Phase 2 Data Support Trastuzumab Deruxtecan in HER2-High Colorectal Cancer

“This longer-term follow up of DESTINY-CRC01 supports the durable antitumor activity of T-DXd in patients with HER2-positive metastatic CRC,” according to the authors of the phase 2 DESTINY-CRC01 trial (NCT03384940).

Data support further study of fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) for the treatment of patients with HER2-expressing, metastatic colorectal cancer (CRC) who progressed after 2 or more prior lines of therapy, according to final results from the phase 2 DESTINY-CRC01 trial (NCT03384940) published in Nature Communications.

Among patients with immunohistochemistry (IHC) 3+ HER2-positive disease or IHC 2+ and in situ hybridization (ISH)-positive disease in cohort A, the median progression-free survival (PFS) was 6.9 months (95% CI, 4.1-8.7), and the median overall survival (OS) was 15.5 months (95% CI, 8.8-20.8).

The confirmed objective response rate (ORR) in this cohort was 45.3% (95% CI, 31.6%-59.6%), which entirely comprised partial responses (PRs), according to independent central review (ICR). Several responses persisted until the end of the follow-up period, and the median duration of response (DOR) was 7.0 months (95% CI, 5.8-9.5). The median time to response was 2.2 months (95% CI, 1.4-2.8), and the disease control rate (DCR) was 83.0% (95% CI, 70.2%-91.9%). The median best percentage change from baseline in target lesions was −35.0% (range, −100% to 33%).

Patients with IHC 2+ and ISH-negative disease, and those with IHC 1+ HER2-positive disease, were assigned to cohorts B and C, respectively. Neither of these cohorts reported reponses. The DCR was 60.0% (95% CI, 32.3%-83.7%) in cohort B and 22.2% (95% CI, 6.4%-47.6%) in cohort C. The median PFS was 2.1 months (95% CI, 1.4-4.1) and 1.4 months (95% CI, 1.3-2.1), and the median OS was 7.3 months (95% CI, 3.0-not estimable) and 7.7 months (95% CI, 2.2-13.9), respectively.

“This longer-term follow up of DESTINY-CRC01 supports the durable antitumor activity of T-DXd in patients with HER2-positive metastatic CRC,” the investigators wrote.

“Importantly, the median OS was 15.5 months, which far exceeds the current standard of care. Responses were also observed in patients across subgroups in cohort A, including those who had previously received anti-HER2–targeted therapy, although a shorter PFS was observed compared with those patients who did not receive anti-HER2 therapy. This updated analysis confirmed the lack of responses in patients with HER2-low metastatic CRC (cohorts B and C).”

Investigators of the multicenter, open-label DESTINY-CRC01 trial enrolled 86 patients across 25 sites in North America (16.3%), Europe (53.5%), and Asia (30.2%) between February 2018 and November 2020. Cohort A included the most patients (n = 53), followed by cohorts C (n = 18) and B (n = 15), and the median treatment durations were 5.1 months (range, 3.9-7.6), 1.4 months (range, 1.3-1.5), and 2.1 months (range, 1.4-2.6) in each respective cohort. All patients had discontinued treatment as of December 28, 2020, most commonly due to disease progression (69.8%).

Most patients (62.8%) had an ECOG performance status of 0. Most (90.7%) had left-sided disease, and most (80.2%) had microsatellite stable tumors. The vast majority of patients had RAS (97.7%) or BRAF (98.8%) wild-type disease, and most (66.3%) had liver metastasis at baseline. This population had received a median of 4 prior lines of treatment (range, 2-11) for metastatic disease.

Most patients (53.5%) were male, and the median age was 58.5 years old (range, 27-79). The median durations of follow-up were 14.4 months (range, 1.2-26.8), 6.2 months (range, 0.5-13.8), and 3.9 months (range, 1.1-18.9) in cohorts A, B, and C, respectively.

Treatment consisted of intravenous T-DXd delivered at a dose of 6.4 mg/kg every 3 weeks.

The primary end point was ORR according to ICR in cohort A. ORR in cohorts B and C were among the secondary end points, as were DOR, DCR, PFS, OS, pharmacokinetics, and toxicity.

Decreased neutrophil count (22.1%) and anemia (14.0%) were the most frequent grade 3 or higher treatment-emergent adverse effects (TEAEs). Drug discontinuation associated with TEAEs occurred across 13 patients (15.1%), and was most commonly caused by interstitial lung disease (ILD; 7.0%). Additionally, 9 patients (10.5%) experienced TEAEs associated with death, of which 3 (3.5%) were drug-related; all of these were deemed to be associated with ILD.

“Since this trial was completed, updated guidelines for monitoring and managing ILD [and] pneumonitis have been implemented; awareness efforts and research on risk factors for [ILD and] pneumonitis are ongoing,” the investigators concluded. “Notably, use of T-DXd in earlier lines of therapy and proactive monitoring is recommended to manage the risk of ILD associated with T-DXd.”

Reference

Yoshino T, Di Bartolomeo M, Raghav K, et al. Final results of DESTINY-CRC01 investigating trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer. Nat Commun. 2023;14(1):3332. doi:10.1038/s41467-023-38032-4