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Enhertu Could Benefit Heavily Pretreated HER2-Positive GI Cancer Patients, ASCO Data Suggests

NEW YORK – Phase II data presented during the American Society of Clinical Oncology's virtual meeting this weekend demonstrated that trastuzumab deruxtecan (AstraZeneca/Daiichi Sankyo's Enhertu) could improve tumor response rates in patients with advanced, HER2-expressing gastrointestinal cancers.

The DESTINY-CRC01 study assessed trastuzumab deruxtecan in metastatic, heavily pre-treated colorectal cancer, while the DESTINY-Gastric01 study focused on metastatic, heavily pre-treated gastric and gastroesophageal carcinoma. The findings from these Phase II studies in these different cancer populations will need further validation. Nonetheless, the data from the two DESTINY trials highlight the potential for this HER2-targeting antibody drug conjugate to benefit patients with gastrointestinal cancers, while underscoring the importance of HER2 testing in these patient populations.

Trastuzumab deruxtecan works by delivering chemotherapy to HER2-expressing tumor cells by way of a HER2 monoclonal antibody attached to a tetrapeptide-based linker. The agent is already approved in the US and in Japan for HER2-positive, unresectable or metastatic breast cancer patients who have had two or more prior anti-HER2 breast cancer treatments. The US Food and Drug Administration has also granted the agent breakthrough therapy designation in HER2-mutated, metastatic non-small cell lung cancer that has progressed after platinum-based therapy and for patients with HER2-positive unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma who have received two or more prior regimens including trastuzumab.

DESTINY-CRC01

Salvatore Siena of the University of Milan's Niguarda Cancer Center presented results from the DESTINY-CRC01 study, which stratified patients with metastatic, HER2-expressing colorectal cancer into three cohorts. Cohort A consisted of HER2 overexpressing patients who had scores of 3 or higher according to immunohistochemistry testing (IHC 3 plus), as well as a score above 2 by in situ hybridization. Cohort B consisted of patients whose tumors were IHC 2 and above but were ISH-negative; and cohort C consisted of patients whose tumors were IHC 1 and above.

All patients enrolled in the trial had HER2-expressing, RAS/BRAF-wildtype disease (except for one patient, who had an NRAS mutation) and had received at least two prior lines of therapy, including other HER2-targeting agents such as trastuzumab (Genentech's Herceptin). The median number of prior therapies was four lines.

DESTINY-CRC01's primary endpoint was overall response rate, which as assessed by an independent central review committee after the data cutoff of August 2019 was 45.3 percent. One patient had a complete response to the treatment and 23 patients had partial responses. Additionally, 20 patients achieved stable disease, resulting in an overall 83 percent disease control rate. In cohorts B and C, there were no confirmed responses.

The median progression-free survival for patients in cohort A was 6.9 months, although neither the median duration of response nor the median overall survival was reached.

Siena noted that the absence of any responses in the two cohorts with low HER2 expression suggests that the promising durable activity seen with trastuzumab deruxtecan is likely restricted to those with high levels of HER2 expression.

The National Comprehensive Cancer Network recommends testing patients for certain biomarkers to guide precision treatment strategies, including for KRAS/RAS and BRAF mutations, HER2 amplifications, mismatch repair deficiency and microsatellite instability, and NTRK fusions. For HER2-amplified metastatic or advanced colorectal cancer that is RAS or BRAF wild-type, the NCCN recommends dual anti-HER2 treatment, combining trastuzumab with either pertuzumab (Genentech's Perjeta) or lapatinib (Novartis' Tykerb).

In addition to these dual anti-HER2 therapies, for patients who progress after treatment with standard cytotoxic chemotherapy, the NCCN suggests regorafenib (Bayer's Stivarga) and TAS-102 (Taiho Oncology's Lonsurf) as options. However, in past randomized studies, these agents demonstrated median progression-free survival of around two months against placebo or best supportive care, and there are no biomarkers to identify best responders.

"If we add [trastuzumab deruxtecan] to the paradigm, we certainly see some trends toward improvement in progression-free survival as well as higher response rates," said Autumn McRee of the University of North Carolina during her discussion of notable colorectal cancer research presented during ASCO.

The fact that patients in cohort A achieved durable responses with trastuzumab deruxtecan, even after their cancers failed to respond to prior HER2-targeting agents such as trastuzumab, is "very promising" for these heavily pretreated patients, said Cathy Eng of Vanderbilt-Ingram Cancer Center in an interview reflecting on the data. She wasn't involved in either DESTINY study.

"This was an excellent degree of response given the degree of prior therapy," Eng said, pointing out that patients with IHC 3-plus HER2 overexpression were the best responders, and that this underscores the importance of testing for HER2 expression in patients with metastatic colorectal cancer.

DESTINY-Gastric01

In gastric cancer, trastuzumab and trastuzumab biosimilars are available for those with HER2-positive disease. However, trastuzumab deruxtecan is also vying to enter the market, having recently garnered FDA breakthrough therapy status from the FDA.

Kohei Shitara of the National Cancer Center Hospital East in Chiba, Japan presented results from the primary cohort of the DESTINY-Gastric01 study, within which patients with pretreated, HER2-positive metastatic gastric cancer were randomized to receive either trastuzumab-deruxtecan or physician's choice of irinotecan or paclitaxel chemotherapy. Patients were defined as HER2 positive if they were IHC3 plus and above 2 by ISH.

The study also enrolled two exploratory cohorts of patients with lower levels of HER2 expression, but the data presented at ASCO focused exclusively on the randomized primary cohort. Patients who were randomized within this primary cohort had all received at least two prior lines of treatment, including various chemotherapy agents or checkpoint inhibitors. Importantly, one of these prior treatment lines had to have been treatment with trastuzumab or a trastuzumab biosimilar.

After the data cutoff in November 2019, results within the primary cohort demonstrated a significant improvement in the overall response rate among patients treated with trastuzumab deruxtecan versus chemotherapy, as assessed by an independent central review. The overall response rate for patients treated with trastuzumab deruxtecan was 51.3 percent versus 14.3 percent with chemotherapy. Eleven patients in the trastuzumab deruxtecan arm achieved a complete response, whereas there were no complete responses observed in the chemotherapy arm.

The median duration of response was 11.3 months with trastuzumab deruxtecan versus 3.9 months with chemotherapy, and the one-year survival rates were 52 percent versus and 29 percent, respectively. "Based on these findings, [trastuzumab-deruxtecan] may be an effective treatment option for patients with otherwise HER2-positive gastric [or gastroesophageal junction] adenocarcinoma who have progressed after trastuzumab," Shitara concluded.

Toxicities and considerations

In the DESTINY-Gastric01 study, Shitara noted that 10 percent of patients in the trastuzumab deruxtecan arm experienced drug-related interstitial lung disease. This was likewise observed in 6.4 percent of patients treated with trastuzumab deruxtecan in the DESTINY-CRC01 study, despite the fact that patients with signs of prior interstitial lung disease were excluded from enrollment.

"It's an important risk and requires careful monitoring and proper intervention," Siena said of interstitial lung disease in the DESTINY-CRC01 study.

In a discussion of the DESTINY-CRC01 results, Michael Lee of the University of North Carolina pointed out that the 6.4 mg/kg dose of trastuzumab deruxtecan that was administered, which was the same dose given in DESTINY-Gastric01, was higher than the 5.4 mg/kg dose that was FDA-approved for treating patients with breast cancer.

"It's not clear if you would expect different side effects or efficacy with the two different doses," he said.

During her discussion McRee raised this dosing issue, wondering whether the dose should be lowered in the colorectal cancer population, since two patients died of interstitial lung disease in the DESTINY-CRC01 trial.

She also pointed out the financial considerations that trastuzumab deruxtecan raises, with its average wholesale price of $11,020 per month. This cost is comparable to that of other agents used in the refractory setting for colorectal cancer, such as regorafenib and TAS-102, which average $15,000 and $13,000 per month, respectively.

"I think it's worth noting that we're using a lot of expensive drugs in the refractory setting," McRee said.