Testing for HER-2 in patients with colorectal cancer (CRC) should become a new standard of care, say experts discussing new results from a phase 2 trial showing benefit with trastuzumab deruxtecan (T-DXd, marketed as Enhertu, AstraZeneca/Daiichi Sankyo).
This drug is approved in the United States for use in the treatment of unresectable or metastatic HER2-positive breast cancer in patients who have already received two or more prior anti-HER2-based regimens in the metastatic setting.
Results come from a phase 2 study, dubbed DESTINY-CRCO1, in patients with previously treated HER2+ advanced CRC.
The results show that, in patients with the highest degree of HER2 positivity, T-DXd was associated with an objective response rate of over 45%, and a median progression-free survival (PFS) of almost 7 months.
They "demonstrate, in our opinion, the potential of T-DXd as a treatment option" for patients with advanced HER2-positive colorectal cancer that is refractory to standard therapies, said lead investigator Salvatore Siena, MD, from Niguarda Cancer Center, in Milan, Italy.
He presented the results at the 2020 annual meeting of the American Society of Clinical Oncology, held virtually because of the coronavirus pandemic.
At the same time, results from another study, this time in gastric cancer patients, were published online in the New England Journal of Medicine .
Interstitial Lung Disease as Adverse Event
The safety profile of T-DXd seen in the colorectal trial "is consistent with what has been previously reported," said Siena, adding that most of the adverse events were low grade. But he noted there was also a serious adverse effect — interstitial lung disease (ILD). This occurred in 6% of patients, two of whom died. This is "an important risk and requires careful monitoring and proper intervention," he emphasized.
The ILD adverse effect in this study is "a concern…and something to consider," commented discussant for the study Michael S. Lee, MD, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill. But he added that these are the "the best data so far for subsequent anti-HER2 therapy in colorectal cancer".
Also, the dose of drug used in this trial was higher than that approved for breast cancer, and the incidence of ILD "begs the question of whether we should be using a lower dose in this patient population," said Autumn J. McRee, MD, also from Lineberger, in a highlights session at the meeting.
"The question here really is whether an HER2-specific approach is superior to what we would offer to these patients in the standard of care setting," McRee said.
She noted that the patients in DESTINY-CRC01 were "heavily pretreated…and if you think about what our options are in the refractory setting, we do have two approved treatments: regorafenib [Stivarga, Bayer] and TAS-102 [Lonsurf, Taiho Oncology]."
The current data suggest, however, that T-DXd is associated with a trend toward higher response rates and improved survival outcomes, as well as lower monthly costs."Without a doubt, this trial is clinically relevant," she said, adding that it's "important not to miss these patients."
"They are rare…but I would argue that testing for HER2 amplification in colorectal cancer should be considered standard of care," she said.
I would argue that testing for HER2 amplification in colorectal cancer should be considered standard of care. Dr Autumn McRee
She added that, based on the current evidence, the trial "may be" practice changing, although it is "still to be determined how to sequence HER2 targeted therapies."
Study Details
The trial was conducted in 78 patients with previously treated unresectable and/or metastatic CRC that was HER2 expressing, RAS/BRAF wild type, and patients had to have received at least two prior regimens, including prior anti-HER2 treatment. Patients with current or suspected ILD were excluded.
Patients were divided into three cohorts based on the degree of HER2 positivity:
- HER2+ with immunohistochemistry (IHC) scoring 3+ or IHC2+/in-situ-hybridization (ISH)+ (cohort A, n = 53)
- HER2 IHC2+/ISH– (cohort B, n = 7)
- HER2 IHC1+ (cohort C, n = 18)
All patients received T-DXd at 6.4 mg/kg intravenously every 3 weeks until progression or intolerable toxicity.
Across the three cohorts, the median age was 58.5 years, and nearly half (47.4%) of patients were female. The vast majority (98.7%) of patents had ECOG performance status 0 or 1, and the primary tumor site was the left colon or rectum in 89.7%.
Siena noted that "the median number of prior lines of standard therapies was four, ranging from two to 11." All patients had previously received irinotecan and oxaliplatin, and 20.5% had received an anti-HER2 drug.
At the data cutoff on August 9, 2019, 38.5% of patients remained on treatment. The reason for discontinuation was progressive disease in 41%, and clinical progression in 9%.
Siena reported that the overall response rate, as confirmed by independent central review, was 45.3% in cohort A, with all but one of the 24 responders having a partial response. No responses were recorded in cohorts B and C.
Stable disease was seen in 37.7% of cohort A patients, giving a disease control rate of 83%. The median duration of response was not reached.
Median PFS was 6.9 months in cohort A, and the medial overall survival was not reached.
In terms of safety, 50.9% of patients in cohort A and 48.7% patients overall experienced drug-related treatment emergent adverse events, with 22.6% and 17.9%, respectively, having serious drug-related events.
The most common treatment-emergent adverse events were nausea, anemia, reduced neutrophil count, fatigue, and decreased appetite.
There were two deaths related to the study drug, as determined by investigator assessment: one from pneumonitis and one as a result of ILD, with both occurring in cohort A.
Looking specifically at ILD, Siena said there were five events — two grade 2, one grade 3, and two grade 5 — at a median time to reported onset of 80 days. All patients received corticosteroids, as per the study protocol, and two recovered.
Study discussant Lee commented that biomarker testing, such as for HER2, "is part of our standard of care for colorectal cancer," although studies such as the current one are providing new data to "better refine" treatment approaches.Lee said that, overall, T-DXd had a response rate and PFS survival "that looked similar to prior data from previous single arm phase 2 studies," with response rates generally ranging from 30% to 50%, "and this compares favorably with other standard of care options" for chemotherapy refractory patients.
Nevertheless, there are several ongoing questions related to the treatment of HER2 amplified metastatic CRC patients, some of which are being addressed in the ongoing SWOG S1613 study.
Lee said that, for now, he would recommend that patients with HER2amplification enroll in a clinical trial, if possible. "However, if that's not feasible, there are a range of options to consider," including trastuzumab plus lapatinib (Tykerb, Novartis), or trastuzumab plus pertuzumab (Perjeta, Roche).
However, "none of these options are FDA-approved so there will be issues potentially with financial toxicity and other regulatory issues," he said.
The study was funded by Daiichi Sankyo Co, Ltd.
Siena reports stock and other ownership interests with Guardant Health and Myriad Genetics; a consulting or advisory role with Amgen, Bayer, Bristol-Myers Squibb, CheckmAb, Clovis Oncology, Daiichi Sankyo, Incyte, Merck, Novartis, Roche/Genentech, Seattle Genetics; research funding from MSD Oncology (Inst); patents, royalties, and other intellectual property from Amgen; and travel, accommodations, expenses from Amgen, Bayer, and Roche. Other coauthors report potential conflicts of interest. The full list can be found with the original article.
Lee reports: Research Funding - Amgen (Inst); Bristol-Myers Squibb (Inst); EMD Serono (Inst); Exelixis (Inst); Genentech/Roche (Inst); Pfizer (Inst); Travel, Accommodations, Expenses - Genentech/Roche.
McRee reports honoraria from Cor2Ed and Onc Live; research funding from AstraZeneca (Inst), BioMed Valley Discoveries (Inst), Boston Biomedical (Inst), Inovio Pharmaceuticals (Inst), Merck (Inst), Novartis (Inst), Rgenix (Inst), and Takeda (Inst); and travel, accommodations, expenses from Cor2Ed.
American Society of Clinical Oncology 2020 Virtual Scientific Program: Abstract4000.
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