Federal Practitioner

A cell-free DNA (cfDNA) blood test, aimed at detecting abnormal DNA signals in people with an average risk of colorectal cancer (CRC), correctly detected CRC in most people confirmed to have the disease, according to a new study.

The cfDNA blood test had 83% sensitivity for CRC, 90% specificity for advanced neoplasia, and 13% sensitivity for advanced precancerous lesions. Other noninvasive screening methods have sensitivity from 67% to 94% for CRC and 22% to 43% for advanced precancerous lesions.

“The results of the study are a promising step toward developing more convenient tools to detect colorectal cancer early while it is more easily treated,” said senior author William M. Grady, MD, AGAF, medical director of the Gastrointestinal Cancer Prevention Program at the Fred Hutchinson Cancer Center in Seattle.

“The test, which has an accuracy rate for colon cancer detection similar to stool tests used for early detection of cancer, could offer an alternative for patients who may otherwise decline current screening options,” he said.

The study was published online on March 14 in The New England Journal of Medicine.
 

Analyzing the Blood Test’s Accuracy 

Dr. Grady and colleagues conducted a multisite clinical trial called ECLIPSE, which compared the sensitivity and specificity of a cfDNA blood test (Shield, Guardant Health) against that obtained with colonoscopy, the gold standard for CRC screening. Guardant led and funded the study.

Guardant’s Shield test is designed to detect CRC through genomic alterations, aberrant methylation status, and fragmentomic patterns, which show up as an “abnormal signal detected” result. Similar blood tests are being developed as “liquid biopsy” tests for other emerging cancer screenings as well.

The study included 7861 people with average CRC risk who underwent routine screening with colonoscopy at 265 sites in the United States, including primary care and endoscopy centers in academic and community-based institutions. Eligible people were aged 45-84 years (average age, 60 years), and 53.7% were women. The race and ethnicity characteristics of the participants closely mirrored the demographic distribution in the 2020 US Census.

Overall, 54 of 65 (83.1%) participants with colonoscopy-detected CRC had a positive cfDNA blood test. However, 11 participants (16.9%) with CRC had a negative test.

The cfDNA blood test identified 42 of 48 stage I, II, or III CRCs, indicating a sensitivity of 87.5%, including 65% for stage I cancers, 100% for stage II cancers, and 100% for stage III cancers. The test also identified all 10 of the stage IV CRC cases. There were no substantial differences in sensitivity for CRC based on primary tumor location, tumor histologic grade, or demographic characteristics.

Among participants without advanced colorectal neoplasia on colonoscopy, 89.6% had a negative cfDNA blood test, and 10.4% had a positive test. 

Among those with a negative colonoscopy — with no CRC, advanced precancerous lesions, or nonadvanced precancerous lesions — specificity was 89.9%.

Among 1116 participants with advanced precancerous lesions identified as the most advanced lesion on colonoscopy, the cfDNA blood test was positive for 147, indicating a sensitivity for advanced precancerous lesions of 13.2%.

Although the blood test has sensitivity similar to stool-based tests for CRC, the accuracy is lower than it is with colonoscopy, which remains the current gold standard for CRC screening, Dr. Grady said.

“Colorectal cancer is common and very preventable with screening, but only about 50% to 60% of people who are eligible for screening actually take those tests,” he said. “Getting people to be screened for cancer works best when we offer them screening options and then let them choose what works best for them.”
 

Future Research

Colorectal cancer is the second leading cause of cancer-related death among US adults and is now the third most diagnosed cancer for people younger than 50 years, Dr. Grady said. Although overall CRC death rates have declined in recent years, the rates among those younger than 55 years have increased since the mid-2000s.

“When colorectal cancer is found earlier and the cancer has not yet spread throughout the body, patient outcomes are much better, as reflected in 5-year survival being much better. It makes sense that an effective blood-based test could have a potential role, in particular for those not getting screened yet,” said Joshua Melson, MD, AGAF, clinical professor of medicine and director of the High-Risk Clinic for Gastrointestinal Cancers at the University of Arizona Cancer Center in Tucson.

Dr. Melson, who wasn’t involved with this study, noted that blood-based testing shows promise for cancer detection but needs additional support for real-world implementation. For instance, the Shield blood test has difficulty detecting precancerous lesions, and it remains unclear what the optimal intervals for repeat testing would be after a negative test, he said. In addition, screening programs will need to ensure they have capacity to effectively deal with a positive test result.

“For a screening program to actually work, when a noninvasive test (whether blood-based or stool-based) is read as positive, those patients need to have a follow-up colonoscopy,” he said. 

Proper communication with patients will be important as well, said Gloria Coronado, PhD, associate director of Population Sciences at the University of Arizona Cancer Center, Tucson. Dr. Coronado, who wasn’t involved with this study, has developed CRC screening messages for specific patient populations and studied patient reactions to CRC blood tests. 

In a study by Dr. Coronado and colleagues, among more than 2000 patients who passively declined fecal testing and had an upcoming clinic visit, CRC screening proportions were 17.5 percentage points higher in the group offered the blood test vs those offered usual care. In qualitative interviews, one patient said of the blood-based testing option, “I was screaming hallelujah!”

“Patients believed that a blood test would be more accurate than a stool-based test. However, for the detection of advanced adenomas, the reverse is true,” she said. “It will be important to balance the high acceptance and enthusiasm for the blood test with the lower performance of the blood test compared to other tests already on the market.”

In a statement accompanying the study’s publication, the American Gastroenterological Association welcomed these results as an exciting development, but cautioned that a blood-based test was not interchangeable with colonoscopy.

“The Centers for Medicare and Medicaid Services (CMS) has determined it will cover a blood test for colorectal cancer screening every three years if the test achieves 74% sensitivity for CRC, 90% specificity, and FDA approval,” the statement reads. “However, a blood test that meets only the CMS criteria will be inferior to current recommended tests and should not be recommended to replace current tests. Such a test could be recommended for patients who decline all other recommended tests, since any screening is better than no screening at all.”

Dr. Grady is a paid member of Guardant’s scientific advisory board and advised on the design and procedure of the clinical trial and data analysis. Dr. Melson previously served as consultant for Guardant. Dr. Coronado reported no relevant disclosures. 

A version of this article appeared on Medscape.com .

A cell-free DNA (cfDNA) blood test, aimed at detecting abnormal DNA signals in people with an average risk of colorectal cancer (CRC), correctly detected CRC in most people confirmed to have the disease, according to a new study.

The cfDNA blood test had 83% sensitivity for CRC, 90% specificity for advanced neoplasia, and 13% sensitivity for advanced precancerous lesions. Other noninvasive screening methods have sensitivity from 67% to 94% for CRC and 22% to 43% for advanced precancerous lesions.

“The results of the study are a promising step toward developing more convenient tools to detect colorectal cancer early while it is more easily treated,” said senior author William M. Grady, MD, AGAF, medical director of the Gastrointestinal Cancer Prevention Program at the Fred Hutchinson Cancer Center in Seattle.

“The test, which has an accuracy rate for colon cancer detection similar to stool tests used for early detection of cancer, could offer an alternative for patients who may otherwise decline current screening options,” he said.

The study was published online on March 14 in The New England Journal of Medicine.
 

Analyzing the Blood Test’s Accuracy 

Dr. Grady and colleagues conducted a multisite clinical trial called ECLIPSE, which compared the sensitivity and specificity of a cfDNA blood test (Shield, Guardant Health) against that obtained with colonoscopy, the gold standard for CRC screening. Guardant led and funded the study.

Guardant’s Shield test is designed to detect CRC through genomic alterations, aberrant methylation status, and fragmentomic patterns, which show up as an “abnormal signal detected” result. Similar blood tests are being developed as “liquid biopsy” tests for other emerging cancer screenings as well.

The study included 7861 people with average CRC risk who underwent routine screening with colonoscopy at 265 sites in the United States, including primary care and endoscopy centers in academic and community-based institutions. Eligible people were aged 45-84 years (average age, 60 years), and 53.7% were women. The race and ethnicity characteristics of the participants closely mirrored the demographic distribution in the 2020 US Census.

Overall, 54 of 65 (83.1%) participants with colonoscopy-detected CRC had a positive cfDNA blood test. However, 11 participants (16.9%) with CRC had a negative test.

The cfDNA blood test identified 42 of 48 stage I, II, or III CRCs, indicating a sensitivity of 87.5%, including 65% for stage I cancers, 100% for stage II cancers, and 100% for stage III cancers. The test also identified all 10 of the stage IV CRC cases. There were no substantial differences in sensitivity for CRC based on primary tumor location, tumor histologic grade, or demographic characteristics.

Among participants without advanced colorectal neoplasia on colonoscopy, 89.6% had a negative cfDNA blood test, and 10.4% had a positive test. 

Among those with a negative colonoscopy — with no CRC, advanced precancerous lesions, or nonadvanced precancerous lesions — specificity was 89.9%.

Among 1116 participants with advanced precancerous lesions identified as the most advanced lesion on colonoscopy, the cfDNA blood test was positive for 147, indicating a sensitivity for advanced precancerous lesions of 13.2%.

Although the blood test has sensitivity similar to stool-based tests for CRC, the accuracy is lower than it is with colonoscopy, which remains the current gold standard for CRC screening, Dr. Grady said.

“Colorectal cancer is common and very preventable with screening, but only about 50% to 60% of people who are eligible for screening actually take those tests,” he said. “Getting people to be screened for cancer works best when we offer them screening options and then let them choose what works best for them.”
 

Future Research

Colorectal cancer is the second leading cause of cancer-related death among US adults and is now the third most diagnosed cancer for people younger than 50 years, Dr. Grady said. Although overall CRC death rates have declined in recent years, the rates among those younger than 55 years have increased since the mid-2000s.

“When colorectal cancer is found earlier and the cancer has not yet spread throughout the body, patient outcomes are much better, as reflected in 5-year survival being much better. It makes sense that an effective blood-based test could have a potential role, in particular for those not getting screened yet,” said Joshua Melson, MD, AGAF, clinical professor of medicine and director of the High-Risk Clinic for Gastrointestinal Cancers at the University of Arizona Cancer Center in Tucson.

Dr. Melson, who wasn’t involved with this study, noted that blood-based testing shows promise for cancer detection but needs additional support for real-world implementation. For instance, the Shield blood test has difficulty detecting precancerous lesions, and it remains unclear what the optimal intervals for repeat testing would be after a negative test, he said. In addition, screening programs will need to ensure they have capacity to effectively deal with a positive test result.

“For a screening program to actually work, when a noninvasive test (whether blood-based or stool-based) is read as positive, those patients need to have a follow-up colonoscopy,” he said. 

Proper communication with patients will be important as well, said Gloria Coronado, PhD, associate director of Population Sciences at the University of Arizona Cancer Center, Tucson. Dr. Coronado, who wasn’t involved with this study, has developed CRC screening messages for specific patient populations and studied patient reactions to CRC blood tests. 

In a study by Dr. Coronado and colleagues, among more than 2000 patients who passively declined fecal testing and had an upcoming clinic visit, CRC screening proportions were 17.5 percentage points higher in the group offered the blood test vs those offered usual care. In qualitative interviews, one patient said of the blood-based testing option, “I was screaming hallelujah!”

“Patients believed that a blood test would be more accurate than a stool-based test. However, for the detection of advanced adenomas, the reverse is true,” she said. “It will be important to balance the high acceptance and enthusiasm for the blood test with the lower performance of the blood test compared to other tests already on the market.”

In a statement accompanying the study’s publication, the American Gastroenterological Association welcomed these results as an exciting development, but cautioned that a blood-based test was not interchangeable with colonoscopy.

“The Centers for Medicare and Medicaid Services (CMS) has determined it will cover a blood test for colorectal cancer screening every three years if the test achieves 74% sensitivity for CRC, 90% specificity, and FDA approval,” the statement reads. “However, a blood test that meets only the CMS criteria will be inferior to current recommended tests and should not be recommended to replace current tests. Such a test could be recommended for patients who decline all other recommended tests, since any screening is better than no screening at all.”

Dr. Grady is a paid member of Guardant’s scientific advisory board and advised on the design and procedure of the clinical trial and data analysis. Dr. Melson previously served as consultant for Guardant. Dr. Coronado reported no relevant disclosures. 

A version of this article appeared on Medscape.com .

A cell-free DNA (cfDNA) blood test, aimed at detecting abnormal DNA signals in people with an average risk of colorectal cancer (CRC), correctly detected CRC in most people confirmed to have the disease, according to a new study.

The cfDNA blood test had 83% sensitivity for CRC, 90% specificity for advanced neoplasia, and 13% sensitivity for advanced precancerous lesions. Other noninvasive screening methods have sensitivity from 67% to 94% for CRC and 22% to 43% for advanced precancerous lesions.

“The results of the study are a promising step toward developing more convenient tools to detect colorectal cancer early while it is more easily treated,” said senior author William M. Grady, MD, AGAF, medical director of the Gastrointestinal Cancer Prevention Program at the Fred Hutchinson Cancer Center in Seattle.

“The test, which has an accuracy rate for colon cancer detection similar to stool tests used for early detection of cancer, could offer an alternative for patients who may otherwise decline current screening options,” he said.

The study was published online on March 14 in The New England Journal of Medicine.
 

Analyzing the Blood Test’s Accuracy 

Dr. Grady and colleagues conducted a multisite clinical trial called ECLIPSE, which compared the sensitivity and specificity of a cfDNA blood test (Shield, Guardant Health) against that obtained with colonoscopy, the gold standard for CRC screening. Guardant led and funded the study.

Guardant’s Shield test is designed to detect CRC through genomic alterations, aberrant methylation status, and fragmentomic patterns, which show up as an “abnormal signal detected” result. Similar blood tests are being developed as “liquid biopsy” tests for other emerging cancer screenings as well.

The study included 7861 people with average CRC risk who underwent routine screening with colonoscopy at 265 sites in the United States, including primary care and endoscopy centers in academic and community-based institutions. Eligible people were aged 45-84 years (average age, 60 years), and 53.7% were women. The race and ethnicity characteristics of the participants closely mirrored the demographic distribution in the 2020 US Census.

Overall, 54 of 65 (83.1%) participants with colonoscopy-detected CRC had a positive cfDNA blood test. However, 11 participants (16.9%) with CRC had a negative test.

The cfDNA blood test identified 42 of 48 stage I, II, or III CRCs, indicating a sensitivity of 87.5%, including 65% for stage I cancers, 100% for stage II cancers, and 100% for stage III cancers. The test also identified all 10 of the stage IV CRC cases. There were no substantial differences in sensitivity for CRC based on primary tumor location, tumor histologic grade, or demographic characteristics.

Among participants without advanced colorectal neoplasia on colonoscopy, 89.6% had a negative cfDNA blood test, and 10.4% had a positive test. 

Among those with a negative colonoscopy — with no CRC, advanced precancerous lesions, or nonadvanced precancerous lesions — specificity was 89.9%.

Among 1116 participants with advanced precancerous lesions identified as the most advanced lesion on colonoscopy, the cfDNA blood test was positive for 147, indicating a sensitivity for advanced precancerous lesions of 13.2%.

Although the blood test has sensitivity similar to stool-based tests for CRC, the accuracy is lower than it is with colonoscopy, which remains the current gold standard for CRC screening, Dr. Grady said.

“Colorectal cancer is common and very preventable with screening, but only about 50% to 60% of people who are eligible for screening actually take those tests,” he said. “Getting people to be screened for cancer works best when we offer them screening options and then let them choose what works best for them.”
 

Future Research

Colorectal cancer is the second leading cause of cancer-related death among US adults and is now the third most diagnosed cancer for people younger than 50 years, Dr. Grady said. Although overall CRC death rates have declined in recent years, the rates among those younger than 55 years have increased since the mid-2000s.

“When colorectal cancer is found earlier and the cancer has not yet spread throughout the body, patient outcomes are much better, as reflected in 5-year survival being much better. It makes sense that an effective blood-based test could have a potential role, in particular for those not getting screened yet,” said Joshua Melson, MD, AGAF, clinical professor of medicine and director of the High-Risk Clinic for Gastrointestinal Cancers at the University of Arizona Cancer Center in Tucson.

Dr. Melson, who wasn’t involved with this study, noted that blood-based testing shows promise for cancer detection but needs additional support for real-world implementation. For instance, the Shield blood test has difficulty detecting precancerous lesions, and it remains unclear what the optimal intervals for repeat testing would be after a negative test, he said. In addition, screening programs will need to ensure they have capacity to effectively deal with a positive test result.

“For a screening program to actually work, when a noninvasive test (whether blood-based or stool-based) is read as positive, those patients need to have a follow-up colonoscopy,” he said. 

Proper communication with patients will be important as well, said Gloria Coronado, PhD, associate director of Population Sciences at the University of Arizona Cancer Center, Tucson. Dr. Coronado, who wasn’t involved with this study, has developed CRC screening messages for specific patient populations and studied patient reactions to CRC blood tests. 

In a study by Dr. Coronado and colleagues, among more than 2000 patients who passively declined fecal testing and had an upcoming clinic visit, CRC screening proportions were 17.5 percentage points higher in the group offered the blood test vs those offered usual care. In qualitative interviews, one patient said of the blood-based testing option, “I was screaming hallelujah!”

“Patients believed that a blood test would be more accurate than a stool-based test. However, for the detection of advanced adenomas, the reverse is true,” she said. “It will be important to balance the high acceptance and enthusiasm for the blood test with the lower performance of the blood test compared to other tests already on the market.”

In a statement accompanying the study’s publication, the American Gastroenterological Association welcomed these results as an exciting development, but cautioned that a blood-based test was not interchangeable with colonoscopy.

“The Centers for Medicare and Medicaid Services (CMS) has determined it will cover a blood test for colorectal cancer screening every three years if the test achieves 74% sensitivity for CRC, 90% specificity, and FDA approval,” the statement reads. “However, a blood test that meets only the CMS criteria will be inferior to current recommended tests and should not be recommended to replace current tests. Such a test could be recommended for patients who decline all other recommended tests, since any screening is better than no screening at all.”

Dr. Grady is a paid member of Guardant’s scientific advisory board and advised on the design and procedure of the clinical trial and data analysis. Dr. Melson previously served as consultant for Guardant. Dr. Coronado reported no relevant disclosures. 

A version of this article appeared on Medscape.com .

Targeted treatments, including antibody-drug conjugates and immunotherapy agents, are now standard of care for breast cancer, but there are limited data on the safety of combining these newer agents alongside radiotherapy.

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.

Targeted treatments, including antibody-drug conjugates and immunotherapy agents, are now standard of care for breast cancer, but there are limited data on the safety of combining these newer agents alongside radiotherapy.

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.

Targeted treatments, including antibody-drug conjugates and immunotherapy agents, are now standard of care for breast cancer, but there are limited data on the safety of combining these newer agents alongside radiotherapy.

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.

As US medical school graduates learned Friday, March 15, where they would spend their residencies, new Match Day 2024 data showed a loss of interest in pediatrics, whereas emergency medicine regained popularity after concern over last year’s unfilled positions.

Hospitals and medical groups offered 41,503 residency positions in 2024, a 3% increase from last year, according to the data released by the National Resident Matching Program. 

Emergency medicine reversed its recent decline, with only 135 unfilled positions, a 13.9% improvement over last year.

But though the number of pediatric residency slots increased slightly from last year, 8% of available positions remained unfilled in 2024 compared with about 3% last year. 

Physician leaders and policymakers alike pay keen attention to Match Day results because they can signal future shortages in certain specialties, including primary care. Unfilled slots also can raise concerns over too many residency programs in a specialty. 

Medical students’ interest in pediatrics continues to decline in part because it pays less than other specialties, Bryan Carmody, MD, MPH, a pediatric nephrologist known for his medical school commentaries, told this news organization. The number of pediatric applicants from US medical schools peaked in 2015 and has fallen since, he said.

“There’s been a lot of soul searching ... this week, with people speculating about lots of (reasons),” Dr. Carmody said. “I don’t think it’s even debt. You can look at the number of unfilled positions, and it correlates with the expected earning potential of those specialties.” 

Family medicine, for example, filled about 88% of its positions this year.

Ob.gyn. residencies retained their popularity despite concerns over abortion and reproductive health rights in many states. The specialty filled 99.6% of its positions, a very slight improvement over last year’s 99% rate. 

Though ob.gyn. applicants might prefer programs in states where there are more liberal policies around reproductive health, many won’t be in a position where they can choose that because of the limited number of ob.gyn. slots, Dr. Carmody said.

Unfilled residency slots likely will be filled through the Supplemental Offer and Acceptance Program (SOAP). Applicants who did not match in the first round participate in SOAP for one of the 2562 positions in 787 programs that went unfilled after the matching algorithm was processed. A total of 2575 positions were placed in SOAP, including positions in programs that did not participate in the algorithm phase of the process. There were 83 fewer positions in SOAP in 2024, a decrease of 3.1% compared with last year’s Match. More detailed data on SOAP results will be released later this year.

A version of this article appeared on Medscape.com.

As US medical school graduates learned Friday, March 15, where they would spend their residencies, new Match Day 2024 data showed a loss of interest in pediatrics, whereas emergency medicine regained popularity after concern over last year’s unfilled positions.

Hospitals and medical groups offered 41,503 residency positions in 2024, a 3% increase from last year, according to the data released by the National Resident Matching Program. 

Emergency medicine reversed its recent decline, with only 135 unfilled positions, a 13.9% improvement over last year.

But though the number of pediatric residency slots increased slightly from last year, 8% of available positions remained unfilled in 2024 compared with about 3% last year. 

Physician leaders and policymakers alike pay keen attention to Match Day results because they can signal future shortages in certain specialties, including primary care. Unfilled slots also can raise concerns over too many residency programs in a specialty. 

Medical students’ interest in pediatrics continues to decline in part because it pays less than other specialties, Bryan Carmody, MD, MPH, a pediatric nephrologist known for his medical school commentaries, told this news organization. The number of pediatric applicants from US medical schools peaked in 2015 and has fallen since, he said.

“There’s been a lot of soul searching ... this week, with people speculating about lots of (reasons),” Dr. Carmody said. “I don’t think it’s even debt. You can look at the number of unfilled positions, and it correlates with the expected earning potential of those specialties.” 

Family medicine, for example, filled about 88% of its positions this year.

Ob.gyn. residencies retained their popularity despite concerns over abortion and reproductive health rights in many states. The specialty filled 99.6% of its positions, a very slight improvement over last year’s 99% rate. 

Though ob.gyn. applicants might prefer programs in states where there are more liberal policies around reproductive health, many won’t be in a position where they can choose that because of the limited number of ob.gyn. slots, Dr. Carmody said.

Unfilled residency slots likely will be filled through the Supplemental Offer and Acceptance Program (SOAP). Applicants who did not match in the first round participate in SOAP for one of the 2562 positions in 787 programs that went unfilled after the matching algorithm was processed. A total of 2575 positions were placed in SOAP, including positions in programs that did not participate in the algorithm phase of the process. There were 83 fewer positions in SOAP in 2024, a decrease of 3.1% compared with last year’s Match. More detailed data on SOAP results will be released later this year.

A version of this article appeared on Medscape.com.

As US medical school graduates learned Friday, March 15, where they would spend their residencies, new Match Day 2024 data showed a loss of interest in pediatrics, whereas emergency medicine regained popularity after concern over last year’s unfilled positions.

Hospitals and medical groups offered 41,503 residency positions in 2024, a 3% increase from last year, according to the data released by the National Resident Matching Program. 

Emergency medicine reversed its recent decline, with only 135 unfilled positions, a 13.9% improvement over last year.

But though the number of pediatric residency slots increased slightly from last year, 8% of available positions remained unfilled in 2024 compared with about 3% last year. 

Physician leaders and policymakers alike pay keen attention to Match Day results because they can signal future shortages in certain specialties, including primary care. Unfilled slots also can raise concerns over too many residency programs in a specialty. 

Medical students’ interest in pediatrics continues to decline in part because it pays less than other specialties, Bryan Carmody, MD, MPH, a pediatric nephrologist known for his medical school commentaries, told this news organization. The number of pediatric applicants from US medical schools peaked in 2015 and has fallen since, he said.

“There’s been a lot of soul searching ... this week, with people speculating about lots of (reasons),” Dr. Carmody said. “I don’t think it’s even debt. You can look at the number of unfilled positions, and it correlates with the expected earning potential of those specialties.” 

Family medicine, for example, filled about 88% of its positions this year.

Ob.gyn. residencies retained their popularity despite concerns over abortion and reproductive health rights in many states. The specialty filled 99.6% of its positions, a very slight improvement over last year’s 99% rate. 

Though ob.gyn. applicants might prefer programs in states where there are more liberal policies around reproductive health, many won’t be in a position where they can choose that because of the limited number of ob.gyn. slots, Dr. Carmody said.

Unfilled residency slots likely will be filled through the Supplemental Offer and Acceptance Program (SOAP). Applicants who did not match in the first round participate in SOAP for one of the 2562 positions in 787 programs that went unfilled after the matching algorithm was processed. A total of 2575 positions were placed in SOAP, including positions in programs that did not participate in the algorithm phase of the process. There were 83 fewer positions in SOAP in 2024, a decrease of 3.1% compared with last year’s Match. More detailed data on SOAP results will be released later this year.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved tislelizumab-jsgr (Tevimbra, BeiGene Ltd.) as second-line monotherapy for certain adult patients with unresectable or metastatic esophageal squamous cell carcinoma (ESCC).

Specifically, the novel checkpoint inhibitor is approved for patients with ESCC after prior systemic chemotherapy that did not include a programmed death–ligand 1 (PD-L1) inhibitor.

Approval was based on findings from the open-label, phase 3 RATIONALE 302 trial showing a statistically significant and clinically meaningful overall survival benefit with tislelizumab vs investigator’s choice of chemotherapy.

Study participants included 512 adults enrolled at 123 research sites in 11 countries in Europe, Asia, and North America. Patients were randomly assigned to receive intravenous tislelizumab, a humanized immunoglobulin G4 anti-programmed cell death protein 1 monoclonal antibody, at a dose of 200 mg every 3 weeks or investigator’s choice of standard chemotherapy with paclitaxel, docetaxel, or irinotecan until disease progression, unacceptable toxicity, or study withdrawal.

Median overall survival in the intention-to-treat population, the primary study endpoint, was 8.6 months vs 6.3 months in the chemotherapy arms (hazard ratio [HR], 0.70). The survival benefit was observed across predefined subgroups, including baseline PD-L1 status and region. The new agent was also associated with improved overall response rate (20.4% vs 9.8%) and more durable response (median duration of response of 7.1 vs 4.0 months; HR, 0.42) compared with chemotherapy. 

The most common adverse reactions for tislelizumab, each occurring in at least 20% of treated patients, included increased glucose and decreased hemoglobin, lymphocytes, sodium, and albumin as well as increased alkaline phosphatase, anemia, fatigue, increased aspartate aminotransferase, musculoskeletal pain, decreased weight, increased alanine aminotransferase, and cough.

Fewer patients in the tislelizumab arm experienced grade 3 or greater treatment-emergent adverse events compared with the chemotherapy arm (46% vs 68%, respectively), and fewer patients discontinued tislelizumab vs chemotherapy due to such an event (7% vs 14%).

“Patients diagnosed with advanced or metastasized ESCC, the most common histologic subtype of esophageal cancer, often progress following initial therapy and are in need of new options,” Syma Iqbal, MD, of the Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, stated in the BeiGene release. “The RATIONALE 302 trial showed that patients with previously treated ESCC who received Tevimbra saw a clinically meaningful survival benefit, highlighting its potential as an important treatment option for these patients.”

The approval, which was deferred in 2022 due to COVID-19-related restrictions, marks the first for the agent in the United States. Tislelizumab should be available in the United States in the second half of 2024, BeiGene noted.

The FDA is also reviewing a Biologics License Application for the agent as a first-line treatment for patients with unresectable, locally advanced, or metastatic ESCC and for those with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma, BeiGene announced in a press release.
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved tislelizumab-jsgr (Tevimbra, BeiGene Ltd.) as second-line monotherapy for certain adult patients with unresectable or metastatic esophageal squamous cell carcinoma (ESCC).

Specifically, the novel checkpoint inhibitor is approved for patients with ESCC after prior systemic chemotherapy that did not include a programmed death–ligand 1 (PD-L1) inhibitor.

Approval was based on findings from the open-label, phase 3 RATIONALE 302 trial showing a statistically significant and clinically meaningful overall survival benefit with tislelizumab vs investigator’s choice of chemotherapy.

Study participants included 512 adults enrolled at 123 research sites in 11 countries in Europe, Asia, and North America. Patients were randomly assigned to receive intravenous tislelizumab, a humanized immunoglobulin G4 anti-programmed cell death protein 1 monoclonal antibody, at a dose of 200 mg every 3 weeks or investigator’s choice of standard chemotherapy with paclitaxel, docetaxel, or irinotecan until disease progression, unacceptable toxicity, or study withdrawal.

Median overall survival in the intention-to-treat population, the primary study endpoint, was 8.6 months vs 6.3 months in the chemotherapy arms (hazard ratio [HR], 0.70). The survival benefit was observed across predefined subgroups, including baseline PD-L1 status and region. The new agent was also associated with improved overall response rate (20.4% vs 9.8%) and more durable response (median duration of response of 7.1 vs 4.0 months; HR, 0.42) compared with chemotherapy. 

The most common adverse reactions for tislelizumab, each occurring in at least 20% of treated patients, included increased glucose and decreased hemoglobin, lymphocytes, sodium, and albumin as well as increased alkaline phosphatase, anemia, fatigue, increased aspartate aminotransferase, musculoskeletal pain, decreased weight, increased alanine aminotransferase, and cough.

Fewer patients in the tislelizumab arm experienced grade 3 or greater treatment-emergent adverse events compared with the chemotherapy arm (46% vs 68%, respectively), and fewer patients discontinued tislelizumab vs chemotherapy due to such an event (7% vs 14%).

“Patients diagnosed with advanced or metastasized ESCC, the most common histologic subtype of esophageal cancer, often progress following initial therapy and are in need of new options,” Syma Iqbal, MD, of the Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, stated in the BeiGene release. “The RATIONALE 302 trial showed that patients with previously treated ESCC who received Tevimbra saw a clinically meaningful survival benefit, highlighting its potential as an important treatment option for these patients.”

The approval, which was deferred in 2022 due to COVID-19-related restrictions, marks the first for the agent in the United States. Tislelizumab should be available in the United States in the second half of 2024, BeiGene noted.

The FDA is also reviewing a Biologics License Application for the agent as a first-line treatment for patients with unresectable, locally advanced, or metastatic ESCC and for those with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma, BeiGene announced in a press release.
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved tislelizumab-jsgr (Tevimbra, BeiGene Ltd.) as second-line monotherapy for certain adult patients with unresectable or metastatic esophageal squamous cell carcinoma (ESCC).

Specifically, the novel checkpoint inhibitor is approved for patients with ESCC after prior systemic chemotherapy that did not include a programmed death–ligand 1 (PD-L1) inhibitor.

Approval was based on findings from the open-label, phase 3 RATIONALE 302 trial showing a statistically significant and clinically meaningful overall survival benefit with tislelizumab vs investigator’s choice of chemotherapy.

Study participants included 512 adults enrolled at 123 research sites in 11 countries in Europe, Asia, and North America. Patients were randomly assigned to receive intravenous tislelizumab, a humanized immunoglobulin G4 anti-programmed cell death protein 1 monoclonal antibody, at a dose of 200 mg every 3 weeks or investigator’s choice of standard chemotherapy with paclitaxel, docetaxel, or irinotecan until disease progression, unacceptable toxicity, or study withdrawal.

Median overall survival in the intention-to-treat population, the primary study endpoint, was 8.6 months vs 6.3 months in the chemotherapy arms (hazard ratio [HR], 0.70). The survival benefit was observed across predefined subgroups, including baseline PD-L1 status and region. The new agent was also associated with improved overall response rate (20.4% vs 9.8%) and more durable response (median duration of response of 7.1 vs 4.0 months; HR, 0.42) compared with chemotherapy. 

The most common adverse reactions for tislelizumab, each occurring in at least 20% of treated patients, included increased glucose and decreased hemoglobin, lymphocytes, sodium, and albumin as well as increased alkaline phosphatase, anemia, fatigue, increased aspartate aminotransferase, musculoskeletal pain, decreased weight, increased alanine aminotransferase, and cough.

Fewer patients in the tislelizumab arm experienced grade 3 or greater treatment-emergent adverse events compared with the chemotherapy arm (46% vs 68%, respectively), and fewer patients discontinued tislelizumab vs chemotherapy due to such an event (7% vs 14%).

“Patients diagnosed with advanced or metastasized ESCC, the most common histologic subtype of esophageal cancer, often progress following initial therapy and are in need of new options,” Syma Iqbal, MD, of the Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, stated in the BeiGene release. “The RATIONALE 302 trial showed that patients with previously treated ESCC who received Tevimbra saw a clinically meaningful survival benefit, highlighting its potential as an important treatment option for these patients.”

The approval, which was deferred in 2022 due to COVID-19-related restrictions, marks the first for the agent in the United States. Tislelizumab should be available in the United States in the second half of 2024, BeiGene noted.

The FDA is also reviewing a Biologics License Application for the agent as a first-line treatment for patients with unresectable, locally advanced, or metastatic ESCC and for those with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma, BeiGene announced in a press release.
 

A version of this article appeared on Medscape.com.

With rates of syphilis rising quickly in the United States and elsewhere, clinicians are having to up their game when it comes to diagnosing and treating an infection that they may not be paying enough attention to.

More than 200,000 cases of syphilis were reported in the United States in 2022, which is the highest number since 1950 and is a 17.3% increase over 2021, according to the latest figures from the Centers for Disease Control and Prevention (CDC). The rate of infection has increased almost every year since a historic low in 2001.

And the trend is not limited to the United States. Last year, the infection rate in the United Kingdom hit a 50-year high, said David Mabey, BCh, DM, from the London School of Hygiene and Tropical Medicine. Syphilis and other sexually transmitted infections are also a major problem in low- and middle-income countries, he added, although good data are not always available.

Many of today’s healthcare professionals have little experience with the disease, shared Ina Park, MD, a sexually transmitted infections specialist at the University of California at San Francisco. “An entire generation of physicians — including myself — did not see any cases until we were well out of our training,” Dr. Park reported. “We’re really playing catch-up.”
 

A Centuries-Old Ailment

Dr. Park offered some advice on the challenges of diagnosing what can be an elusive infection at the Conference on Retroviruses and Opportunistic Infections (CROI) 2024 Annual Meeting in Denver. That advice boiled down to one simple rule: “Test, test, test.”

Because syphilis can mimic so many other conditions and can have long periods of latency, it can be easily missed or even misdiagnosed by experienced physicians, said Dr. Park. Clinicians need to keep it front of mind and have a lower threshold for testing, even if there are no obvious symptoms.

Following the CDC’s new recommendations for syphilis screening will help, she noted; every sexually active patient aged between 15 and 44 years who lives in a county with a syphilis infection rate of 4.6 per 100,000 people or higher should get the test. And clinicians should remain vigilant, even in areas with a lower prevalence. “If you can’t account for new symptoms in a sexually active patient, order a test,” said Dr. Park.
 

Complicated Cases

The lack of experience with syphilis affects not just diagnosis but also treatment, particularly for complex cases, said Khalil Ghanem, MD, PhD, from the Johns Hopkins University School of Medicine in Baltimore. “When you don’t have to deal with something for a while, you forget how to deal with it,” he added.

At CROI, Dr. Ghanem offered suggestions for how to navigate complicated cases of ocular syphilis, otic syphilis, and neurosyphilis, and how to interpret test results when a patient’s antigen titers are being “unruly.”

With potential ocular or otic syphilis, you shouldn’t wait for a specialist like an ophthalmologist to weigh in but instead refer the patient directly to the emergency department because of the risk that the symptoms may become irreversible and result in permanent blindness or deafness. “You don’t want to dilly-dally with those conditions,” Dr. Ghanem said.

Closely monitoring a patient’s rapid plasma regain and venereal disease research laboratory antigen levels is the only way to manage syphilis and to determine whether the infection is responding to treatment, he noted, but sometimes those titers “don’t do what you think they should be doing” and fail to decline or even go up after treatment.

“You don’t know if they went up because the patient was re-infected, or they developed neurosyphilis, or there was a problem at the lab,” he said. “It can be challenging to interpret.”

To decipher confusing test results, Dr. Ghanem recommended getting a detailed history to understand whether a patient is at risk for reinfection, whether there are signs of neurosyphilis or other complications, whether pregnancy is possible, and so on. “Based on the answers, you can determine what the most rational approach to treatment would be,” he shared.
 

Drug Shortages

Efforts to get the infection under control have become more complicated. Last summer, Pfizer announced that it had run out of penicillin G benzathine (Bicillin), an injectable, long-acting drug that is one of the main treatments for syphilis and the only one that can be given to pregnant people. Supplies for children ran out at the end of June 2023, and supplies for adults were gone by the end of September.

Because Pfizer is the only company that manufactures penicillin G benzathine, there is no one to pick up the slack in the short-term, so the shortage is expected to continue until at least the middle of 2024.

In response, the US Food and Drug Administration has temporarily allowed the use of benzylpenicillin benzathine (Extencilline), a French formulation that has not been approved in the United States, until supplies of penicillin G benzathine are stabilized.

The shortage has shone a spotlight on the important issue of a lack of alternatives for the treatment of syphilis during pregnancy, which increases the risk for congenital syphilis. “Hopefully, this pushes the National Institutes of Health and others to step up their game on studies for alternative drugs for use in pregnancy,” Dr. Ghanem said.
 

A version of this article appeared on Medscape.com.

With rates of syphilis rising quickly in the United States and elsewhere, clinicians are having to up their game when it comes to diagnosing and treating an infection that they may not be paying enough attention to.

More than 200,000 cases of syphilis were reported in the United States in 2022, which is the highest number since 1950 and is a 17.3% increase over 2021, according to the latest figures from the Centers for Disease Control and Prevention (CDC). The rate of infection has increased almost every year since a historic low in 2001.

And the trend is not limited to the United States. Last year, the infection rate in the United Kingdom hit a 50-year high, said David Mabey, BCh, DM, from the London School of Hygiene and Tropical Medicine. Syphilis and other sexually transmitted infections are also a major problem in low- and middle-income countries, he added, although good data are not always available.

Many of today’s healthcare professionals have little experience with the disease, shared Ina Park, MD, a sexually transmitted infections specialist at the University of California at San Francisco. “An entire generation of physicians — including myself — did not see any cases until we were well out of our training,” Dr. Park reported. “We’re really playing catch-up.”
 

A Centuries-Old Ailment

Dr. Park offered some advice on the challenges of diagnosing what can be an elusive infection at the Conference on Retroviruses and Opportunistic Infections (CROI) 2024 Annual Meeting in Denver. That advice boiled down to one simple rule: “Test, test, test.”

Because syphilis can mimic so many other conditions and can have long periods of latency, it can be easily missed or even misdiagnosed by experienced physicians, said Dr. Park. Clinicians need to keep it front of mind and have a lower threshold for testing, even if there are no obvious symptoms.

Following the CDC’s new recommendations for syphilis screening will help, she noted; every sexually active patient aged between 15 and 44 years who lives in a county with a syphilis infection rate of 4.6 per 100,000 people or higher should get the test. And clinicians should remain vigilant, even in areas with a lower prevalence. “If you can’t account for new symptoms in a sexually active patient, order a test,” said Dr. Park.
 

Complicated Cases

The lack of experience with syphilis affects not just diagnosis but also treatment, particularly for complex cases, said Khalil Ghanem, MD, PhD, from the Johns Hopkins University School of Medicine in Baltimore. “When you don’t have to deal with something for a while, you forget how to deal with it,” he added.

At CROI, Dr. Ghanem offered suggestions for how to navigate complicated cases of ocular syphilis, otic syphilis, and neurosyphilis, and how to interpret test results when a patient’s antigen titers are being “unruly.”

With potential ocular or otic syphilis, you shouldn’t wait for a specialist like an ophthalmologist to weigh in but instead refer the patient directly to the emergency department because of the risk that the symptoms may become irreversible and result in permanent blindness or deafness. “You don’t want to dilly-dally with those conditions,” Dr. Ghanem said.

Closely monitoring a patient’s rapid plasma regain and venereal disease research laboratory antigen levels is the only way to manage syphilis and to determine whether the infection is responding to treatment, he noted, but sometimes those titers “don’t do what you think they should be doing” and fail to decline or even go up after treatment.

“You don’t know if they went up because the patient was re-infected, or they developed neurosyphilis, or there was a problem at the lab,” he said. “It can be challenging to interpret.”

To decipher confusing test results, Dr. Ghanem recommended getting a detailed history to understand whether a patient is at risk for reinfection, whether there are signs of neurosyphilis or other complications, whether pregnancy is possible, and so on. “Based on the answers, you can determine what the most rational approach to treatment would be,” he shared.
 

Drug Shortages

Efforts to get the infection under control have become more complicated. Last summer, Pfizer announced that it had run out of penicillin G benzathine (Bicillin), an injectable, long-acting drug that is one of the main treatments for syphilis and the only one that can be given to pregnant people. Supplies for children ran out at the end of June 2023, and supplies for adults were gone by the end of September.

Because Pfizer is the only company that manufactures penicillin G benzathine, there is no one to pick up the slack in the short-term, so the shortage is expected to continue until at least the middle of 2024.

In response, the US Food and Drug Administration has temporarily allowed the use of benzylpenicillin benzathine (Extencilline), a French formulation that has not been approved in the United States, until supplies of penicillin G benzathine are stabilized.

The shortage has shone a spotlight on the important issue of a lack of alternatives for the treatment of syphilis during pregnancy, which increases the risk for congenital syphilis. “Hopefully, this pushes the National Institutes of Health and others to step up their game on studies for alternative drugs for use in pregnancy,” Dr. Ghanem said.
 

A version of this article appeared on Medscape.com.

With rates of syphilis rising quickly in the United States and elsewhere, clinicians are having to up their game when it comes to diagnosing and treating an infection that they may not be paying enough attention to.

More than 200,000 cases of syphilis were reported in the United States in 2022, which is the highest number since 1950 and is a 17.3% increase over 2021, according to the latest figures from the Centers for Disease Control and Prevention (CDC). The rate of infection has increased almost every year since a historic low in 2001.

And the trend is not limited to the United States. Last year, the infection rate in the United Kingdom hit a 50-year high, said David Mabey, BCh, DM, from the London School of Hygiene and Tropical Medicine. Syphilis and other sexually transmitted infections are also a major problem in low- and middle-income countries, he added, although good data are not always available.

Many of today’s healthcare professionals have little experience with the disease, shared Ina Park, MD, a sexually transmitted infections specialist at the University of California at San Francisco. “An entire generation of physicians — including myself — did not see any cases until we were well out of our training,” Dr. Park reported. “We’re really playing catch-up.”
 

A Centuries-Old Ailment

Dr. Park offered some advice on the challenges of diagnosing what can be an elusive infection at the Conference on Retroviruses and Opportunistic Infections (CROI) 2024 Annual Meeting in Denver. That advice boiled down to one simple rule: “Test, test, test.”

Because syphilis can mimic so many other conditions and can have long periods of latency, it can be easily missed or even misdiagnosed by experienced physicians, said Dr. Park. Clinicians need to keep it front of mind and have a lower threshold for testing, even if there are no obvious symptoms.

Following the CDC’s new recommendations for syphilis screening will help, she noted; every sexually active patient aged between 15 and 44 years who lives in a county with a syphilis infection rate of 4.6 per 100,000 people or higher should get the test. And clinicians should remain vigilant, even in areas with a lower prevalence. “If you can’t account for new symptoms in a sexually active patient, order a test,” said Dr. Park.
 

Complicated Cases

The lack of experience with syphilis affects not just diagnosis but also treatment, particularly for complex cases, said Khalil Ghanem, MD, PhD, from the Johns Hopkins University School of Medicine in Baltimore. “When you don’t have to deal with something for a while, you forget how to deal with it,” he added.

At CROI, Dr. Ghanem offered suggestions for how to navigate complicated cases of ocular syphilis, otic syphilis, and neurosyphilis, and how to interpret test results when a patient’s antigen titers are being “unruly.”

With potential ocular or otic syphilis, you shouldn’t wait for a specialist like an ophthalmologist to weigh in but instead refer the patient directly to the emergency department because of the risk that the symptoms may become irreversible and result in permanent blindness or deafness. “You don’t want to dilly-dally with those conditions,” Dr. Ghanem said.

Closely monitoring a patient’s rapid plasma regain and venereal disease research laboratory antigen levels is the only way to manage syphilis and to determine whether the infection is responding to treatment, he noted, but sometimes those titers “don’t do what you think they should be doing” and fail to decline or even go up after treatment.

“You don’t know if they went up because the patient was re-infected, or they developed neurosyphilis, or there was a problem at the lab,” he said. “It can be challenging to interpret.”

To decipher confusing test results, Dr. Ghanem recommended getting a detailed history to understand whether a patient is at risk for reinfection, whether there are signs of neurosyphilis or other complications, whether pregnancy is possible, and so on. “Based on the answers, you can determine what the most rational approach to treatment would be,” he shared.
 

Drug Shortages

Efforts to get the infection under control have become more complicated. Last summer, Pfizer announced that it had run out of penicillin G benzathine (Bicillin), an injectable, long-acting drug that is one of the main treatments for syphilis and the only one that can be given to pregnant people. Supplies for children ran out at the end of June 2023, and supplies for adults were gone by the end of September.

Because Pfizer is the only company that manufactures penicillin G benzathine, there is no one to pick up the slack in the short-term, so the shortage is expected to continue until at least the middle of 2024.

In response, the US Food and Drug Administration has temporarily allowed the use of benzylpenicillin benzathine (Extencilline), a French formulation that has not been approved in the United States, until supplies of penicillin G benzathine are stabilized.

The shortage has shone a spotlight on the important issue of a lack of alternatives for the treatment of syphilis during pregnancy, which increases the risk for congenital syphilis. “Hopefully, this pushes the National Institutes of Health and others to step up their game on studies for alternative drugs for use in pregnancy,” Dr. Ghanem said.
 

A version of this article appeared on Medscape.com.