Siena Showcases Trastuzumab Deruxtecan Activity in HER2-Expressing mCRC

Salvatore Siena, MD

Fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) has shown impressive clinical activity in patients with HER2-expressing metastatic colorectal cancer (CRC) that is refractory to standard therapies, according to Salvatore Siena, MD, and the potency of the drug combined with its favorable safety profile might make it a candidate for regulatory approval down the line.

Data from the phase 2 DESTINY-CRC01 trial (NCT03384940) presented at the 2020 ASCO Virtual Scientific Program showed that the antibody-drug conjugate led to an objective response rate (ORR) of 45.3% in patients with HER2-positive metastatic CRC who were refractory to standard treatment (95% CI, 31.6%-59.6%). Additionally, the median duration of response (DOR) had not yet been reached (95% CI, 4.2 months–not evaluable). Notably, responses observed with the agent proved to be consistent across subgroups, including those who received previous treatment with anti-HER2 therapy. The median progression-free survival (PFS) with trastuzumab deruxtecan was 6.9 months.

“Trastuzumab deruxtecan has been shown to be an active and potent drug for [patients with] HER2-positive metastatic breast cancer, and it is also active in HER2-amplified CRC,” said Siena. “Again, because of its activity and safety profile, it should be considered as a candidate as a new therapy for CRC. I cannot say it is a therapy simply because it has not been approved yet, but certainly, it is a brilliant candidate.”

In an interview with OncLive, Siena, professor of medical oncology at Università degli Studi di Milano and director of Niguarda Cancer Center at Grande Ospedale Metropolitano Niguarda in Italy, further discussed the DESTINY-CRC01 trial with trastuzumab deruxtecan and projected the impact of these findings on patients with HER2-expressing metastatic CRC.

OncLive: Could you provide an overview of the phase 2 DESTINY-CRC01 study?

Siena: This is a phase 2 trial of a new drug called trastuzumab deruxtecan. This a monoclonal antibody conjugated with a cleavable tetrapeptide-based linker with a topoisomerase 1 inhibitor. This compound is also being developed for HER2-positive breast cancer, lung cancer, CRC, and other HER2-expressing cancers.

Patients enrolled on the study [were divided into] 3 cohorts. The first and the largest cohort, cohort A, [was comprised of] patients with either primary tumors or metastasis expressing HER2 to a level of immunohistochemistry (IHC) 3+ or 2+ and in-situ hybridization–positive. We treated 54 patients in that cohort. Then, there is cohort B in which patients with IHC 2+ but in-situ hybridization–negative tumors were treated. Lastly, cohort C in which patients with IHC 1+ were treated.

What was the rationale for this research?

A small fraction, but still a significant fraction, of patients with CRC has tumors that grow in response to activation of HER2 amplification, which is the main oncogenic driver of the tumor. Based on our previous preclinical and clinical studies that we published years ago, we know that HER2-targeted therapy in metastatic CRC is a successful approach. As such, we were very interested in testing this new compound that is designed to be very powerful because the ratio between the payload at the topoisomerase inhibitor and the target of the antibodies 8 to 1. In addition, we know that CRC cells are very sensitive to topoisomerase I inhibitors; for example, irinotecan is one of the main drugs used for this disease.

Could you expand on the patient population enrolled on the trial and the methods used?

We started this study and we elected to choose patients with eithermetastatic or not resectable, measurable disease, HER2-positive, KRAS-, BRAF-, and NRAS-negative, and patients without presence of interstitial lung disease (ILD). These patients also had to be resistant to standard therapies, including oxaliplatin, irinotecan, and fluoropyrimidine. What is very important to mention is that patient who had previously received anti-HER2 treatment were permitted to enroll on the trial. One-third of the patients who entered the study [progressed on] anti-HER2 therapies, such as trastuzumab (Herceptin), lapatinib (Tykerb), ado-trastuzumab emtansine (T-DM1; Kadcyla), tucatinib (Tukysa), and pertuzumab (Perjeta). Patients were treated with a dose of 6.4 mg/kg of trastuzumab deruxtecan, which was delivered intravenously every 3 weeks until disease progression or intolerable toxicity.

What were the findings?

The results of the study were quite remarkable, because we saw a confirmed ORR of 45.3% in cohort A. One patient achieved a complete response with the treatment and 23 patients experienced partial responses. An additional 20 patients had stable disease; this translated to a disease control rate of 83.0%. In cohorts B and C, however, no confirmed responses were reported. The therapy, as expected, is active in patients with truly HER2-amplified tumors. Additionally, the PFS with trastuzumab deruxtecan was 6.9 months in cohort A, which is very good. The median overall survival was not reached yet [in any cohort].

What did the safety data look like?

As far as safety is concerned, the treatment duration of treatment was 4.8 months in the HER2-positive patients enrolled on cohort A and most of the toxicities were mild and grade 1 or 2 in severity with fewer grades 3 or 4 [events reported]. Most of the latter toxicities were gastrointestinal or hematologic. The toxicity we should pay special attention to is ILD because, overall, among the 78 patients, 5 developed ILD with a median onset of 80 days.

All patients [with ILD] received corticosteroids; 2 patients recovered, 1 did not recover and later died of tumor progression, and 2 died of ILD. Both received the corticosteroids and they died 6 to 18 days after diagnosis.

What is your take-home message regarding this trial?

Overall, the results are quite good with an ORR of 45.3% and a median DOR yet not reached. Consistent responses were observed across subgroups, including those who received prior anti-HER2 therapy; this is important to mention. This drug is very promising and its activity is proving to be very durable; trastuzumab deruxtecan is a potent anti-HER2 treatment. If this drug is eventually approved, it is going to become a new option for patients with HER2-positive CRC. These data certainly [support] further research to achieve the objective of utilizing [this therapy] in clinical practice for this patient population.

Reference

1. Siena S, Bartolomeo MD, Raghav KPS, et al. A phase II, multicenter, open-label study of trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): DESTINY-CRC01. J Clin Oncol.2020;38(suppl 15):4000. doi:10.1200/JCO.2020.38.15_suppl.4000