AstraZeneca and Daiichi Sankyo’s antibody-drug conjugate (ADC) staved off cancer for a median of 16.4 months and shrank tumors in 61% of patients with HER2-positive breast cancer. The treatment could become an option for patients whose cancer worsens despite undergoing HER2-targeted therapies.
The phase 2 data, presented Wednesday at the San Antonio Breast Cancer Symposium, come from 184 patients who received the ADC, [fam-] trastuzumab deruxtecan, which is also called T-DXd or DS-8201. In addition to shrinking tumors in 61% and eliminating them in 6% of patients, the treatment posted a disease control rate of 97%. This figure includes patients who saw some tumor shrinkage, but not enough to be considered responders.
The patients in the study had tried a median of six prior treatments but had essentially run out of options. Patients with HER2-positive breast cancer typically receive Herceptin (trastuzumab) and Perjeta (pertuzumab) from Roche's Genentech early in their treatment, and when they relapse, they can go on Kadcyla, Genentech’s HER2-targeting ADC.
“But if they relapse again, there is a problem because there is no standard of care for those patients,” Gilles Gallant, Ph.D., who leads the DS-8201 team at Daiichi, told FierceBiotech. “What that means is that the [National Comprehensive Cancer Network] will tell you to try combinations, to try chemotherapy, to try something, but there’s no real effective standard of care for this patient population. The expectation in that setting is that 75% to 80% of patients unfortunately won’t have a response to their treatments.”
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AstraZeneca bet up to $6.9 billion on Daiichi and DS-8201, forking over $1.35 billion upfront in March this year. Under the deal, the partners will jointly develop and sell the drug as a single agent or as part of a combination, except in Japan where Daiichi holds onto exclusive rights. It is in tests for HER2-expressing cancers, including gastric cancer, colorectal cancer and non-small cell lung cancer, as well as breast cancer.
Like Kadcyla, DS-8201 comprises a monoclonal antibody targeted toward HER2, but it uses a different drug payload: a topoisomerase 1 inhibitor rather than a microtubule inhibitor, Ian Krop, M.D., Ph.D., said in a statement from the American Association for Cancer Research. Daiichi and AstraZeneca’s treatment also carries twice as many molecules of the payload.
But the data weren't all rosy. Nearly all of the patients (99%) experienced side effects, including nausea, vomiting and low white blood cell counts. Fifteen percent of patients decided to stop treatment due to side effects, according to the statement.
Twenty-five patients developed interstitial lung disease (ILD), which is characterized by scarring in the lungs. Most of them had mild cases, but four people died from the disease.
“Because of this potential toxicity, close monitoring for signs and symptoms of ILD is recommended for early detection,” Krop said. “If ILD is suspected, evaluations should include high-resolution CT, pulmonologist consultation, pulmonary function tests, and other tests. Although data on treatment for T-DXd-induced ILD are limited, if diagnosed, interruption of treatment and prompt intervention with glucocorticoids is recommended.”
Analysts at Jefferies said that while the data “show impressive efficacy” they note that that big risk of ILD (which requires attention to pulmonary symptoms and careful monitoring), which it said in a note to clients was “a focus adverse event of concern.”
They added: “Commercially this risk will require careful monitoring and could limit potential to expand the drug's use into earlier lines, in our view, a key thesis for bulls.” It still see sales of around $1.5 billion at peak.RELATED: AstraZeneca and Daiichi get Q2 2020 PDUFA date for breast cancer ADC
Daiichi and AstraZeneca put an ILD management guideline in place for that trial and for future trials: “It’s something that we learned and implemented in all of our studies because it is a known risk,” Gallant said. “We have to look at benefit-risk ratio and the benefit-risk ratio, we think, in this particular patient population with very advanced disease, is still something that is positive in our minds.”
The phase 2 data echo a phase 1 study of DS-8201, in which the treatment shrank tumors in 59% of patients who had previously received Kadcyla. At the data cutoff in August, there were still patients too early to evaluate for responses—about 43%, Gallant said.
“There is always a possibility that the response rate will improve over time, but I think the 60.9% rate is stellar and even the complete response rate of 6% is actually very good. We have to put this in context of this patient population and how advanced their disease is,” he said.
Relapsed patients tend to go about six months before their cancer worsens, but it is difficult to compare the data from this study to that historical figure as it comes from a range of different studies and patient populations. DS-8201 is in multiple phase 3 studies to make such comparisons, including a trial pitting it against chemotherapy and another comparing it to Kadcyla in patients for whom Herceptin did not work but who have not received Kadcyla.