Trastuzumab deruxtecan effective in patients with HER2-positive advanced gastric or gastroesophageal junction adenocarcinoma

Data form the phase II DESTINY-Gastric01 study demonstrate that trastuzumab deruxtecan (T-DXd) results in a clinically meaningful and statistically significant improvement in objective response rate (ORR) compared to physician’s choice of chemotherapy in patients with HER2-positive advanced gastric or gastroesophageal junction adenocarcinoma. Compared to chemotherapy with irinotecan or paclitaxel, T-DXd improved the ORR from 14.3% to 51.3%. In addition, patients treated with T-DXd had a significantly longer overall survival (OS) and also the median progression-free survival (PFS) and the duration of response was improved. The safety profile of T-DXd was generally manageable and consistent with previous studies with this agent.

Background

Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug conjugate (ADC) designed to deliver an optimal antitumour effect. T-DXd consists of three components; a humanized anti-HER2 IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab, a topoisomerase I inhibitor payload and a tetrapeptide-based cleavable linker. In a previous phase I study, T-DXd demonstrated an ORR of 43% in previously treated patients with gastric cancer. Based on these results, the phase II DESTINY-Gastric01 study was initiated.

DESTINY-Gastric01 trial is an open-label, multicentre, randomised phase II study enrolling patients with HER2-expressing advanced gastric or GEJ adenocarcinoma who received at least two prior regimens that must have included a fluoropyrimidine and a platinum agent. In the primary cohort of the study, patients (N= 187) were randomised (2:1) to either T-DXd (6.4 mg/kg, 3-week cycle) or physician’s choice of irinotecan or paclitaxel.

Results

Patient’s baseline characteristics were well balanced between both study arms with a median age of 65 years, all patients were from Japanese or Korean origin, a quarter was female and 86% of patients suffered from gastric cancer (14% GEJ cancer). Patients in both arms received a median of two prior lines of cancer treatment. All patients were previously treated with trastuzumab, around 85% received prior taxanes and about one third of the patients previously received an immune checkpoint inhibitor.

The ORR by independent central review (ICR) was reported at 51.3% for patients in the T-DXd arm as compared to 14.3% for patients in the physician’s choice of treatment arm (p< 0.0001). Also the confirmed ORR, as confirmed by a follow-up scan at least four weeks after the initial complete or partial response, was significantly higher with T-DXd (42.9% vs. 12.5%). Confirmed disease control rates were 85.7% and 62.5% for T-DXd and controls, respectively, with a median confirmed duration of response of 11.3 vs. 3.9 months. Most of the patients in the T-DXd arm experienced some degree of tumour shrinkage. Moreover, this reduction in tumour size was also more durable with T-DXd compared to patients receiving chemotherapy. The median OS was 12.5 months in the T-DXd arm vs. 8.4 months in the control arm with 12-month OS rates of 52.1% and 28.9%, respectively. This represents a 41% reduction in the risk of death (HR[95%CI]: 0.59[0.39-0.88], p= 0.0097) for patients treated with the antibody-drug-conjugate. In addition, patients in the T-DXd arm had a 53% reduction in the risk of disease progression or death as compared to patients receiving chemotherapy (median PFS of 5.6 vs. 3.5 months, HR[95%CI]: 0.47[0.31-0.71]).

The clinical benefit did come at the cost of increased toxicity with higher rates of grade ≥ 3 treatment-emergent adverse events (TEAEs) and serious TEAEs with T-DXd than with physician’s choice of treatment arm (85.6% vs. 56.5% and 44.0% vs. 24.2%, respectively). As a result, patients in the T-DXd arm also needed more TEAE-related treatment discontinuations (15.2% vs. 6.5%), dose reductions (32.0% vs. 33.9%), dose interruptions (62.4% vs. 37.1%) and deaths (6.4% vs. 3.2%). Of note, these higher rates may also be related to the longer median treatment duration for patients in the T-DXd arm compared to patients in the control arm (4.6 vs. 2.8 months). The most commonly observed TEAE’s of all grade were gastrointestinal or hematologic in nature and included nausea, neutropenia, decreased appetite, thrombocytopenia and a decreased white blood cell count. Drug-related interstitial lung disease/pneumonitis, as determined by an independent adjudication committee was only observed in patients receiving T-DXd. IN total, 12 such events were reported twelve events (three of grade 1, six of grade 2, two of grade 3 and one of grade 4), with a median time to first onset of 84.5 days. In this light, it is recommended to closely monitor patients for any symptoms that might point into the direction of interstitial lung disease and hold T-DXd and start steroids as soon as interstitial lung disease is confirmed.

Conclusions

Patients with previously treated HER2-positive advanced gastric or gastroesophageal junction adenocarcinoma receiving T-DXd had a significantly higher ORR than those receiving standard chemotherapy. Importantly, this higher response rate was also translated in a better PFS and OS. The observed safety profile of T-DXd was generally manageable and consistent with previous studies. Based on these findings, T-DXd should be seen as an effective treatment option for patients with advanced, HER2-positive gastric or GEJ adenocarcinoma who progressed after a trastuzumab-containing treatment.

Reference

Yamaguchi K. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: A randomized, phase 2, multicenter, open-label study (DESTINY-Gastric01). Presented at ESMO World GI 2020; Abstract Oral-11.