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The antibody-drug conjugate trastuzumab deruxtecan (T-DXd, Enhertu) proved active in a phase II study of advanced HER2-positive colorectal cancer (CRC).

Almost 40% of patients treated with the recommended dose had objective responses and almost half had stable disease. The patients had a median progression-free survival (PFS) of 5.8 months and overall survival (OS) of 13.4 months. The agent had activity in cancers with and without RAS mutations.

The treatment was associated with a manageable safety profile, reported Kanwal Raghav, MD, of the University of Texas MD Anderson Cancer Center in Houston, and co-authors in .

"Given scarce data on HER2-targeting treatments in patients with HER2-positive metastatic colorectal cancer, trastuzumab deruxtecan offers a promising option to meet a substantial clinical need," the authors stated. "Although HER2 amplification and RAS wild-type status are required for patients to benefit from dual HER2-directed therapy [with trastuzumab and pertuzumab [Perjeta]), results from [this study and an earlier one] suggest that patients with HER2 immunochemistry score 3+ might derive greater clinical benefit from trastuzumab deruxtecan than patients with lower levels of HER2 expression ... including patients with RAS mutations and previous dual HER2 therapy."

"As the efficacy of dual HER2 inhibition after treatment with trastuzumab deruxtecan is not yet known, the order of targeted therapies remains to be elucidated," they added.

The trial had a focus on T-DXd activity in RAS-mutant HER2-positive metastatic CRC, a group that does not benefit from dual HER2-targeting strategies, noted the authors of an . The results included a 28.6% response rate in patients with RAS-mutant tumors. The trial's exploratory analysis of circulating tumor (ct)DNA also has implications for future use.

"Trastuzumab deruxtecan 5.4 mg/kg has the potential to provide an additional line of treatment for patients with HER2-positive metastatic colorectal cancer after dual HER2 inhibition," stated Jeanine M.L. Roodhart, MD, PhD, and Miriam Koopman, MD, PhD, of Utrecht University in the Netherlands. "This is especially relevant given the ongoing randomized phase III trial, which evaluates standard-of-care plus bevacizumab [Avastin] or cetuximab [Erbitux] versus FOLFOX plus trastuzumab and tucatinib [Tukysa] in first-line treatment of RAS wild-type HER2-positive metastatic colorectal cancer."

"Furthermore, DESTINY-CRC02 shows the potential of using ctDNA as a biomarker to optimize patient selection, thereby increasing the likelihood of therapeutic benefit," they concluded.

From 3-11% of CRCs exhibit HER2 overexpression. In metastatic CRC, HER2 overexpression occurs primarily in RAS and BRAF wild-type, left-sided tumors and is associated with poor prognosis, brain metastases, and anti-EGFR resistance, Raghav and co-authors noted in the introduction.

In previously treated metastatic HER2-positive CRC, dual HER2-targeting therapy with trastuzumab in combination with lapatinib (Tykerb), tucatinib, pertuzumab, or pyrotinib has resulted in response rates of 28-50%, the authors continued. However, not all patients respond to dual HER2 inhibition, and RAS-mutant tumors show minimal response. RAS mutations occur in 27-50% of metastatic CRC.

A of T-DXd 6.4 mg/kg demonstrated favorable antitumor activity and a manageable safety profile in HER2-positive, RAS wild-type metastatic CRC, leading to a (NCCN) recommendation as a second-line option for HER2-positive metastatic CRC. NCCN subsequently updated the recommendation to a 5.4-mg/kg dose. The efficacy of the 5.4-mg/kg dose has been demonstrated in HER2-positive metastatic breast cancer, but had not been tested in patients with HER2-positive metastatic CRC.

In DESTINY-CRC02, investigators evaluated both doses of T-DXd in HER2-positive, RAS wild-type or mutant metastatic CRC previously treated with chemotherapy. The trial comprised of two stages. In stage I, 40 patients were randomized to each of the two doses. Stage II expanded the evaluation of the 5.4-mg/kg dose in an additional 42 patients. The primary endpoint was objective response determined by blinded independent central review.

The results of both stages combined showed objective responses in 31 of 82 (37.8%) patients treated with 5.4 mg/kg of T-DXd as compared with 11 of 40 (27.5%) patients who received the higher dose. Grade ≥3 drug-related treatment-emergent adverse events (TEAEs) occurred in 41% of the 5.4-mg/kg group and 49% of the 6.4-mg/kg group.

The most common drug-related TEAEs with 5.4 mg/kg were decreased neutrophil count (16%), anemia (7%), nausea (7%), and decreased white blood cell count (6%). In the 6.4-mg/kg group, the most common grade ≥3 drug-related TEAEs were decreased neutrophil count (26%), anemia (21%), decreased platelet count (10%), and decreased white blood cell count (10%). Serious drug-related TEAEs occurred in 13% of the 5.4-mg/kg group and 15% of the 6.4-mg/kg group. One fatal drug-related TEAE (liver failure) occurred in the 5.4-mg/kg group.

All but four patients had evaluable baseline ctDNA data. The DNA analysis identified RAS mutations in 40 patients as compared with 20 identified by tissue-based testing.

"Trastuzumab deruxtecan showed activity in patients with HER2 immunohistochemistry score 3+ status across all key subgroups, including patients with RAS-mutant status in the trastuzumab deruxtecan 5.4-mg/kg group," the authors noted. "This activity is unique to trastuzumab deruxtecan because dual HER2 inhibition has shown only minimal activity in this key subgroup of patients with metastatic colorectal cancer."

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