In line with responses seen at the primary analysis, final results of a phase 2 trial support activity of trastuzumab deruxtecan in HER2-positive metastatic CRC.
Fam-trastuzumab deruxtecan-nxki (Enhertu) continued to demonstrate antitumor activity in patients with HER2-overexpressing metastatic colorectal cancer (mCRC), according to final results of the phase 2 DESTINY-CRC01 trial (NCT03384940) that were reported during the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.
Data from a cohort of 53 patients with HER2-positive mCRC (cohort A) showed that treatment with trastuzumab deruxtecan elicited a confirmed objective response rate (ORR) of 45.3% (95% CI, 31.6%-59.6%). All responses were partial response (PR), and stable disease was observed in 37.7% of patients. The disease control rate (DCR) was 83.0% (95% CI, 70.2%-91.9%). The median duration of response (DOR) of 7.0 months (95% CI, 5.8-9.5).
Patients included in cohort A had HER2-overexpressing disease defined by investigators as immunohistochemistry (IHC) score 3+ or IHC 2+/in situ hybridization (ISH)+. The ORR for these patients served as the primary end point of the study.
“In the primary analysis of cohort A, results yielded promising primary antitumor activity and a manageable safety profile,” Takayuki Yoshino, MD, said in a presentation of the data. “These [continued] promising results support continued exploration of [trastuzumab deruxtecan] in patients with HER2-positive mCRC.” Yohshino is the director of gastroenterology and gastrointestinal oncology and the head of the Clinical Research Coordinating Division at the National Cancer Center Hospital Japan in Tokyo.
Trastuzumab deruxtecan has demonstrated efficacy across cancers with HER2 expression, including breast and lung cancers. Approximately 25% of patients with CRC have metastatic disease and 2% to 3% of those patients have HER2-amplified tumors. Median overall survival (OS) with available options does not surpass 8 months, representing an unmet clinical need for approved targeted therapies in this patient population.
The study enrolled patients with unresectable and/or mCRC with HER2 expression via central confirmation whose disease is also RAS/BRAF V600E wild type. Patients must have received at least 2 prior therapies and prior treatment with anti-HER2 therapy was allowed. Patients were stratified into one of 3 cohorts based on HER2 expression: IHC 3+, IHC 2+/ISH+ (cohort A; n = 53), ICH2+/ISH- (cohort B; n = 15), or IHC 1+ (cohort C; n = 18). All patients received trastuzumab deruxtecan 6.4 mg/kg administered once every 3 weeks.
Median follow up at the time of final analysis was 62.4 weeks for cohort A, 27.0 weeks for cohort B, and 16.9 weeks for cohort C. No patients remained on treatment at data cutoff of December 28, 2020. The secondary end points of the study included ORR for cohorts B and C, progression-free survival (PFS), overall survival (OS), DOR, DCR, and safety.
The baseline patient characteristics were consistent across groups (N = 86) with a median age of 58.5 years (range, 27-79), more than half of patients in each cohort were from Europe (53.5%) and left-sided primary tumors were dominant (90.7%). Further, a majority of patients were microsatellite stable (80.2%).
In cohort A, 75.5% of patients had a HER2 status of IHC 3+, 24.5% had IHC 2+, and 98.1% reported ISH+. Because of the overexpression of HER2 in this cohort, 30.2% of patients had prior anti-HER2 treatment which accounted for the total number of patients in the study with prior HER2-targeted therapy.
The median number of prior regimens for metastatic disease was 4 (range, 2-11) and all patients received prior irinotecan.
Additional efficacy results for all cohorts were presented by Yoshino; no patients in cohort B or cohort C had a confirmed response. Stable disease was reported in 60% and 22.2% of patients, respectively, and corresponded with a 60% (95% CI, 32.3%-83.7%) and a 22.2% (95% CI, 6.4%-47.6%) DCR in each cohort, respectively.
The median treatment duration across cohorts A, B, and C was 5.1 months (95% CI, 3.9-7.6), 2.1 months (95% CI, 1.4-2.6), and 1.4 (95% CI, 1.3-1.5), respectively.
The median PFS for cohort A was 6.9 months (95% CI, 4.1-8.7) and the median OS was 15.5 months (95% CI, 8.8-20.8), which Yoshino noted was “very impressive for heavily pretreated patients.” The median PFS for cohorts B and C was 2.1 months (95% CI, 1.4-4.1) and 1.4 months (95% CI, 1.3-2.1), respectively; median OS was 7.3 months (95% CI, 3.0-not estimable) and 7.7 months (95% CI, 2.2-13.9), respectively.
In a subgroup analysis of ORR in cohort A, Yoshino said that no difference exists stratified by age, gender, region, or prior anti-HER2 treatment. However, he highlighted that “some difference exists when stratified by ECOG performance status and HER2 status, with ECOG [performance status] of 0 and [IHC 3+] as good indicators of response.” Specifically, the ORR in patients with ECOG performance status of 0 (n = 37) was 54.1% (95% CI, 36.9%-70.5%) compared with 25.0% (95% CI, 7.3%-52.4%) in those with ECOG performance status of 1 (n = 16). Patients with IHC 3+ (n = 40) had an ORR of 57.5% (95% CI, 40.9%-73.0%) compared with only 7.7% in patients with ICH 2+/ISH+ disease (n = 13).
Finally, the best change in tumor size was reported for cohort A and Yoshino noted that “most patients had tumor reduction regardless of prior HER2-treatment [and] IHC 3+ seemed to be a good indicator of treatment response compared [with] IHC 2+/ISH+.”
The safety profile of trastuzumab deruxtecan was consistent with low grade gastrointestinal and hematologic treatment-emergent adverse effects (TEAEs) being the most common in the overall population (N = 86). The most common TEAEs included nausea (61.6%), anemia (36.0%), fatigue (36.0%), and decreased appetite (34.9%). The most common grade 3 or higher TEAEs were neutropenia (22.1%), anemia (14.0%), decreased platelet count (9.3%), and nausea (5.8%).
TEAEs associated with death were reported in 10.5% of the overall patient population. Drug-related TEAEs associated with death were reported in 3 patients overall (3.5%); 2 patients in cohort A and 1 in cohort B. TEAEs led to drug discontinuation, dose reduction, drug and drug interruption in 15.1%, 17.4%, 39.5% of the overall population, respectively.
Interstitial lung disease (ILD), an AE of special interest, was observed in 8 patients (9.3%); ILD grade 2 was reported in 4 patients, grade 3 was reported in 1 patient, and grade 5 ILD occurred in 3 patients. In the 3 fatal cases, median onset of ILD was 22 days (range, 9-120) and death occurred a median of 6 days after diagnosis (range, 6-19).
For all instances of adjudicated drug-related ILS, the median time to onset was 61 days (range, 9-165) and all 8 patients were treated with corticosteroids; all 4 patients with grade 2 ILD recovered.
Yoshino noted that updated ILD guidelines should be followed which recommend interruption or discontinuation of trastuzumab deruxtecan as soon as ILD is suspected. “[ILD] is an important risk and required careful monitoring and prompt intervention,” he said.
Yoshino T, Di Bartolomeo M, Singh Raghav KP, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): final results from a phase 2, multicenter, open-label study (DESTINY-CRC01). J Clin Oncol. 2021;39(suppl 15):3505.doi:10.1200/JCO.2021.39.15_suppl.3505