Trastuzumab Deruxtecan Confers Response in HER2+ Gastric/GEJ Cancer in Updated Analysis

Treatment with the HER2-directed antibody-drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (Enhertu) resulted in clinically meaningful efficacy in patients with HER2-positive gastric or gastroesophageal junction (GEJ) cancer following disease progression on or after a trastuzumab(Herceptin)-containing regimen, according to findings from the primary and updated analyses of the phase 2 DESTINY-Gastric02 trial (NCT04014075). The results were published concurrently in Lancet Oncology.¹

Results from the primary analysis of the study showed that, at a data cutoff of April 9, 2021, patients treated with the ADC (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