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One reason is studies of new drugs typically exclude concurrent radiotherapy, said Kathy Miller, MD, a contributor to this news organization and professor of oncology and medicine at the Indiana University School of Medicine, Indianapolis, Indiana.
If trials evaluating new targeted therapies included concurrent radiotherapy, it would be challenging to identify whether toxicities came from the drug itself, the radiation, or the combination, Dr. Miller explained.
Given the limited evidence, “we tend to be cautious and conservative” and not combine therapies that “we don’t know are safe or appropriate for patients,” said Chirag Shah, MD, director of breast radiology at the Cleveland Clinic, Cleveland, Ohio.
Below is a guide to what we do and don’t know about combining radiotherapy and systemic treatments in breast cancer.
1. Immunotherapy plus radiotherapy likely safe but evidence is limited
Safety data on combining immune checkpoint inhibitors and radiotherapy in breast cancer are limited because concurrent radiotherapy has typically been excluded in pivotal trials.
The 2020 KEYNOTE-522 trial did provide a rare look at concurrent radiotherapy and immunotherapy in early triple-negative breast cancer. The analysis found “no safety concerns” with concurrent radiotherapy and pembrolizumab, lead investigator Peter Schmid, MD, of Queen Mary University of London, England, told this news organization.
Research on other solid tumor types also suggests that radiotherapy “can be considered safe” alongside immunotherapy, the authors of a recent ESTRO consensus said.
Despite evidence indicating radiotherapy alongside immunotherapy can be safe in patients with breast cancer, “certain aspects, such as patient selection, total dose, and dose per fraction, remain open for debate to achieve the best therapeutic outcomes,” the ESTRO experts cautioned.
2. CDK4/6 inhibitors may be offered with radiotherapy in some settings, not others
CDK4/6 inhibitors are now standard of care for first- or second-line treatment in patients with advanced or metastatic hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer.
“Unfortunately, we found no information regarding concurrent radiotherapy in the adjuvant setting” in pivotal trials for palbociclib, abemaciclib, and ribociclib, the ESTRO authors said. In the pivotal trials for palbociclib and abemaciclib, patients had to discontinue immunotherapy before initiating radiotherapy, and in the trial for ribociclib, palliative radiotherapy was allowed for relieving bone pain only.
However, in 2023, a team of experts from 12 countries attempted to piece together the available evidence, publishing a meta-analysis of 11 retrospective studies on the safety of CDK4/6 inhibitors given concurrently with radiotherapy in patients with metastatic disease.
Although most of these studies had small patient populations, the analysis revealed that CDK4/6 inhibitors given concurrently with radiotherapy in patients with metastatic breast cancer led to a similar side-effect profile to that observed in trials of the inhibitors given sequentially with adjuvant radiotherapy.
“These findings suggest that the simultaneous administration of CDK4/6 inhibitors and radiotherapy is generally well tolerated,” the ESTRO authors concluded but added that CDK4/6 inhibitors and concomitant radiotherapy should be investigated more in the adjuvant locoregional, whole brain, and intracranial stereotactic radiotherapy settings.
The expert panel did note, however, that CDK4/6 inhibitors and concomitant radiotherapy “could be offered” during palliative and ablative extracranial radiotherapy.
3. Only offer poly (ADP-ribose) polymerase (PARP) inhibitors plus radiotherapy in clinical trial setting
PARP inhibitors olaparib (Lynparza) and talazoprib (Talzenna) are standard of care in patients with metastatic breast cancer who have BRCA1/2 gene mutations. Olaparib is also indicated for high-risk early breast cancer following neoadjuvant or adjuvant chemotherapy.
But data on combining PARP inhibitors with radiotherapy in breast cancer also remain limited.
One ongoing phase 2 trial, comparing olaparib plus radiotherapy to radiotherapy alone in 300 people with inflammatory breast cancer, is aiming to tease out the safety of the combination and whether it improves local control in patients with aggressive disease.
“The desire is to explore the exciting possibility that low doses of PARP inhibition may radiosensitize tumor cells more than normal tissues,” Reshma Jagsi, MD, chair of the Department of Radiation Oncology at Emory University School of Medicine in Atlanta, Georgia, who is leading the study.
Because of potential good or bad interactions between new systemic therapies and radiotherapy, “intentional trial design” is important, Dr. Jagsi said, so we “know the best way to combine treatments in practice to optimize outcomes.”
But given the evidence to date, the ESTRO experts advised waiting until “further research provides more comprehensive safety and efficacy data” in the primary, adjuvant, and metastatic settings. The experts also advised not offering PARP inhibitors and concomitant radiotherapy to treat advanced breast cancer outside of clinical trials.
4. Phosphoinositide 3-kinase inhibitors (PI3K) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and newer targeted agents should not be offered concurrently with radiotherapy
Clinical trial data on the safety of combining PI3K and mTOR inhibitors with radiation are thin, especially in advanced breast cancer. Typically, radiotherapy within 4 weeks before randomization, or 2 weeks for palliative radiation, was excluded in pivotal trials.
For this reason, the ESTRO team recommended that concurrent radiation with either PI3K inhibitors or mTOR inhibitors “should not be offered.”
ESTRO also cautioned against providing radiation concurrently with newer anti-HER2 tyrosine-kinase drugs, such as neratinib or tucatinib, or newer antibody-drug conjugates such as trastuzumab deruxtecan, until more data emerge on the safety of these combinations.
5. Combining older HER2-targeted drugs and radiotherapy generally safe
The ESTRO authors agreed that older anti-HER2 drugs trastuzumab (Herceptin), pertuzumab (Perjeta), and lapatinib (Tykerb) can be safely used concurrently with locoregional radiotherapy as well.
One of the biggest concerns in the field is how to combine radiation with systemic therapies in the setting of brain metastases, and the data on these older anti-HER2 drugs are relatively clear that it’s safe, Dr. Miller said.
For instance, in a 2019 study of 84 patients with 487 brain metastases, stereotactic radiosurgery given alongside lapatinib led to significantly higher rates of complete responses than stereotactic radiosurgery alone (35% vs 11%) with no increased risk for radiation necrosis.
The ESTRO team agreed, noting that the latest evidence supports the use of trastuzumab, pertuzumab, or lapatinib alongside radiotherapy for whole brain and ablative intracranial stereotactic radiotherapy.
As for older antibody-drug conjugates, trastuzumab emtansine (T-DM1) plus radiotherapy “might be considered” during adjuvant locoregional radiotherapy for breast cancer but should not be offered for whole brain and ablative intracranial stereotactic radiotherapy, the ESTRO team said.
Dr. Jagsi declared the following conflicts in a recent 2024 publication: Stock options for advisory board role in Equity Quotient; grants or contracts from Genentech; and expert witness for Kleinbard, LLC, and Hawks Quindel Law. In the Keynote-522 trial publication Dr. Schmid declared relationships with AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, Hoffmann-La Roche, Genetech, Merck, Novartis, and Pfizer. Dr. Shah reported consulting for Impedimed, Videra Surgical, and PreludeDX.
A version of this article appeared on Medscape.com.
One reason is studies of new drugs typically exclude concurrent radiotherapy, said Kathy Miller, MD, a contributor to this news organization and professor of oncology and medicine at the Indiana University School of Medicine, Indianapolis, Indiana.
If trials evaluating new targeted therapies included concurrent radiotherapy, it would be challenging to identify whether toxicities came from the drug itself, the radiation, or the combination, Dr. Miller explained.
Given the limited evidence, “we tend to be cautious and conservative” and not combine therapies that “we don’t know are safe or appropriate for patients,” said Chirag Shah, MD, director of breast radiology at the Cleveland Clinic, Cleveland, Ohio.
Below is a guide to what we do and don’t know about combining radiotherapy and systemic treatments in breast cancer.
1. Immunotherapy plus radiotherapy likely safe but evidence is limited
Safety data on combining immune checkpoint inhibitors and radiotherapy in breast cancer are limited because concurrent radiotherapy has typically been excluded in pivotal trials.
The 2020 KEYNOTE-522 trial did provide a rare look at concurrent radiotherapy and immunotherapy in early triple-negative breast cancer. The analysis found “no safety concerns” with concurrent radiotherapy and pembrolizumab, lead investigator Peter Schmid, MD, of Queen Mary University of London, England, told this news organization.
Research on other solid tumor types also suggests that radiotherapy “can be considered safe” alongside immunotherapy, the authors of a recent ESTRO consensus said.
Despite evidence indicating radiotherapy alongside immunotherapy can be safe in patients with breast cancer, “certain aspects, such as patient selection, total dose, and dose per fraction, remain open for debate to achieve the best therapeutic outcomes,” the ESTRO experts cautioned.
2. CDK4/6 inhibitors may be offered with radiotherapy in some settings, not others
CDK4/6 inhibitors are now standard of care for first- or second-line treatment in patients with advanced or metastatic hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer.
“Unfortunately, we found no information regarding concurrent radiotherapy in the adjuvant setting” in pivotal trials for palbociclib, abemaciclib, and ribociclib, the ESTRO authors said. In the pivotal trials for palbociclib and abemaciclib, patients had to discontinue immunotherapy before initiating radiotherapy, and in the trial for ribociclib, palliative radiotherapy was allowed for relieving bone pain only.
However, in 2023, a team of experts from 12 countries attempted to piece together the available evidence, publishing a meta-analysis of 11 retrospective studies on the safety of CDK4/6 inhibitors given concurrently with radiotherapy in patients with metastatic disease.
Although most of these studies had small patient populations, the analysis revealed that CDK4/6 inhibitors given concurrently with radiotherapy in patients with metastatic breast cancer led to a similar side-effect profile to that observed in trials of the inhibitors given sequentially with adjuvant radiotherapy.
“These findings suggest that the simultaneous administration of CDK4/6 inhibitors and radiotherapy is generally well tolerated,” the ESTRO authors concluded but added that CDK4/6 inhibitors and concomitant radiotherapy should be investigated more in the adjuvant locoregional, whole brain, and intracranial stereotactic radiotherapy settings.
The expert panel did note, however, that CDK4/6 inhibitors and concomitant radiotherapy “could be offered” during palliative and ablative extracranial radiotherapy.
3. Only offer poly (ADP-ribose) polymerase (PARP) inhibitors plus radiotherapy in clinical trial setting
PARP inhibitors olaparib (Lynparza) and talazoprib (Talzenna) are standard of care in patients with metastatic breast cancer who have BRCA1/2 gene mutations. Olaparib is also indicated for high-risk early breast cancer following neoadjuvant or adjuvant chemotherapy.
But data on combining PARP inhibitors with radiotherapy in breast cancer also remain limited.
One ongoing phase 2 trial, comparing olaparib plus radiotherapy to radiotherapy alone in 300 people with inflammatory breast cancer, is aiming to tease out the safety of the combination and whether it improves local control in patients with aggressive disease.
“The desire is to explore the exciting possibility that low doses of PARP inhibition may radiosensitize tumor cells more than normal tissues,” Reshma Jagsi, MD, chair of the Department of Radiation Oncology at Emory University School of Medicine in Atlanta, Georgia, who is leading the study.
Because of potential good or bad interactions between new systemic therapies and radiotherapy, “intentional trial design” is important, Dr. Jagsi said, so we “know the best way to combine treatments in practice to optimize outcomes.”
But given the evidence to date, the ESTRO experts advised waiting until “further research provides more comprehensive safety and efficacy data” in the primary, adjuvant, and metastatic settings. The experts also advised not offering PARP inhibitors and concomitant radiotherapy to treat advanced breast cancer outside of clinical trials.
4. Phosphoinositide 3-kinase inhibitors (PI3K) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and newer targeted agents should not be offered concurrently with radiotherapy
Clinical trial data on the safety of combining PI3K and mTOR inhibitors with radiation are thin, especially in advanced breast cancer. Typically, radiotherapy within 4 weeks before randomization, or 2 weeks for palliative radiation, was excluded in pivotal trials.
For this reason, the ESTRO team recommended that concurrent radiation with either PI3K inhibitors or mTOR inhibitors “should not be offered.”
ESTRO also cautioned against providing radiation concurrently with newer anti-HER2 tyrosine-kinase drugs, such as neratinib or tucatinib, or newer antibody-drug conjugates such as trastuzumab deruxtecan, until more data emerge on the safety of these combinations.
5. Combining older HER2-targeted drugs and radiotherapy generally safe
The ESTRO authors agreed that older anti-HER2 drugs trastuzumab (Herceptin), pertuzumab (Perjeta), and lapatinib (Tykerb) can be safely used concurrently with locoregional radiotherapy as well.
One of the biggest concerns in the field is how to combine radiation with systemic therapies in the setting of brain metastases, and the data on these older anti-HER2 drugs are relatively clear that it’s safe, Dr. Miller said.
For instance, in a 2019 study of 84 patients with 487 brain metastases, stereotactic radiosurgery given alongside lapatinib led to significantly higher rates of complete responses than stereotactic radiosurgery alone (35% vs 11%) with no increased risk for radiation necrosis.
The ESTRO team agreed, noting that the latest evidence supports the use of trastuzumab, pertuzumab, or lapatinib alongside radiotherapy for whole brain and ablative intracranial stereotactic radiotherapy.
As for older antibody-drug conjugates, trastuzumab emtansine (T-DM1) plus radiotherapy “might be considered” during adjuvant locoregional radiotherapy for breast cancer but should not be offered for whole brain and ablative intracranial stereotactic radiotherapy, the ESTRO team said.
Dr. Jagsi declared the following conflicts in a recent 2024 publication: Stock options for advisory board role in Equity Quotient; grants or contracts from Genentech; and expert witness for Kleinbard, LLC, and Hawks Quindel Law. In the Keynote-522 trial publication Dr. Schmid declared relationships with AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, Hoffmann-La Roche, Genetech, Merck, Novartis, and Pfizer. Dr. Shah reported consulting for Impedimed, Videra Surgical, and PreludeDX.
A version of this article appeared on Medscape.com.
One reason is studies of new drugs typically exclude concurrent radiotherapy, said Kathy Miller, MD, a contributor to this news organization and professor of oncology and medicine at the Indiana University School of Medicine, Indianapolis, Indiana.
If trials evaluating new targeted therapies included concurrent radiotherapy, it would be challenging to identify whether toxicities came from the drug itself, the radiation, or the combination, Dr. Miller explained.
Given the limited evidence, “we tend to be cautious and conservative” and not combine therapies that “we don’t know are safe or appropriate for patients,” said Chirag Shah, MD, director of breast radiology at the Cleveland Clinic, Cleveland, Ohio.
Below is a guide to what we do and don’t know about combining radiotherapy and systemic treatments in breast cancer.
1. Immunotherapy plus radiotherapy likely safe but evidence is limited
Safety data on combining immune checkpoint inhibitors and radiotherapy in breast cancer are limited because concurrent radiotherapy has typically been excluded in pivotal trials.
The 2020 KEYNOTE-522 trial did provide a rare look at concurrent radiotherapy and immunotherapy in early triple-negative breast cancer. The analysis found “no safety concerns” with concurrent radiotherapy and pembrolizumab, lead investigator Peter Schmid, MD, of Queen Mary University of London, England, told this news organization.
Research on other solid tumor types also suggests that radiotherapy “can be considered safe” alongside immunotherapy, the authors of a recent ESTRO consensus said.
Despite evidence indicating radiotherapy alongside immunotherapy can be safe in patients with breast cancer, “certain aspects, such as patient selection, total dose, and dose per fraction, remain open for debate to achieve the best therapeutic outcomes,” the ESTRO experts cautioned.
2. CDK4/6 inhibitors may be offered with radiotherapy in some settings, not others
CDK4/6 inhibitors are now standard of care for first- or second-line treatment in patients with advanced or metastatic hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer.
“Unfortunately, we found no information regarding concurrent radiotherapy in the adjuvant setting” in pivotal trials for palbociclib, abemaciclib, and ribociclib, the ESTRO authors said. In the pivotal trials for palbociclib and abemaciclib, patients had to discontinue immunotherapy before initiating radiotherapy, and in the trial for ribociclib, palliative radiotherapy was allowed for relieving bone pain only.
However, in 2023, a team of experts from 12 countries attempted to piece together the available evidence, publishing a meta-analysis of 11 retrospective studies on the safety of CDK4/6 inhibitors given concurrently with radiotherapy in patients with metastatic disease.
Although most of these studies had small patient populations, the analysis revealed that CDK4/6 inhibitors given concurrently with radiotherapy in patients with metastatic breast cancer led to a similar side-effect profile to that observed in trials of the inhibitors given sequentially with adjuvant radiotherapy.
“These findings suggest that the simultaneous administration of CDK4/6 inhibitors and radiotherapy is generally well tolerated,” the ESTRO authors concluded but added that CDK4/6 inhibitors and concomitant radiotherapy should be investigated more in the adjuvant locoregional, whole brain, and intracranial stereotactic radiotherapy settings.
The expert panel did note, however, that CDK4/6 inhibitors and concomitant radiotherapy “could be offered” during palliative and ablative extracranial radiotherapy.
3. Only offer poly (ADP-ribose) polymerase (PARP) inhibitors plus radiotherapy in clinical trial setting
PARP inhibitors olaparib (Lynparza) and talazoprib (Talzenna) are standard of care in patients with metastatic breast cancer who have BRCA1/2 gene mutations. Olaparib is also indicated for high-risk early breast cancer following neoadjuvant or adjuvant chemotherapy.
But data on combining PARP inhibitors with radiotherapy in breast cancer also remain limited.
One ongoing phase 2 trial, comparing olaparib plus radiotherapy to radiotherapy alone in 300 people with inflammatory breast cancer, is aiming to tease out the safety of the combination and whether it improves local control in patients with aggressive disease.
“The desire is to explore the exciting possibility that low doses of PARP inhibition may radiosensitize tumor cells more than normal tissues,” Reshma Jagsi, MD, chair of the Department of Radiation Oncology at Emory University School of Medicine in Atlanta, Georgia, who is leading the study.
Because of potential good or bad interactions between new systemic therapies and radiotherapy, “intentional trial design” is important, Dr. Jagsi said, so we “know the best way to combine treatments in practice to optimize outcomes.”
But given the evidence to date, the ESTRO experts advised waiting until “further research provides more comprehensive safety and efficacy data” in the primary, adjuvant, and metastatic settings. The experts also advised not offering PARP inhibitors and concomitant radiotherapy to treat advanced breast cancer outside of clinical trials.
4. Phosphoinositide 3-kinase inhibitors (PI3K) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and newer targeted agents should not be offered concurrently with radiotherapy
Clinical trial data on the safety of combining PI3K and mTOR inhibitors with radiation are thin, especially in advanced breast cancer. Typically, radiotherapy within 4 weeks before randomization, or 2 weeks for palliative radiation, was excluded in pivotal trials.
For this reason, the ESTRO team recommended that concurrent radiation with either PI3K inhibitors or mTOR inhibitors “should not be offered.”
ESTRO also cautioned against providing radiation concurrently with newer anti-HER2 tyrosine-kinase drugs, such as neratinib or tucatinib, or newer antibody-drug conjugates such as trastuzumab deruxtecan, until more data emerge on the safety of these combinations.
5. Combining older HER2-targeted drugs and radiotherapy generally safe
The ESTRO authors agreed that older anti-HER2 drugs trastuzumab (Herceptin), pertuzumab (Perjeta), and lapatinib (Tykerb) can be safely used concurrently with locoregional radiotherapy as well.
One of the biggest concerns in the field is how to combine radiation with systemic therapies in the setting of brain metastases, and the data on these older anti-HER2 drugs are relatively clear that it’s safe, Dr. Miller said.
For instance, in a 2019 study of 84 patients with 487 brain metastases, stereotactic radiosurgery given alongside lapatinib led to significantly higher rates of complete responses than stereotactic radiosurgery alone (35% vs 11%) with no increased risk for radiation necrosis.
The ESTRO team agreed, noting that the latest evidence supports the use of trastuzumab, pertuzumab, or lapatinib alongside radiotherapy for whole brain and ablative intracranial stereotactic radiotherapy.
As for older antibody-drug conjugates, trastuzumab emtansine (T-DM1) plus radiotherapy “might be considered” during adjuvant locoregional radiotherapy for breast cancer but should not be offered for whole brain and ablative intracranial stereotactic radiotherapy, the ESTRO team said.
Dr. Jagsi declared the following conflicts in a recent 2024 publication: Stock options for advisory board role in Equity Quotient; grants or contracts from Genentech; and expert witness for Kleinbard, LLC, and Hawks Quindel Law. In the Keynote-522 trial publication Dr. Schmid declared relationships with AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, Hoffmann-La Roche, Genetech, Merck, Novartis, and Pfizer. Dr. Shah reported consulting for Impedimed, Videra Surgical, and PreludeDX.
A version of this article appeared on Medscape.com.
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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>Targeted treatments, including antibody-drug conjugates and immunotherapy agents, are now standard of care for breast cancer, but there are limited data on the </metaDescription> <articlePDF/> <teaserImage/> <teaser>What is known and unknown about combining radiotherapy and systemic treatments in breast cancer?</teaser> <title>Combining Targeted Drugs and Radiation in Breast Cancer: What’s Safe?</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>ob</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term canonical="true">31</term> <term>23</term> </publications> <sections> <term canonical="true">27980</term> <term>39313</term> </sections> <topics> <term canonical="true">192</term> <term>270</term> <term>27442</term> <term>39570</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>Combining Targeted Drugs and Radiation in Breast Cancer: What’s Safe?</title> <deck/> </itemMeta> <itemContent> <p><span class="tag metaDescription">Targeted treatments, including antibody-drug conjugates and immunotherapy agents, are now standard of care for <span class="Hyperlink"><a href="https://emedicine.medscape.com/article/1947145-overview">breast cancer</a></span>, but there are limited data on the safety of combining these newer agents alongside radiotherapy.</span><br/><br/>One reason is studies of new drugs typically exclude concurrent radiotherapy, said Kathy Miller, MD, a contributor to this news organization and professor of oncology and medicine at the Indiana University School of Medicine, Indianapolis, Indiana.<br/><br/>If trials evaluating new targeted therapies included concurrent radiotherapy, it would be challenging to identify whether toxicities came from the drug itself, the radiation, or the combination, Dr. Miller explained.<br/><br/>Given the limited evidence, “we tend to be cautious and conservative” and not combine therapies that “we don’t know are safe or appropriate for patients,” said Chirag Shah, MD, director of breast radiology at the Cleveland Clinic, Cleveland, Ohio.<br/><br/>Below is a guide to what we do and don’t know about combining radiotherapy and systemic treatments in breast cancer.</p> <p> <strong>1. Immunotherapy plus radiotherapy likely safe but evidence is limited</strong> </p> <p>Safety data on combining immune checkpoint inhibitors and radiotherapy in breast cancer are limited because concurrent radiotherapy has typically been excluded in pivotal trials.<br/><br/>The 2020 <span class="Hyperlink"><a href="https://www.nejm.org/doi/full/10.1056/NEJMoa1910549">KEYNOTE-522</a></span> trial did provide a rare look at concurrent radiotherapy and immunotherapy in early triple-negative breast cancer. The analysis found “no safety concerns” with concurrent radiotherapy and <span class="Hyperlink"><a href="https://reference.medscape.com/drug/keytruda-pembrolizumab-999962">pembrolizumab</a></span>, lead investigator Peter Schmid, MD, of Queen Mary University of London, England, told this news organization.<br/><br/>Research on other solid tumor types also suggests that radiotherapy “can be considered safe” alongside immunotherapy, the authors of a recent <span class="Hyperlink"><a href="https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00534-X/abstract">ESTRO consensus</a></span> said.<br/><br/>Despite evidence indicating radiotherapy alongside immunotherapy can be safe in patients with breast cancer, “certain aspects, such as patient selection, total dose, and dose per fraction, remain open for debate to achieve the best therapeutic outcomes,” the ESTRO experts cautioned.</p> <p> <strong>2. CDK4/6 inhibitors may be offered with radiotherapy in some settings, not others</strong> </p> <p>CDK4/6 inhibitors are now standard of care for first- or second-line treatment in patients with advanced or metastatic hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer.<br/><br/>“Unfortunately, we found no information regarding concurrent radiotherapy in the adjuvant setting” in pivotal trials for palbociclib, abemaciclib, and ribociclib, the ESTRO authors said. In the pivotal trials for <span class="Hyperlink"><a href="https://www.medscape.com/viewarticle/839171">palbociclib</a></span> and <span class="Hyperlink"><a href="https://www.medscape.com/viewarticle/942404">abemaciclib</a></span>, patients had to discontinue immunotherapy before initiating radiotherapy, and in the trial for <span class="Hyperlink"><a href="https://www.medscape.com/viewarticle/919167">ribociclib</a></span>, palliative radiotherapy was allowed for relieving bone pain only.<br/><br/>However, in 2023, a team of experts from 12 countries attempted to piece together the available evidence, publishing <span class="Hyperlink"><a href="https://pubmed.ncbi.nlm.nih.gov/37336117/">a meta-analysis</a></span> of 11 retrospective studies on the safety of CDK4/6 inhibitors given concurrently with radiotherapy in patients with metastatic disease.<br/><br/>Although most of these studies had small patient populations, the analysis revealed that CDK4/6 inhibitors given concurrently with radiotherapy in patients with metastatic breast cancer led to a similar side-effect profile to that observed in trials of the inhibitors given sequentially with adjuvant radiotherapy.<br/><br/>“These findings suggest that the simultaneous administration of CDK4/6 inhibitors and radiotherapy is generally well tolerated,” the ESTRO authors concluded but added that CDK4/6 inhibitors and concomitant radiotherapy should be investigated more in the adjuvant locoregional, whole brain, and intracranial stereotactic radiotherapy settings.<br/><br/>The expert panel did note, however, that CDK4/6 inhibitors and concomitant radiotherapy “could be offered” during palliative and ablative extracranial radiotherapy.</p> <p> <strong>3. Only offer poly (ADP-ribose) polymerase (PARP) inhibitors plus radiotherapy in clinical trial setting</strong> </p> <p>PARP inhibitors <span class="Hyperlink"><a href="https://reference.medscape.com/drug/lynparza-olaparib-999934">olaparib</a></span> (Lynparza) and talazoprib (Talzenna) are standard of care in patients with metastatic breast cancer who have BRCA1/2 gene mutations. Olaparib is also indicated for high-risk early breast cancer following neoadjuvant or adjuvant chemotherapy.<br/><br/>But data on combining PARP inhibitors with radiotherapy in breast cancer also remain limited.<br/><br/>One ongoing phase 2 trial, comparing olaparib plus radiotherapy to radiotherapy alone in 300 people with inflammatory breast cancer, is aiming to tease out the safety of the combination and whether it improves local control in patients with aggressive disease.<br/><br/>“The desire is to explore the exciting possibility that low doses of PARP inhibition may radiosensitize tumor cells more than normal tissues,” Reshma Jagsi, MD, chair of the Department of Radiation Oncology at Emory University School of Medicine in Atlanta, Georgia, who is leading the study.<br/><br/>Because of potential good or bad interactions between new systemic therapies and radiotherapy, “intentional trial design” is important, Dr. Jagsi said, so we “know the best way to combine treatments in practice to optimize outcomes.”<br/><br/>But given the evidence to date, the ESTRO experts advised waiting until “further research provides more comprehensive safety and efficacy data” in the primary, adjuvant, and metastatic settings. The experts also advised not offering PARP inhibitors and concomitant radiotherapy to treat advanced breast cancer outside of clinical trials.</p> <p> <strong>4. Phosphoinositide 3-kinase inhibitors (PI3K) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and newer targeted agents should not be offered concurrently with radiotherapy</strong> </p> <p>Clinical trial data on the safety of combining PI3K and mTOR inhibitors with radiation are thin, especially in advanced breast cancer. Typically, radiotherapy within 4 weeks before randomization, or 2 weeks for palliative radiation, was excluded in pivotal trials.<br/><br/>For this reason, the ESTRO team recommended that concurrent radiation with either PI3K inhibitors or mTOR inhibitors “should not be offered.”<br/><br/>ESTRO also cautioned against providing radiation concurrently with newer anti-HER2 tyrosine-kinase drugs, such as <span class="Hyperlink"><a href="https://reference.medscape.com/drug/nerlynx-neratinib-1000157">neratinib</a></span> or <span class="Hyperlink"><a href="https://reference.medscape.com/drug/tukysa-tucatinib-4000071">tucatinib</a></span>, or newer antibody-drug conjugates such as <span class="Hyperlink"><a href="https://reference.medscape.com/drug/enhertu-trastuzumab-deruxtecan-4000032">trastuzumab deruxtecan</a></span>, until more data emerge on the safety of these combinations.</p> <p> <strong>5. Combining older HER2-targeted drugs and radiotherapy generally safe</strong> </p> <p>The ESTRO authors agreed that older anti-HER2 drugs trastuzumab (Herceptin), <span class="Hyperlink"><a href="https://reference.medscape.com/drug/perjeta-pertuzumab-999749">pertuzumab</a></span> (Perjeta), and <span class="Hyperlink"><a href="https://reference.medscape.com/drug/tykerb-lapatinib-342235">lapatinib</a></span> (Tykerb) can be safely used concurrently with locoregional radiotherapy as well.<br/><br/>One of the biggest concerns in the field is how to combine radiation with systemic therapies in the setting of <span class="Hyperlink"><a href="https://emedicine.medscape.com/article/1157902-overview">brain metastases</a></span>, and the data on these older anti-HER2 drugs are relatively clear that it’s safe, Dr. Miller said.<br/><br/>For instance, in <span class="Hyperlink"><a href="https://pubmed.ncbi.nlm.nih.gov/30726965/">a 2019 study</a></span> of 84 patients with 487 brain metastases, stereotactic radiosurgery given alongside lapatinib led to significantly higher rates of complete responses than stereotactic radiosurgery alone (35% vs 11%) with no increased risk for <span class="Hyperlink"><a href="https://emedicine.medscape.com/article/1157533-overview">radiation necrosis</a></span>.<br/><br/>The ESTRO team agreed, noting that the latest evidence supports the use of trastuzumab, pertuzumab, or lapatinib alongside radiotherapy for whole brain and ablative intracranial stereotactic radiotherapy.<br/><br/>As for older antibody-drug conjugates, trastuzumab emtansine (T-DM1) plus radiotherapy “might be considered” during adjuvant locoregional radiotherapy for breast cancer but should not be offered for whole brain and ablative intracranial stereotactic radiotherapy, the ESTRO team said.<br/><br/>Dr. Jagsi declared the following conflicts in a recent 2024 publication: Stock options for advisory board role in Equity Quotient; grants or contracts from Genentech; and expert witness for Kleinbard, LLC, and Hawks Quindel Law. In the Keynote-522 trial publication Dr. Schmid declared relationships with AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, Hoffmann-La Roche, Genetech, Merck, Novartis, and Pfizer. Dr. Shah reported consulting for Impedimed, Videra Surgical, and PreludeDX.<span class="end"/></p> <p> <em>A version of this article appeared on <span class="Hyperlink"><a href="https://www.medscape.com/viewarticle/combining-targeted-drugs-and-radiation-breast-cancer-whats-2024a10004sz">Medscape.com</a></span>.</em> </p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>teaser</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> </itemContent> </newsItem> </itemSet></root>