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HER2 Expression Level Associated With Antitumor Activity of Trastuzumab Deruxtecan for HER2-Positive mCRC - Cancer Network

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There are currently no approved HER2-directed treatments for patients with HER2-amplified CRC, said Siena, a population which comprises 2% to 3% of patients with the malignancy.

The multicenter, open-label trial enrolled patients with unresectable or metastatic HER2-expressing, RAS/BRAF V600E wild-type CRC who had received at least 2 prior regimens. Prior HER2-directed treatment was allowed. Patients with a history of or current suspected interstitial lung disease were excluded from enrollment.

Patients were divided into 1 of 3 cohorts: A, B, or C. All patients received 6.4 mg/kg of T-DXd every 3 weeks. Cohort A comprised patients with HER2-positive CRC (n = 53), defined by immunohistochemistry (IHC) 3+ or IHC2+/in situ hybridization (ISH)+. Cohort B comprised patients with HER2 IHC2+/ISH- disease (n = 15). Cohort C comprised patients with HER2-positive IHC1+ disease (n = 18).

The objective response rate (ORR) in cohort A served as the primary end point of the study. Secondary end points included the ORR in cohorts B and C, progression-free survival (PFS), overall survival (OS), duration of response (DOR), disease control rate (DCR), and safety and tolerability.

Biomarkers, including ctDNA and HER2 extracellular domain, were evaluated as an exploratory end point.

As of the December 28, 2020, cutoff, in cohort A, the ORR was 45.3% (n = 24; 95% CI, 31.6%-59.6%), which consisted of all partial responses (PRs). A total of 37.7% (n = 20) of patients experienced stable disease, 9.4% (n = 5) of patients experienced progressive disease, and 7.5% (n = 4) of patients were not evaluable.

The median PFS was 6.9 months (95% CI, 4.1-8.7), and the median OS was 15.5 months (95% CI, 8.8-20.8). The median DOR was 7.0 months (95% CI, 5.8-9.5), and the DCR was 83.0% (95% CI, 70.2%-91.9%). The median treatment duration was 5.1 months (95% CI, 3.9-7.6).

For the exploratory analysis, plasma levels for ctDNA were collected at baseline, day 1 of cycle 4, and at the end of treatment, and serum samples for HER2 extracellular domain were collected at baseline.

The ORR was higher in patients with higher baseline HER2 expression in tissue (IHC/ISH) and liquid (plasma ERBB2 copy number and HER2 extracellular domain) samples. Additionally, objective response was reported in patients with and without RAS and PIK3CA mutations in ctDNA, as well as across bTMB levels.

By HER2 status, the ORR was 7.7% in the IHC2+/ISH+ group vs 57.5% in the IHC3+ group.

By serum HER2 in the extracellular domain, the ORR was 29.6% in the less than 23.5 ng/mL group vs 63.6% in the above 23.5 ng/mL group.

By ERBB2 adjusted plasma copy number, the ORR was 32.1% in the below/not detected (ND; <30.9) group vs 62.5% in the above (≥30.9) group.

By plasma ERBB2 amplification type, the ORR was 25.0% in the aneuploidy/ND group vs 55.6% in the focal amplification group.

The ORR was 47.8% in patients with RAS and PIK3CA wild-type disease/other mutations vs 33.3% in patients with RAS and PIK3CA activating mutations.

The ORR was 53.8% in patients with a bTMB level of less than 20 mut/Mb vs 23.1% in patients with a bTMB level of at least 20 mut/Mb.

By HER2 status, the median PFS was 4.1 months (95% CI, 1.3-not evaluable [NE]) in the IHC2+/ISH+ group (n = 13) vs 8.3 months (95% CI, 95% CI, 5.4-10.9) in the IHC3+ group (n = 40).

By serum HER2 in the extracellular domain, the median PFS was 4.1 months (95% CI, 2.9-7.3) in the less than 23.5 ng/mL group (n = 27) vs 8.3 months (95% CI, 5.4-11.3) in the above 23.5 ng/mL group (n = 22).

By ERBB2 adjusted plasma copy number, the median PFS was 4.1 months (95% CI, 2.8-6.9) in the below/not detected (ND; <30.9) group (n = 28) vs 10.9 months (95% CI, 8.3-12.7) in the above (≥30.9) group (n = 24).

By plasma ERBB2 amplification type, the median PFS was 4.1 months (95% CI, 1.6-6.9) in the aneuploidy/ND group (n = 16) vs 8.7 months (95% CI, 4.1-11.3) in the focal amplification group (n = 36).

Additional findings showed that T-DXd led to activity in patients with or without activating RAS mutations in ctDNA. Specifically, the median PFS was 7.6 months (95% CI, 4.1-10.8) in patients with RAS wild-type disease/other mutations (n= 46) vs 4.1 months (95% CI, 1.3-NE) in patients with RAS activating mutations (n = 6).

Moreover, antitumor activity was seen in patients with or without activating PIK3CA mutations in ctDNA. Specifically, the median PFS was 7.3 months (95% CI, 4.1-10.9) in patients with wild-type PIK3CA/other mutations (n = 46) vs 4.1 months (95% CI, 1.3-NE) in patients with activating PIK3CA mutations (n = 6).

Additional acquired mutations were identified at the time of disease progression in 20 of 30 patients, including mutations in BRAF V600, CASP8, and KEAP1.

“In paired ctDNA samples collected at baseline and disease progression from 30 patients, acquired alterations were observed in several genes, but none were common across patients,” said Siena.

“Interpretation is limited by the small sample size; therefore, further investigation into potential mechanisms of resistance and response to and patient selection for T-DXd in HER2-positive mCRC is warranted,” concluded Siena.

The efficacy and safety of T-DXd is also under study in patients with HER2-overexpressing, RAS-mutant or wild-type mCRC in the ongoing phase 2 DESTINY-CRC02 trial (NCT04744831).

Reference

Siena S, Raghav K, Masuishi T, et al. Exploratory biomarker analysis of DESTINY-CRC01, a phase 2, multicenter, open-label study of trastuzumab deruxtecan (T-DXd, DS-8201) in patients with HER2-expressing metastatic colorectal cancer. Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract 386O.

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