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Low vitamin D linked to paclitaxel-induced peripheral neuropathy
TOPLINE:
, suggesting that correcting levels before treatment might help prevent the condition.
METHODOLOGY:
- Past studies have suggested an association between vitamin D insufficiency and paclitaxel-induced peripheral neuropathy, a largely untreatable and sometimes permanent side effect of chemotherapy.
- To confirm the association, investigators reviewed data and samples from 1,191 women in the phase 3 SWOG S0221 trial, which compared weekly and biweekly paclitaxel regimens for early-stage breast cancer.
- Using serum samples collected at baseline, the team evaluated the relationship between insufficient vitamin D levels (20 ng/mL or less) before treatment and grade 3 or higher sensory chemotherapy-induced peripheral neuropathy.
TAKEAWAY:
- Overall, 33.3% of the women had insufficient vitamin D levels at baseline, and 16.4% developed grade 3 or worse sensory chemotherapy-induced peripheral neuropathy.
- The incidence of peripheral neuropathy of grade 3 or greater was higher among patients with pretreatment vitamin D insufficiency (20.7% vs. 14.2%; odds ratio, 1.57; P = .005).
- The association grew stronger after adjusting for age and paclitaxel schedule (adjusted OR, 1.65; P = .003), but not after adjusting for race (adjusted OR, 1.39; P = .066).
IN PRACTICE:
The study “confirms that patients with pretreatment vitamin D insufficiency have a higher incidence of [chemotherapy-induced peripheral neuropathy],” the authors concluded. These results also “suggest that vitamin D supplementation in patients with lower levels of vitamin D may reduce peripheral neuropathy, and particularly high-grade peripheral neuropathy, which would improve these patients’ long-term quality of life,” senior researcher Daniel L. Hertz, PharmD, PhD, University of Michigan College of Pharmacy, Ann Arbor, said in a press release.
SOURCE:
The study, led by Ciao-Sin Chen, PharmD, of the University of Michigan, Ann Arbor, was published in the Journal of the National Comprehensive Cancer Network.
LIMITATIONS:
The trial did not collect data on other peripheral neuropathy risk factors, including preexisting peripheral neuropathy and diabetes. The study included a limited number of non-White participants (16%); larger numbers are needed to elucidate a potential interplay between race, vitamin D, and chemotherapy-induced peripheral neuropathy. The researchers also did not collect data on grade 1 and 2 chemotherapy-induced peripheral neuropathy.
DISCLOSURES:
The study was funded by Amgen, the American Cancer Society, and others. The investigators disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
TOPLINE:
, suggesting that correcting levels before treatment might help prevent the condition.
METHODOLOGY:
- Past studies have suggested an association between vitamin D insufficiency and paclitaxel-induced peripheral neuropathy, a largely untreatable and sometimes permanent side effect of chemotherapy.
- To confirm the association, investigators reviewed data and samples from 1,191 women in the phase 3 SWOG S0221 trial, which compared weekly and biweekly paclitaxel regimens for early-stage breast cancer.
- Using serum samples collected at baseline, the team evaluated the relationship between insufficient vitamin D levels (20 ng/mL or less) before treatment and grade 3 or higher sensory chemotherapy-induced peripheral neuropathy.
TAKEAWAY:
- Overall, 33.3% of the women had insufficient vitamin D levels at baseline, and 16.4% developed grade 3 or worse sensory chemotherapy-induced peripheral neuropathy.
- The incidence of peripheral neuropathy of grade 3 or greater was higher among patients with pretreatment vitamin D insufficiency (20.7% vs. 14.2%; odds ratio, 1.57; P = .005).
- The association grew stronger after adjusting for age and paclitaxel schedule (adjusted OR, 1.65; P = .003), but not after adjusting for race (adjusted OR, 1.39; P = .066).
IN PRACTICE:
The study “confirms that patients with pretreatment vitamin D insufficiency have a higher incidence of [chemotherapy-induced peripheral neuropathy],” the authors concluded. These results also “suggest that vitamin D supplementation in patients with lower levels of vitamin D may reduce peripheral neuropathy, and particularly high-grade peripheral neuropathy, which would improve these patients’ long-term quality of life,” senior researcher Daniel L. Hertz, PharmD, PhD, University of Michigan College of Pharmacy, Ann Arbor, said in a press release.
SOURCE:
The study, led by Ciao-Sin Chen, PharmD, of the University of Michigan, Ann Arbor, was published in the Journal of the National Comprehensive Cancer Network.
LIMITATIONS:
The trial did not collect data on other peripheral neuropathy risk factors, including preexisting peripheral neuropathy and diabetes. The study included a limited number of non-White participants (16%); larger numbers are needed to elucidate a potential interplay between race, vitamin D, and chemotherapy-induced peripheral neuropathy. The researchers also did not collect data on grade 1 and 2 chemotherapy-induced peripheral neuropathy.
DISCLOSURES:
The study was funded by Amgen, the American Cancer Society, and others. The investigators disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
TOPLINE:
, suggesting that correcting levels before treatment might help prevent the condition.
METHODOLOGY:
- Past studies have suggested an association between vitamin D insufficiency and paclitaxel-induced peripheral neuropathy, a largely untreatable and sometimes permanent side effect of chemotherapy.
- To confirm the association, investigators reviewed data and samples from 1,191 women in the phase 3 SWOG S0221 trial, which compared weekly and biweekly paclitaxel regimens for early-stage breast cancer.
- Using serum samples collected at baseline, the team evaluated the relationship between insufficient vitamin D levels (20 ng/mL or less) before treatment and grade 3 or higher sensory chemotherapy-induced peripheral neuropathy.
TAKEAWAY:
- Overall, 33.3% of the women had insufficient vitamin D levels at baseline, and 16.4% developed grade 3 or worse sensory chemotherapy-induced peripheral neuropathy.
- The incidence of peripheral neuropathy of grade 3 or greater was higher among patients with pretreatment vitamin D insufficiency (20.7% vs. 14.2%; odds ratio, 1.57; P = .005).
- The association grew stronger after adjusting for age and paclitaxel schedule (adjusted OR, 1.65; P = .003), but not after adjusting for race (adjusted OR, 1.39; P = .066).
IN PRACTICE:
The study “confirms that patients with pretreatment vitamin D insufficiency have a higher incidence of [chemotherapy-induced peripheral neuropathy],” the authors concluded. These results also “suggest that vitamin D supplementation in patients with lower levels of vitamin D may reduce peripheral neuropathy, and particularly high-grade peripheral neuropathy, which would improve these patients’ long-term quality of life,” senior researcher Daniel L. Hertz, PharmD, PhD, University of Michigan College of Pharmacy, Ann Arbor, said in a press release.
SOURCE:
The study, led by Ciao-Sin Chen, PharmD, of the University of Michigan, Ann Arbor, was published in the Journal of the National Comprehensive Cancer Network.
LIMITATIONS:
The trial did not collect data on other peripheral neuropathy risk factors, including preexisting peripheral neuropathy and diabetes. The study included a limited number of non-White participants (16%); larger numbers are needed to elucidate a potential interplay between race, vitamin D, and chemotherapy-induced peripheral neuropathy. The researchers also did not collect data on grade 1 and 2 chemotherapy-induced peripheral neuropathy.
DISCLOSURES:
The study was funded by Amgen, the American Cancer Society, and others. The investigators disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Prior authorizations interfere with recommended cancer care
Of 178 respondents with a prior authorization (PA) experience, 39 (22%) did not receive the care recommended by their treatment team because of a PA requirement, and 123 (69%) experienced a delay in receiving the recommended care, Fumiko Chino, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues reported.
Reasons for not receiving recommended care included complete denial by the insurance company (26 of 39 patients), and a change in treatment plan because of initial denial (13 of 39 patients). Delays in receiving recommended care were 2 or more weeks for 90 of 123 patients, and 1 month or more in 40 of 123 patients.
Delays in receiving recommended care were associated with increased patient anxiety, a negative perception of the PA process, and patient administrative burden, the investigators noted.
The findings, which capture patient-based perspectives in the ongoing PA debacle, were reported online in JAMA Network Open.
“Prior authorization requires clinicians and patients to navigate a complex approval pathway. Resultant delays and denial can be particularly problematic for patients with cancer, who often need urgent treatment or symptom management,” the investigators explained. “Focusing on patient experiences with PA highlights a missing perspective in policy discussions and suggests another potential factor associated with eroding trust in the health care system.”
To assess the impact of PA, they conducted an anonymous survey using a convenience sample of patients with any cancer-related PA experience from July 1 to Oct. 6, 2022. Mean self-reported PA-related anxiety scores were 74.7 on a scale of 0-100, whereas usual anxiety scores were 37.5.
PA-related anxiety scores were significantly correlated with the length of treatment delay (P = .04), time spent on PA (P < .001), and overall PA experience (P < .001).
“Dealing with PA issues adds an extra layer of stress, which is known to increase anxiety and can worsen treatment-related and disease-related symptoms and adverse effects,” the investigators noted.
PA issues also eroded trust: 89% of respondents trusted their insurance company less, and 83% trusted the health care system less after a PA experience. Patient involvement in the PA process increased the likelihood of such distrust and of having a negative experience.
Of the 178 respondents, most were women (88%), non-Hispanic White individuals (84%), college graduates (84%), and young (18-39 years, 41%; 40-54 years, 33%). Most (67%) had to personally become involved in the PA process by calling their insurance or filing an appeal.
The investigators noted that “efforts to create national health policy solutions that streamline PA and make the process more transparent have been a major lobbying effort of large oncology societies,” and that bipartisan legislation to “establish regulations on the quality and timeliness of PA in the Medicare Advantage population” has stalled.
“In the meantime, the Centers for Medicare & Medicaid Services acted directly by issuing a final rule in April 2023 aimed at improving PA processes within the Medicare Advantage population by 2024,” they wrote, adding that “streamlining the PA process is key to optimizing the quality of care delivered and improving patients’ experience with cancer care.
“Policy interventions will be necessary to reform the PA process, as will advocacy efforts at the patient, clinician, and hospital level,” they concluded.
Chino reported funding through a National Institutes of Health/National Cancer Institute Cancer Center Support Grant.
Of 178 respondents with a prior authorization (PA) experience, 39 (22%) did not receive the care recommended by their treatment team because of a PA requirement, and 123 (69%) experienced a delay in receiving the recommended care, Fumiko Chino, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues reported.
Reasons for not receiving recommended care included complete denial by the insurance company (26 of 39 patients), and a change in treatment plan because of initial denial (13 of 39 patients). Delays in receiving recommended care were 2 or more weeks for 90 of 123 patients, and 1 month or more in 40 of 123 patients.
Delays in receiving recommended care were associated with increased patient anxiety, a negative perception of the PA process, and patient administrative burden, the investigators noted.
The findings, which capture patient-based perspectives in the ongoing PA debacle, were reported online in JAMA Network Open.
“Prior authorization requires clinicians and patients to navigate a complex approval pathway. Resultant delays and denial can be particularly problematic for patients with cancer, who often need urgent treatment or symptom management,” the investigators explained. “Focusing on patient experiences with PA highlights a missing perspective in policy discussions and suggests another potential factor associated with eroding trust in the health care system.”
To assess the impact of PA, they conducted an anonymous survey using a convenience sample of patients with any cancer-related PA experience from July 1 to Oct. 6, 2022. Mean self-reported PA-related anxiety scores were 74.7 on a scale of 0-100, whereas usual anxiety scores were 37.5.
PA-related anxiety scores were significantly correlated with the length of treatment delay (P = .04), time spent on PA (P < .001), and overall PA experience (P < .001).
“Dealing with PA issues adds an extra layer of stress, which is known to increase anxiety and can worsen treatment-related and disease-related symptoms and adverse effects,” the investigators noted.
PA issues also eroded trust: 89% of respondents trusted their insurance company less, and 83% trusted the health care system less after a PA experience. Patient involvement in the PA process increased the likelihood of such distrust and of having a negative experience.
Of the 178 respondents, most were women (88%), non-Hispanic White individuals (84%), college graduates (84%), and young (18-39 years, 41%; 40-54 years, 33%). Most (67%) had to personally become involved in the PA process by calling their insurance or filing an appeal.
The investigators noted that “efforts to create national health policy solutions that streamline PA and make the process more transparent have been a major lobbying effort of large oncology societies,” and that bipartisan legislation to “establish regulations on the quality and timeliness of PA in the Medicare Advantage population” has stalled.
“In the meantime, the Centers for Medicare & Medicaid Services acted directly by issuing a final rule in April 2023 aimed at improving PA processes within the Medicare Advantage population by 2024,” they wrote, adding that “streamlining the PA process is key to optimizing the quality of care delivered and improving patients’ experience with cancer care.
“Policy interventions will be necessary to reform the PA process, as will advocacy efforts at the patient, clinician, and hospital level,” they concluded.
Chino reported funding through a National Institutes of Health/National Cancer Institute Cancer Center Support Grant.
Of 178 respondents with a prior authorization (PA) experience, 39 (22%) did not receive the care recommended by their treatment team because of a PA requirement, and 123 (69%) experienced a delay in receiving the recommended care, Fumiko Chino, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues reported.
Reasons for not receiving recommended care included complete denial by the insurance company (26 of 39 patients), and a change in treatment plan because of initial denial (13 of 39 patients). Delays in receiving recommended care were 2 or more weeks for 90 of 123 patients, and 1 month or more in 40 of 123 patients.
Delays in receiving recommended care were associated with increased patient anxiety, a negative perception of the PA process, and patient administrative burden, the investigators noted.
The findings, which capture patient-based perspectives in the ongoing PA debacle, were reported online in JAMA Network Open.
“Prior authorization requires clinicians and patients to navigate a complex approval pathway. Resultant delays and denial can be particularly problematic for patients with cancer, who often need urgent treatment or symptom management,” the investigators explained. “Focusing on patient experiences with PA highlights a missing perspective in policy discussions and suggests another potential factor associated with eroding trust in the health care system.”
To assess the impact of PA, they conducted an anonymous survey using a convenience sample of patients with any cancer-related PA experience from July 1 to Oct. 6, 2022. Mean self-reported PA-related anxiety scores were 74.7 on a scale of 0-100, whereas usual anxiety scores were 37.5.
PA-related anxiety scores were significantly correlated with the length of treatment delay (P = .04), time spent on PA (P < .001), and overall PA experience (P < .001).
“Dealing with PA issues adds an extra layer of stress, which is known to increase anxiety and can worsen treatment-related and disease-related symptoms and adverse effects,” the investigators noted.
PA issues also eroded trust: 89% of respondents trusted their insurance company less, and 83% trusted the health care system less after a PA experience. Patient involvement in the PA process increased the likelihood of such distrust and of having a negative experience.
Of the 178 respondents, most were women (88%), non-Hispanic White individuals (84%), college graduates (84%), and young (18-39 years, 41%; 40-54 years, 33%). Most (67%) had to personally become involved in the PA process by calling their insurance or filing an appeal.
The investigators noted that “efforts to create national health policy solutions that streamline PA and make the process more transparent have been a major lobbying effort of large oncology societies,” and that bipartisan legislation to “establish regulations on the quality and timeliness of PA in the Medicare Advantage population” has stalled.
“In the meantime, the Centers for Medicare & Medicaid Services acted directly by issuing a final rule in April 2023 aimed at improving PA processes within the Medicare Advantage population by 2024,” they wrote, adding that “streamlining the PA process is key to optimizing the quality of care delivered and improving patients’ experience with cancer care.
“Policy interventions will be necessary to reform the PA process, as will advocacy efforts at the patient, clinician, and hospital level,” they concluded.
Chino reported funding through a National Institutes of Health/National Cancer Institute Cancer Center Support Grant.
FROM JAMA NETWORK OPEN
T-DXd benefits persist for HER2-low breast cancer
and low HER2 expression in the randomized phase 3 DESTINY-Breast04 study, according to 32-month follow-up data.
The overall safety profile of the HER2-directed antibody drug conjugate was also comparable to that observed at the primary analysis in 2022, and longer exposure did not appear to increase toxicity, Shanu Modi, MD, reported on behalf of the DESTINY-Breast04 investigators at the European Society of Medical Oncology (ESMO) Congress 2023.
“These results continue to support the use of T-DXd as the new standard of care after one line of chemotherapy in patients with HER2-low metastatic breast cancer,” said Dr. Modi, a breast oncologist and attending physician at Memorial Sloan Kettering Cancer Center, New York.
DESTINY-Breast04 enrolled 557 patients 2:1 to receive 5.4 mg/kg of T-DXd every 3 weeks or physicians’ choice of capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel, and established HER2-low mBC as “a new targetable patient population with T-DXd as a new standard of care,” she explained.
Median overall survival (mOS) with a median of 18.4 months of follow-up at the Jan. 11, 2022, primary data cut-off was 23.4 months in the T-DXd arm versus 16.8 months in the TPC arm and 23.9 versus 17.5 months, respectively, in the hormone receptor–positive (HR+) cohort (hazard ratio, 0.64 for both groups). At the preplanned extended follow-up with data cut-off on March 1, 2023, the mOS was 22.9 versus 16.8 months for T-DXd versus TPC, and 23.9 versus 17.6 months for the HR+ cohort, respectively (HR, 0.69 for both).
Median progression-free survival (PFS) by investigator assessment was 8.8 versus 4.2 months for the full cohort, and 9.6 versus 4.2 months for the HR+ cohort (HR, 0.36 and 0.37, respectively). PFS was consistent with the results from the primary analysis.
The benefits in the HR+ patients were consistent across all patient subgroups, Dr. Modi noted.
“I do think it’s interesting to point out that at the landmark 2-year point, all patients on standard chemotherapy discontinued study treatment, whereas 15% on T-DXd remain [on treatment] without any evidence of disease progression, Dr. Modi added
An exploratory analysis in the hormone receptor–negative (HR–) cohort showed mOS of 18.2 versus 8.3 months at the primary analysis (HR, 0.48), and a “clinically meaningful and numerical advantage for T-DXd” persisted at the planned follow-up (mOS, 17.1 vs. 8.3; HR, 0.58), she said.
PFS in the HR- cohort was 8.5 versus 2.9 months at the primary analysis, and 6.3 versus 2.9 months at the update (HR, 0.46 and 0.29, respectively).
An assessment of post-study therapies received by patients showed that those therapies did not account for the significant survival advantage conferred by T-DXd, Dr. Modi said.
She noted, however, that while no new safety signals were observed at follow-up, lung toxicity remains a “toxicity of special interest,” having occurred in 12.1% of cases at the time of the primary analysis.
Most cases were grade 1 or 2, and no new cases were observed at follow-up, but one patient with lung toxicity and an initial grade 3 event experienced clinical deterioration and later died from lung toxicity, which underscores the importance of remaining vigilant and intervening promptly in all cases of lung toxicity, Dr. Modi stressed.
Invited discussant Giampaolo Bianchini, MD, reiterated that T-DXd is an effective treatment option and said, “we must accurately identify patients and avoid improperly denying this important therapeutic option.”
Although HER2-low disease is not a unique biological disease entity, it is a “practical and pragmatic definition used to select patients with ‘some degree’ of HER2 protein expression adopting a test and a scoring system already implemented in the routine clinical practice,” said Dr. Bianchini, head of the breast cancer group and head of clinical translational and immunotherapy research at IRCCS Ospedale, San Raffaele, Milan.
However, the current definition may be inadequate, he said, explaining that the ongoing DESTINY-Breast06 study “will challenge the current definition of what we consider HER2-low definition,” potentially extending the T-DXd indication to HER2 ultra-low.
Furthermore, current HER2 testing was designed to discriminate cases with high abundant protein – not for the low HER2 dynamic range, which leads to technical inaccuracy.
Given these considerations, he suggested considering a new biopsy, if feasible, in patients with an immunohistochemistry (IHC) score of 0 in all tumor biopsies, and having a revision performed by the pathologist.
In patients with an IHC score of 1 or greater only in one biopsy, there is no need to confirm the HER2-low status, he said.
DESTINY-Breast04 is funded by Daiichi Sankyo Inc. and AstraZeneca. Dr. Modi reported relationships with Daiichi Sankyo, Genentech, AstraZeneca, Seagen, and MacroGenics. Dr. Bianchini reported relationships with AstraZeneca, Daiichi Sankyo, Gilead, MSD, Seagen, Roche, Sanofi, Lilly, EISAI, Novartis, Pfizer, Stemline, Exact Science, and Agendia.
and low HER2 expression in the randomized phase 3 DESTINY-Breast04 study, according to 32-month follow-up data.
The overall safety profile of the HER2-directed antibody drug conjugate was also comparable to that observed at the primary analysis in 2022, and longer exposure did not appear to increase toxicity, Shanu Modi, MD, reported on behalf of the DESTINY-Breast04 investigators at the European Society of Medical Oncology (ESMO) Congress 2023.
“These results continue to support the use of T-DXd as the new standard of care after one line of chemotherapy in patients with HER2-low metastatic breast cancer,” said Dr. Modi, a breast oncologist and attending physician at Memorial Sloan Kettering Cancer Center, New York.
DESTINY-Breast04 enrolled 557 patients 2:1 to receive 5.4 mg/kg of T-DXd every 3 weeks or physicians’ choice of capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel, and established HER2-low mBC as “a new targetable patient population with T-DXd as a new standard of care,” she explained.
Median overall survival (mOS) with a median of 18.4 months of follow-up at the Jan. 11, 2022, primary data cut-off was 23.4 months in the T-DXd arm versus 16.8 months in the TPC arm and 23.9 versus 17.5 months, respectively, in the hormone receptor–positive (HR+) cohort (hazard ratio, 0.64 for both groups). At the preplanned extended follow-up with data cut-off on March 1, 2023, the mOS was 22.9 versus 16.8 months for T-DXd versus TPC, and 23.9 versus 17.6 months for the HR+ cohort, respectively (HR, 0.69 for both).
Median progression-free survival (PFS) by investigator assessment was 8.8 versus 4.2 months for the full cohort, and 9.6 versus 4.2 months for the HR+ cohort (HR, 0.36 and 0.37, respectively). PFS was consistent with the results from the primary analysis.
The benefits in the HR+ patients were consistent across all patient subgroups, Dr. Modi noted.
“I do think it’s interesting to point out that at the landmark 2-year point, all patients on standard chemotherapy discontinued study treatment, whereas 15% on T-DXd remain [on treatment] without any evidence of disease progression, Dr. Modi added
An exploratory analysis in the hormone receptor–negative (HR–) cohort showed mOS of 18.2 versus 8.3 months at the primary analysis (HR, 0.48), and a “clinically meaningful and numerical advantage for T-DXd” persisted at the planned follow-up (mOS, 17.1 vs. 8.3; HR, 0.58), she said.
PFS in the HR- cohort was 8.5 versus 2.9 months at the primary analysis, and 6.3 versus 2.9 months at the update (HR, 0.46 and 0.29, respectively).
An assessment of post-study therapies received by patients showed that those therapies did not account for the significant survival advantage conferred by T-DXd, Dr. Modi said.
She noted, however, that while no new safety signals were observed at follow-up, lung toxicity remains a “toxicity of special interest,” having occurred in 12.1% of cases at the time of the primary analysis.
Most cases were grade 1 or 2, and no new cases were observed at follow-up, but one patient with lung toxicity and an initial grade 3 event experienced clinical deterioration and later died from lung toxicity, which underscores the importance of remaining vigilant and intervening promptly in all cases of lung toxicity, Dr. Modi stressed.
Invited discussant Giampaolo Bianchini, MD, reiterated that T-DXd is an effective treatment option and said, “we must accurately identify patients and avoid improperly denying this important therapeutic option.”
Although HER2-low disease is not a unique biological disease entity, it is a “practical and pragmatic definition used to select patients with ‘some degree’ of HER2 protein expression adopting a test and a scoring system already implemented in the routine clinical practice,” said Dr. Bianchini, head of the breast cancer group and head of clinical translational and immunotherapy research at IRCCS Ospedale, San Raffaele, Milan.
However, the current definition may be inadequate, he said, explaining that the ongoing DESTINY-Breast06 study “will challenge the current definition of what we consider HER2-low definition,” potentially extending the T-DXd indication to HER2 ultra-low.
Furthermore, current HER2 testing was designed to discriminate cases with high abundant protein – not for the low HER2 dynamic range, which leads to technical inaccuracy.
Given these considerations, he suggested considering a new biopsy, if feasible, in patients with an immunohistochemistry (IHC) score of 0 in all tumor biopsies, and having a revision performed by the pathologist.
In patients with an IHC score of 1 or greater only in one biopsy, there is no need to confirm the HER2-low status, he said.
DESTINY-Breast04 is funded by Daiichi Sankyo Inc. and AstraZeneca. Dr. Modi reported relationships with Daiichi Sankyo, Genentech, AstraZeneca, Seagen, and MacroGenics. Dr. Bianchini reported relationships with AstraZeneca, Daiichi Sankyo, Gilead, MSD, Seagen, Roche, Sanofi, Lilly, EISAI, Novartis, Pfizer, Stemline, Exact Science, and Agendia.
and low HER2 expression in the randomized phase 3 DESTINY-Breast04 study, according to 32-month follow-up data.
The overall safety profile of the HER2-directed antibody drug conjugate was also comparable to that observed at the primary analysis in 2022, and longer exposure did not appear to increase toxicity, Shanu Modi, MD, reported on behalf of the DESTINY-Breast04 investigators at the European Society of Medical Oncology (ESMO) Congress 2023.
“These results continue to support the use of T-DXd as the new standard of care after one line of chemotherapy in patients with HER2-low metastatic breast cancer,” said Dr. Modi, a breast oncologist and attending physician at Memorial Sloan Kettering Cancer Center, New York.
DESTINY-Breast04 enrolled 557 patients 2:1 to receive 5.4 mg/kg of T-DXd every 3 weeks or physicians’ choice of capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel, and established HER2-low mBC as “a new targetable patient population with T-DXd as a new standard of care,” she explained.
Median overall survival (mOS) with a median of 18.4 months of follow-up at the Jan. 11, 2022, primary data cut-off was 23.4 months in the T-DXd arm versus 16.8 months in the TPC arm and 23.9 versus 17.5 months, respectively, in the hormone receptor–positive (HR+) cohort (hazard ratio, 0.64 for both groups). At the preplanned extended follow-up with data cut-off on March 1, 2023, the mOS was 22.9 versus 16.8 months for T-DXd versus TPC, and 23.9 versus 17.6 months for the HR+ cohort, respectively (HR, 0.69 for both).
Median progression-free survival (PFS) by investigator assessment was 8.8 versus 4.2 months for the full cohort, and 9.6 versus 4.2 months for the HR+ cohort (HR, 0.36 and 0.37, respectively). PFS was consistent with the results from the primary analysis.
The benefits in the HR+ patients were consistent across all patient subgroups, Dr. Modi noted.
“I do think it’s interesting to point out that at the landmark 2-year point, all patients on standard chemotherapy discontinued study treatment, whereas 15% on T-DXd remain [on treatment] without any evidence of disease progression, Dr. Modi added
An exploratory analysis in the hormone receptor–negative (HR–) cohort showed mOS of 18.2 versus 8.3 months at the primary analysis (HR, 0.48), and a “clinically meaningful and numerical advantage for T-DXd” persisted at the planned follow-up (mOS, 17.1 vs. 8.3; HR, 0.58), she said.
PFS in the HR- cohort was 8.5 versus 2.9 months at the primary analysis, and 6.3 versus 2.9 months at the update (HR, 0.46 and 0.29, respectively).
An assessment of post-study therapies received by patients showed that those therapies did not account for the significant survival advantage conferred by T-DXd, Dr. Modi said.
She noted, however, that while no new safety signals were observed at follow-up, lung toxicity remains a “toxicity of special interest,” having occurred in 12.1% of cases at the time of the primary analysis.
Most cases were grade 1 or 2, and no new cases were observed at follow-up, but one patient with lung toxicity and an initial grade 3 event experienced clinical deterioration and later died from lung toxicity, which underscores the importance of remaining vigilant and intervening promptly in all cases of lung toxicity, Dr. Modi stressed.
Invited discussant Giampaolo Bianchini, MD, reiterated that T-DXd is an effective treatment option and said, “we must accurately identify patients and avoid improperly denying this important therapeutic option.”
Although HER2-low disease is not a unique biological disease entity, it is a “practical and pragmatic definition used to select patients with ‘some degree’ of HER2 protein expression adopting a test and a scoring system already implemented in the routine clinical practice,” said Dr. Bianchini, head of the breast cancer group and head of clinical translational and immunotherapy research at IRCCS Ospedale, San Raffaele, Milan.
However, the current definition may be inadequate, he said, explaining that the ongoing DESTINY-Breast06 study “will challenge the current definition of what we consider HER2-low definition,” potentially extending the T-DXd indication to HER2 ultra-low.
Furthermore, current HER2 testing was designed to discriminate cases with high abundant protein – not for the low HER2 dynamic range, which leads to technical inaccuracy.
Given these considerations, he suggested considering a new biopsy, if feasible, in patients with an immunohistochemistry (IHC) score of 0 in all tumor biopsies, and having a revision performed by the pathologist.
In patients with an IHC score of 1 or greater only in one biopsy, there is no need to confirm the HER2-low status, he said.
DESTINY-Breast04 is funded by Daiichi Sankyo Inc. and AstraZeneca. Dr. Modi reported relationships with Daiichi Sankyo, Genentech, AstraZeneca, Seagen, and MacroGenics. Dr. Bianchini reported relationships with AstraZeneca, Daiichi Sankyo, Gilead, MSD, Seagen, Roche, Sanofi, Lilly, EISAI, Novartis, Pfizer, Stemline, Exact Science, and Agendia.
FROM ESMO 2023
Breaking barriers to colorectal cancer care for Black patients
Black Americans are about 40% more likely to die from the disease than most other groups of patients. A recent study also found that 26% of Black Americans are diagnosed with CRC that has already metastasized, meaning the cancer has spread to other places in the body.
“The impact of social determinants of health on CRC diagnosis and treatment is clear to me as a practicing [cancer doctor] and person of color,” said Jason Willis, MD, PhD, a clinical investigator in the departments of Gastrointestinal Medical Oncology and Genomic Medicine at the University of Texas MD Anderson Cancer Center, Houston. “At a systemic level, we know that inequalities in health care access disproportionately impact many racial and ethnic minority groups. This is especially important when it comes to accessing preventative care and routine screening for common cancers, like CRC.”
The problem often exists throughout entire neighborhoods or cities.
“It may reflect a lack of access to primary care, inadequate referrals for screening, cultural barriers, and/or community-level factors,” Dr. Willis said. “Evidence has also suggested that some of the differences in CRC risk observed among various racial/ethnic communities may also be driven by differences in the prevalence of its underlying risk factors, such as tobacco use and type 2 diabetes.”
Black patients can also face information roadblocks when it comes to early CRC evaluation, said Christina M. Annunziata, MD, PhD, senior vice president of extramural discovery science at the American Cancer Society.
Other barriers may include a fear of the invasiveness of a colonoscopy, a lack of understanding of the benefits of screening, and lack of understanding of how family history with the disease plays a role, Dr. Annunziata said. “These apply across the U.S. population and are amplified with Black patients.”
Then there are disparities in treatment, which may come from a lack of health care access, including insurance coverage, transportation challenges, and the time required for treatment such as surgery, radiation, and chemotherapy, she said. “In addition, Black patients diagnosed with advanced-stage cancers require more intensive, expensive, and time-consuming treatment regimens that can be unattainable due to social and economic barriers,” she said.
Are there biological reasons Black people are more at risk for colorectal cancer?
Most likely, no. When Black patients received high-quality colonoscopies, there was no difference in the number of precancerous CRC polyps, or CRC tumors, when compared to White patients tested with the same equipment, according to data from Memorial Sloan Kettering Cancer Center. This further shows the importance of Black patients receiving early and effective screening for the disease.
But genetics may be one reason why CRC in Black patients can be difficult to treat. Additional research from Memorial Sloan Kettering found that colon cancer patients of African ancestry may have tumors that don’t respond well to immunotherapy and targeted cancer therapy.
The researchers found that these patients’ tumors were less likely to have the molecular profiles needed for these treatments to work.
But more research is needed. For now, researchers have very few clues as to why, when, and how these molecular and biological differences of CRC exist among various racial/ethnic and ancestral backgrounds, he said.
Black patients are also more likely to be diagnosed under the age of 50 as well. Researchers don’t know why this is exactly yet, but they think that poor diet, unhealthy bacteria in the gut, and inflammation may contribute to the cause. (Healthy eating and more exercise may lower a person’s risk.)
What are the symptoms of colorectal cancer?
Colorectal polyps, which are growths that can turn into colon cancer, and colon cancer itself can come without symptoms. If a person does have symptoms, they can include:
- Changes in bowel habits
- Blood in bowel movements
- Diarrhea
- Constipation
- The sensation that bowel movements aren’t complete
- Persistent stomachache, stomach pain, or cramps
- Weight loss without any explanation
Any or all of these symptoms warrant a trip to the doctor. These symptoms are the same for all racial and ethnic groups. Because CRC symptoms aren’t always obvious, this makes screening all the more important.
Where colon cancer spreads
Once cancerous cells break off from a tumor, what areas of the body does it spread to first?
What can Black patients do to lower their risk of getting colorectal cancer?
There are a number of solutions patients can pursue themselves.
Learn about CRC online
The untimely death of Oscar-nominated actor Chadwick Boseman from colon cancer at age 43 significantly boosted awareness of the disease, particularly for Black Americans. A study from the University of British Columbia and Simon Fraser University’s Beedie School of Business found there was an increase in internet searches about colon cancer in the months after Mr. Boseman’s August 2020 passing, particularly in areas where many Black Americans live. The study authors emphasized the importance of public health leaders discussing Mr. Mr. Boseman’s diagnosis with their Black patient population, so they will not only be inspired by his brave battle against the disease but will be proactive about getting tested for colon cancer themselves.
Reading about Mr. Boseman’s journey is an important start to patient education. It’s also key to learn about the disease itself, plus how colon cancer screening works specifically. Then, writing down questions to bring to the doctor before screening is an excellent way to feel empowered, and to understand what specific test results will mean.
Be proactive
Find out about family history.
“It’s challenging to determine the best age for screening if the patient doesn’t know their family history,” said Dr. Annunziata. Asking older members of the family whether CRC has affected previous generations is a helpful step.
If there is a strong family history, a patient will likely need earlier screening.
“[Doctors] should explain the benefits of colon cancer screening with colonoscopy starting at age 45 in the general population or earlier if the person has a family history of colon cancer,” Dr. Annunziata said. If a patient’s doctor doesn’t offer this information upfront, it’s definitely the right move to ask for the testing directly.
If a Black patient gets diagnosed with CRC, they should educate themselves about critical follow-up care after a diagnosis. Doctors should also be more proactive about enrolling patients in key clinical trials. According to additional data from the American Cancer Society, only 7% of patients enrolled in the FDA’s clinical cancer drug trials are Black. Doctors should also be more proactive about enrolling patients in these and other key clinical trials; it’s completely appropriate for a patient to search out trials on their own and bring them to their doctor’s attention too.
And attending all appointments and completing chemo or radiation treatment is vital.
“For patients undergoing treatment, physicians can ensure that the patients understand the importance of receiving the full recommended course of treatment and receive the support to tolerate the anticipated side effects,” Dr. Annunziata said.
Reach out for reassurance
Patients who are diagnosed with colorectal cancer have many resources for emotional support. The American Cancer Society offers support for all physical and emotional aspects of cancer 24 hours a day. The Colorectal Cancer Alliance offers comprehensive resource guides as well.
Support groups, through local hospitals or communities, can also be extremely helpful.
Reading the stories of Black patients who are surviving and thriving despite a colorectal cancer diagnosis can be incredibly inspiring as well.
It’s also very important for Black patients to let their doctors know if they don’t have the support they need. A doctor can help by navigating extra help within a patient’s community – an approach that is truly breaking down barriers to CRC care.
“What’s very encouraging is that meaningful improvements in CRC screening rates and early detection among Black communities have been seen through purposeful interventions and outreach,” Dr. Willis said. “In this way, all doctors can play a significant role at a broad and systemic level by advocating for and implementing interventions in their communities.”
A version of this article appeared on WebMD.com.
Black Americans are about 40% more likely to die from the disease than most other groups of patients. A recent study also found that 26% of Black Americans are diagnosed with CRC that has already metastasized, meaning the cancer has spread to other places in the body.
“The impact of social determinants of health on CRC diagnosis and treatment is clear to me as a practicing [cancer doctor] and person of color,” said Jason Willis, MD, PhD, a clinical investigator in the departments of Gastrointestinal Medical Oncology and Genomic Medicine at the University of Texas MD Anderson Cancer Center, Houston. “At a systemic level, we know that inequalities in health care access disproportionately impact many racial and ethnic minority groups. This is especially important when it comes to accessing preventative care and routine screening for common cancers, like CRC.”
The problem often exists throughout entire neighborhoods or cities.
“It may reflect a lack of access to primary care, inadequate referrals for screening, cultural barriers, and/or community-level factors,” Dr. Willis said. “Evidence has also suggested that some of the differences in CRC risk observed among various racial/ethnic communities may also be driven by differences in the prevalence of its underlying risk factors, such as tobacco use and type 2 diabetes.”
Black patients can also face information roadblocks when it comes to early CRC evaluation, said Christina M. Annunziata, MD, PhD, senior vice president of extramural discovery science at the American Cancer Society.
Other barriers may include a fear of the invasiveness of a colonoscopy, a lack of understanding of the benefits of screening, and lack of understanding of how family history with the disease plays a role, Dr. Annunziata said. “These apply across the U.S. population and are amplified with Black patients.”
Then there are disparities in treatment, which may come from a lack of health care access, including insurance coverage, transportation challenges, and the time required for treatment such as surgery, radiation, and chemotherapy, she said. “In addition, Black patients diagnosed with advanced-stage cancers require more intensive, expensive, and time-consuming treatment regimens that can be unattainable due to social and economic barriers,” she said.
Are there biological reasons Black people are more at risk for colorectal cancer?
Most likely, no. When Black patients received high-quality colonoscopies, there was no difference in the number of precancerous CRC polyps, or CRC tumors, when compared to White patients tested with the same equipment, according to data from Memorial Sloan Kettering Cancer Center. This further shows the importance of Black patients receiving early and effective screening for the disease.
But genetics may be one reason why CRC in Black patients can be difficult to treat. Additional research from Memorial Sloan Kettering found that colon cancer patients of African ancestry may have tumors that don’t respond well to immunotherapy and targeted cancer therapy.
The researchers found that these patients’ tumors were less likely to have the molecular profiles needed for these treatments to work.
But more research is needed. For now, researchers have very few clues as to why, when, and how these molecular and biological differences of CRC exist among various racial/ethnic and ancestral backgrounds, he said.
Black patients are also more likely to be diagnosed under the age of 50 as well. Researchers don’t know why this is exactly yet, but they think that poor diet, unhealthy bacteria in the gut, and inflammation may contribute to the cause. (Healthy eating and more exercise may lower a person’s risk.)
What are the symptoms of colorectal cancer?
Colorectal polyps, which are growths that can turn into colon cancer, and colon cancer itself can come without symptoms. If a person does have symptoms, they can include:
- Changes in bowel habits
- Blood in bowel movements
- Diarrhea
- Constipation
- The sensation that bowel movements aren’t complete
- Persistent stomachache, stomach pain, or cramps
- Weight loss without any explanation
Any or all of these symptoms warrant a trip to the doctor. These symptoms are the same for all racial and ethnic groups. Because CRC symptoms aren’t always obvious, this makes screening all the more important.
Where colon cancer spreads
Once cancerous cells break off from a tumor, what areas of the body does it spread to first?
What can Black patients do to lower their risk of getting colorectal cancer?
There are a number of solutions patients can pursue themselves.
Learn about CRC online
The untimely death of Oscar-nominated actor Chadwick Boseman from colon cancer at age 43 significantly boosted awareness of the disease, particularly for Black Americans. A study from the University of British Columbia and Simon Fraser University’s Beedie School of Business found there was an increase in internet searches about colon cancer in the months after Mr. Boseman’s August 2020 passing, particularly in areas where many Black Americans live. The study authors emphasized the importance of public health leaders discussing Mr. Mr. Boseman’s diagnosis with their Black patient population, so they will not only be inspired by his brave battle against the disease but will be proactive about getting tested for colon cancer themselves.
Reading about Mr. Boseman’s journey is an important start to patient education. It’s also key to learn about the disease itself, plus how colon cancer screening works specifically. Then, writing down questions to bring to the doctor before screening is an excellent way to feel empowered, and to understand what specific test results will mean.
Be proactive
Find out about family history.
“It’s challenging to determine the best age for screening if the patient doesn’t know their family history,” said Dr. Annunziata. Asking older members of the family whether CRC has affected previous generations is a helpful step.
If there is a strong family history, a patient will likely need earlier screening.
“[Doctors] should explain the benefits of colon cancer screening with colonoscopy starting at age 45 in the general population or earlier if the person has a family history of colon cancer,” Dr. Annunziata said. If a patient’s doctor doesn’t offer this information upfront, it’s definitely the right move to ask for the testing directly.
If a Black patient gets diagnosed with CRC, they should educate themselves about critical follow-up care after a diagnosis. Doctors should also be more proactive about enrolling patients in key clinical trials. According to additional data from the American Cancer Society, only 7% of patients enrolled in the FDA’s clinical cancer drug trials are Black. Doctors should also be more proactive about enrolling patients in these and other key clinical trials; it’s completely appropriate for a patient to search out trials on their own and bring them to their doctor’s attention too.
And attending all appointments and completing chemo or radiation treatment is vital.
“For patients undergoing treatment, physicians can ensure that the patients understand the importance of receiving the full recommended course of treatment and receive the support to tolerate the anticipated side effects,” Dr. Annunziata said.
Reach out for reassurance
Patients who are diagnosed with colorectal cancer have many resources for emotional support. The American Cancer Society offers support for all physical and emotional aspects of cancer 24 hours a day. The Colorectal Cancer Alliance offers comprehensive resource guides as well.
Support groups, through local hospitals or communities, can also be extremely helpful.
Reading the stories of Black patients who are surviving and thriving despite a colorectal cancer diagnosis can be incredibly inspiring as well.
It’s also very important for Black patients to let their doctors know if they don’t have the support they need. A doctor can help by navigating extra help within a patient’s community – an approach that is truly breaking down barriers to CRC care.
“What’s very encouraging is that meaningful improvements in CRC screening rates and early detection among Black communities have been seen through purposeful interventions and outreach,” Dr. Willis said. “In this way, all doctors can play a significant role at a broad and systemic level by advocating for and implementing interventions in their communities.”
A version of this article appeared on WebMD.com.
Black Americans are about 40% more likely to die from the disease than most other groups of patients. A recent study also found that 26% of Black Americans are diagnosed with CRC that has already metastasized, meaning the cancer has spread to other places in the body.
“The impact of social determinants of health on CRC diagnosis and treatment is clear to me as a practicing [cancer doctor] and person of color,” said Jason Willis, MD, PhD, a clinical investigator in the departments of Gastrointestinal Medical Oncology and Genomic Medicine at the University of Texas MD Anderson Cancer Center, Houston. “At a systemic level, we know that inequalities in health care access disproportionately impact many racial and ethnic minority groups. This is especially important when it comes to accessing preventative care and routine screening for common cancers, like CRC.”
The problem often exists throughout entire neighborhoods or cities.
“It may reflect a lack of access to primary care, inadequate referrals for screening, cultural barriers, and/or community-level factors,” Dr. Willis said. “Evidence has also suggested that some of the differences in CRC risk observed among various racial/ethnic communities may also be driven by differences in the prevalence of its underlying risk factors, such as tobacco use and type 2 diabetes.”
Black patients can also face information roadblocks when it comes to early CRC evaluation, said Christina M. Annunziata, MD, PhD, senior vice president of extramural discovery science at the American Cancer Society.
Other barriers may include a fear of the invasiveness of a colonoscopy, a lack of understanding of the benefits of screening, and lack of understanding of how family history with the disease plays a role, Dr. Annunziata said. “These apply across the U.S. population and are amplified with Black patients.”
Then there are disparities in treatment, which may come from a lack of health care access, including insurance coverage, transportation challenges, and the time required for treatment such as surgery, radiation, and chemotherapy, she said. “In addition, Black patients diagnosed with advanced-stage cancers require more intensive, expensive, and time-consuming treatment regimens that can be unattainable due to social and economic barriers,” she said.
Are there biological reasons Black people are more at risk for colorectal cancer?
Most likely, no. When Black patients received high-quality colonoscopies, there was no difference in the number of precancerous CRC polyps, or CRC tumors, when compared to White patients tested with the same equipment, according to data from Memorial Sloan Kettering Cancer Center. This further shows the importance of Black patients receiving early and effective screening for the disease.
But genetics may be one reason why CRC in Black patients can be difficult to treat. Additional research from Memorial Sloan Kettering found that colon cancer patients of African ancestry may have tumors that don’t respond well to immunotherapy and targeted cancer therapy.
The researchers found that these patients’ tumors were less likely to have the molecular profiles needed for these treatments to work.
But more research is needed. For now, researchers have very few clues as to why, when, and how these molecular and biological differences of CRC exist among various racial/ethnic and ancestral backgrounds, he said.
Black patients are also more likely to be diagnosed under the age of 50 as well. Researchers don’t know why this is exactly yet, but they think that poor diet, unhealthy bacteria in the gut, and inflammation may contribute to the cause. (Healthy eating and more exercise may lower a person’s risk.)
What are the symptoms of colorectal cancer?
Colorectal polyps, which are growths that can turn into colon cancer, and colon cancer itself can come without symptoms. If a person does have symptoms, they can include:
- Changes in bowel habits
- Blood in bowel movements
- Diarrhea
- Constipation
- The sensation that bowel movements aren’t complete
- Persistent stomachache, stomach pain, or cramps
- Weight loss without any explanation
Any or all of these symptoms warrant a trip to the doctor. These symptoms are the same for all racial and ethnic groups. Because CRC symptoms aren’t always obvious, this makes screening all the more important.
Where colon cancer spreads
Once cancerous cells break off from a tumor, what areas of the body does it spread to first?
What can Black patients do to lower their risk of getting colorectal cancer?
There are a number of solutions patients can pursue themselves.
Learn about CRC online
The untimely death of Oscar-nominated actor Chadwick Boseman from colon cancer at age 43 significantly boosted awareness of the disease, particularly for Black Americans. A study from the University of British Columbia and Simon Fraser University’s Beedie School of Business found there was an increase in internet searches about colon cancer in the months after Mr. Boseman’s August 2020 passing, particularly in areas where many Black Americans live. The study authors emphasized the importance of public health leaders discussing Mr. Mr. Boseman’s diagnosis with their Black patient population, so they will not only be inspired by his brave battle against the disease but will be proactive about getting tested for colon cancer themselves.
Reading about Mr. Boseman’s journey is an important start to patient education. It’s also key to learn about the disease itself, plus how colon cancer screening works specifically. Then, writing down questions to bring to the doctor before screening is an excellent way to feel empowered, and to understand what specific test results will mean.
Be proactive
Find out about family history.
“It’s challenging to determine the best age for screening if the patient doesn’t know their family history,” said Dr. Annunziata. Asking older members of the family whether CRC has affected previous generations is a helpful step.
If there is a strong family history, a patient will likely need earlier screening.
“[Doctors] should explain the benefits of colon cancer screening with colonoscopy starting at age 45 in the general population or earlier if the person has a family history of colon cancer,” Dr. Annunziata said. If a patient’s doctor doesn’t offer this information upfront, it’s definitely the right move to ask for the testing directly.
If a Black patient gets diagnosed with CRC, they should educate themselves about critical follow-up care after a diagnosis. Doctors should also be more proactive about enrolling patients in key clinical trials. According to additional data from the American Cancer Society, only 7% of patients enrolled in the FDA’s clinical cancer drug trials are Black. Doctors should also be more proactive about enrolling patients in these and other key clinical trials; it’s completely appropriate for a patient to search out trials on their own and bring them to their doctor’s attention too.
And attending all appointments and completing chemo or radiation treatment is vital.
“For patients undergoing treatment, physicians can ensure that the patients understand the importance of receiving the full recommended course of treatment and receive the support to tolerate the anticipated side effects,” Dr. Annunziata said.
Reach out for reassurance
Patients who are diagnosed with colorectal cancer have many resources for emotional support. The American Cancer Society offers support for all physical and emotional aspects of cancer 24 hours a day. The Colorectal Cancer Alliance offers comprehensive resource guides as well.
Support groups, through local hospitals or communities, can also be extremely helpful.
Reading the stories of Black patients who are surviving and thriving despite a colorectal cancer diagnosis can be incredibly inspiring as well.
It’s also very important for Black patients to let their doctors know if they don’t have the support they need. A doctor can help by navigating extra help within a patient’s community – an approach that is truly breaking down barriers to CRC care.
“What’s very encouraging is that meaningful improvements in CRC screening rates and early detection among Black communities have been seen through purposeful interventions and outreach,” Dr. Willis said. “In this way, all doctors can play a significant role at a broad and systemic level by advocating for and implementing interventions in their communities.”
A version of this article appeared on WebMD.com.
How can we improve our approach to cancer-related fatigue?
MADRID – These were the messages delivered by speakers at the annual meeting of the European Society for Medical Oncology during a session titled “The Multiple Faces of Fatigue in the Cancer Ecosystem.”
Cancer-related fatigue is said to affect 40% of patients at the time of cancer diagnosis, 65% of patients during active or maintenance treatment, 21%-52% of patients in the 5 years following cancer diagnosis, and even one quarter of patients who are between 5 and 30 years post diagnosis, said Florian Scotté, MD, PhD, head of the interdisciplinary department for the Organization of Patient Pathways at Gustave Roussy Institute in Villejuif, France.
However, he underlines that “up to 50% of cancer survivors report never having discussed their cancer-related fatigue or received advice or support on how to manage it.”
What exactly is this fatigue? According to the definition set out in the ESMO 2020 recommendations and repeated word for word in the latest recommendations issued by the National Comprehensive Cancer Network published on Oct. 6, cancer-related fatigue is “a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.”
Mechanisms at play
The mechanisms at play in cancer-related fatigue are clinical, molecular, and psychological, stated Dr. Scotté.
In terms of the clinical factors responsible for patients’ fatigue, comorbidities such as anemia, diabetes, heart disease, and even psychological conditions are significant elements. In addition, taking medicinal products such as antidepressants or beta-blockers can also cause fatigue. Furthermore, cancer treatment itself has many possible side effects, such as anemia, hypothyroidism, insomnia, pain, and hypopituitarism.
In terms of molecular and physiologic factors, central nervous system dysfunction (inflammation, hypothalamic-pituitary-adrenal axis) leads to perceived reduced physical and mental capacity with no clear motor or cognitive deficiencies. Changes in the peripheral nervous system also cause reduced energy metabolism, which hampers the response of muscles to stimuli, possibly even limiting endurance. Finally, several studies have shown that systemic inflammation is involved in the onset of fatigue.
Dr. Scotté also highlighted the importance of psychological factors, citing depression, psychosocial stress before treatment, negative attention to symptoms, and fear of relapse as key features in the development of cancer-related fatigue.
Among the risk factors for developing cancer-related fatigue, the speaker mentioned a combination of genetic, psychological, and biobehavioral factors (such as preexisting risk factors, depression, sleep disorders, physical inactivity, BMI, smoking, alcohol consumption, and adaptability).
Screen and diagnose
“Cancer-related fatigue is one of the most underestimated and least researched side effects,” said Christina Ruhlmann, MD, PhD, an oncology consultant at Odense (Denmark) University Hospital. “It is important to screen for fatigue in cancer patients.”
There are several tools available to enable this screening, she noted. The EORTC Core Quality of Life Questionnaire (EORTC QLQ-C30) is a three-item subscale evaluating the symptoms of fatigue, weakness, and lack of energy. The MD Anderson Symptom Inventory (13 items) assesses fatigue, sleep disorders, and drowsiness. The numeric rating scale (NRS) for fatigue is an 11-point visual self-assessment scale comprising a single element, with 0 representing no fatigue and 10 representing intense fatigue.
When screening for cancer-related fatigue, whenever a score of 4 or more is obtained on the NRS, a diagnostic assessment is needed based on clinical history-taking, fatigue assessment, and evaluation of comorbidities.
When taking the clinical history, information should be obtained on the type of condition, its stage, any relapse or progression, metastases, the date of diagnosis, length of treatment, any cancer or surgical treatments carried out, other treatments administered, and the risk for drug interactions.
In addition, to assess fatigue, the diagnostic process consists of documenting the start, type, and duration of the fatigue, as well as the presence of attenuating factors and interference with activities of daily living and leisure activities.
Seeking information regarding environmental factors such as availability of a support network of family and friends or financial resources is also paramount, said Dr. Ruhlmann.
Finally, contributory factors that may require treatment must be assessed. They include pain, emotional distress, anemia, sleep disorders, nutritional deficiencies, inactivity, smoking and alcohol consumption, and comorbidities (such as cardiac, endocrine, gastrointestinal, hepatic, infectious, and renal conditions).
The following two simple questions can be used to screen for symptoms of depression quickly:
- Over the past month, have you often felt despondent, sad, depressed, or in despair?
- Over the past month, have you found less pleasure than usual in doing the things you normally enjoy doing?
How to treat?
“All of the elements associated with fatigue that can be taken into account ought to be,” stressed Dr. Ruhlmann before insisting on the key role played by physical activity in combating the feeling of exhaustion.
The ESMO recommendations indicate that, according to the results of randomized clinical trials and systematic literature reviews, physical exercise can be recommended in patients with cancer who do not have cachexia (level of evidence I, B).
The type of physical activity recommended is moderate, aerobic, and functional strength exercises (I, B). Walking, aerobic exercises at home, and strength exercises are recommended to improve cancer-related fatigue and quality of life (II, B). “They help with fatigue and also with side effects such as depression, anxiety, pain, and muscle strength,” said Dr. Ruhlmann.
Alongside exercise, and with a lower level of evidence, pharmacologic treatments can sometimes be used (II, B; II, D). Short-term use of dexamethasone or methylprednisolone is recommended for managing fatigue linked to metastatic cancer except during the course of immunotherapy (II, B).
The ESMO expert group did not reach a consensus on the use of methylphenidate, dexmethylphenidate, slow-release methylphenidate, and dexamphetamine.
Modafinil and armodafinil, antidepressants (especially paroxetine), donepezil and eszopiclone, megestrol acetate, and melatonin are not recommended (II, D).
No consensus could be reached on nutraceuticals, and they are not recommended, said Dr. Ruhlmann (II, C; II, D).
Finally, psychosocial interventions in the form of information, advice, psychoeducation, and cognitive-behavioral therapy are useful tools (II, B).
Another area being explored is the gut microbiota. “Research into the microbiota and its role in systemic inflammation is underway and could pave the way for future strategies for managing cancer-related fatigue,” said Dr. Ruhlmann. “Fatigue is a subjective experience, unlike other symptoms. It’s what those people suffering from it say it is!”
This article was translated from the Medscape French edition.
MADRID – These were the messages delivered by speakers at the annual meeting of the European Society for Medical Oncology during a session titled “The Multiple Faces of Fatigue in the Cancer Ecosystem.”
Cancer-related fatigue is said to affect 40% of patients at the time of cancer diagnosis, 65% of patients during active or maintenance treatment, 21%-52% of patients in the 5 years following cancer diagnosis, and even one quarter of patients who are between 5 and 30 years post diagnosis, said Florian Scotté, MD, PhD, head of the interdisciplinary department for the Organization of Patient Pathways at Gustave Roussy Institute in Villejuif, France.
However, he underlines that “up to 50% of cancer survivors report never having discussed their cancer-related fatigue or received advice or support on how to manage it.”
What exactly is this fatigue? According to the definition set out in the ESMO 2020 recommendations and repeated word for word in the latest recommendations issued by the National Comprehensive Cancer Network published on Oct. 6, cancer-related fatigue is “a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.”
Mechanisms at play
The mechanisms at play in cancer-related fatigue are clinical, molecular, and psychological, stated Dr. Scotté.
In terms of the clinical factors responsible for patients’ fatigue, comorbidities such as anemia, diabetes, heart disease, and even psychological conditions are significant elements. In addition, taking medicinal products such as antidepressants or beta-blockers can also cause fatigue. Furthermore, cancer treatment itself has many possible side effects, such as anemia, hypothyroidism, insomnia, pain, and hypopituitarism.
In terms of molecular and physiologic factors, central nervous system dysfunction (inflammation, hypothalamic-pituitary-adrenal axis) leads to perceived reduced physical and mental capacity with no clear motor or cognitive deficiencies. Changes in the peripheral nervous system also cause reduced energy metabolism, which hampers the response of muscles to stimuli, possibly even limiting endurance. Finally, several studies have shown that systemic inflammation is involved in the onset of fatigue.
Dr. Scotté also highlighted the importance of psychological factors, citing depression, psychosocial stress before treatment, negative attention to symptoms, and fear of relapse as key features in the development of cancer-related fatigue.
Among the risk factors for developing cancer-related fatigue, the speaker mentioned a combination of genetic, psychological, and biobehavioral factors (such as preexisting risk factors, depression, sleep disorders, physical inactivity, BMI, smoking, alcohol consumption, and adaptability).
Screen and diagnose
“Cancer-related fatigue is one of the most underestimated and least researched side effects,” said Christina Ruhlmann, MD, PhD, an oncology consultant at Odense (Denmark) University Hospital. “It is important to screen for fatigue in cancer patients.”
There are several tools available to enable this screening, she noted. The EORTC Core Quality of Life Questionnaire (EORTC QLQ-C30) is a three-item subscale evaluating the symptoms of fatigue, weakness, and lack of energy. The MD Anderson Symptom Inventory (13 items) assesses fatigue, sleep disorders, and drowsiness. The numeric rating scale (NRS) for fatigue is an 11-point visual self-assessment scale comprising a single element, with 0 representing no fatigue and 10 representing intense fatigue.
When screening for cancer-related fatigue, whenever a score of 4 or more is obtained on the NRS, a diagnostic assessment is needed based on clinical history-taking, fatigue assessment, and evaluation of comorbidities.
When taking the clinical history, information should be obtained on the type of condition, its stage, any relapse or progression, metastases, the date of diagnosis, length of treatment, any cancer or surgical treatments carried out, other treatments administered, and the risk for drug interactions.
In addition, to assess fatigue, the diagnostic process consists of documenting the start, type, and duration of the fatigue, as well as the presence of attenuating factors and interference with activities of daily living and leisure activities.
Seeking information regarding environmental factors such as availability of a support network of family and friends or financial resources is also paramount, said Dr. Ruhlmann.
Finally, contributory factors that may require treatment must be assessed. They include pain, emotional distress, anemia, sleep disorders, nutritional deficiencies, inactivity, smoking and alcohol consumption, and comorbidities (such as cardiac, endocrine, gastrointestinal, hepatic, infectious, and renal conditions).
The following two simple questions can be used to screen for symptoms of depression quickly:
- Over the past month, have you often felt despondent, sad, depressed, or in despair?
- Over the past month, have you found less pleasure than usual in doing the things you normally enjoy doing?
How to treat?
“All of the elements associated with fatigue that can be taken into account ought to be,” stressed Dr. Ruhlmann before insisting on the key role played by physical activity in combating the feeling of exhaustion.
The ESMO recommendations indicate that, according to the results of randomized clinical trials and systematic literature reviews, physical exercise can be recommended in patients with cancer who do not have cachexia (level of evidence I, B).
The type of physical activity recommended is moderate, aerobic, and functional strength exercises (I, B). Walking, aerobic exercises at home, and strength exercises are recommended to improve cancer-related fatigue and quality of life (II, B). “They help with fatigue and also with side effects such as depression, anxiety, pain, and muscle strength,” said Dr. Ruhlmann.
Alongside exercise, and with a lower level of evidence, pharmacologic treatments can sometimes be used (II, B; II, D). Short-term use of dexamethasone or methylprednisolone is recommended for managing fatigue linked to metastatic cancer except during the course of immunotherapy (II, B).
The ESMO expert group did not reach a consensus on the use of methylphenidate, dexmethylphenidate, slow-release methylphenidate, and dexamphetamine.
Modafinil and armodafinil, antidepressants (especially paroxetine), donepezil and eszopiclone, megestrol acetate, and melatonin are not recommended (II, D).
No consensus could be reached on nutraceuticals, and they are not recommended, said Dr. Ruhlmann (II, C; II, D).
Finally, psychosocial interventions in the form of information, advice, psychoeducation, and cognitive-behavioral therapy are useful tools (II, B).
Another area being explored is the gut microbiota. “Research into the microbiota and its role in systemic inflammation is underway and could pave the way for future strategies for managing cancer-related fatigue,” said Dr. Ruhlmann. “Fatigue is a subjective experience, unlike other symptoms. It’s what those people suffering from it say it is!”
This article was translated from the Medscape French edition.
MADRID – These were the messages delivered by speakers at the annual meeting of the European Society for Medical Oncology during a session titled “The Multiple Faces of Fatigue in the Cancer Ecosystem.”
Cancer-related fatigue is said to affect 40% of patients at the time of cancer diagnosis, 65% of patients during active or maintenance treatment, 21%-52% of patients in the 5 years following cancer diagnosis, and even one quarter of patients who are between 5 and 30 years post diagnosis, said Florian Scotté, MD, PhD, head of the interdisciplinary department for the Organization of Patient Pathways at Gustave Roussy Institute in Villejuif, France.
However, he underlines that “up to 50% of cancer survivors report never having discussed their cancer-related fatigue or received advice or support on how to manage it.”
What exactly is this fatigue? According to the definition set out in the ESMO 2020 recommendations and repeated word for word in the latest recommendations issued by the National Comprehensive Cancer Network published on Oct. 6, cancer-related fatigue is “a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.”
Mechanisms at play
The mechanisms at play in cancer-related fatigue are clinical, molecular, and psychological, stated Dr. Scotté.
In terms of the clinical factors responsible for patients’ fatigue, comorbidities such as anemia, diabetes, heart disease, and even psychological conditions are significant elements. In addition, taking medicinal products such as antidepressants or beta-blockers can also cause fatigue. Furthermore, cancer treatment itself has many possible side effects, such as anemia, hypothyroidism, insomnia, pain, and hypopituitarism.
In terms of molecular and physiologic factors, central nervous system dysfunction (inflammation, hypothalamic-pituitary-adrenal axis) leads to perceived reduced physical and mental capacity with no clear motor or cognitive deficiencies. Changes in the peripheral nervous system also cause reduced energy metabolism, which hampers the response of muscles to stimuli, possibly even limiting endurance. Finally, several studies have shown that systemic inflammation is involved in the onset of fatigue.
Dr. Scotté also highlighted the importance of psychological factors, citing depression, psychosocial stress before treatment, negative attention to symptoms, and fear of relapse as key features in the development of cancer-related fatigue.
Among the risk factors for developing cancer-related fatigue, the speaker mentioned a combination of genetic, psychological, and biobehavioral factors (such as preexisting risk factors, depression, sleep disorders, physical inactivity, BMI, smoking, alcohol consumption, and adaptability).
Screen and diagnose
“Cancer-related fatigue is one of the most underestimated and least researched side effects,” said Christina Ruhlmann, MD, PhD, an oncology consultant at Odense (Denmark) University Hospital. “It is important to screen for fatigue in cancer patients.”
There are several tools available to enable this screening, she noted. The EORTC Core Quality of Life Questionnaire (EORTC QLQ-C30) is a three-item subscale evaluating the symptoms of fatigue, weakness, and lack of energy. The MD Anderson Symptom Inventory (13 items) assesses fatigue, sleep disorders, and drowsiness. The numeric rating scale (NRS) for fatigue is an 11-point visual self-assessment scale comprising a single element, with 0 representing no fatigue and 10 representing intense fatigue.
When screening for cancer-related fatigue, whenever a score of 4 or more is obtained on the NRS, a diagnostic assessment is needed based on clinical history-taking, fatigue assessment, and evaluation of comorbidities.
When taking the clinical history, information should be obtained on the type of condition, its stage, any relapse or progression, metastases, the date of diagnosis, length of treatment, any cancer or surgical treatments carried out, other treatments administered, and the risk for drug interactions.
In addition, to assess fatigue, the diagnostic process consists of documenting the start, type, and duration of the fatigue, as well as the presence of attenuating factors and interference with activities of daily living and leisure activities.
Seeking information regarding environmental factors such as availability of a support network of family and friends or financial resources is also paramount, said Dr. Ruhlmann.
Finally, contributory factors that may require treatment must be assessed. They include pain, emotional distress, anemia, sleep disorders, nutritional deficiencies, inactivity, smoking and alcohol consumption, and comorbidities (such as cardiac, endocrine, gastrointestinal, hepatic, infectious, and renal conditions).
The following two simple questions can be used to screen for symptoms of depression quickly:
- Over the past month, have you often felt despondent, sad, depressed, or in despair?
- Over the past month, have you found less pleasure than usual in doing the things you normally enjoy doing?
How to treat?
“All of the elements associated with fatigue that can be taken into account ought to be,” stressed Dr. Ruhlmann before insisting on the key role played by physical activity in combating the feeling of exhaustion.
The ESMO recommendations indicate that, according to the results of randomized clinical trials and systematic literature reviews, physical exercise can be recommended in patients with cancer who do not have cachexia (level of evidence I, B).
The type of physical activity recommended is moderate, aerobic, and functional strength exercises (I, B). Walking, aerobic exercises at home, and strength exercises are recommended to improve cancer-related fatigue and quality of life (II, B). “They help with fatigue and also with side effects such as depression, anxiety, pain, and muscle strength,” said Dr. Ruhlmann.
Alongside exercise, and with a lower level of evidence, pharmacologic treatments can sometimes be used (II, B; II, D). Short-term use of dexamethasone or methylprednisolone is recommended for managing fatigue linked to metastatic cancer except during the course of immunotherapy (II, B).
The ESMO expert group did not reach a consensus on the use of methylphenidate, dexmethylphenidate, slow-release methylphenidate, and dexamphetamine.
Modafinil and armodafinil, antidepressants (especially paroxetine), donepezil and eszopiclone, megestrol acetate, and melatonin are not recommended (II, D).
No consensus could be reached on nutraceuticals, and they are not recommended, said Dr. Ruhlmann (II, C; II, D).
Finally, psychosocial interventions in the form of information, advice, psychoeducation, and cognitive-behavioral therapy are useful tools (II, B).
Another area being explored is the gut microbiota. “Research into the microbiota and its role in systemic inflammation is underway and could pave the way for future strategies for managing cancer-related fatigue,” said Dr. Ruhlmann. “Fatigue is a subjective experience, unlike other symptoms. It’s what those people suffering from it say it is!”
This article was translated from the Medscape French edition.
AT ESMO 2023
ADC with radiotherapy for brain mets ups risk of necrosis
TOPLINE:
, a new retrospective study suggests.
METHODOLOGY:
- Stereotactic radiotherapy is a key treatment for patients with brain metastases, but some develop radiation necrosis. Because ADCs can help shrink brain metastases as well, the researchers wanted to see whether adding an ADC to stereotactic radiotherapy increased patients’ risk of symptomatic radiation necrosis.
- The study included 98 patients (84% women; median age, 55 years) with brain metastases who received at least one course of stereotactic radiotherapy for intact brain metastases and at least one dose of trastuzumab emtansine, trastuzumab deruxtecan, or sacituzumab govitecan.
- Stereotactic radiotherapy was considered concurrent with ADC therapy if delivered within 7 days before the ADC or within 21 days after the ADC. The control cohort included patients with brain metastases treated sequentially with stereotactic radiotherapy and an ADC.
- Symptomatic radiation necrosis was the primary outcome, and the researchers used competing risks regression models to analyze the impact of concurrent therapy.
TAKEAWAY:
- For the entire cohort, the 24-month cumulative incidence of symptomatic radiation necrosis was 8.5%. ADC therapy given concurrently with stereotactic radiotherapy was associated with higher risk for symptomatic radiation necrosis in univariable analysis (subdistribution hazard ratio, 4.01) and multivariable analysis (SHR, 4.31) that controlled for prior radiotherapy and volume of brain metastases.
- The risk of symptomatic radiation necrosis with concurrent ADC was modest for patients with small brain metastases who received a first course of stereotactic radiotherapy but was substantial for those with larger and reirradiated lesions treated with concurrent ADC.
- For previously radiated lesions, the 24-month risk of necrosis was 42% with concurrent ADC versus 9.4% without concurrent ADC.
- Grade 4-5 symptomatic radiation necrosis following stereotactic radiotherapy was observed in 7.1% of brain metastases treated with concurrent ADC versus 0.7% treated without concurrent ADC. There was no difference in risk between different ADC agents.
IN PRACTICE:
On the basis of current findings, the researchers concluded that “clinicians should be cognizant of the [symptomatic radiation necrosis] risk and monitor patients closely when treating concurrently with ADCs.”
SOURCE:
The study, with first author Emily S. Lebow, MD, of Memorial Sloan Kettering Cancer Center in New York, was published online in JAMA Oncology.
LIMITATIONS:
Limitations include the retrospective study design as well as uncertainty in discriminating between radiation necrosis and local treatment failure.
DISCLOSURES:
The study had no specific funding. Four of the six authors reported various relationships with industry.
A version of this article first appeared on Medscape.com.
TOPLINE:
, a new retrospective study suggests.
METHODOLOGY:
- Stereotactic radiotherapy is a key treatment for patients with brain metastases, but some develop radiation necrosis. Because ADCs can help shrink brain metastases as well, the researchers wanted to see whether adding an ADC to stereotactic radiotherapy increased patients’ risk of symptomatic radiation necrosis.
- The study included 98 patients (84% women; median age, 55 years) with brain metastases who received at least one course of stereotactic radiotherapy for intact brain metastases and at least one dose of trastuzumab emtansine, trastuzumab deruxtecan, or sacituzumab govitecan.
- Stereotactic radiotherapy was considered concurrent with ADC therapy if delivered within 7 days before the ADC or within 21 days after the ADC. The control cohort included patients with brain metastases treated sequentially with stereotactic radiotherapy and an ADC.
- Symptomatic radiation necrosis was the primary outcome, and the researchers used competing risks regression models to analyze the impact of concurrent therapy.
TAKEAWAY:
- For the entire cohort, the 24-month cumulative incidence of symptomatic radiation necrosis was 8.5%. ADC therapy given concurrently with stereotactic radiotherapy was associated with higher risk for symptomatic radiation necrosis in univariable analysis (subdistribution hazard ratio, 4.01) and multivariable analysis (SHR, 4.31) that controlled for prior radiotherapy and volume of brain metastases.
- The risk of symptomatic radiation necrosis with concurrent ADC was modest for patients with small brain metastases who received a first course of stereotactic radiotherapy but was substantial for those with larger and reirradiated lesions treated with concurrent ADC.
- For previously radiated lesions, the 24-month risk of necrosis was 42% with concurrent ADC versus 9.4% without concurrent ADC.
- Grade 4-5 symptomatic radiation necrosis following stereotactic radiotherapy was observed in 7.1% of brain metastases treated with concurrent ADC versus 0.7% treated without concurrent ADC. There was no difference in risk between different ADC agents.
IN PRACTICE:
On the basis of current findings, the researchers concluded that “clinicians should be cognizant of the [symptomatic radiation necrosis] risk and monitor patients closely when treating concurrently with ADCs.”
SOURCE:
The study, with first author Emily S. Lebow, MD, of Memorial Sloan Kettering Cancer Center in New York, was published online in JAMA Oncology.
LIMITATIONS:
Limitations include the retrospective study design as well as uncertainty in discriminating between radiation necrosis and local treatment failure.
DISCLOSURES:
The study had no specific funding. Four of the six authors reported various relationships with industry.
A version of this article first appeared on Medscape.com.
TOPLINE:
, a new retrospective study suggests.
METHODOLOGY:
- Stereotactic radiotherapy is a key treatment for patients with brain metastases, but some develop radiation necrosis. Because ADCs can help shrink brain metastases as well, the researchers wanted to see whether adding an ADC to stereotactic radiotherapy increased patients’ risk of symptomatic radiation necrosis.
- The study included 98 patients (84% women; median age, 55 years) with brain metastases who received at least one course of stereotactic radiotherapy for intact brain metastases and at least one dose of trastuzumab emtansine, trastuzumab deruxtecan, or sacituzumab govitecan.
- Stereotactic radiotherapy was considered concurrent with ADC therapy if delivered within 7 days before the ADC or within 21 days after the ADC. The control cohort included patients with brain metastases treated sequentially with stereotactic radiotherapy and an ADC.
- Symptomatic radiation necrosis was the primary outcome, and the researchers used competing risks regression models to analyze the impact of concurrent therapy.
TAKEAWAY:
- For the entire cohort, the 24-month cumulative incidence of symptomatic radiation necrosis was 8.5%. ADC therapy given concurrently with stereotactic radiotherapy was associated with higher risk for symptomatic radiation necrosis in univariable analysis (subdistribution hazard ratio, 4.01) and multivariable analysis (SHR, 4.31) that controlled for prior radiotherapy and volume of brain metastases.
- The risk of symptomatic radiation necrosis with concurrent ADC was modest for patients with small brain metastases who received a first course of stereotactic radiotherapy but was substantial for those with larger and reirradiated lesions treated with concurrent ADC.
- For previously radiated lesions, the 24-month risk of necrosis was 42% with concurrent ADC versus 9.4% without concurrent ADC.
- Grade 4-5 symptomatic radiation necrosis following stereotactic radiotherapy was observed in 7.1% of brain metastases treated with concurrent ADC versus 0.7% treated without concurrent ADC. There was no difference in risk between different ADC agents.
IN PRACTICE:
On the basis of current findings, the researchers concluded that “clinicians should be cognizant of the [symptomatic radiation necrosis] risk and monitor patients closely when treating concurrently with ADCs.”
SOURCE:
The study, with first author Emily S. Lebow, MD, of Memorial Sloan Kettering Cancer Center in New York, was published online in JAMA Oncology.
LIMITATIONS:
Limitations include the retrospective study design as well as uncertainty in discriminating between radiation necrosis and local treatment failure.
DISCLOSURES:
The study had no specific funding. Four of the six authors reported various relationships with industry.
A version of this article first appeared on Medscape.com.
Omitting surgery may be safe in early BC after neoadjuvant pCR
A small trial headed by MD Anderson Cancer Center, Houston, has helped to further identify women who can safely skip surgery after neoadjuvant therapy for early breast cancer.
Among 50 women in the study with cT1-2N0-1M0 triple negative or HER2-positive disease, 31 (62%) had a complete pathologic response (pCR) to neoadjuvant therapy on image-guided vacuum-assisted core biopsy (VACB).
They went onto whole breast radiation with a boost, but given their response to neoadjuvant treatment and the accuracy of VACB, the women did not have surgery.
So far, it seems to have been the right call: At 3 years, there’s been no tumor recurrences and disease-free and overall survival are both 100%.
Eliminating “breast surgery in highly-selected patients with image-guided VACB-determined pCR following” neoadjuvant systemic therapy has “very promising 3-year results,” lead investigator Henry M. Kuerer, MD, PhD, a breast cancer surgeon at MD Anderson, who presented the findings at the European Society for Medical Oncology (ESMO) 2023 annual meeting.
With the success of modern systemic therapy, “it’s only natural that we think this way,” said Ava Kwong, PhD, chief of breast surgery at the University of Hong Kong, who discussed Dr. Kuerer’s presentation at the meeting.
“This study is really important,” she said. “It’s addressing a very important question whether we can omit surgery in certain groups of patients ... We do want to deescalate surgery,” and the study results are “very good,” she said.
However, larger trials with longer follow-up are needed to draw any firm conclusions, she said.
Dr. Kuerer agreed. He and his team will continue to follow the study subjects, and they have opened up a new trial with 100 patients. A similar study is ongoing in Korea, as well, he noted.
Study details
Women in the trial were a median of 60.4 years old; 58% had HER2-positive and the rest triple-negative unicentric breast cancer. Mean baseline tumor size was 2.8 cm. Just 12% of the participants had lymph node involvement. Neoadjuvant systemic therapy was clinician’s choice.
Breast lesions had to shrink to less than 2 cm on imaging after systemic therapy to be eligible for the study, and a minimum of 12 cores had to be obtained on VACB.
The 38% of women in the study with residual disease after systemic treatment went on to surgery.
Two patients were circulating tumor cell (CTC)-positive at baseline, two were positive at 6 months, and one at 12 months. No patients had CTCs detected at more than one timepoint.
The work was funded by the National Cancer Institute. Dr. Kuerer is an adviser for Merck. Dr. Kwong is an adviser/speaker/reviewer/author for Stryker, AstraZeneca, Merck, and Roche. She also disclosed research funding from Merck, Roche, and Gilead and funding for genetic testing from AstraZeneca.
A small trial headed by MD Anderson Cancer Center, Houston, has helped to further identify women who can safely skip surgery after neoadjuvant therapy for early breast cancer.
Among 50 women in the study with cT1-2N0-1M0 triple negative or HER2-positive disease, 31 (62%) had a complete pathologic response (pCR) to neoadjuvant therapy on image-guided vacuum-assisted core biopsy (VACB).
They went onto whole breast radiation with a boost, but given their response to neoadjuvant treatment and the accuracy of VACB, the women did not have surgery.
So far, it seems to have been the right call: At 3 years, there’s been no tumor recurrences and disease-free and overall survival are both 100%.
Eliminating “breast surgery in highly-selected patients with image-guided VACB-determined pCR following” neoadjuvant systemic therapy has “very promising 3-year results,” lead investigator Henry M. Kuerer, MD, PhD, a breast cancer surgeon at MD Anderson, who presented the findings at the European Society for Medical Oncology (ESMO) 2023 annual meeting.
With the success of modern systemic therapy, “it’s only natural that we think this way,” said Ava Kwong, PhD, chief of breast surgery at the University of Hong Kong, who discussed Dr. Kuerer’s presentation at the meeting.
“This study is really important,” she said. “It’s addressing a very important question whether we can omit surgery in certain groups of patients ... We do want to deescalate surgery,” and the study results are “very good,” she said.
However, larger trials with longer follow-up are needed to draw any firm conclusions, she said.
Dr. Kuerer agreed. He and his team will continue to follow the study subjects, and they have opened up a new trial with 100 patients. A similar study is ongoing in Korea, as well, he noted.
Study details
Women in the trial were a median of 60.4 years old; 58% had HER2-positive and the rest triple-negative unicentric breast cancer. Mean baseline tumor size was 2.8 cm. Just 12% of the participants had lymph node involvement. Neoadjuvant systemic therapy was clinician’s choice.
Breast lesions had to shrink to less than 2 cm on imaging after systemic therapy to be eligible for the study, and a minimum of 12 cores had to be obtained on VACB.
The 38% of women in the study with residual disease after systemic treatment went on to surgery.
Two patients were circulating tumor cell (CTC)-positive at baseline, two were positive at 6 months, and one at 12 months. No patients had CTCs detected at more than one timepoint.
The work was funded by the National Cancer Institute. Dr. Kuerer is an adviser for Merck. Dr. Kwong is an adviser/speaker/reviewer/author for Stryker, AstraZeneca, Merck, and Roche. She also disclosed research funding from Merck, Roche, and Gilead and funding for genetic testing from AstraZeneca.
A small trial headed by MD Anderson Cancer Center, Houston, has helped to further identify women who can safely skip surgery after neoadjuvant therapy for early breast cancer.
Among 50 women in the study with cT1-2N0-1M0 triple negative or HER2-positive disease, 31 (62%) had a complete pathologic response (pCR) to neoadjuvant therapy on image-guided vacuum-assisted core biopsy (VACB).
They went onto whole breast radiation with a boost, but given their response to neoadjuvant treatment and the accuracy of VACB, the women did not have surgery.
So far, it seems to have been the right call: At 3 years, there’s been no tumor recurrences and disease-free and overall survival are both 100%.
Eliminating “breast surgery in highly-selected patients with image-guided VACB-determined pCR following” neoadjuvant systemic therapy has “very promising 3-year results,” lead investigator Henry M. Kuerer, MD, PhD, a breast cancer surgeon at MD Anderson, who presented the findings at the European Society for Medical Oncology (ESMO) 2023 annual meeting.
With the success of modern systemic therapy, “it’s only natural that we think this way,” said Ava Kwong, PhD, chief of breast surgery at the University of Hong Kong, who discussed Dr. Kuerer’s presentation at the meeting.
“This study is really important,” she said. “It’s addressing a very important question whether we can omit surgery in certain groups of patients ... We do want to deescalate surgery,” and the study results are “very good,” she said.
However, larger trials with longer follow-up are needed to draw any firm conclusions, she said.
Dr. Kuerer agreed. He and his team will continue to follow the study subjects, and they have opened up a new trial with 100 patients. A similar study is ongoing in Korea, as well, he noted.
Study details
Women in the trial were a median of 60.4 years old; 58% had HER2-positive and the rest triple-negative unicentric breast cancer. Mean baseline tumor size was 2.8 cm. Just 12% of the participants had lymph node involvement. Neoadjuvant systemic therapy was clinician’s choice.
Breast lesions had to shrink to less than 2 cm on imaging after systemic therapy to be eligible for the study, and a minimum of 12 cores had to be obtained on VACB.
The 38% of women in the study with residual disease after systemic treatment went on to surgery.
Two patients were circulating tumor cell (CTC)-positive at baseline, two were positive at 6 months, and one at 12 months. No patients had CTCs detected at more than one timepoint.
The work was funded by the National Cancer Institute. Dr. Kuerer is an adviser for Merck. Dr. Kwong is an adviser/speaker/reviewer/author for Stryker, AstraZeneca, Merck, and Roche. She also disclosed research funding from Merck, Roche, and Gilead and funding for genetic testing from AstraZeneca.
FROM ESMO 2023
Neoadjuvant, adjuvant, or both? The debate in NSCLC rages on
MADRID – Should patients with resectable non–small cell lung cancer (NSCLC) receive adjuvant therapy, neoadjuvant therapy, or both, experts asked during a special session at the European Society for Medical Oncology 2023 Congress.
said Silke Gillessen, MD, head of the department of medical oncology, Università della Svizzera Italiana in Lugano, Switzerland.
Opening the session, Enriqueta Felip, MD, PhD, argued in favor of adjuvant therapy alone in resectable NSCLC.
Adjuvant immunotherapy after adjuvant chemotherapy is already considered standard of care for patients with resected NSCLC who don’t harbor EGFR and ALK mutations, explained Dr. Felip, head of the lung cancer unit at Vall d’Hebron University Hospital in Barcelona.
One major benefit to providing adjuvant therapy is that curative surgery won’t be delayed. Neoadjuvant therapy, on the other hand, leads about 15% of patients to forgo surgery, and about 30% who have both neoadjuvant therapy and surgery end up not receiving their planned adjuvant immunotherapy.
Another benefit: Emerging evidence suggests that the adjuvant-only option can improve disease-free and overall survival in select patients.
In the IMpower010 trial, for instance, adjuvant atezolizumab led to a marked improvement in disease-free survival, compared with best supportive care in patients with stage II-IIIA NSCLC. Patients with programmed death–ligand 1 expression of 50% or higher also demonstrated an overall survival benefit (hazard ratio, 0.42).
In the KEYNOTE-091 trial, adjuvant pembrolizumab significantly improved disease-free survival in all comers vs. placebo in patients with stage IB, II, or IIIA NSCLC who had surgery (HR, 0.76).
Providing adjuvant-only immunotherapy also allows for biomarker testing in resected specimens, Dr. Felip said, which may affect the choice of systemic therapy.
Next, Rafal Dziadziuszko, MD, PhD, argued in favor of neoadjuvant therapy alone in the setting of resectable NSCLC.
The advantages of providing treatment before surgery include initiating systemic treatment at an earlier point when most relapses are distant, possibly reducing the risk for tumor cell seeding during surgery as well as potentially leading to less invasive surgery by shrinking the tumors.
Dr. Dziadziuszko, from the Medical University of Gdansk in Poland, highlighted data from the Checkmate 816 trial, which showed that neoadjuvant nivolumab plus chemotherapy vs. chemotherapy alone increased the chance of having a pathologic complete response by nearly 14-fold in patients with IB-IIIA resectable NSCLC. Patients in the combination arm also demonstrated marked improvements in event-free survival, 31.6 months vs. 20.8 months, and overall survival.
The NADIM II trial, which coupled nivolumab and chemotherapy in stage III disease, found that neoadjuvant chemoimmunotherapy led to a pathologic complete response as well as a 52% improvement in progression-free survival and a 60% improvement in overall survival, compared with chemotherapy alone.
Despite these findings, several important questions remain, said Dr. Dziadziuszko. How many cycles of neoadjuvant immunochemotherapy should a patient receive before surgery? Will neoadjuvant therapy lead to treatment-related adverse events that preclude surgery? And for those who don’t have a strong response to neoadjuvant therapy, who should also receive adjuvant immunotherapy and for how long?
The latter question represents the “elephant in the room,” session chair Tony S. K. Mok, MD, chairman, department of clinical oncology, The Chinese University of Hong Kong.
With a paucity of overall survival data to provide a definitive answer, oncologists still face the age-old concern of “giving too much therapy in those who don’t need it” and “giving not enough therapy for those who need more,” said Dr. Mok.
Federico Cappuzzo, MD, PhD, argued that the key to patient selection for adjuvant therapy after neoadjuvant therapy and surgery lies in who has a pathologic complete response.
The current data suggest that patients receiving neoadjuvant therapy who achieve a pathologic complete response likely do not need adjuvant therapy whereas those who don’t achieve a complete response should receive adjuvant therapy, explained Dr. Cappuzzo, director of the department of oncology and hematology, AUSL della Romagna, Ravenna, Italy.
But, Dr. Mok asked, what about patients who achieve a major pathologic response in which the percentage of residual viable tumor is 10% or less or achieve less than a major pathologic response?
Dr. Mok suggested that measurable residual disease, which is indicative of recurrence, could potentially be used to determine the treatment pathway after neoadjuvant therapy and signal who may benefit from adjuvant therapy. However, he noted, studies evaluating the benefit of adjuvant therapy in this population would need to be done.
For patients who don’t respond well to neoadjuvant therapy and may benefit from adjuvant therapy, the question also becomes: “Do we give more of that same therapy?” asked Zofia Piotrowska, MD, a lung cancer medical oncologist at Massachusetts General Hospital Cancer Center, Boston, who was not involved in the debate.
“I think we really need to rethink that paradigm and try to develop new therapies that may work more effectively for those patients, to improve their outcomes,” Dr. Piotrowska said.
Dr. Mok declared relationships with a range of companies, including AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, SFJ Pharmaceuticals Roche, Merck Sharp & Dohme, and HutchMed. Dr. Felip declared relationships with AbbVie, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, F Hoffman–La Roche, Genentech, GlaxoSmithKline, Novartis, and others. Dr. Dziadziuszko declared relationships with Roche, AstraZeneca, Bristol-Myers Squibb, Takeda, Pfizer, Novartis, and others. Dr. Cappuzzo declared relationships with Roche, AstraZeneca, Bristol-Myers Squibb, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, and others.
A version of this article first appeared on Medscape.com.
MADRID – Should patients with resectable non–small cell lung cancer (NSCLC) receive adjuvant therapy, neoadjuvant therapy, or both, experts asked during a special session at the European Society for Medical Oncology 2023 Congress.
said Silke Gillessen, MD, head of the department of medical oncology, Università della Svizzera Italiana in Lugano, Switzerland.
Opening the session, Enriqueta Felip, MD, PhD, argued in favor of adjuvant therapy alone in resectable NSCLC.
Adjuvant immunotherapy after adjuvant chemotherapy is already considered standard of care for patients with resected NSCLC who don’t harbor EGFR and ALK mutations, explained Dr. Felip, head of the lung cancer unit at Vall d’Hebron University Hospital in Barcelona.
One major benefit to providing adjuvant therapy is that curative surgery won’t be delayed. Neoadjuvant therapy, on the other hand, leads about 15% of patients to forgo surgery, and about 30% who have both neoadjuvant therapy and surgery end up not receiving their planned adjuvant immunotherapy.
Another benefit: Emerging evidence suggests that the adjuvant-only option can improve disease-free and overall survival in select patients.
In the IMpower010 trial, for instance, adjuvant atezolizumab led to a marked improvement in disease-free survival, compared with best supportive care in patients with stage II-IIIA NSCLC. Patients with programmed death–ligand 1 expression of 50% or higher also demonstrated an overall survival benefit (hazard ratio, 0.42).
In the KEYNOTE-091 trial, adjuvant pembrolizumab significantly improved disease-free survival in all comers vs. placebo in patients with stage IB, II, or IIIA NSCLC who had surgery (HR, 0.76).
Providing adjuvant-only immunotherapy also allows for biomarker testing in resected specimens, Dr. Felip said, which may affect the choice of systemic therapy.
Next, Rafal Dziadziuszko, MD, PhD, argued in favor of neoadjuvant therapy alone in the setting of resectable NSCLC.
The advantages of providing treatment before surgery include initiating systemic treatment at an earlier point when most relapses are distant, possibly reducing the risk for tumor cell seeding during surgery as well as potentially leading to less invasive surgery by shrinking the tumors.
Dr. Dziadziuszko, from the Medical University of Gdansk in Poland, highlighted data from the Checkmate 816 trial, which showed that neoadjuvant nivolumab plus chemotherapy vs. chemotherapy alone increased the chance of having a pathologic complete response by nearly 14-fold in patients with IB-IIIA resectable NSCLC. Patients in the combination arm also demonstrated marked improvements in event-free survival, 31.6 months vs. 20.8 months, and overall survival.
The NADIM II trial, which coupled nivolumab and chemotherapy in stage III disease, found that neoadjuvant chemoimmunotherapy led to a pathologic complete response as well as a 52% improvement in progression-free survival and a 60% improvement in overall survival, compared with chemotherapy alone.
Despite these findings, several important questions remain, said Dr. Dziadziuszko. How many cycles of neoadjuvant immunochemotherapy should a patient receive before surgery? Will neoadjuvant therapy lead to treatment-related adverse events that preclude surgery? And for those who don’t have a strong response to neoadjuvant therapy, who should also receive adjuvant immunotherapy and for how long?
The latter question represents the “elephant in the room,” session chair Tony S. K. Mok, MD, chairman, department of clinical oncology, The Chinese University of Hong Kong.
With a paucity of overall survival data to provide a definitive answer, oncologists still face the age-old concern of “giving too much therapy in those who don’t need it” and “giving not enough therapy for those who need more,” said Dr. Mok.
Federico Cappuzzo, MD, PhD, argued that the key to patient selection for adjuvant therapy after neoadjuvant therapy and surgery lies in who has a pathologic complete response.
The current data suggest that patients receiving neoadjuvant therapy who achieve a pathologic complete response likely do not need adjuvant therapy whereas those who don’t achieve a complete response should receive adjuvant therapy, explained Dr. Cappuzzo, director of the department of oncology and hematology, AUSL della Romagna, Ravenna, Italy.
But, Dr. Mok asked, what about patients who achieve a major pathologic response in which the percentage of residual viable tumor is 10% or less or achieve less than a major pathologic response?
Dr. Mok suggested that measurable residual disease, which is indicative of recurrence, could potentially be used to determine the treatment pathway after neoadjuvant therapy and signal who may benefit from adjuvant therapy. However, he noted, studies evaluating the benefit of adjuvant therapy in this population would need to be done.
For patients who don’t respond well to neoadjuvant therapy and may benefit from adjuvant therapy, the question also becomes: “Do we give more of that same therapy?” asked Zofia Piotrowska, MD, a lung cancer medical oncologist at Massachusetts General Hospital Cancer Center, Boston, who was not involved in the debate.
“I think we really need to rethink that paradigm and try to develop new therapies that may work more effectively for those patients, to improve their outcomes,” Dr. Piotrowska said.
Dr. Mok declared relationships with a range of companies, including AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, SFJ Pharmaceuticals Roche, Merck Sharp & Dohme, and HutchMed. Dr. Felip declared relationships with AbbVie, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, F Hoffman–La Roche, Genentech, GlaxoSmithKline, Novartis, and others. Dr. Dziadziuszko declared relationships with Roche, AstraZeneca, Bristol-Myers Squibb, Takeda, Pfizer, Novartis, and others. Dr. Cappuzzo declared relationships with Roche, AstraZeneca, Bristol-Myers Squibb, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, and others.
A version of this article first appeared on Medscape.com.
MADRID – Should patients with resectable non–small cell lung cancer (NSCLC) receive adjuvant therapy, neoadjuvant therapy, or both, experts asked during a special session at the European Society for Medical Oncology 2023 Congress.
said Silke Gillessen, MD, head of the department of medical oncology, Università della Svizzera Italiana in Lugano, Switzerland.
Opening the session, Enriqueta Felip, MD, PhD, argued in favor of adjuvant therapy alone in resectable NSCLC.
Adjuvant immunotherapy after adjuvant chemotherapy is already considered standard of care for patients with resected NSCLC who don’t harbor EGFR and ALK mutations, explained Dr. Felip, head of the lung cancer unit at Vall d’Hebron University Hospital in Barcelona.
One major benefit to providing adjuvant therapy is that curative surgery won’t be delayed. Neoadjuvant therapy, on the other hand, leads about 15% of patients to forgo surgery, and about 30% who have both neoadjuvant therapy and surgery end up not receiving their planned adjuvant immunotherapy.
Another benefit: Emerging evidence suggests that the adjuvant-only option can improve disease-free and overall survival in select patients.
In the IMpower010 trial, for instance, adjuvant atezolizumab led to a marked improvement in disease-free survival, compared with best supportive care in patients with stage II-IIIA NSCLC. Patients with programmed death–ligand 1 expression of 50% or higher also demonstrated an overall survival benefit (hazard ratio, 0.42).
In the KEYNOTE-091 trial, adjuvant pembrolizumab significantly improved disease-free survival in all comers vs. placebo in patients with stage IB, II, or IIIA NSCLC who had surgery (HR, 0.76).
Providing adjuvant-only immunotherapy also allows for biomarker testing in resected specimens, Dr. Felip said, which may affect the choice of systemic therapy.
Next, Rafal Dziadziuszko, MD, PhD, argued in favor of neoadjuvant therapy alone in the setting of resectable NSCLC.
The advantages of providing treatment before surgery include initiating systemic treatment at an earlier point when most relapses are distant, possibly reducing the risk for tumor cell seeding during surgery as well as potentially leading to less invasive surgery by shrinking the tumors.
Dr. Dziadziuszko, from the Medical University of Gdansk in Poland, highlighted data from the Checkmate 816 trial, which showed that neoadjuvant nivolumab plus chemotherapy vs. chemotherapy alone increased the chance of having a pathologic complete response by nearly 14-fold in patients with IB-IIIA resectable NSCLC. Patients in the combination arm also demonstrated marked improvements in event-free survival, 31.6 months vs. 20.8 months, and overall survival.
The NADIM II trial, which coupled nivolumab and chemotherapy in stage III disease, found that neoadjuvant chemoimmunotherapy led to a pathologic complete response as well as a 52% improvement in progression-free survival and a 60% improvement in overall survival, compared with chemotherapy alone.
Despite these findings, several important questions remain, said Dr. Dziadziuszko. How many cycles of neoadjuvant immunochemotherapy should a patient receive before surgery? Will neoadjuvant therapy lead to treatment-related adverse events that preclude surgery? And for those who don’t have a strong response to neoadjuvant therapy, who should also receive adjuvant immunotherapy and for how long?
The latter question represents the “elephant in the room,” session chair Tony S. K. Mok, MD, chairman, department of clinical oncology, The Chinese University of Hong Kong.
With a paucity of overall survival data to provide a definitive answer, oncologists still face the age-old concern of “giving too much therapy in those who don’t need it” and “giving not enough therapy for those who need more,” said Dr. Mok.
Federico Cappuzzo, MD, PhD, argued that the key to patient selection for adjuvant therapy after neoadjuvant therapy and surgery lies in who has a pathologic complete response.
The current data suggest that patients receiving neoadjuvant therapy who achieve a pathologic complete response likely do not need adjuvant therapy whereas those who don’t achieve a complete response should receive adjuvant therapy, explained Dr. Cappuzzo, director of the department of oncology and hematology, AUSL della Romagna, Ravenna, Italy.
But, Dr. Mok asked, what about patients who achieve a major pathologic response in which the percentage of residual viable tumor is 10% or less or achieve less than a major pathologic response?
Dr. Mok suggested that measurable residual disease, which is indicative of recurrence, could potentially be used to determine the treatment pathway after neoadjuvant therapy and signal who may benefit from adjuvant therapy. However, he noted, studies evaluating the benefit of adjuvant therapy in this population would need to be done.
For patients who don’t respond well to neoadjuvant therapy and may benefit from adjuvant therapy, the question also becomes: “Do we give more of that same therapy?” asked Zofia Piotrowska, MD, a lung cancer medical oncologist at Massachusetts General Hospital Cancer Center, Boston, who was not involved in the debate.
“I think we really need to rethink that paradigm and try to develop new therapies that may work more effectively for those patients, to improve their outcomes,” Dr. Piotrowska said.
Dr. Mok declared relationships with a range of companies, including AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, SFJ Pharmaceuticals Roche, Merck Sharp & Dohme, and HutchMed. Dr. Felip declared relationships with AbbVie, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, F Hoffman–La Roche, Genentech, GlaxoSmithKline, Novartis, and others. Dr. Dziadziuszko declared relationships with Roche, AstraZeneca, Bristol-Myers Squibb, Takeda, Pfizer, Novartis, and others. Dr. Cappuzzo declared relationships with Roche, AstraZeneca, Bristol-Myers Squibb, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, and others.
A version of this article first appeared on Medscape.com.
AT ESMO 2023
Induction chemotherapy in first line improves survival for locally advanced cervical cancer
and should be considered the new standard of care, according to Mary McCormack, MBBS, PhD, a gynecologic and breast oncologist at the University College Hospital, London.
Dr. McCormack was the lead investigator on a phase 3 trial called INTERLACE that tested the approach against stand-alone chemoradiation – the current standard of care – in 500 women, majority in the United Kingdom and Mexico.
She made her comments after presenting the results at the annual meeting of the European Society for Medical Oncology.
The 250 women randomized to induction chemotherapy before chemoradiation (CRT) had a 35% improvement in progression-free survival (PFS), with a 5-year PFS of 73% versus 64% among 250 randomized to CRT alone. Likewise, overall survival (OS) improved 39% in the induction group, with a 5-year OS of 80% versus 72% among women who went straight to CRT.
Induction chemotherapy consisted of 6 weekly doses of carboplatin AUC2 and paclitaxel 80 mg/m2 followed by CRT within 7 days. CRT consisted of 5 weekly doses of cisplatin 40 mg/m2 plus external beam radiotherapy and brachytherapy. Compliance in both arms was high.
“Induction chemotherapy with weekly paclitaxel and carboplatin delivered immediately before chemoradiotherapy should be considered the new standard in locally advanced cervical cancer, and [it] is feasible across diverse healthcare settings,” Dr. McCormack said.
Study discussant Krishnansu Tewari, MD, a gynecologic oncologist at the University of California, Irvine, was impressed by the results.
“This is the first phase 3 randomized trial in locally advanced cervical cancer that has shown [an overall] survival benefit in over 2 decades. Physicians taking care of these patients could consider induction chemotherapy ... tomorrow morning,” he said.
Dr. Tewari brought up how to incorporate the findings with another trial presented earlier at the meeting, KEYNOTE-A18.
KEYNOTE-A18 added pembrolizumab to CRT, which resulted in substantially better PFS and a strong trend towards better OS that could reach statistical significance with additional follow-up.
Both trials are “practice changing” for locally advanced cervical cancer. “I think we are ready for a paradigm shift,” Dr. Tewari said.
He noted a limit in the INTERLACE presentation was that outcomes were not broken down by tumor stage.
Over three-quarters of the women had stage 2 disease; 9% had stage 1 disease, and only 14% had stage 3B or 4A tumors. Almost 60% of the women were node negative.
It’s unclear at this point if women who have node-negative stage 1B3 or stage 2A-B disease “really need induction chemotherapy. I would think that those patients are probably curable by standard chemoradiation plus brachytherapy, and that the real [benefit would be] for stage 3B and 4A patients,” he said.
The median age in the study was 46 years, and 82% of the women had squamous cell tumors.
Grade 3/4 adverse events were higher in the induction arm, 59% versus 48%, driven mostly by a higher incidence of neutropenia and other hematologic adverse events with induction.
One woman died of adverse events in the induction arm and two died in the CRT-alone arm.
Local and pelvic relapse rates were equal in both groups at 16%, but total distant relapses were lower with induction chemotherapy, 12% versus 20%, over a median follow-up of 64 months.
The work was funded by Cancer Research UK. Dr. McCormack is a consultant for AstraZeneca, Eisai, and GSK, and disclosed honoraria/meeting expenses from Daiicho Sankyo, Roche, and Medscape, the publisher of this article. Among other industry ties, Dr. Tewari is an advisor/consultant, researcher, and speaker for Merck, SeaGen, and AstraZeneca.
and should be considered the new standard of care, according to Mary McCormack, MBBS, PhD, a gynecologic and breast oncologist at the University College Hospital, London.
Dr. McCormack was the lead investigator on a phase 3 trial called INTERLACE that tested the approach against stand-alone chemoradiation – the current standard of care – in 500 women, majority in the United Kingdom and Mexico.
She made her comments after presenting the results at the annual meeting of the European Society for Medical Oncology.
The 250 women randomized to induction chemotherapy before chemoradiation (CRT) had a 35% improvement in progression-free survival (PFS), with a 5-year PFS of 73% versus 64% among 250 randomized to CRT alone. Likewise, overall survival (OS) improved 39% in the induction group, with a 5-year OS of 80% versus 72% among women who went straight to CRT.
Induction chemotherapy consisted of 6 weekly doses of carboplatin AUC2 and paclitaxel 80 mg/m2 followed by CRT within 7 days. CRT consisted of 5 weekly doses of cisplatin 40 mg/m2 plus external beam radiotherapy and brachytherapy. Compliance in both arms was high.
“Induction chemotherapy with weekly paclitaxel and carboplatin delivered immediately before chemoradiotherapy should be considered the new standard in locally advanced cervical cancer, and [it] is feasible across diverse healthcare settings,” Dr. McCormack said.
Study discussant Krishnansu Tewari, MD, a gynecologic oncologist at the University of California, Irvine, was impressed by the results.
“This is the first phase 3 randomized trial in locally advanced cervical cancer that has shown [an overall] survival benefit in over 2 decades. Physicians taking care of these patients could consider induction chemotherapy ... tomorrow morning,” he said.
Dr. Tewari brought up how to incorporate the findings with another trial presented earlier at the meeting, KEYNOTE-A18.
KEYNOTE-A18 added pembrolizumab to CRT, which resulted in substantially better PFS and a strong trend towards better OS that could reach statistical significance with additional follow-up.
Both trials are “practice changing” for locally advanced cervical cancer. “I think we are ready for a paradigm shift,” Dr. Tewari said.
He noted a limit in the INTERLACE presentation was that outcomes were not broken down by tumor stage.
Over three-quarters of the women had stage 2 disease; 9% had stage 1 disease, and only 14% had stage 3B or 4A tumors. Almost 60% of the women were node negative.
It’s unclear at this point if women who have node-negative stage 1B3 or stage 2A-B disease “really need induction chemotherapy. I would think that those patients are probably curable by standard chemoradiation plus brachytherapy, and that the real [benefit would be] for stage 3B and 4A patients,” he said.
The median age in the study was 46 years, and 82% of the women had squamous cell tumors.
Grade 3/4 adverse events were higher in the induction arm, 59% versus 48%, driven mostly by a higher incidence of neutropenia and other hematologic adverse events with induction.
One woman died of adverse events in the induction arm and two died in the CRT-alone arm.
Local and pelvic relapse rates were equal in both groups at 16%, but total distant relapses were lower with induction chemotherapy, 12% versus 20%, over a median follow-up of 64 months.
The work was funded by Cancer Research UK. Dr. McCormack is a consultant for AstraZeneca, Eisai, and GSK, and disclosed honoraria/meeting expenses from Daiicho Sankyo, Roche, and Medscape, the publisher of this article. Among other industry ties, Dr. Tewari is an advisor/consultant, researcher, and speaker for Merck, SeaGen, and AstraZeneca.
and should be considered the new standard of care, according to Mary McCormack, MBBS, PhD, a gynecologic and breast oncologist at the University College Hospital, London.
Dr. McCormack was the lead investigator on a phase 3 trial called INTERLACE that tested the approach against stand-alone chemoradiation – the current standard of care – in 500 women, majority in the United Kingdom and Mexico.
She made her comments after presenting the results at the annual meeting of the European Society for Medical Oncology.
The 250 women randomized to induction chemotherapy before chemoradiation (CRT) had a 35% improvement in progression-free survival (PFS), with a 5-year PFS of 73% versus 64% among 250 randomized to CRT alone. Likewise, overall survival (OS) improved 39% in the induction group, with a 5-year OS of 80% versus 72% among women who went straight to CRT.
Induction chemotherapy consisted of 6 weekly doses of carboplatin AUC2 and paclitaxel 80 mg/m2 followed by CRT within 7 days. CRT consisted of 5 weekly doses of cisplatin 40 mg/m2 plus external beam radiotherapy and brachytherapy. Compliance in both arms was high.
“Induction chemotherapy with weekly paclitaxel and carboplatin delivered immediately before chemoradiotherapy should be considered the new standard in locally advanced cervical cancer, and [it] is feasible across diverse healthcare settings,” Dr. McCormack said.
Study discussant Krishnansu Tewari, MD, a gynecologic oncologist at the University of California, Irvine, was impressed by the results.
“This is the first phase 3 randomized trial in locally advanced cervical cancer that has shown [an overall] survival benefit in over 2 decades. Physicians taking care of these patients could consider induction chemotherapy ... tomorrow morning,” he said.
Dr. Tewari brought up how to incorporate the findings with another trial presented earlier at the meeting, KEYNOTE-A18.
KEYNOTE-A18 added pembrolizumab to CRT, which resulted in substantially better PFS and a strong trend towards better OS that could reach statistical significance with additional follow-up.
Both trials are “practice changing” for locally advanced cervical cancer. “I think we are ready for a paradigm shift,” Dr. Tewari said.
He noted a limit in the INTERLACE presentation was that outcomes were not broken down by tumor stage.
Over three-quarters of the women had stage 2 disease; 9% had stage 1 disease, and only 14% had stage 3B or 4A tumors. Almost 60% of the women were node negative.
It’s unclear at this point if women who have node-negative stage 1B3 or stage 2A-B disease “really need induction chemotherapy. I would think that those patients are probably curable by standard chemoradiation plus brachytherapy, and that the real [benefit would be] for stage 3B and 4A patients,” he said.
The median age in the study was 46 years, and 82% of the women had squamous cell tumors.
Grade 3/4 adverse events were higher in the induction arm, 59% versus 48%, driven mostly by a higher incidence of neutropenia and other hematologic adverse events with induction.
One woman died of adverse events in the induction arm and two died in the CRT-alone arm.
Local and pelvic relapse rates were equal in both groups at 16%, but total distant relapses were lower with induction chemotherapy, 12% versus 20%, over a median follow-up of 64 months.
The work was funded by Cancer Research UK. Dr. McCormack is a consultant for AstraZeneca, Eisai, and GSK, and disclosed honoraria/meeting expenses from Daiicho Sankyo, Roche, and Medscape, the publisher of this article. Among other industry ties, Dr. Tewari is an advisor/consultant, researcher, and speaker for Merck, SeaGen, and AstraZeneca.
FROM ESMO CONGRESS 2023
Enfortumab vedotin/pembrolizumab hailed as new standard for upfront mUC
following a phase 3 trial presented at the 2023 European Society for Medical Oncology annual meeting.
The combination soundly beat the current standard of care – platinum-based chemotherapy – with a median overall survival of 31.5 months among 442 subjects versus 16.1 months among 444 randomized to gemcitabine with cisplatin or carboplatin, an unprecedented 53% drop in the risk of mortality (P < .00001).
The elimination of chemotherapy also meant that there were substantially fewer grade 3 or higher adverse events with the new combination.
“This is the first time we’ve managed to beat chemotherapy in the first-line setting for overall survival despite multiple previous attempts.” The 30% remission rate with enfortumab vedotin plus pembrolizumab “is not something we’ve seen before,” said lead investigator Thomas Powles, MBBS, MD, a urologic oncologist and researcher at the University of London, who presented the findings.
“We welcome a new standard of care in the management of advanced, metastatic urothelial carcinoma, enfortumab vedotin plus pembrolizumab,” said Andrea Apolo, MD, a urologic oncology researcher at the National Cancer Institute in Bethesda, Md., and discussant on the trial, dubbed EV-302/KEYNOTE-A39.
The news overshadowed a second trial presented immediately after Dr. Powles’ that also showed improvement in overall survival versus standard platinum-based chemotherapy, CheckMate 901.
Instead of replacing chemotherapy, CheckMate 901 added nivolumab. With 304 patients randomized to each arm, nivolumab add-on led to a median overall survival of 21.7 months versus 18.9 months with stand-alone gemcitabine/cisplatin, a 22% drop in the risk of mortality (P = .0171).
It’s the first time that adding immunotherapy to first-line chemotherapy improved survival in metastatic urothelial carcinoma, said lead investigator Michiel van der Heijden, MD, PhD, a urologic oncologist and researcher at the Netherlands Cancer Institute, Amsterdam.
After decades of stagnation, Dr. Apolo said, it’s “monumental for our field” to have two trials that beat chemotherapy in the first-line setting.
However, she said that the much better survival with enfortumab vedotin/pembrolizumab means that the combination now “takes first place as the best first-line regimen in urothelial carcinoma.”
Major disruptions in the treatment paradigm
The crowning of a new first-line standard for locally advanced/metastatic urothelial carcinoma means that everything else in the treatment paradigm has to shift, Dr. Apolo said, and there are many new questions that need to be answered.
Among the most pressing, should the previous first-line standard – platinum-based chemotherapy – now move to the second line and be considered the treatment of choice after progression? Also, is there still a role for the previous second-line standards, pembrolizumab and other immunotherapies, if pembrolizumab fails in the first line?
Dr. Apolo said investigators also need to figure out if there is a role for enfortumab vedotin/pembrolizumab in earlier-stage disease, such as muscle-invasive bladder cancer, and if the dose and duration of enfortumab vedotin can be reduced to limit its peculiar ocular and other toxicities.
Finally, “we must discuss cost,” she said. Enfortumab vedotin plus pembrolizumab (EV+P) is expensive. “Will payers be able to afford” it?
Dr. Powles, the lead investigator on EV-302/KEYNOTE-A39, said he doesn’t know how negotiations are going with payers, but that he hopes they move quickly. “We’ve seen transformative results” with the combination for even aggressive cancers in very sick people. “I think it’s going to be a challenge with patients not to talk about these data.”
EV-302/KEYNOTE-059 details
Merck, the maker of pembrolizumab, and the makers/marketers of enfortumab vedotin, Astellas and Seagen, said they will use EV-302/KEYNOTE-059 to seek a first-line indication for locally advanced/metastatic urothelial carcinoma from the U.S. Food and Drug Administration and other regulators.
They also said the results serve as the confirmation FDA required when it gave accelerated approval to the combination in April 2023 for cisplatin-ineligible patients based on tumor response rates and response durability, according to press releases from the companies.
Pembrolizumab (P) in the trial was dosed at 200 mg on the first day of 3-week treatment cycles to a maximum of 35 cycles; enfortumab vedotin (EV) was given on the first and eighth day of the cycle with no limit in the number of cycles until progression or unacceptable toxicity.
Cisplatin or carboplatin (C) in the control arm was delivered on the first day and gemcitabine (G) on the first and eighth days for up to six 3-week cycles.
Patients in both arms were split about equally between performance statuses of 0 or 1; less than 4% in each group had statuses of 2.
Echoing the overall survival (OS) results, progression-free survival (PFS) was a median of 12.5 months with EV-P versus 6.3 months with GC, a 55% drop in the risk of progression or death (P < .00001).
The results held regardless of PD-L1 expression, cisplatin eligibility, and the presence or absence of visceral metastases.
Follow-up treatments in the trial begin to address Dr. Apolo’s questions: Almost 60% of GC patients went on to a PD-1/L1 for subsequent maintenance or progression, and almost a quarter of EV+P patients went on to subsequent platinum-based chemotherapy.
Grade 3 or higher adverse events occurred in 55.9% of subjects in the EV+P group versus 69.5% in the GC arm.
The most common in the chemotherapy arm were anemia, neutropenia, thrombocytopenia, fatigue, and nausea. The most common with EV+P were skin reactions, hyperglycemia, neutropenia, peripheral neuropathy, diarrhea, and anemia,
CheckMate 901 details
In CheckMate 901, gemcitabine and cisplatin were administered on the first day of 3-week treatment cycles for up to 6 cycles; subjects randomized to nivolumab add-on received 360 mg on day 1 of each cycle, followed by 480 mg every 4 weeks until disease progression or unacceptable toxicity for up to 2 years.
PFS results again mirrored OS, with a median PFS of 7.9 months in the nivolumab arm versus 7.6 months with stand-alone chemotherapy, a 28% drop in the risk of progression or death (P = .0012).
Although OS and PFS benefits were statistically significant overall, they were not significant in subgroup analyses of patients 65 years and older, women, or in patients with liver metastases.
Trends in OS and PFS actually favored chemotherapy in the 40 U.S. subjects (HR OS, 1.92; 95% confidence interval, 0.95-3.88).
The rate of grade 3 or higher adverse events was 61.8% with nivolumab add-on versus 51.7% with chemotherapy alone. Anemia and neutropenia were the most common in both arms, and higher in the nivolumab group.
EV-302/KEYNOTE-A39 was funded by Seagen, Astellas, and Merck. CheckMate 901 was funded by Bristol-Myers Squibb, the maker of nivolumab.
Dr. Powles reported extensive financial ties to pharmaceutical companies, including being an advisor to and receiving research funding from Bristol-Myers Squibb, Merck, SeaGen, and Astellas, as well as travel expenses from Merck. Among other disclosures, Dr. Heijden is an advisor to Seagen and an advisor and researcher for Bristol-Myers Squibb. Dr. Apolo is an unpaid consultant to Merck, Astellas, Seagen, Bristol-Myers Squibb, and other companies.
following a phase 3 trial presented at the 2023 European Society for Medical Oncology annual meeting.
The combination soundly beat the current standard of care – platinum-based chemotherapy – with a median overall survival of 31.5 months among 442 subjects versus 16.1 months among 444 randomized to gemcitabine with cisplatin or carboplatin, an unprecedented 53% drop in the risk of mortality (P < .00001).
The elimination of chemotherapy also meant that there were substantially fewer grade 3 or higher adverse events with the new combination.
“This is the first time we’ve managed to beat chemotherapy in the first-line setting for overall survival despite multiple previous attempts.” The 30% remission rate with enfortumab vedotin plus pembrolizumab “is not something we’ve seen before,” said lead investigator Thomas Powles, MBBS, MD, a urologic oncologist and researcher at the University of London, who presented the findings.
“We welcome a new standard of care in the management of advanced, metastatic urothelial carcinoma, enfortumab vedotin plus pembrolizumab,” said Andrea Apolo, MD, a urologic oncology researcher at the National Cancer Institute in Bethesda, Md., and discussant on the trial, dubbed EV-302/KEYNOTE-A39.
The news overshadowed a second trial presented immediately after Dr. Powles’ that also showed improvement in overall survival versus standard platinum-based chemotherapy, CheckMate 901.
Instead of replacing chemotherapy, CheckMate 901 added nivolumab. With 304 patients randomized to each arm, nivolumab add-on led to a median overall survival of 21.7 months versus 18.9 months with stand-alone gemcitabine/cisplatin, a 22% drop in the risk of mortality (P = .0171).
It’s the first time that adding immunotherapy to first-line chemotherapy improved survival in metastatic urothelial carcinoma, said lead investigator Michiel van der Heijden, MD, PhD, a urologic oncologist and researcher at the Netherlands Cancer Institute, Amsterdam.
After decades of stagnation, Dr. Apolo said, it’s “monumental for our field” to have two trials that beat chemotherapy in the first-line setting.
However, she said that the much better survival with enfortumab vedotin/pembrolizumab means that the combination now “takes first place as the best first-line regimen in urothelial carcinoma.”
Major disruptions in the treatment paradigm
The crowning of a new first-line standard for locally advanced/metastatic urothelial carcinoma means that everything else in the treatment paradigm has to shift, Dr. Apolo said, and there are many new questions that need to be answered.
Among the most pressing, should the previous first-line standard – platinum-based chemotherapy – now move to the second line and be considered the treatment of choice after progression? Also, is there still a role for the previous second-line standards, pembrolizumab and other immunotherapies, if pembrolizumab fails in the first line?
Dr. Apolo said investigators also need to figure out if there is a role for enfortumab vedotin/pembrolizumab in earlier-stage disease, such as muscle-invasive bladder cancer, and if the dose and duration of enfortumab vedotin can be reduced to limit its peculiar ocular and other toxicities.
Finally, “we must discuss cost,” she said. Enfortumab vedotin plus pembrolizumab (EV+P) is expensive. “Will payers be able to afford” it?
Dr. Powles, the lead investigator on EV-302/KEYNOTE-A39, said he doesn’t know how negotiations are going with payers, but that he hopes they move quickly. “We’ve seen transformative results” with the combination for even aggressive cancers in very sick people. “I think it’s going to be a challenge with patients not to talk about these data.”
EV-302/KEYNOTE-059 details
Merck, the maker of pembrolizumab, and the makers/marketers of enfortumab vedotin, Astellas and Seagen, said they will use EV-302/KEYNOTE-059 to seek a first-line indication for locally advanced/metastatic urothelial carcinoma from the U.S. Food and Drug Administration and other regulators.
They also said the results serve as the confirmation FDA required when it gave accelerated approval to the combination in April 2023 for cisplatin-ineligible patients based on tumor response rates and response durability, according to press releases from the companies.
Pembrolizumab (P) in the trial was dosed at 200 mg on the first day of 3-week treatment cycles to a maximum of 35 cycles; enfortumab vedotin (EV) was given on the first and eighth day of the cycle with no limit in the number of cycles until progression or unacceptable toxicity.
Cisplatin or carboplatin (C) in the control arm was delivered on the first day and gemcitabine (G) on the first and eighth days for up to six 3-week cycles.
Patients in both arms were split about equally between performance statuses of 0 or 1; less than 4% in each group had statuses of 2.
Echoing the overall survival (OS) results, progression-free survival (PFS) was a median of 12.5 months with EV-P versus 6.3 months with GC, a 55% drop in the risk of progression or death (P < .00001).
The results held regardless of PD-L1 expression, cisplatin eligibility, and the presence or absence of visceral metastases.
Follow-up treatments in the trial begin to address Dr. Apolo’s questions: Almost 60% of GC patients went on to a PD-1/L1 for subsequent maintenance or progression, and almost a quarter of EV+P patients went on to subsequent platinum-based chemotherapy.
Grade 3 or higher adverse events occurred in 55.9% of subjects in the EV+P group versus 69.5% in the GC arm.
The most common in the chemotherapy arm were anemia, neutropenia, thrombocytopenia, fatigue, and nausea. The most common with EV+P were skin reactions, hyperglycemia, neutropenia, peripheral neuropathy, diarrhea, and anemia,
CheckMate 901 details
In CheckMate 901, gemcitabine and cisplatin were administered on the first day of 3-week treatment cycles for up to 6 cycles; subjects randomized to nivolumab add-on received 360 mg on day 1 of each cycle, followed by 480 mg every 4 weeks until disease progression or unacceptable toxicity for up to 2 years.
PFS results again mirrored OS, with a median PFS of 7.9 months in the nivolumab arm versus 7.6 months with stand-alone chemotherapy, a 28% drop in the risk of progression or death (P = .0012).
Although OS and PFS benefits were statistically significant overall, they were not significant in subgroup analyses of patients 65 years and older, women, or in patients with liver metastases.
Trends in OS and PFS actually favored chemotherapy in the 40 U.S. subjects (HR OS, 1.92; 95% confidence interval, 0.95-3.88).
The rate of grade 3 or higher adverse events was 61.8% with nivolumab add-on versus 51.7% with chemotherapy alone. Anemia and neutropenia were the most common in both arms, and higher in the nivolumab group.
EV-302/KEYNOTE-A39 was funded by Seagen, Astellas, and Merck. CheckMate 901 was funded by Bristol-Myers Squibb, the maker of nivolumab.
Dr. Powles reported extensive financial ties to pharmaceutical companies, including being an advisor to and receiving research funding from Bristol-Myers Squibb, Merck, SeaGen, and Astellas, as well as travel expenses from Merck. Among other disclosures, Dr. Heijden is an advisor to Seagen and an advisor and researcher for Bristol-Myers Squibb. Dr. Apolo is an unpaid consultant to Merck, Astellas, Seagen, Bristol-Myers Squibb, and other companies.
following a phase 3 trial presented at the 2023 European Society for Medical Oncology annual meeting.
The combination soundly beat the current standard of care – platinum-based chemotherapy – with a median overall survival of 31.5 months among 442 subjects versus 16.1 months among 444 randomized to gemcitabine with cisplatin or carboplatin, an unprecedented 53% drop in the risk of mortality (P < .00001).
The elimination of chemotherapy also meant that there were substantially fewer grade 3 or higher adverse events with the new combination.
“This is the first time we’ve managed to beat chemotherapy in the first-line setting for overall survival despite multiple previous attempts.” The 30% remission rate with enfortumab vedotin plus pembrolizumab “is not something we’ve seen before,” said lead investigator Thomas Powles, MBBS, MD, a urologic oncologist and researcher at the University of London, who presented the findings.
“We welcome a new standard of care in the management of advanced, metastatic urothelial carcinoma, enfortumab vedotin plus pembrolizumab,” said Andrea Apolo, MD, a urologic oncology researcher at the National Cancer Institute in Bethesda, Md., and discussant on the trial, dubbed EV-302/KEYNOTE-A39.
The news overshadowed a second trial presented immediately after Dr. Powles’ that also showed improvement in overall survival versus standard platinum-based chemotherapy, CheckMate 901.
Instead of replacing chemotherapy, CheckMate 901 added nivolumab. With 304 patients randomized to each arm, nivolumab add-on led to a median overall survival of 21.7 months versus 18.9 months with stand-alone gemcitabine/cisplatin, a 22% drop in the risk of mortality (P = .0171).
It’s the first time that adding immunotherapy to first-line chemotherapy improved survival in metastatic urothelial carcinoma, said lead investigator Michiel van der Heijden, MD, PhD, a urologic oncologist and researcher at the Netherlands Cancer Institute, Amsterdam.
After decades of stagnation, Dr. Apolo said, it’s “monumental for our field” to have two trials that beat chemotherapy in the first-line setting.
However, she said that the much better survival with enfortumab vedotin/pembrolizumab means that the combination now “takes first place as the best first-line regimen in urothelial carcinoma.”
Major disruptions in the treatment paradigm
The crowning of a new first-line standard for locally advanced/metastatic urothelial carcinoma means that everything else in the treatment paradigm has to shift, Dr. Apolo said, and there are many new questions that need to be answered.
Among the most pressing, should the previous first-line standard – platinum-based chemotherapy – now move to the second line and be considered the treatment of choice after progression? Also, is there still a role for the previous second-line standards, pembrolizumab and other immunotherapies, if pembrolizumab fails in the first line?
Dr. Apolo said investigators also need to figure out if there is a role for enfortumab vedotin/pembrolizumab in earlier-stage disease, such as muscle-invasive bladder cancer, and if the dose and duration of enfortumab vedotin can be reduced to limit its peculiar ocular and other toxicities.
Finally, “we must discuss cost,” she said. Enfortumab vedotin plus pembrolizumab (EV+P) is expensive. “Will payers be able to afford” it?
Dr. Powles, the lead investigator on EV-302/KEYNOTE-A39, said he doesn’t know how negotiations are going with payers, but that he hopes they move quickly. “We’ve seen transformative results” with the combination for even aggressive cancers in very sick people. “I think it’s going to be a challenge with patients not to talk about these data.”
EV-302/KEYNOTE-059 details
Merck, the maker of pembrolizumab, and the makers/marketers of enfortumab vedotin, Astellas and Seagen, said they will use EV-302/KEYNOTE-059 to seek a first-line indication for locally advanced/metastatic urothelial carcinoma from the U.S. Food and Drug Administration and other regulators.
They also said the results serve as the confirmation FDA required when it gave accelerated approval to the combination in April 2023 for cisplatin-ineligible patients based on tumor response rates and response durability, according to press releases from the companies.
Pembrolizumab (P) in the trial was dosed at 200 mg on the first day of 3-week treatment cycles to a maximum of 35 cycles; enfortumab vedotin (EV) was given on the first and eighth day of the cycle with no limit in the number of cycles until progression or unacceptable toxicity.
Cisplatin or carboplatin (C) in the control arm was delivered on the first day and gemcitabine (G) on the first and eighth days for up to six 3-week cycles.
Patients in both arms were split about equally between performance statuses of 0 or 1; less than 4% in each group had statuses of 2.
Echoing the overall survival (OS) results, progression-free survival (PFS) was a median of 12.5 months with EV-P versus 6.3 months with GC, a 55% drop in the risk of progression or death (P < .00001).
The results held regardless of PD-L1 expression, cisplatin eligibility, and the presence or absence of visceral metastases.
Follow-up treatments in the trial begin to address Dr. Apolo’s questions: Almost 60% of GC patients went on to a PD-1/L1 for subsequent maintenance or progression, and almost a quarter of EV+P patients went on to subsequent platinum-based chemotherapy.
Grade 3 or higher adverse events occurred in 55.9% of subjects in the EV+P group versus 69.5% in the GC arm.
The most common in the chemotherapy arm were anemia, neutropenia, thrombocytopenia, fatigue, and nausea. The most common with EV+P were skin reactions, hyperglycemia, neutropenia, peripheral neuropathy, diarrhea, and anemia,
CheckMate 901 details
In CheckMate 901, gemcitabine and cisplatin were administered on the first day of 3-week treatment cycles for up to 6 cycles; subjects randomized to nivolumab add-on received 360 mg on day 1 of each cycle, followed by 480 mg every 4 weeks until disease progression or unacceptable toxicity for up to 2 years.
PFS results again mirrored OS, with a median PFS of 7.9 months in the nivolumab arm versus 7.6 months with stand-alone chemotherapy, a 28% drop in the risk of progression or death (P = .0012).
Although OS and PFS benefits were statistically significant overall, they were not significant in subgroup analyses of patients 65 years and older, women, or in patients with liver metastases.
Trends in OS and PFS actually favored chemotherapy in the 40 U.S. subjects (HR OS, 1.92; 95% confidence interval, 0.95-3.88).
The rate of grade 3 or higher adverse events was 61.8% with nivolumab add-on versus 51.7% with chemotherapy alone. Anemia and neutropenia were the most common in both arms, and higher in the nivolumab group.
EV-302/KEYNOTE-A39 was funded by Seagen, Astellas, and Merck. CheckMate 901 was funded by Bristol-Myers Squibb, the maker of nivolumab.
Dr. Powles reported extensive financial ties to pharmaceutical companies, including being an advisor to and receiving research funding from Bristol-Myers Squibb, Merck, SeaGen, and Astellas, as well as travel expenses from Merck. Among other disclosures, Dr. Heijden is an advisor to Seagen and an advisor and researcher for Bristol-Myers Squibb. Dr. Apolo is an unpaid consultant to Merck, Astellas, Seagen, Bristol-Myers Squibb, and other companies.
FROM ESMO 2023