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Although rates are generally low, interstitial lung disease (ILD) can occur at any point in the first year of treatment with trastuzumab deruxtecan (T-DXd) for HER2-positive metastatic breast cancer (MBC).
That’s according to a pooled analysis of three early clinical trials with the drug that was reported at the European Society for Medical Oncology (ESMO): Breast Cancer virtual meeting.
Over a 5-year analysis period, the rate of any grade of ILD was 15.5%. The majority (79%) of those events were grade 1 or 2, observed pulmonologist Charles A. Powell, MD, of Icahn School of Medicine at Mount Sinai in New York, who presented the findings.
Of the 245 patients who were included in the analysis, 38 had an ILD event deemed related to treatment. A respective 9 (3.7%) and 21 (8.6%) had events graded as 1 or 2, 1 patient each (0.4%) had a grade 3 or 4 event, and 6 (2.4%) patients had a grade 5 event.
The timing of the first identified ILD event varied from 1.1 months to 20.8 months, given a median of 5.6 months overall. “This highlights an opportunity for more timely detection of ILD,” Dr. Powell suggested. He added that in almost all (97%) cases, ILD occurred before 12 months and the risk may even decrease over time “suggesting that the risk is not cumulative.”
He cautioned, however: “It is important to note that this analysis is exploratory and hypothesis generating in nature.”
ILD occurs with other cancer drugs
ILD is not just associated with T-DXd treatment, said the invited discussant for the trial, Harold J. Burstein, MD, PhD, of the Dana-Farber Cancer Institute in Boston.
“It’s important for clinicians to remember that ILD/pneumonitis is an uncommon, but potentially very serious side effect that affects many breast cancer treatments,” he said.
That not only includes T-DXd, but other newer drugs such the cyclin dependent kinase (CDK) 4/6 inhibitors and immune checkpoint inhibitors, as well as other older more established drugs including taxanes, cyclophosphamide and even the mTOR inhibitor everolimus.
“Both clinicians and patients need to be aware of this risk. It’s part of the differential diagnosis for any patient who develops either ground glass changes or other infiltrates on a CT scan, or who has symptoms,” Dr. Burstein added.
Investigating ILD in T-DXd trials
T-DXd (Enhertu) is an anti-HER2-antibody drug conjugate that contains a humanized anti-HER2 IgG1 monoclonal antibody akin to trastuzumab that is linked to DXd, a topoisomerase I inhibitor that is a derivative of exatecan.
It has been approved for use in patients with HER2-positive metastatic breast cancer after two other HER2 treatments fail in the United States and Europe, and after chemotherapy in Japan, noted Dr. Powell. This is largely due to the results from the phase 2, open-label DESTINY-Breast01 trial.
“In breast cancer, T-DXd continues to demonstrate clinically meaningful efficacy with a median duration of response of more than 20 months in a heavily pretreated population,” he said. Objective response rates seen in the DESTINY-Breast01 trial were around 60%, and the median progression-free survival was a little over 19 months.
To look at the issue of drug-related ILD events in patients treated with T-DXd for HER2-positive MBC, an independent adjudication committee was formed to look at all the imaging and clinical data from the DESTINY-Breast01 trial and two single-arm phase 1 trials (NCT02564900 and NCT03383692).
In all, data on 245 patients who had been treated with T-DXd at the approved dose of 5.4 mg/kg in those trials between August 2015 and June 2020 were analyzed.
Dealing with lung toxicity
“We are getting new drugs to improve the treatment of cancer, but they always come with a price in terms of toxicity,” observed David Cameron, MD, professor of medical oncology at Edinburgh University in Scotland. Dr. Cameron chaired the session.
“Several measures were taken to identify and mitigate ILD,” across all the T-DXd studies, Dr. Powell explained. As well as the independent adjudication committee, available guidelines were followed and updated on how to diagnose and treat drug-induced lung injuries, and a “safe use” campaign was run in 2019.
Many patients in the early MBC studies were recruited before these measures were in place, such as the use of systemic steroids to manage low-grade events.
The bottom line, however, is that if a patient develops ILD then treatment should be stopped, Dr. Powell said. “Patients with grade 1 events may restart once the ILD has resolved, but those with grade 2 to 4 events must discontinue treatment.”
Dr. Powell concluded: “The overall clinical data support the positive risk-benefit profile of T-DXd. Phase 3 randomized controlled trials in breast cancer are ongoing.”
ILD also seen in monarchE trial with abemaciclib
Data on ILD events seen in the phase 3 monarchE trial were also reported separately at the ESMO Breast Cancer virtual meeting. The analysis population included 2,971 patients who had been treated with the CDK 4/6 inhibitor abemaciclib (Verzenio) together with endocrine therapy and 2,800 who had received endocrine therapy alone in the early-stage, adjuvant advanced breast cancer setting.
Most ILD (97%) events that occurred were single occurrences, with any grade of ILD occurring in a higher percentage of patients treated with abemaciclib with endocrine therapy than endocrine therapy alone (2.9% vs. 1.2%). Grade 3 events occurred in a respective 0.4% and 0.0% of patients.
So who’s at risk?
The risk factors for ILD and pneumonitis are not well characterized with either of the two drugs discussed, Dr. Burstein observed.
“In the abemaciclib experience, it looked like obesity might be a predisposing factor, with trastuzumab deruxtecan, it looked like patients of Asian ancestry were greater risk, but we need more data to really understand who’s at jeopardy.”
Dr. Burstein observed: “This is something patients need to be aware of as they’re contemplating this treatment.”
While data to prove the benefit of the drug need to mature, Dr. Burstein “would likely discontinue therapy” if a patient were to develop ILD or pneumonitis and treat accordingly.
As for T-DXd, he said: “It’s important that patients know that lung disease is a potentially severe side effect of treatment and that any respiratory symptoms need to be jumped on quickly.”
While prospective studies are now needed, and the phase 3 data should help to better understand the risk of ILD with T-DXd, Dr. Burstein believes it will be important to develop algorithms to ensure the safe administration of the drug.
These algorithms should include “appropriate surveillance and monitoring, especially as we think about trying to move this drug forward into the early stage setting where we’re using it in women who have favorable prognosis, and potentially curative situations for breast cancer.”
The trastuzumab deruxtecan trials were cosponsored by Daiichi Sankyo and AstraZeneca. The monarchE trial was supported by Eli Lilly.
Dr. Powell acknowledged receiving personal fees for acting as an advisory or consultant to both companies as well as to Voluntis. Dr. Burstein had nothing to disclose, and Dr. Cameron had no relevant financial interests in the data being presented.
Although rates are generally low, interstitial lung disease (ILD) can occur at any point in the first year of treatment with trastuzumab deruxtecan (T-DXd) for HER2-positive metastatic breast cancer (MBC).
That’s according to a pooled analysis of three early clinical trials with the drug that was reported at the European Society for Medical Oncology (ESMO): Breast Cancer virtual meeting.
Over a 5-year analysis period, the rate of any grade of ILD was 15.5%. The majority (79%) of those events were grade 1 or 2, observed pulmonologist Charles A. Powell, MD, of Icahn School of Medicine at Mount Sinai in New York, who presented the findings.
Of the 245 patients who were included in the analysis, 38 had an ILD event deemed related to treatment. A respective 9 (3.7%) and 21 (8.6%) had events graded as 1 or 2, 1 patient each (0.4%) had a grade 3 or 4 event, and 6 (2.4%) patients had a grade 5 event.
The timing of the first identified ILD event varied from 1.1 months to 20.8 months, given a median of 5.6 months overall. “This highlights an opportunity for more timely detection of ILD,” Dr. Powell suggested. He added that in almost all (97%) cases, ILD occurred before 12 months and the risk may even decrease over time “suggesting that the risk is not cumulative.”
He cautioned, however: “It is important to note that this analysis is exploratory and hypothesis generating in nature.”
ILD occurs with other cancer drugs
ILD is not just associated with T-DXd treatment, said the invited discussant for the trial, Harold J. Burstein, MD, PhD, of the Dana-Farber Cancer Institute in Boston.
“It’s important for clinicians to remember that ILD/pneumonitis is an uncommon, but potentially very serious side effect that affects many breast cancer treatments,” he said.
That not only includes T-DXd, but other newer drugs such the cyclin dependent kinase (CDK) 4/6 inhibitors and immune checkpoint inhibitors, as well as other older more established drugs including taxanes, cyclophosphamide and even the mTOR inhibitor everolimus.
“Both clinicians and patients need to be aware of this risk. It’s part of the differential diagnosis for any patient who develops either ground glass changes or other infiltrates on a CT scan, or who has symptoms,” Dr. Burstein added.
Investigating ILD in T-DXd trials
T-DXd (Enhertu) is an anti-HER2-antibody drug conjugate that contains a humanized anti-HER2 IgG1 monoclonal antibody akin to trastuzumab that is linked to DXd, a topoisomerase I inhibitor that is a derivative of exatecan.
It has been approved for use in patients with HER2-positive metastatic breast cancer after two other HER2 treatments fail in the United States and Europe, and after chemotherapy in Japan, noted Dr. Powell. This is largely due to the results from the phase 2, open-label DESTINY-Breast01 trial.
“In breast cancer, T-DXd continues to demonstrate clinically meaningful efficacy with a median duration of response of more than 20 months in a heavily pretreated population,” he said. Objective response rates seen in the DESTINY-Breast01 trial were around 60%, and the median progression-free survival was a little over 19 months.
To look at the issue of drug-related ILD events in patients treated with T-DXd for HER2-positive MBC, an independent adjudication committee was formed to look at all the imaging and clinical data from the DESTINY-Breast01 trial and two single-arm phase 1 trials (NCT02564900 and NCT03383692).
In all, data on 245 patients who had been treated with T-DXd at the approved dose of 5.4 mg/kg in those trials between August 2015 and June 2020 were analyzed.
Dealing with lung toxicity
“We are getting new drugs to improve the treatment of cancer, but they always come with a price in terms of toxicity,” observed David Cameron, MD, professor of medical oncology at Edinburgh University in Scotland. Dr. Cameron chaired the session.
“Several measures were taken to identify and mitigate ILD,” across all the T-DXd studies, Dr. Powell explained. As well as the independent adjudication committee, available guidelines were followed and updated on how to diagnose and treat drug-induced lung injuries, and a “safe use” campaign was run in 2019.
Many patients in the early MBC studies were recruited before these measures were in place, such as the use of systemic steroids to manage low-grade events.
The bottom line, however, is that if a patient develops ILD then treatment should be stopped, Dr. Powell said. “Patients with grade 1 events may restart once the ILD has resolved, but those with grade 2 to 4 events must discontinue treatment.”
Dr. Powell concluded: “The overall clinical data support the positive risk-benefit profile of T-DXd. Phase 3 randomized controlled trials in breast cancer are ongoing.”
ILD also seen in monarchE trial with abemaciclib
Data on ILD events seen in the phase 3 monarchE trial were also reported separately at the ESMO Breast Cancer virtual meeting. The analysis population included 2,971 patients who had been treated with the CDK 4/6 inhibitor abemaciclib (Verzenio) together with endocrine therapy and 2,800 who had received endocrine therapy alone in the early-stage, adjuvant advanced breast cancer setting.
Most ILD (97%) events that occurred were single occurrences, with any grade of ILD occurring in a higher percentage of patients treated with abemaciclib with endocrine therapy than endocrine therapy alone (2.9% vs. 1.2%). Grade 3 events occurred in a respective 0.4% and 0.0% of patients.
So who’s at risk?
The risk factors for ILD and pneumonitis are not well characterized with either of the two drugs discussed, Dr. Burstein observed.
“In the abemaciclib experience, it looked like obesity might be a predisposing factor, with trastuzumab deruxtecan, it looked like patients of Asian ancestry were greater risk, but we need more data to really understand who’s at jeopardy.”
Dr. Burstein observed: “This is something patients need to be aware of as they’re contemplating this treatment.”
While data to prove the benefit of the drug need to mature, Dr. Burstein “would likely discontinue therapy” if a patient were to develop ILD or pneumonitis and treat accordingly.
As for T-DXd, he said: “It’s important that patients know that lung disease is a potentially severe side effect of treatment and that any respiratory symptoms need to be jumped on quickly.”
While prospective studies are now needed, and the phase 3 data should help to better understand the risk of ILD with T-DXd, Dr. Burstein believes it will be important to develop algorithms to ensure the safe administration of the drug.
These algorithms should include “appropriate surveillance and monitoring, especially as we think about trying to move this drug forward into the early stage setting where we’re using it in women who have favorable prognosis, and potentially curative situations for breast cancer.”
The trastuzumab deruxtecan trials were cosponsored by Daiichi Sankyo and AstraZeneca. The monarchE trial was supported by Eli Lilly.
Dr. Powell acknowledged receiving personal fees for acting as an advisory or consultant to both companies as well as to Voluntis. Dr. Burstein had nothing to disclose, and Dr. Cameron had no relevant financial interests in the data being presented.
Although rates are generally low, interstitial lung disease (ILD) can occur at any point in the first year of treatment with trastuzumab deruxtecan (T-DXd) for HER2-positive metastatic breast cancer (MBC).
That’s according to a pooled analysis of three early clinical trials with the drug that was reported at the European Society for Medical Oncology (ESMO): Breast Cancer virtual meeting.
Over a 5-year analysis period, the rate of any grade of ILD was 15.5%. The majority (79%) of those events were grade 1 or 2, observed pulmonologist Charles A. Powell, MD, of Icahn School of Medicine at Mount Sinai in New York, who presented the findings.
Of the 245 patients who were included in the analysis, 38 had an ILD event deemed related to treatment. A respective 9 (3.7%) and 21 (8.6%) had events graded as 1 or 2, 1 patient each (0.4%) had a grade 3 or 4 event, and 6 (2.4%) patients had a grade 5 event.
The timing of the first identified ILD event varied from 1.1 months to 20.8 months, given a median of 5.6 months overall. “This highlights an opportunity for more timely detection of ILD,” Dr. Powell suggested. He added that in almost all (97%) cases, ILD occurred before 12 months and the risk may even decrease over time “suggesting that the risk is not cumulative.”
He cautioned, however: “It is important to note that this analysis is exploratory and hypothesis generating in nature.”
ILD occurs with other cancer drugs
ILD is not just associated with T-DXd treatment, said the invited discussant for the trial, Harold J. Burstein, MD, PhD, of the Dana-Farber Cancer Institute in Boston.
“It’s important for clinicians to remember that ILD/pneumonitis is an uncommon, but potentially very serious side effect that affects many breast cancer treatments,” he said.
That not only includes T-DXd, but other newer drugs such the cyclin dependent kinase (CDK) 4/6 inhibitors and immune checkpoint inhibitors, as well as other older more established drugs including taxanes, cyclophosphamide and even the mTOR inhibitor everolimus.
“Both clinicians and patients need to be aware of this risk. It’s part of the differential diagnosis for any patient who develops either ground glass changes or other infiltrates on a CT scan, or who has symptoms,” Dr. Burstein added.
Investigating ILD in T-DXd trials
T-DXd (Enhertu) is an anti-HER2-antibody drug conjugate that contains a humanized anti-HER2 IgG1 monoclonal antibody akin to trastuzumab that is linked to DXd, a topoisomerase I inhibitor that is a derivative of exatecan.
It has been approved for use in patients with HER2-positive metastatic breast cancer after two other HER2 treatments fail in the United States and Europe, and after chemotherapy in Japan, noted Dr. Powell. This is largely due to the results from the phase 2, open-label DESTINY-Breast01 trial.
“In breast cancer, T-DXd continues to demonstrate clinically meaningful efficacy with a median duration of response of more than 20 months in a heavily pretreated population,” he said. Objective response rates seen in the DESTINY-Breast01 trial were around 60%, and the median progression-free survival was a little over 19 months.
To look at the issue of drug-related ILD events in patients treated with T-DXd for HER2-positive MBC, an independent adjudication committee was formed to look at all the imaging and clinical data from the DESTINY-Breast01 trial and two single-arm phase 1 trials (NCT02564900 and NCT03383692).
In all, data on 245 patients who had been treated with T-DXd at the approved dose of 5.4 mg/kg in those trials between August 2015 and June 2020 were analyzed.
Dealing with lung toxicity
“We are getting new drugs to improve the treatment of cancer, but they always come with a price in terms of toxicity,” observed David Cameron, MD, professor of medical oncology at Edinburgh University in Scotland. Dr. Cameron chaired the session.
“Several measures were taken to identify and mitigate ILD,” across all the T-DXd studies, Dr. Powell explained. As well as the independent adjudication committee, available guidelines were followed and updated on how to diagnose and treat drug-induced lung injuries, and a “safe use” campaign was run in 2019.
Many patients in the early MBC studies were recruited before these measures were in place, such as the use of systemic steroids to manage low-grade events.
The bottom line, however, is that if a patient develops ILD then treatment should be stopped, Dr. Powell said. “Patients with grade 1 events may restart once the ILD has resolved, but those with grade 2 to 4 events must discontinue treatment.”
Dr. Powell concluded: “The overall clinical data support the positive risk-benefit profile of T-DXd. Phase 3 randomized controlled trials in breast cancer are ongoing.”
ILD also seen in monarchE trial with abemaciclib
Data on ILD events seen in the phase 3 monarchE trial were also reported separately at the ESMO Breast Cancer virtual meeting. The analysis population included 2,971 patients who had been treated with the CDK 4/6 inhibitor abemaciclib (Verzenio) together with endocrine therapy and 2,800 who had received endocrine therapy alone in the early-stage, adjuvant advanced breast cancer setting.
Most ILD (97%) events that occurred were single occurrences, with any grade of ILD occurring in a higher percentage of patients treated with abemaciclib with endocrine therapy than endocrine therapy alone (2.9% vs. 1.2%). Grade 3 events occurred in a respective 0.4% and 0.0% of patients.
So who’s at risk?
The risk factors for ILD and pneumonitis are not well characterized with either of the two drugs discussed, Dr. Burstein observed.
“In the abemaciclib experience, it looked like obesity might be a predisposing factor, with trastuzumab deruxtecan, it looked like patients of Asian ancestry were greater risk, but we need more data to really understand who’s at jeopardy.”
Dr. Burstein observed: “This is something patients need to be aware of as they’re contemplating this treatment.”
While data to prove the benefit of the drug need to mature, Dr. Burstein “would likely discontinue therapy” if a patient were to develop ILD or pneumonitis and treat accordingly.
As for T-DXd, he said: “It’s important that patients know that lung disease is a potentially severe side effect of treatment and that any respiratory symptoms need to be jumped on quickly.”
While prospective studies are now needed, and the phase 3 data should help to better understand the risk of ILD with T-DXd, Dr. Burstein believes it will be important to develop algorithms to ensure the safe administration of the drug.
These algorithms should include “appropriate surveillance and monitoring, especially as we think about trying to move this drug forward into the early stage setting where we’re using it in women who have favorable prognosis, and potentially curative situations for breast cancer.”
The trastuzumab deruxtecan trials were cosponsored by Daiichi Sankyo and AstraZeneca. The monarchE trial was supported by Eli Lilly.
Dr. Powell acknowledged receiving personal fees for acting as an advisory or consultant to both companies as well as to Voluntis. Dr. Burstein had nothing to disclose, and Dr. Cameron had no relevant financial interests in the data being presented.
FROM ESMO BREAST CANCER 2021