Antibody-drug conjugate provides ‘unprecedented’ benefit in metastatic HER2-positive breast cancer
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SAN ANTONIO — Trastuzumab deruxtecan conferred durable benefit to women with heavily pretreated HER2-positive metastatic breast cancer, according to results of the phase 2 DESTINY-Breast01 study presented at San Antonio Breast Cancer Symposium.
More than 60% of patients responded to treatment.
The trial confirmed interstitial lung disease is an important risk of this therapy, but the efficacy results — published simultaneously in The New England Journal of Medicine — demonstrate the potential of the agent to be a new standard of care in this setting, Ian E. Krop, MD, PhD, associate chief of the division of breast oncology at Dana-Farber Cancer institute, told Healio.
“A phase 1 trial of 115 patients showed this drug is very active in a heavily pretreated population, so it was nice to confirm those results in the phase 2 trial,” Krop said in an interview. “If you look at the aggregate information about this drug, it is somewhat unprecedented in a population like this. We have done a lot of studies of other drugs for heavily pretreated patients, and we don’t see anything close to this.”
HER2-directed therapies have improved outcomes for patients with HER2-positive advanced breast cancer; however, many patients develop resistance, and no clear standard of care exists once resistance occurs, Krop said.
Trastuzumab deruxtecan (AstraZeneca/Daiichi Sankyo) is a novel antibody-drug conjugate with three components: a humanized anti-HER2 immunoglobulin G1 monoclonal antibody with the same amino acid sequence as trastuzumab (Herceptin, Genentech); a topoisomerase 1 inhibitor payload; and a tetrapeptide-based cleavable linker.
The FDA granted priority review to the agent in October for treatment of HER2-positive breast cancer.
The open-label, multicenter DESTINY-Breast01 study included 253 adults with centrally confirmed HER2-positive breast cancer, all of whom received prior treatment with ado-trastuzumab emtansine (Kadcyla, Genentech). Patients with stable treated brain metastases were eligible; however, those with a history of significant interstitial lung disease were not.
The trial had three parts: a pharmacokinetic stage, a dose-finding stage and a continuation stage.
The intent-to-treat population consisted of 184 women (median age, 55 years; range, 28-96; 24% aged 65 years or older; 55% white; 38% Asian) who received the recommended phase 2 dose of 5.4 mg/kg via IV every 3 weeks.
More than half (53%) of those patients were hormone receptor positive. Patients received a median six prior treatments (range, 2-27), including trastuzumab (100%), ado-trastuzumab emtansine (100%), pertuzumab (Perjeta, Genentech; 65.8%), other HER2-targeted regimens (54.3%), hormone therapy (48.9%) or other systemic therapy (99.5%).
Objective response rate by independent central imaging facility review served as the primary endpoint. Secondary endpoints included investigator-assessed ORR, disease control rate, duration of response, clinical benefit rate, PFS, OS and pharmacokinetics.
At data cutoff, 79 patients (42.9%) remained on study and 105 patients (57.1%) had discontinued treatment primarily due to progressive disease.
Researchers reported a confirmed ORR by independent central review of 60.9% (95% CI, 53.4-68). This included 11 complete responses (6%) and 101 partial responses (54.9%). Median duration of response was 14.8 months (95% CI, 13.8-16.9) and median time to response was 1.6 months (95% CI, 13.8-16.9).
Sixty-seven women (36.4%) had stable disease, three (1.6%) had progressive disease and two (1.1%) were not evaluable. This translated to a disease control rate of 97.3% (95% CI, 93.8-99.1) and a clinical benefit rate at 6 months of 76.1% (95% CI, 69.3-82.1).
Researchers observed consistent benefit with trastuzumab deruxtecan across patient subgroups, including those who had prior pertuzumab.
Median follow-up for the survival analysis was 11.1 months (range, 0.7-19.9).
Median PFS was 16.4 months (95% CI, 12.7-not estimable) in the entire intent-to-treat population. Median PFS was 18.1 months (95% CI, 6.7-18.1) for patients with prior brain metastases; however, that group was small (n = 24). Median OS had not been reached.
Median treatment duration was 10 months (range, 0.7-20.5).
Nearly all patients (99.5%) experienced drug-related treatment-emergent adverse events, the most common of which were low-grade gastrointestinal or hematologic events.
About half (48.4%) experienced grade 3 or higher drug-related treatment emergent events, and 12.5% experienced drug-related serious treatment-emergent events. Drug-related events prompted 14.7% to discontinue treatment; these events included 11 cases of pneumonitis and five cases of interstitial lung disease.
Twenty-one percent of patients required dose reductions and 28.8% required dose interruption due to drug-related events. Two patients (1.1%) experienced treatment-emergent events associated with death.
The phase 1 study revealed a risk for interstitial lung disease with trastuzumab deruxtecan, Krop said.
In the phase 2 study, an independent adjudication committee determined 25 patients (13.6%) developed interstitial lung disease. Twenty cases were grade 1 or grade 2; 13 of them received corticosteroids.
Researchers reported one grade 3 case of interstitial lung disease, and four patients had fatal cases believed to be drug related.
Median time to onset of all interstitial lung disease cases was 193 days (range, 42-535); onset of the four fatal cases ranged from 63 to 148 days.
“Interstitial lung disease is confirmed as an important risk of trastuzumab deruxtecan,” Krop said. “It can be severe and requires careful monitoring and prompt intervention.”
That intervention should include evaluations with high-resolution CT, pulmonologist consultation and pulmonary function tests. If interstitial lung disease is diagnosed, treatment should be interrupted and prompt treatment with glucocorticoids should begin, Krop said.
Researchers acknowledged the single-arm design of the trial as a limitation, as it was not possible to determine if trastuzumab deruxtecan is more effective than other therapies.
However, enrollment is underway for three phase 3 trials. The DESTINY-Breast02 study will compare trastuzumab deruxtecan with standard of care after ado-trastuzumab emtansine in HER2-posiitve breast cancer, the DESTINY-Breast03 study will evaluate the agent vs. ado-trastuzumab emtansine in HER2-positive disease, and the DESTINY-Breast04 study will evaluate it vs. chemotherapy for patients with HER2 low-expressing disease. – by Mark Leiser
Reference: Krop IE, et al. Abstract GS1-03. Presented at: San Antonio Breast Cancer Symposium; Dec. 10-14, 2019; San Antonio.
Disclosures: AstraZeneca and Daiichi Sankyo sponsored this study. Krop reports research support from Genentech/Roche and Pfizer; consultant fees or honoraria from AstraZeneca, Context Therapeutics, Daiichi Sankyo, Genentech/Roche, Macrogenics; and data safety monitoring board roles with Merck and Novartis. Please see the abstract for all other authors’ relevant financial disclosures.
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Charles L. Shapiro, MD
This is a very exciting molecule and the results are extremely impressive considering the population of heavily pretreated patients, all of whom had failure ado-trastuzumab emtansine. I’m sure this agent will get FDA approval for this indication. The single-agent activity in previously treated patients is impressive, so the natural tendency is to try it in earlier stages and maybe even in the adjuvant setting, where it really could be a home run. Hopefully it will be as effective in those other settings, if not even more so. I’m participating in a limited-institution phase 1 trial of this molecule in combination with nivolumab (Opdivo). We don’t have any results yet but we’re anxious to see if this jacks up the response rate in that population.
There is toxicity but, overall, the side effects are not too bad. Investigators on this study did observe Interstitial pneumonitis in a small number of patients, and it led to a couple deaths, so you definitely have to be aware of it. I don’t think we understand the mechanism yet, but early recognition is the key. You have to have a low threshold for symptoms such as shortness of breath or cough to make sure you can treat it early.
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Debu Tripathy, MD
The immunoconjugate trastuzumab deruxtecan is important in two ways. Number one, it hones in specifically on HER2-expressing cells. It also uses a drug that most patients have not been exposed to. Topoisomerase 1 inhibitors are typically not used, yet we know there can be activity. There have been trials a long time ago with irinotecan showing activity, but with much more toxicity than you see when it is linked to an antibody. That is one reason why it has been a successful drug in early testing.
The other unique thing about this antibody-drug conjugate — especially the deruxtecan component — is that, when it gets released into the cell, it is membrane permeable. It can diffuse back out of the cell and it can affect other cells in the neighborhood and kill them, as well.
One of the challenges we have with HER2-positive cancers is that not all of the cells express HER2 at the same level. Many cases are heterogenous, where you have some positive and some negative, and it is hypothesized that oftentimes you’re only taking care of the positive ones and the negative ones can outgrow. In this case, you get an effect on neighboring cells that may not express HER2, so you may get a complete kill of all of the HER2 cells. That may be why it is more effective.
Clearly there was a lot of promise from the phase 1 study, where response rates of 50% to 55% were seen. Responses even were seen in HER2-low disease and non-breast cancers, such as gastric cancer.
This phase 2 study includes a larger number of patients and gives us more information about safety. We were very impressed by the 61% response rate, but we are very concerned about the toxicity profile. It was generally well-tolerated, with low-grade nausea and vomiting. The concern is the more infrequent problem with interstitial lung disease, with 2% actually having fatal complications. We’re going to need to better understand if we can identify who those patients are, or if we can monitor them in a different way or screen them out in the beginning. We don’t know at this point what the vulnerabilities are that these patients have, and we don’t know much about the mechanism of this. We clearly need to know more, and that might impede the movement of this drug into earlier lines.
Hopefully we can work that out. Trastuzumab has a black box warning for interstitial lung disease, too, mostly for patients who have extensive lung disease. It also has a warning for cardiomyopathy, and we have learned how to navigate around that. I feel confident that we’ll learn how to use this drug.
Clearly, it will be an important part of our armamentarium and, similarly, it will move into earlier stages, but probably in a more measured way.
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G. Thomas Budd, MD
This study is very exciting. It is important to keep in mind it was a phase 2 trial, so there was no comparator group, but still the response rates appeared very promising. This has led to three large phase 3 trials that essentially bracket the HER2-positive space — even patients who are HER2 weakly positive. Hopefully this will be an another addition to our armamentarium for HER2-positive disease, and maybe even a new approach for a large group of patients who are HER2-low, for which we have no specific targeted treatment.
Interstitial lung disease is a concern but, unfortunately, it is a toxicity with which we have some familiarity as we are seeing it more frequently with targeted agents. It will be important to learn more about the natural history in these patients. Protocols emphasize close monitoring and specify what to do if interstitial lung disease is suspected, so hopefully after the phase 3 trials we will have a better sense of how big of a problem this will be.
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