n = 1), lymphangiosis carcinomatosa (n = 1), cerebrovascular accident (n = 1), and intestinal obstruction (n = 1). Two deaths, both because of ILD/pneumonitis, related to treatment with trastuzumab deruxtecan per investigator review.¹

Fifteen patients discontinued treatment because of a TEAE, 10 of these instances were deemed to be drug related. TEAEs leading to dose reductions occurred in 22% of patients, 18% of these were related to trastuzumab deruxtecan. Finally, dose interruption occurred in 29% of patients, including 10% that were drug related.¹

Study authors noted that their trial was limited by the lack of a comparator arm and its relatively small size. However, they concluded: “DESTINY-Gastric02 provides data supporting clinically meaningful activity and a manageable safety profile and thus, compellingevidence that trastuzumab deruxtecan is a valuable second-line HER2-targeted treatment option for patients from the [United States] or Europe, similar to the findings of DESTINY-Gastric01 for Asian patients in the third-line and later settings.”¹

References

1. Van Cutsem E, di Bartolomeo M, Smyth E, et al. Trastuzumab deruxtecan in patients in the USA and Europe with HER2-positive advanced gastric or gastroesophageal junction cancer with disease progression on or after a trastuzumab-containing regimen (DESTINY-Gastric02): primary and updated analyses from a single-arm, phase 2 study. Lancet Oncol. Published online June 14, 2023. doi:10.1016/S1470-2045(23)00215-2
2. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas. FDA. January 15, 2021. Accessed June 27, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-her2-positive-gastric-adenocarcinomas