T-DXd Monotherapy Reveals Promising Results in Patients with HER2+ mCRC

Promising study results support continued research of T-DXd in patients with HER2-positive mCRC while the risk of potential ILD/pneumonitis requires monitoring.

An extended follow-up study evaluating the monotherapy trastuzumab deruxtecan (T-DXd) shows promising results in patients with HER2-positive metastatic colorectal cancer (mCRC). These results were presented by Takayuki Yoshino, MD, PhD, from the National Cancer Center Hospital East in Kashiwa, Japan, at the 2022 Gastrointestinal Cancers Symposium.1

In the final analysis of the open-label, multicenter, phase 2 DESTINY-CRC01 trial (NCT03384940), patients were randomized to 3 cohorts: cohort A (n = 53) had patients who were immunohistochemistry (IHC) 3-positive or IHC 2-positive/in situ hybridization (ISH)-positive; cohort B (n = 15) had patients who were IHC 2-positive/ISH-negative; and cohort C (n = 18) had patients who were IHC 1-positive.

Patients in cohort A had an overall response rate (ORR) of 45.3% (95% CI, 31.6%-59.6%), a median duration of response (DOR) of 7.0 months (95% CI, 5.8-9.5), a median progression-free survival (PFS) of 6.9 months (95% CI, 4.1-8.7), and a median overall survival (OS) of 15.5 months (95% CI, 8.8-20.8). No patients remain on treatment.

This study evaluated a total of 86 patients. All cohorts received 6.4 mg/kg of T-DXd every 3 weeks. The primary end point of this study was ORR in cohort A, and the secondary end points were ORR in cohorts B and C, PFS, OS, DOR, disease control rate (DCR), and safety. The median follow-up at the end of the study was 62.4 weeks for cohort A and 27.0 weeks for cohorts B and C.

Eligible patients must have had unresectable and/or mCRC, HER2 expression, RAS/BRAFV600E wild type, and at least 2 prior regimens. Patients were excluded if they had a history of or currently have interstitial lung disease (ILD).

The median age of patients was 58.5 years (27-59), with 46.5% being female. Patients had an ECOG performance score of 0 or 1, with 62.8% scoring 0. The median prior regimens for metastatic disease were 4 (range, 2-11).

DCR among cohorts was 83.0% (95% CI, 70.2%-91.9%) for cohort A, 60.0% (95% CI, 32.3%-83.7%) for cohort B, and 22.2% (95% CI, 6.4%-47.6%) for cohort C. Median treatment duration was 5.1 months (95% CI, 3.9-7.6) for cohort A, 2.1 months (95% CI, 1.4-2.6) for cohort B, and 1.4 months (95% CI, 1.3-1.5) for cohort C.

In a subgroup analysis of cohort A, patients with an ECOG score of 0 (n = 37) had an ORR of 54.1% (95% CI, 36.9-70.5%), and patients with an ECOG score of 1 (n = 16) had and an ORR of 25.0% (95% CI, 7.3%-52.4%). Forty patients with IHC 3+ disease had an ORR of 57.5% (95% CI, 40.9%-73.0%). Those with IHC 2+/ISH+ disease (n = 13) had an ORR of 7.7% (95% CI, 0.2%-36.0%). Sixteen patients had prior HER2 treatment and had an ORR of 43.8% (95% CI, 19.8%-70.1%), and 37 patients without prior HER2 treatment had an ORR of 45.9% (95% CI, 29.5%-63.1%).

Safety data remained consistent with what is known for T-DXd from previous studies. Overall, 65.1% of patients experienced grade 3 and higher treatment-emergent adverse events (TEAEs). Overall, 13 patients (15.1%) had TEAEs leading to drug discontinuation, 15 patients (17.4%) had TEAEs leading to dose reduction, and 34 patients (39.5%) had TEAEs leading to drug interruption. Nine patients (10.5%) had TEAEs associated with death.

Investigators noted patients with ILD/pneumonitis AEs. Eight patients (9.3%) had adjudicated drug-related ILD/pneumonitis. Median time to adjudicated onset was 61.0 days (range, 9-165). Of these 8 patients, 4 had grade 2, 1 had grade 3, and 3 had grade 5 AEs. All 8 patients received corticosteroids in response. The 4 patients with grade 2 recovered, and the patients with grade 3 did not recover due to later disease progression. The 3 patients with grade 5 ILD/pneumonitis died with a median onset of 22.0 days (9-120), and death occurred 6 to 9 days after diagnosis.

These promising results support continued research of T-DXd in patients with HER2-positive mCRC while the risk of potential ILD/pneumonitis requires monitoring.

Reference

Yoshino T, Di Bartolomeo M, Raghav K, 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). Rapid abstract presented at: 2022 Gastrointestinal Cancers Symposium; January 20-22, 2022; San Francisco, CA. Accessed January 22, 2022.