NEW YORK – After a final outcomes analysis in the Phase II DESTINY-CRC01 trial showed the benefits of Daiichi Sankyo's trastuzumab deruxtecan (Enhertu) in unresectable or metastatic HER2-expressing colorectal cancer, the drugmaker is closer to taking the drug into a registrational study in this tumor type.
In DESTINY-CRC01, from which data were presented at the American Society of Clinical Oncology's virtual annual meeting, researchers looked at trastuzumab deruxtecan's efficacy in 86 previously treated colorectal cancer patients across three cohorts: a HER2-positive group, which included those with HER2 expression scores of 3 or higher according to immunohistochemistry testing (dubbed IHC3-plus), and two HER2-low expressing groups, in which patients had IHC scores of 1 and 2 (IHC2 and IHC3). There were 53 IHC3-plus patients in cohort A; 15 IHC2 patients in cohort B; and 18 IHC1 patients in cohort C.
Lead investigator Takayuki Yoshino, director of the department of gastroenterology and gastrointestinal oncology at National Cancer Center Hospital East in Japan, presented the final analysis, as of a Dec. 28 data cutoff, at the meeting. At that time, no patients remained on treatment in the study.
HER2-positive, IHC3 patients in cohort A had the best response to trastuzumab deruxtecan, with a response rate of 45 percent; 24 patients had a partial response but no patients had a complete response. The median duration of response was seven months and median duration of treatment was five months.
In the two cohorts with HER2-low expressing patients, none had partial or complete responses. However, nine patients in cohort B and four patients in cohort C reached stable disease.
"These cohorts are similar to the breast cancer cohorts we have previously defined, which are HER2-positive and HER2-low," Ken Takeshita, global head of R&D at Daiichi Sankyo, said in an investor call following the meeting presentation. "The cohort A patients, the HER2-positive patients, have a much better outcome to this agent Enhertu compared to the other two categories."
Trastuzumab deruxtecan is currently available in the US for the treatment of unresectable or metastatic HER2-positive breast cancer and advanced or metastatic HER2-positive gastric or gastroesophageal junction cancer.
In DESTINY-CRC01, HER2-positive colorectal cancer patients in cohort A also experienced better progression-free survival and overall survival outcomes. This group had a median progression-free survival of 6.9 months compared to 2.1 and 1.4 months for patients in cohorts B and C, respectively. The median overall survival for cohort A was 15.5 months, which Yoshino called "very impressive in heavily pretreated patients." Comparatively, the median overall survival was 7.3 months for cohort B and 7.7 months for cohort C.
In the study, three patients developed severe interstitial lung disease, or ILD, which led to their deaths. ILD has previously been associated with trastuzumab deruxtecan, and Yoshino said patients taking the drug should be carefully monitored for ILD, which requires prompt intervention. Daiichi Sankyo also has a campaign to educate physicians prescribing trastuzumab deruxtecan about the risk of ILD and how to monitor patients for the adverse event, said CEO Sunao Manabe during the investor call.
Meanwhile, Daiichi Sankyo will continue to study trastuzumab deruxtecan in HER2-positive colorectal cancer. Based on data from the DESTINY-CRC01 trial, the company is currently conducting another Phase II study, DESTINY-CRC02, focused on the HER2-positive IHC3-plus group.
That trial is exploring trastuzumab deruxtecan at two doses, 5.4 mg and 6.4 mg. In the DESTINY-CRC01 study, patients were treated with a 6.4 mg dose of trastuzumab deruxtecan, but the company hopes to determine if a lower dose has the same efficacy, Takeshita said.
"This study will define the optimal dose for HER2-positive colorectal cancer that we can then take into a pivotal registration study," he added.