‘Smart Bomb’ Salvage in HER+ Metastatic CRC

The higher the HER2 expression, the more benefit patients get from the antibody-drug conjugate trastuzumab deruxtecan (Enhertu) for HER2-positive metastatic colorectal cancer in the salvage setting, according to a phase 2 report.

Among the 53 patients with the highest expression in the study – defined as 3+ expression on immune histochemical staining or 2+ with positive in situ hybridization – median progression median progression-free survival (mPFS) was 6.9 months after failure of a median of four prior regimens.

With standard drugs, mPFS would be expected to be about 2 months or less, said investigator Kanwal Pratap Singh Raghav, MD, an associate professor of GI medical oncology at MD Anderson Cancer Center, Houston.

Many of the 86 study participants were enrolled at MD Anderson, and “they all derived some benefit from the conjugate. “It’s fairly well tolerated,” and “our experience has been pretty good; I think it’s actually a pretty good drug,” Raghav said shortly before presenting the findings at the American Society of Clinical Oncology Annual Meeting.

HER2 is over-expressed in about 5% of colorectal cancer patients. The conjugate is a kind of “smart bomb” for them that combines the anti-HER2 antibody trastuzumab (Herceptin) with a potent topoisomerase I inhibitor. The trastuzumab portion of the combination zeros in on cancer cells expressing HER2, delivering the cytotoxic agent directly to them.

“The amount of [cytotoxic] drug delivered by the antibody inside the cell is far in excess” to the standard approach of delivering chemotherapy agents individually, Raghav said.

“Single-agent treatments targeting HER2 only have modest activity. Seeing a response rate of [almost] 50% in colorectal cancer tumors that have high expression of HER2 is very exciting,” Muhammad Beg, MD, a GI oncologist and associate professor at UT Southwestern Medical Center, Dallas, said when asked for comment.

Trastuzumab deruxtecan already is approved for metastatic HER2-positive breast cancer after at least two anti-HER2-based regimens and locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma after a prior trastuzumab-based regime.

The phase 2 study, dubbed DESTINY-CRC01, divided patients by HER2 expression. In addition to the 53 “high-expressors,” there were 15 medium-expressors – defined as 2+ on immunohistochemical staining and no in situ hybridization – and 18 low-expressors with 1+ HER2 expression.

The patients had run out of other options, having experienced progression on 2 to 11 previous regimens. All participants had been on the topoisomerase I inhibitor irinotecan before, and almost a third of the high-expressors had been on anti-HER2 regimen.

They were treated with 6.4 mg/kg trastuzumab deruxtecan every 3 weeks for a median of 3 months. There was no control group.

The overall response rate was 45.3% among high-expressors. In addition to the mPFS of 6.9 months, median overall survival was 15.5 months. Among those on prior anti-HER2 therapy, the overall response rate was 43.8%.

Benefit was minimal in the lower-expression groups, with a mPFS of 2.1 months and overall survival of 7.3 months in medium-expressors and a mPFS of 1.4 months and overall survival of 7.7 months in low-expressors.

Sixty-five percent of patients (56) had treatment-emergent grade 3 or worse adverse events, most commonly hematologic and gastrointestinal; 13 subjects (15.1%) discontinued due to adverse events.

Eight patients (9.3%) developed interstitial lung disease, a particular concern with trastuzumab deruxtecan; it was fatal for three. “We need to study the lung toxicity. It will become a bigger factor as we think about using this drug for earlier lines of treatment,” Beg noted.

The median age in the study was 58.5 years, just over half the subjects were men, and more than 90% had left-sided colon or rectum cancer.

The next step in development is a randomized trial in unresectable/metastatic HER2-positive colorectal cancer dubbed DESTINY-CRC02, comparing the 6.4 mg dose with 5.4 mg. It’s already started recruiting.

The work was funded by trastuzumab deruxtecan maker Daiichi Sankyo. Raghav is an advisor and researcher for the company; Beg had no relationships with it.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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