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HER2-low cancers express levels of human epidermal growth factor receptor 2 that are below standard thresholds for HER2-positive immunohistochemistry. In 2022, results from the DESTINY-Breast04 trial showed T-DXd (Enhertu, AstraZeneca) to be an effective second-line chemotherapy in patients with HER2-low metastatic breast cancer.
The highly awaited new findings, from the manufacturer-sponsored, open-label Phase 3 DESTINY-Breast06 trial, were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Illinois.
The findings not only definitively establish a role for T-DXd earlier in the treatment sequence for HER2-low cancers, they also suggest benefit in a group of patients designated for the purposes of this trial to be HER2-ultralow. These patients have cancers with only faintly detectable HER2 expression on currently used assays (J Clin Oncol 42, 2024 [suppl 17; abstr LBA 1000]).
In a separate set of findings also presented at ASCO, from the randomized phase 1B open-label study, DESTINY-Breast07, T-Dxd showed efficacy in previously untreated HER2-positive metastatic breast cancer patients both alone and in combination with the monoclonal antibody pertuzumab (Perjeta, Genentech).
DESTINY-Breast06 Methods and Results
The DESTINY-Breast06 findings were presented by lead investigator Guiseppe Curigliano, MD, PhD, of the University of Milan and European Institute of Oncology. Dr. Curigliano and his colleagues randomized 866 patients with metastatic breast cancer: 436 to intravenous T-Dxd and 430 to the investigator’s choice of capecitabine, nab-paclitaxel, or paclitaxel chemotherapy. The investigators chose capecitabine 60% of the time.
Most patients had cancers classed as HER2 low (immunohistochemistry 1+ or 2+), while 153 had cancers classed by investigators as HER2-ultralow (IHC 0 with membrane staining or IHC under 1+). Patients enrolled in the study were those whose disease had progressed after endocrine therapy with or without targeted therapy. Patients’ median age was between 57 and 58, and all were chemotherapy-naive in the metastatic breast cancer setting.
The main outcome of the study was median progression-free survival in the HER2-low group. T-Dxd was seen improving progression-free survival, with median 13.2 months vs. 8.1 months (hazard ratio, 0.62; 95% confidence interval, 0.51-0.74; P < .0001). In the intention-to-treat population, which included the HER2 ultralow patients, the benefit was the same (HR, 0.63; 95% CI, 0.53-0.75; P < .0001). This suggested that T-DXd is also effective in these patients, and it will be extremely important going forward to identify the lowest level of HER2 expression in metastatic breast cancers that can still benefit from therapy with T-DxD, Dr. Curigliano said.
Overall survival could not be assessed in the study cohort because complete data were not yet available, Dr. Curigliano said. However, trends pointed to an advantage for T-DXd, and tumor response rates were markedly higher with T-DXd: 57% compared with 31% for standard chemotherapy in the full cohort.
Serious treatment-emergent adverse events were more common in the T-Dxd–treated patients, with 11% of that arm developing drug-related interstitial lung disease, and three patients dying of it. Five patients in the T-DXd arm died of adverse events deemed treatment-related, and none died from treatment-related adverse events in the standard chemotherapy arm. Altogether 11 patients died in the T-DXd arm and 6 in the chemotherapy arm.
Clinical Implications of DESTINY-Breast06
The DESTINY-Breast06 data show that “we have to again change how we think about HER2 expression. Even very low levels of HER2 expression matter, and they can be leveraged to improve the treatment for our patients,” said Ian Krop, MD, PhD, of the Yale Cancer Center in New Haven, Connecticut, during the session where the results were presented.
But T-DXd may not be an appropriate first choice for all patients, especially given the safety concerns associated with T-DXd, he continued. With overall survival and quality-of-life data still lacking, clinicians will have to determine on a case-by-case basis who should get T-DXd in the first line.
“For patients who have symptomatic metastatic disease, who need a response to address those symptoms, those in whom you think chemotherapy may not work as well because they had, for example, a short recurrence interval after their adjuvant chemotherapy — using T-DXd in that first-line setting makes perfect sense to take advantage of the substantially higher response rate compared to chemo,” Dr. Krop said. “But for patients who have asymptomatic low burdens of disease, it seems very reasonable to consider using a well-tolerated chemotherapy like capecitabine in the first line, and then using T-DXd in the second line.”
In an interview, Erica Mayer, MD, of the Dana Farber Cancer Institute in Boston, Massachusetts, said patient choice will also matter in determining whether T-DXd is a first-line option. The known toxicity of T-DXd was underscored by the latest findings, she noted, while capecitabine, one of the chemotherapy choices in the control arm of the study, “really reflects what the majority of breast cancer doctors tend to offer, both because of the efficacy of the drug, but also because it’s oral, it’s well tolerated, and you don’t lose your hair.”
DESTINY-Breast07 Results
The DESTINY-Breast07 findings, from a Phase 1B open-label trial measuring safety and tolerability, were presented by Fabrice Andre, MD, PhD, of Université Paris Saclay in Paris, France. Dr. Andre and his colleagues presented the first data comparing T-DXd monotherapy and T-DXd with pertuzumab — a monoclonal antibody targeting HER2 — as a first-line treatment in patients with HER2-overexpressing (immunohistochemistry 3 and above) metastatic breast cancer. (J Clin Oncol 42, 2024 [suppl 16; abstr 1009]).
Current first-line standard of care for these patients is pertuzumab, trastuzumab, and docetaxel, based on results from the 2015 CLEOPATRA trial. T-DXd is currently approved as a second-line treatment.
Dr. Andre and his colleagues randomized 75 patients to monotherapy with T-DXd and 50 to combined therapy, with a median follow-up of 2 years.
After 1 year of treatment, combination of T-DXd and pertuzumab was seen to be associated with a progression-free survival of 89% at 1 year (80% CI, 81.9-93.9), compared with 80% in patients treated with T-DXd alone (80% CI, 73.7-86.1). Objective tumor response rate was 84% for the combined therapy at 12 weeks, with 20% of patients seeing a complete response, compared with 76% and 8%, respectively, for monotherapy.
As in the DESTINY-Breast06 trial, adverse events were high, with interstitial lung disease seen in 9% of patients in the monotherapy group and in 14% of the combined-therapy patients, although no treatment-related deaths occurred.
A randomized phase 3 trial, DESTINY Breast09, will now compare the monotherapy and the combined therapy with standard care.
T-DXd has seen a rapidly expanding role in treating breast and other solid tumors. The DESTINY Breast06 findings will move up its place in the treatment algorithm for metastatic breast cancer, “allowing us to now offer T-DXd as the first chemotherapy choice for patients who are making that transition to chemotherapy over many of the traditional provider choices that we previously have offered,” Dr. Mayer said.
The results “support the use of not only this specific agent, but also the concept of antibody drug conjugates as a very effective way to treat malignancy,” she added.
Dr. Curigliano reported receiving speaker’s fees, research funding, and other support from AstraZeneca and Daiichi Sankyo, among other companies, as did most of his co-authors, of whom three were AstraZeneca employees. Dr. Fabrice disclosed receiving research funding, travel compensation, and/or advisory fees from AstraZeneca and other entities, as did several of his co-authors. Two of his co-authors were employed by AstraZeneca and Roche, manufacturers of the study drugs. Dr. Krop and Dr. Mayer disclosed relationships with AstraZeneca and others.
HER2-low cancers express levels of human epidermal growth factor receptor 2 that are below standard thresholds for HER2-positive immunohistochemistry. In 2022, results from the DESTINY-Breast04 trial showed T-DXd (Enhertu, AstraZeneca) to be an effective second-line chemotherapy in patients with HER2-low metastatic breast cancer.
The highly awaited new findings, from the manufacturer-sponsored, open-label Phase 3 DESTINY-Breast06 trial, were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Illinois.
The findings not only definitively establish a role for T-DXd earlier in the treatment sequence for HER2-low cancers, they also suggest benefit in a group of patients designated for the purposes of this trial to be HER2-ultralow. These patients have cancers with only faintly detectable HER2 expression on currently used assays (J Clin Oncol 42, 2024 [suppl 17; abstr LBA 1000]).
In a separate set of findings also presented at ASCO, from the randomized phase 1B open-label study, DESTINY-Breast07, T-Dxd showed efficacy in previously untreated HER2-positive metastatic breast cancer patients both alone and in combination with the monoclonal antibody pertuzumab (Perjeta, Genentech).
DESTINY-Breast06 Methods and Results
The DESTINY-Breast06 findings were presented by lead investigator Guiseppe Curigliano, MD, PhD, of the University of Milan and European Institute of Oncology. Dr. Curigliano and his colleagues randomized 866 patients with metastatic breast cancer: 436 to intravenous T-Dxd and 430 to the investigator’s choice of capecitabine, nab-paclitaxel, or paclitaxel chemotherapy. The investigators chose capecitabine 60% of the time.
Most patients had cancers classed as HER2 low (immunohistochemistry 1+ or 2+), while 153 had cancers classed by investigators as HER2-ultralow (IHC 0 with membrane staining or IHC under 1+). Patients enrolled in the study were those whose disease had progressed after endocrine therapy with or without targeted therapy. Patients’ median age was between 57 and 58, and all were chemotherapy-naive in the metastatic breast cancer setting.
The main outcome of the study was median progression-free survival in the HER2-low group. T-Dxd was seen improving progression-free survival, with median 13.2 months vs. 8.1 months (hazard ratio, 0.62; 95% confidence interval, 0.51-0.74; P < .0001). In the intention-to-treat population, which included the HER2 ultralow patients, the benefit was the same (HR, 0.63; 95% CI, 0.53-0.75; P < .0001). This suggested that T-DXd is also effective in these patients, and it will be extremely important going forward to identify the lowest level of HER2 expression in metastatic breast cancers that can still benefit from therapy with T-DxD, Dr. Curigliano said.
Overall survival could not be assessed in the study cohort because complete data were not yet available, Dr. Curigliano said. However, trends pointed to an advantage for T-DXd, and tumor response rates were markedly higher with T-DXd: 57% compared with 31% for standard chemotherapy in the full cohort.
Serious treatment-emergent adverse events were more common in the T-Dxd–treated patients, with 11% of that arm developing drug-related interstitial lung disease, and three patients dying of it. Five patients in the T-DXd arm died of adverse events deemed treatment-related, and none died from treatment-related adverse events in the standard chemotherapy arm. Altogether 11 patients died in the T-DXd arm and 6 in the chemotherapy arm.
Clinical Implications of DESTINY-Breast06
The DESTINY-Breast06 data show that “we have to again change how we think about HER2 expression. Even very low levels of HER2 expression matter, and they can be leveraged to improve the treatment for our patients,” said Ian Krop, MD, PhD, of the Yale Cancer Center in New Haven, Connecticut, during the session where the results were presented.
But T-DXd may not be an appropriate first choice for all patients, especially given the safety concerns associated with T-DXd, he continued. With overall survival and quality-of-life data still lacking, clinicians will have to determine on a case-by-case basis who should get T-DXd in the first line.
“For patients who have symptomatic metastatic disease, who need a response to address those symptoms, those in whom you think chemotherapy may not work as well because they had, for example, a short recurrence interval after their adjuvant chemotherapy — using T-DXd in that first-line setting makes perfect sense to take advantage of the substantially higher response rate compared to chemo,” Dr. Krop said. “But for patients who have asymptomatic low burdens of disease, it seems very reasonable to consider using a well-tolerated chemotherapy like capecitabine in the first line, and then using T-DXd in the second line.”
In an interview, Erica Mayer, MD, of the Dana Farber Cancer Institute in Boston, Massachusetts, said patient choice will also matter in determining whether T-DXd is a first-line option. The known toxicity of T-DXd was underscored by the latest findings, she noted, while capecitabine, one of the chemotherapy choices in the control arm of the study, “really reflects what the majority of breast cancer doctors tend to offer, both because of the efficacy of the drug, but also because it’s oral, it’s well tolerated, and you don’t lose your hair.”
DESTINY-Breast07 Results
The DESTINY-Breast07 findings, from a Phase 1B open-label trial measuring safety and tolerability, were presented by Fabrice Andre, MD, PhD, of Université Paris Saclay in Paris, France. Dr. Andre and his colleagues presented the first data comparing T-DXd monotherapy and T-DXd with pertuzumab — a monoclonal antibody targeting HER2 — as a first-line treatment in patients with HER2-overexpressing (immunohistochemistry 3 and above) metastatic breast cancer. (J Clin Oncol 42, 2024 [suppl 16; abstr 1009]).
Current first-line standard of care for these patients is pertuzumab, trastuzumab, and docetaxel, based on results from the 2015 CLEOPATRA trial. T-DXd is currently approved as a second-line treatment.
Dr. Andre and his colleagues randomized 75 patients to monotherapy with T-DXd and 50 to combined therapy, with a median follow-up of 2 years.
After 1 year of treatment, combination of T-DXd and pertuzumab was seen to be associated with a progression-free survival of 89% at 1 year (80% CI, 81.9-93.9), compared with 80% in patients treated with T-DXd alone (80% CI, 73.7-86.1). Objective tumor response rate was 84% for the combined therapy at 12 weeks, with 20% of patients seeing a complete response, compared with 76% and 8%, respectively, for monotherapy.
As in the DESTINY-Breast06 trial, adverse events were high, with interstitial lung disease seen in 9% of patients in the monotherapy group and in 14% of the combined-therapy patients, although no treatment-related deaths occurred.
A randomized phase 3 trial, DESTINY Breast09, will now compare the monotherapy and the combined therapy with standard care.
T-DXd has seen a rapidly expanding role in treating breast and other solid tumors. The DESTINY Breast06 findings will move up its place in the treatment algorithm for metastatic breast cancer, “allowing us to now offer T-DXd as the first chemotherapy choice for patients who are making that transition to chemotherapy over many of the traditional provider choices that we previously have offered,” Dr. Mayer said.
The results “support the use of not only this specific agent, but also the concept of antibody drug conjugates as a very effective way to treat malignancy,” she added.
Dr. Curigliano reported receiving speaker’s fees, research funding, and other support from AstraZeneca and Daiichi Sankyo, among other companies, as did most of his co-authors, of whom three were AstraZeneca employees. Dr. Fabrice disclosed receiving research funding, travel compensation, and/or advisory fees from AstraZeneca and other entities, as did several of his co-authors. Two of his co-authors were employed by AstraZeneca and Roche, manufacturers of the study drugs. Dr. Krop and Dr. Mayer disclosed relationships with AstraZeneca and others.
HER2-low cancers express levels of human epidermal growth factor receptor 2 that are below standard thresholds for HER2-positive immunohistochemistry. In 2022, results from the DESTINY-Breast04 trial showed T-DXd (Enhertu, AstraZeneca) to be an effective second-line chemotherapy in patients with HER2-low metastatic breast cancer.
The highly awaited new findings, from the manufacturer-sponsored, open-label Phase 3 DESTINY-Breast06 trial, were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Illinois.
The findings not only definitively establish a role for T-DXd earlier in the treatment sequence for HER2-low cancers, they also suggest benefit in a group of patients designated for the purposes of this trial to be HER2-ultralow. These patients have cancers with only faintly detectable HER2 expression on currently used assays (J Clin Oncol 42, 2024 [suppl 17; abstr LBA 1000]).
In a separate set of findings also presented at ASCO, from the randomized phase 1B open-label study, DESTINY-Breast07, T-Dxd showed efficacy in previously untreated HER2-positive metastatic breast cancer patients both alone and in combination with the monoclonal antibody pertuzumab (Perjeta, Genentech).
DESTINY-Breast06 Methods and Results
The DESTINY-Breast06 findings were presented by lead investigator Guiseppe Curigliano, MD, PhD, of the University of Milan and European Institute of Oncology. Dr. Curigliano and his colleagues randomized 866 patients with metastatic breast cancer: 436 to intravenous T-Dxd and 430 to the investigator’s choice of capecitabine, nab-paclitaxel, or paclitaxel chemotherapy. The investigators chose capecitabine 60% of the time.
Most patients had cancers classed as HER2 low (immunohistochemistry 1+ or 2+), while 153 had cancers classed by investigators as HER2-ultralow (IHC 0 with membrane staining or IHC under 1+). Patients enrolled in the study were those whose disease had progressed after endocrine therapy with or without targeted therapy. Patients’ median age was between 57 and 58, and all were chemotherapy-naive in the metastatic breast cancer setting.
The main outcome of the study was median progression-free survival in the HER2-low group. T-Dxd was seen improving progression-free survival, with median 13.2 months vs. 8.1 months (hazard ratio, 0.62; 95% confidence interval, 0.51-0.74; P < .0001). In the intention-to-treat population, which included the HER2 ultralow patients, the benefit was the same (HR, 0.63; 95% CI, 0.53-0.75; P < .0001). This suggested that T-DXd is also effective in these patients, and it will be extremely important going forward to identify the lowest level of HER2 expression in metastatic breast cancers that can still benefit from therapy with T-DxD, Dr. Curigliano said.
Overall survival could not be assessed in the study cohort because complete data were not yet available, Dr. Curigliano said. However, trends pointed to an advantage for T-DXd, and tumor response rates were markedly higher with T-DXd: 57% compared with 31% for standard chemotherapy in the full cohort.
Serious treatment-emergent adverse events were more common in the T-Dxd–treated patients, with 11% of that arm developing drug-related interstitial lung disease, and three patients dying of it. Five patients in the T-DXd arm died of adverse events deemed treatment-related, and none died from treatment-related adverse events in the standard chemotherapy arm. Altogether 11 patients died in the T-DXd arm and 6 in the chemotherapy arm.
Clinical Implications of DESTINY-Breast06
The DESTINY-Breast06 data show that “we have to again change how we think about HER2 expression. Even very low levels of HER2 expression matter, and they can be leveraged to improve the treatment for our patients,” said Ian Krop, MD, PhD, of the Yale Cancer Center in New Haven, Connecticut, during the session where the results were presented.
But T-DXd may not be an appropriate first choice for all patients, especially given the safety concerns associated with T-DXd, he continued. With overall survival and quality-of-life data still lacking, clinicians will have to determine on a case-by-case basis who should get T-DXd in the first line.
“For patients who have symptomatic metastatic disease, who need a response to address those symptoms, those in whom you think chemotherapy may not work as well because they had, for example, a short recurrence interval after their adjuvant chemotherapy — using T-DXd in that first-line setting makes perfect sense to take advantage of the substantially higher response rate compared to chemo,” Dr. Krop said. “But for patients who have asymptomatic low burdens of disease, it seems very reasonable to consider using a well-tolerated chemotherapy like capecitabine in the first line, and then using T-DXd in the second line.”
In an interview, Erica Mayer, MD, of the Dana Farber Cancer Institute in Boston, Massachusetts, said patient choice will also matter in determining whether T-DXd is a first-line option. The known toxicity of T-DXd was underscored by the latest findings, she noted, while capecitabine, one of the chemotherapy choices in the control arm of the study, “really reflects what the majority of breast cancer doctors tend to offer, both because of the efficacy of the drug, but also because it’s oral, it’s well tolerated, and you don’t lose your hair.”
DESTINY-Breast07 Results
The DESTINY-Breast07 findings, from a Phase 1B open-label trial measuring safety and tolerability, were presented by Fabrice Andre, MD, PhD, of Université Paris Saclay in Paris, France. Dr. Andre and his colleagues presented the first data comparing T-DXd monotherapy and T-DXd with pertuzumab — a monoclonal antibody targeting HER2 — as a first-line treatment in patients with HER2-overexpressing (immunohistochemistry 3 and above) metastatic breast cancer. (J Clin Oncol 42, 2024 [suppl 16; abstr 1009]).
Current first-line standard of care for these patients is pertuzumab, trastuzumab, and docetaxel, based on results from the 2015 CLEOPATRA trial. T-DXd is currently approved as a second-line treatment.
Dr. Andre and his colleagues randomized 75 patients to monotherapy with T-DXd and 50 to combined therapy, with a median follow-up of 2 years.
After 1 year of treatment, combination of T-DXd and pertuzumab was seen to be associated with a progression-free survival of 89% at 1 year (80% CI, 81.9-93.9), compared with 80% in patients treated with T-DXd alone (80% CI, 73.7-86.1). Objective tumor response rate was 84% for the combined therapy at 12 weeks, with 20% of patients seeing a complete response, compared with 76% and 8%, respectively, for monotherapy.
As in the DESTINY-Breast06 trial, adverse events were high, with interstitial lung disease seen in 9% of patients in the monotherapy group and in 14% of the combined-therapy patients, although no treatment-related deaths occurred.
A randomized phase 3 trial, DESTINY Breast09, will now compare the monotherapy and the combined therapy with standard care.
T-DXd has seen a rapidly expanding role in treating breast and other solid tumors. The DESTINY Breast06 findings will move up its place in the treatment algorithm for metastatic breast cancer, “allowing us to now offer T-DXd as the first chemotherapy choice for patients who are making that transition to chemotherapy over many of the traditional provider choices that we previously have offered,” Dr. Mayer said.
The results “support the use of not only this specific agent, but also the concept of antibody drug conjugates as a very effective way to treat malignancy,” she added.
Dr. Curigliano reported receiving speaker’s fees, research funding, and other support from AstraZeneca and Daiichi Sankyo, among other companies, as did most of his co-authors, of whom three were AstraZeneca employees. Dr. Fabrice disclosed receiving research funding, travel compensation, and/or advisory fees from AstraZeneca and other entities, as did several of his co-authors. Two of his co-authors were employed by AstraZeneca and Roche, manufacturers of the study drugs. Dr. Krop and Dr. Mayer disclosed relationships with AstraZeneca and others.
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<root generator="drupal.xsl" gversion="1.7"> <header> <fileName>168352</fileName> <TBEID>0C050750.SIG</TBEID> <TBUniqueIdentifier>MD_0C050750</TBUniqueIdentifier> <newsOrJournal>News</newsOrJournal> <publisherName>Frontline Medical Communications</publisherName> <storyname>Destiny06and07</storyname> <articleType>2</articleType> <TBLocation>QC Done-All Pubs</TBLocation> <QCDate>20240610T135320</QCDate> <firstPublished>20240610T135502</firstPublished> <LastPublished>20240610T135502</LastPublished> <pubStatus qcode="stat:"/> <embargoDate/> <killDate/> <CMSDate>20240610T135502</CMSDate> <articleSource>FROM ASCO</articleSource> <facebookInfo/> <meetingNumber>3035-24</meetingNumber> <byline>Jennie Smith</byline> <bylineText>JENNIE SMITH</bylineText> <bylineFull>JENNIE SMITH</bylineFull> <bylineTitleText>MDedge News</bylineTitleText> <USOrGlobal/> <wireDocType/> <newsDocType>News</newsDocType> <journalDocType/> <linkLabel/> <pageRange/> <citation/> <quizID/> <indexIssueDate/> <itemClass qcode="ninat:text"/> <provider qcode="provider:imng"> <name>IMNG Medical Media</name> <rightsInfo> <copyrightHolder> <name>Frontline Medical News</name> </copyrightHolder> <copyrightNotice>Copyright (c) 2015 Frontline Medical News, a Frontline Medical Communications Inc. company. All rights reserved. This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>The antibody-drug conjugate trastuzumab deruxtecan, or T-DXd, is an effective first-line treatment in patients with HER2-low metastatic breast cancer, conferrin</metaDescription> <articlePDF/> <teaserImage/> <teaser>New results from DESTINY trials support use of the antibody-drug conjugate earlier in the treatment algorithm for cancers expressing even the lowest detectable levels of HER2, but toxicity remains a concern.</teaser> <title>T-DXd Moves Toward the Front Line for HER2-Low Metastatic BC</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>oncr</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>chph</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term canonical="true">31</term> <term>6</term> </publications> <sections> <term>39313</term> <term canonical="true">53</term> <term>27980</term> </sections> <topics> <term canonical="true">39570</term> <term>192</term> <term>270</term> <term>284</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>T-DXd Moves Toward the Front Line for HER2-Low Metastatic BC</title> <deck/> </itemMeta> <itemContent> <p><span class="tag metaDescription">The antibody-drug conjugate trastuzumab deruxtecan, or T-DXd, is an effective first-line treatment in patients with HER2-low metastatic breast cancer, conferring an additional 5 months’ progression-free survival over chemotherapy.</span> </p> <p>HER2-low cancers express levels of human epidermal growth factor receptor 2 that are below standard thresholds for HER2-positive immunohistochemistry. In 2022, results from the <span class="Hyperlink"><a href="https://www.nejm.org/doi/full/10.1056/NEJMoa2203690">DESTINY-Breast04 trial</a></span> showed T-DXd (Enhertu, AstraZeneca) to be an effective second-line chemotherapy in patients with HER2-low metastatic breast cancer.<br/><br/>The highly awaited new findings, from the manufacturer-sponsored, open-label Phase 3 <a href="https://clinicaltrials.gov/study/NCT04494425">DESTINY-Breast06 trial</a>, were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Illinois. <br/><br/>The findings not only definitively establish a role for T-DXd earlier in the treatment sequence for HER2-low cancers, they also suggest benefit in a group of patients designated for the purposes of this trial to be HER2-ultralow. These patients have cancers with only faintly detectable HER2 expression on currently used assays (<em>J Clin Oncol</em> 42, 2024 [suppl 17; abstr LBA 1000]). <br/><br/>In a separate set of findings also presented at ASCO, from the randomized phase 1B open-label study, DESTINY-Breast07, T-Dxd showed efficacy in previously untreated HER2-positive metastatic breast cancer patients both alone and in combination with the monoclonal antibody pertuzumab (Perjeta, Genentech).<br/><br/><br/><br/></p> <h2>DESTINY-Breast06 Methods and Results </h2> <p>The DESTINY-Breast06 findings were presented by lead investigator Guiseppe Curigliano, MD, PhD, of the University of Milan and European Institute of Oncology. Dr. Curigliano and his colleagues randomized 866 patients with metastatic breast cancer: 436 to intravenous T-Dxd and 430 to the investigator’s choice of capecitabine, nab-paclitaxel, or paclitaxel chemotherapy. The investigators chose capecitabine 60% of the time. </p> <p>Most patients had cancers classed as HER2 low (immunohistochemistry 1+ or 2+), while 153 had cancers classed by investigators as HER2-ultralow (IHC 0 with membrane staining or IHC under 1+). Patients enrolled in the study were those whose disease had progressed after endocrine therapy with or without targeted therapy. Patients’ median age was between 57 and 58, and all were chemotherapy-naive in the metastatic breast cancer setting. <br/><br/>The main outcome of the study was median progression-free survival in the HER2-low group. T-Dxd was seen improving progression-free survival, with median 13.2 months vs. 8.1 months (hazard ratio, 0.62; 95% confidence interval, 0.51-0.74; <em>P</em> < .0001). In the intention-to-treat population, which included the HER2 ultralow patients, the benefit was the same (HR, 0.63; 95% CI, 0.53-0.75; <em>P</em> < .0001). This suggested that T-DXd is also effective in these patients, and it will be extremely important going forward to identify the lowest level of HER2 expression in metastatic breast cancers that can still benefit from therapy with T-DxD, Dr. Curigliano said. <br/><br/>Overall survival could not be assessed in the study cohort because complete data were not yet available, Dr. Curigliano said. However, trends pointed to an advantage for T-DXd, and tumor response rates were markedly higher with T-DXd: 57% compared with 31% for standard chemotherapy in the full cohort.<br/><br/>Serious treatment-emergent adverse events were more common in the T-Dxd–treated patients, with 11% of that arm developing drug-related interstitial lung disease, and three patients dying of it. Five patients in the T-DXd arm died of adverse events deemed treatment-related, and none died from treatment-related adverse events in the standard chemotherapy arm. Altogether 11 patients died in the T-DXd arm and 6 in the chemotherapy arm.<br/><br/></p> <h2>Clinical Implications of DESTINY-Breast06</h2> <p>The DESTINY-Breast06 data show that “we have to again change how we think about HER2 expression. Even very low levels of HER2 expression matter, and they can be leveraged to improve the treatment for our patients,” said Ian Krop, MD, PhD, of the Yale Cancer Center in New Haven, Connecticut, during the session where the results were presented.</p> <p>But T-DXd may not be an appropriate first choice for all patients, especially given the safety concerns associated with T-DXd, he continued. With overall survival and quality-of-life data still lacking, clinicians will have to determine on a case-by-case basis who should get T-DXd in the first line. <br/><br/>“For patients who have symptomatic metastatic disease, who need a response to address those symptoms, those in whom you think chemotherapy may not work as well because they had, for example, a short recurrence interval after their adjuvant chemotherapy — using T-DXd in that first-line setting makes perfect sense to take advantage of the substantially higher response rate compared to chemo,” Dr. Krop said. “But for patients who have asymptomatic low burdens of disease, it seems very reasonable to consider using a well-tolerated chemotherapy like capecitabine in the first line, and then using T-DXd in the second line.” <br/><br/>In an interview, Erica Mayer, MD, of the Dana Farber Cancer Institute in Boston, Massachusetts, said patient choice will also matter in determining whether T-DXd is a first-line option. The known toxicity of T-DXd was underscored by the latest findings, she noted, while capecitabine, one of the chemotherapy choices in the control arm of the study, “really reflects what the majority of breast cancer doctors tend to offer, both because of the efficacy of the drug, but also because it’s oral, it’s well tolerated, and you don’t lose your hair.” <br/><br/></p> <h2>DESTINY-Breast07 Results</h2> <p>The DESTINY-Breast07 findings, from a Phase 1B open-label trial measuring safety and tolerability, were presented by Fabrice Andre, MD, PhD, of Université Paris Saclay in Paris, France. Dr. Andre and his colleagues presented the first data comparing T-DXd monotherapy and T-DXd with pertuzumab — a monoclonal antibody targeting HER2 — as a first-line treatment in patients with HER2-overexpressing (immunohistochemistry 3 and above) metastatic breast cancer. (<em>J Clin Oncol </em>42, 2024 [suppl 16; abstr 1009]).</p> <p>Current first-line standard of care for these patients is pertuzumab, trastuzumab, and docetaxel, based on results from the 2015 <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa1413513">CLEOPATRA trial</a>. T-DXd is currently approved as a second-line treatment. <br/><br/>Dr. Andre and his colleagues randomized 75 patients to monotherapy with T-DXd and 50 to combined therapy, with a median follow-up of 2 years. <br/><br/>After 1 year of treatment, combination of T-DXd and pertuzumab was seen to be associated with a progression-free survival of 89% at 1 year (80% CI, 81.9-93.9), compared with 80% in patients treated with T-DXd alone (80% CI, 73.7-86.1). Objective tumor response rate was 84% for the combined therapy at 12 weeks, with 20% of patients seeing a complete response, compared with 76% and 8%, respectively, for monotherapy. <br/><br/>As in the DESTINY-Breast06 trial, adverse events were high, with interstitial lung disease seen in 9% of patients in the monotherapy group and in 14% of the combined-therapy patients, although no treatment-related deaths occurred. <br/><br/>A randomized <a href="https://clinicaltrials.gov/study/NCT04784715">phase 3 trial</a>, DESTINY Breast09, will now compare the monotherapy and the combined therapy with standard care. <br/><br/>T-DXd has seen a rapidly expanding role in treating breast and other solid tumors. The DESTINY Breast06 findings will move up its place in the treatment algorithm for metastatic breast cancer, “allowing us to now offer T-DXd as the first chemotherapy choice for patients who are making that transition to chemotherapy over many of the traditional provider choices that we previously have offered,” Dr. Mayer said.<br/><br/>The results “support the use of not only this specific agent, but also the concept of antibody drug conjugates as a very effective way to treat malignancy,” she added.<br/><br/>Dr. Curigliano reported receiving speaker’s fees, research funding, and other support from AstraZeneca and Daiichi Sankyo, among other companies, as did most of his co-authors, of whom three were AstraZeneca employees. Dr. Fabrice disclosed receiving research funding, travel compensation, and/or advisory fees from AstraZeneca and other entities, as did several of his co-authors. Two of his co-authors were employed by AstraZeneca and Roche, manufacturers of the study drugs. Dr. Krop and Dr. Mayer disclosed relationships with AstraZeneca and others.<span class="end"/></p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>teaser</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> </itemContent> </newsItem> </itemSet></root>
FROM ASCO