Trastuzumab Deruxtecan Shows Promising Clinical Activity in CRC and Gastric/GEJ Tumors

The antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (Enhertu) demonstrated promising clinical activity in patients with HER2-positive metastatic colorectal cancer (CRC), as well as in those with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to findings from 2 phase 2 trials that were presented at the 2020 ASCO Virtual Scientific Program.^1,2

In one of the trials, DESTINY-CRC01 trial (NCT03384940), data showed that trastuzumab deruxtecan led to an objective response rate (ORR) of 45.3% in patients with HER2-positive metastatic CRC who were refractory to standard treatment (95% CI, 31.6%-59.6%), and the median duration of response (DOR) had not yet been reached (95% CI, 4.2 months—not evaluable [NE]). Responses were consistent across subgroups, including those who had received prior anti-HER2 therapy. The median progression-free survival (PFS) was 6.9 months.

The agent proved to demonstrate further efficacy in patients with advanced, HER2-positive gastric or GEJ adenocarcinoma who had progressed after trastuzumab (Herceptin)-containing treatment. Results from the DESTINY-Gastric01 trial (NCT03329690) showed that trastuzumab deruxtecan induced a higher ORR compared with chemotherapy, at 51.3% versus 14.3%, respectively, including 11 complete responses (CRs) in the investigational arm.

The ADC also resulted in a longer median overall survival (OS) versus chemotherapy, at 12.5 months versus 8.4 months, respectively. Furthermore, median PFS and median duration of confirmed response were also longer with trastuzumab deruxtecan.

DESTINY-CRC01

In the open-label, multicenter, phase 2 DESTINY-CRC01 trial, investigators enrolled patients with HER2-expressing, as well as RAS/BRAF wild-type, unresectable, and/or metastatic CRC, who had previously received 2 or more lines of treatment. Notably, prior anti-HER2 therapies was permitted. Patients who had a history of, currently had, or were suspected to have interstitial lung disease (ILD) were ineligible for enrollment.

In the trial, trastuzumab deruxtecan was administered at 6.4 mg/kg intravenously every 3 weeks until either disease progression or unacceptable toxicity. Cohort A was comprised of 53 patients with HER2-positive disease as defined by immunohistochemistry (IHC) 3+ or IHC 2+. Futility monitoring was conducted after at least 20 patients in the cohort had 12 weeks of follow-up to inform opening up cohorts B and C. Cohort B included 7 patients with HER2-positive and fluorescence in situ hybridization (ISH)—negative tumors. Cohort C enrolled 18 patients with HER2-positive disease as defined by IHC 1+.

At the data cutoff of August 9, 2019, 38.5% (n = 30/78) patients were still receiving treatment. More than half of patients (61.5%) discontinued treatment, primarily because of disease progression (41.0%) and clinical progression (9.0%). The primary end point was confirmed ORR via independent central review (ICR) in cohort A.

Overall, the 78 patients across the 3 cohorts had a median age of 58.5 years; 47.4% of patients were female. A total 52.6% of patients were from Europe, while the other half were from North America and Asia. The sum of target lesions in these patients was a median of 8.8 cm. Nearly 90% of patients’ primary tumors were located in their left intestine, including the rectum. Additionally, 79.5% of patients had microsatellite stable disease and the remaining were either unknown or had no known microsatellite instability. Most patients (98.7%) had RAS and BRAF wild-type disease. In cohort A specifically, 75.5% of patients were IHC 3+ and 24.5% were IHC 2+ and ISH positive.

The median number of prior lines of therapy was 4 (range, 2-11), and all patients had received irinotecan, as well as oxaliplatin. In cohort A, all patients also received cetuximab (Erbitux) or panitumumab (Vectibix), and one-third of patients received prior anti-HER2 agents, which included pertuzumab (Perjeta; 24.5%), trastuzumab (22.6%), ado-trastuzumab emtansine (T-DM1; Kadcyla; 5.7%), lapatinib (Tykerb; 5.7%), and tucatinib (Tukysa; 1.9%).

Results showed that the ADC resulted in a confirmed ORR by ICR of 45.3% (n = 24/53) in cohort A. Of the 24 patients, 1 achieved a CR and 23 experienced a partial response (PR); an additional 20 patients had stable disease. Overall, the disease control rate (DCR) was 83.0% (95% CI, 70.2%-91.9%). No confirmed responses were reported in cohorts B or C.

“Based on the data from DESTINY-CRC01, trastuzumab deruxtecan, given at 6.4 mg/kg every 3 weeks, demonstrated promising and durable activity in patients with HER2-positive metastatic CRC refractory to standard therapies,” Salvatore Siena, MD, lead author of the study, a professor of medical oncology at Università degli Studi di Milano, and director of Niguarda Cancer Center at Grande Ospedale Metropolitano Niguarda in Italy, in a presentation during the meeting. “These data demonstrate the potential of [the agent] for patients with HER2-positive CRC.”

An analysis of responses by predefined subgroups revealed that only HER2 status IHC 3+ versus IHC 2+/ISH+ discriminates better responses with trastuzumab deruxtecan, with an ORR of 57.5% (95% CI, 40.9-73.0) versus 7.7% (95% CI, 0.2-36.0).

With regard to survival, median PFS was 6.9 months in cohort A (95% CI, 4.1-NE) and the median OS was not yet reached in any cohort (overall 95% CI, 0.74—NE).

The median duration of treatment in patients with HER2-positive disease was 4.8 months (range, 1-11) and 3.5 months in all patients (range, 1-11). All-grade treatment-emergent adverse events (TEAEs) occurred in all patients; treatment-related AEs were observed in 96.2% of patients in cohort A and 93.6% in the overall patient population. Grade 3 or higher TEAEs were observed in 60.4% of those in cohort A and 61.5% in all patients; 50.9% versus 48.7%, respectively, were related to treatment. Serious TEAEs were reported in 34.0% and 33.3% in cohort A and all patients, respectively, while serious treatment-related AEs (TRAEs) occurred in 22.6% of patients in cohort A and in 17.9% of all patients.

TRAEs that resulted in treatment discontinuation were reported in 3.8% of patients in cohort A and 2.6% of all patients. TRAEs that led to dose reductions occurred in 18.9% of those in cohort A versus 17.9% in all patients; those that resulted in dose interruptions were reported in 28.3% and 24.4% of patients, respectively. Two deaths were determined to be treatment related per investigator assessment; one was due to pneumonitis and the other was due to ILD. Both patients were enrolled in cohort A.

TEAEs that occurred in more than 15% of patients across all cohorts consisted of nausea, anemia, decreased neutrophil count, fatigue, decreased appetite, decreased platelet count, vomiting, diarrhea, alopecia, hypokalemia, and decreased white blood cell count (WBC). A minority of these events were grade 3 or higher in severity. Low-grade gastrointestinal and hematologic AEs were most commonly reported with the study drug.

ILD was considered an AE of special interest. Among 78 patients who received the ADC, 5 patients experienced ILD, with a median time to onset of 80 days (range, 22-132). All of these patients received corticosteroids and 2 recovered; 1 did not recover and later died because of progressive disease, and 2 died. In those who died, onset ranged from 40 to 126 days. Both patients were given steroids and deaths occurred 6 to 18 days following diagnosis.

DESTINY-Gastric01

In the open-label, multicenter, randomized phase 2 DESTINY-Gastric01 trial, investigators compared the use of trastuzumab deruxtecan with physician’s choice of standard chemotherapy in patients with HER2-expressing advanced gastric or GEJ adenocarcinoma who had received at least 2 prior regimens, including fluoropyrimidine, a platinum-based agent, and trastuzumab or approved biosimilar.

A total 187 patients were randomized to receive trastuzumab deruxtecan arm (n = 125) and or chemotherapy (n = 62). Eighty-six percent of patients had previously received treatment with a taxane agent, 71% also received ramucirumab (Cyramza), and 31% were treated with PD-1/PD-L1 inhibitors. At the data cutoff date of November 8, 2019, 22.4% of those on the ADC arm were still on treatment versus 4.8% of those on chemotherapy.

The primary end point of the trial was ORR by ICR, and key secondary end points included OS, DOR, PFS, confirmed ORR, and safety.

Results showed that the ORR by ICR was significantly higher with trastuzumab deruxtecan compared with chemotherapy, at 51.3% (n = 61; 95% CI, 41.9%-60.5%; P <.0001) and 14.3% (95% CI, 6.4%-26.2%), respectively. Notably, the CR rate was 8.4% on the ADC arm; there were no CRs on the chemotherapy arm.

Moreover, confirmed ORR by ICR was 42.9% (n = 51; 95% CI, 33.8-91.5) versus 12.5% (n = 7; 95% CI, 5.2-24.1) and the confirmed DCR was 85.7% (n = 102; 95% CI, 78.1-91.5) with the ADC versus 62.5% (n = 35; 95% CI, 48.5-75.1) with chemotherapy. The median confirmed DOR was 11.3 months (95% CI, 5.6—NE) versus 3.9 months (95% CI, 3.0-4.9) with trastuzumab deruxtecan and chemotherapy, respectively.

Results also showed that trastuzumab deruxtecan also resulted in a statistically significant improvement in OS. Specifically, the median OS was 12.5 (95% CI, 9.6-14.3) with the ADC versus 8.4 months (95% CI, 6.9-10.7) with physician’s choice of chemotherapy (HR, 0.59; 95% CI, 0.39-0.88; P = .0097). One-year OS rates were 52.1% versus 28.9% with trastuzumab deruxtecan and chemotherapy, respectively; 6-month OS rates were 80.3% versus 66.4%, respectively.

The median PFS with the ADC was 5.6 months (95% CI, 4.3-6.9) versus 3.5 months (95% CI, 2.0-4.3) with physician’s choice of chemotherapy (HR, 0.47; 95% CI, 0.31-0.71). The 1-year PFS rates were 29.9% versus 0% with trastuzumab deruxtecan versus chemotherapy, respectively; 6-month PFS rates were 42.8% versus 20.6%, respectively.

Regarding safety, the most common AEs of grade 3 or higher with the ADC were neutropenia, decreased appetite, anemia, thrombocytopenia, and decreased white blood cell count. TEAEs associated with drug discontinuation was 15.2% with the ADC versus 6.5% with chemotherapy; events linked with dose reductions was 32.0% versus 33.9%, respectively; events that led to dose interruptions were 62.4% versus 37.1%, respectively.

“The safety profile of trastuzumab deruxtecan was generally manageable and consistent with previous studies,” said Kohei Shitara, MD, lead author of the study and staff doctor of the Department of Experimental Therapeutics (and Gastrointestinal Oncology) at the National Cancer Center Hospital East, Kashiwa in Japan in a presentation during the meeting. “Signs and symptoms of ILD, a known risk with [this agent], were actively monitored and managed with dose modification or discontinuation, corticosteroids, and supportive care in accordance with the study protocol.”

One treatment-related death, due to pneumonia, was reported with the study treatment versus no deaths on the chemotherapy arm. Twelve patients, or 9.6%, experienced ILD/pneumonitis that was determined by an independent adjudication committee to be associated with trastuzumab deruxtecan. The median time to first onset was 84.5 days (range, 36-638), and most events were grade 1 or 2 in severity.References

1. Siena S, Bartolomeo MD, Raghav K, et al. A phase 2, multicenter, open-label study of trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-expressing metastatic colorectal cancer: DESTINY-CRC0 J Clin Oncol. 2020;38(suppl 15; abstr 4000). doi:10.1200/JCO.2020.38.15_suppl.4000
2. Shitara K, Bang Y-J, Iwasa S, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: a randomized, phase II, multicenter, open-label study (DESTINY-Gastric01). J Clin Oncol. 2020;38(suppl 15; abstr 4513). doi:10.1200/JCO.2020.38.15_suppl.4513

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