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Abemaciclib cuts early recurrence in high-risk breast cancer
First advance in 20 years
The research was presented Sept. 19 at the ESMO Virtual Congress 2020 and simultaneously published in the Journal of Clinical Oncology.
The monarchE trial compared 2 years of abemaciclib plus endocrine therapy vs endocrine therapy alone among 5,600 patients and found that the combination was associated with a 25% relative risk reduction in the primary endpoint – invasive disease-free survival (P =.0096; HR, 0.75; 95% CI, 0.60 - 0.93)
At 2 years, the rate of invasive disease-free survival was 92.2% in the abemaciclib arm vs 88.7% in the group that took endocrine therapy alone.
“This is the first time in more than 20 years that we have seen an advance in the adjuvant treatment of this form of breast cancer,” said lead investigator Stephen Johnston, MD, PhD, from the Royal Marsden Hospital NHS Foundation Trust in London, UK, in a meeting press release.
He told Medscape Medical News that the high-risk patients in their study “are predicted to relapse quite quickly” as a result of having a degree of endocrine resistance, “and by intervening early we are stopping these recurrences within the first 2 years.”
He continued: “The key issue ... is whether you need 2 years of treatment or perhaps even longer. One other trial is looking at 3 years with another drug, and we’ll just have to await further follow-up of the data to see if the [monarchE] curves continue to separate while on treatment.”
According to Giuseppe Curigliano, MD, PhD, head of the Division of Early Drug Development at the European Institute of Oncology, Milan, Italy, “This is a very important trial and the findings will change practice. Once approved for high risk HR+ HER2-negative early breast cancer, the new standard of care for these patients will be to add two years of abemaciclib to endocrine therapy.”
Curigliano, who was not involved with the study, further commented during a meeting press conference that a randomized trial will be needed to answer a new important question: Can these high-risk patients treated with a CDK4/6 inhibitor be spared chemotherapy?
Investigator Johnston pointed out that many patients diagnosed with HR+, HER2 breast cancer will not experience recurrence with standard-of-care therapies.
But he also explained “that up to 20% may develop recurrence or distant relapse in the first 10 years” and that the risk of recurrence is “much greater” for patients who have high-risk clinical or pathological features, “especially during the first few years on their adjuvant endocrine therapy.”
Study details
Abemaciclib was approved by the US Food and Drug Administration in 2017 and is approved in combination with the endocrine therapy fulvestrant for the treatment of HR+, HER2-negative advanced or metastatic breast cancer that has progressed after endocrine therapy.
The approval was, in part, based on data from the MONARCH-2 trial, which showed consistent overall survival benefits with the combination.
MonarchE, on the other hand, examined the impact of abemaciclib in the first-line adjuvant setting, enrolling patients with HR+, HER2-negative, node-positive early breast cancer who had a tumor size of ≥5 cm, histologic grade 3 disease, and/or Ki67 index of ≥20%.
They were randomly assigned in a 1:1 fashion to abemaciclib 150 mg twice daily for up to 2 years plus standard of care endocrine therapy or standard of care endocrine therapy alone.
The choice of endocrine therapy was left to the physician and was continued for 5-10 years, as clinically indicated.
The trial included 5,637 patients. An efficacy interim analysis was planned for when 75% of the estimated invasive disease-free survival events had occurred, which equated to 323 events in the intention-to-treat population.
This occurred after approximately 15.5 months of follow-up in each arm, when 12.5% of patients had completed the 2-year treatment period, leaving 70% still in treatment.
The intention-to-treat population included 2,808 patients from the abemaciclib plus endocrine therapy group and 2,829 in the group taking endocrine therapy alone.
The two groups were well balanced in terms of their baseline characteristics. The vast majority (approximately 85%) of patients were younger than 65 years, and 56.5% were postmenopausal.
Also, 37% had previously received neoadjuvant chemotherapy, and approximately 58% had adjuvant chemotherapy.
Distant relapse-free survival was significantly reduced with abemaciclib plus endocrine therapy vs endocrine therapy alone, at a hazard ratio of 0.72 (P = .0085), and a 2-year rate of 93.6% and 90.3%, respectively.
Johnston highlighted that not only was the number of patients with distant recurrences reduced with the combination therapy, at 92 vs 142 with endocrine therapy alone, but also the reductions were in key locations.
The number of patients with recurrences in the bone were 32 with abemaciclib and 81 with endocrine therapy alone; 29 patients with abemaciclib and 42 with endocrine therapy alone had recurrences in the liver.
The results show that the most frequent adverse events in the abemaciclib arm were diarrhea (82%), neutropenia (45%), and fatigue (38%), whereas arthralgia (31%), hot flush (21%), and fatigue (15%) were seen most often in the control group.
Venous thromboembolic events were recorded in 2.3% of patients in the abemaciclib group versus 0.5% of those on endocrine therapy alone; interstitial lung disease was seen in 2.7% and 1.2%, respectively.
Despite the protocol allowing dose reductions from 150 mg to 100 mg twice daily if required, 463 (16.6%) patients discontinued abemaciclib as a result of adverse events. Of those, 306 continued on endocrine therapy.
“Adherence to treatment will be an important issue to be considered in the real-life population of patients when this treatment is approved and used in clinical practice,” Johnston said.
Nevertheless, diarrhea frequency and severity decreased significantly over time, and only 4.8% of the abemaciclib group discontinued use as a result of this adverse event.
Questions remain
George W. Sledge Jr, MD, professor of medicine (oncology) at Stanford University Medical Center, Palo Alto, California, was the invited discussant after the presentation.
He said that “positive trials raise as many questions as they answer, and monarchE is no exception.”
For example, there is the conundrum posed by the negative results of the very similar PALLAS trial, which looked at the addition of palbociclib to adjuvant endocrine therapy for HR+, HER2-negative early breast cancer and was also presented at the ESMO meeting.
Returning to monarchE, Sledge asked what the ultimate increase in invasive disease- and distant relapse-free survival will be with the drug combination, noting that the trial has “very, very short follow-up.”
“Second, will the improvements seen in disease-free survival lead to what we really care about: improved overall survival? Again, time will tell, but health care systems and patients care deeply about the answer to this question.”
Sledge continued: “How about late recurrence? Do CDK4/6 inhibitors kill off dormant or slow-growing micro-mets that lead to recurrences 5 or more years out?”
He also asked what the optimum duration of therapy would be: “Is it more than we need, or not enough?”
Sledge wondered whether it is possible to determine who benefits “and why the drug fails some patients.”
Finally, Sledge said, “These drugs are expensive. ... 2 years of adjuvant therapy is simply out of reach for the majority of patients around the globe who might be candidates for adjuvant CDK4/6 inhibitor therapy.”
And he observed an important truism: “A patient cannot benefit from a drug she cannot take.”
The study was funded by Eli Lilly. Johnston, Sledge, and Curigliano have financial ties to Eli Lilly and multiple other drug companies.
This article first appeared on Medscape.com.
First advance in 20 years
First advance in 20 years
The research was presented Sept. 19 at the ESMO Virtual Congress 2020 and simultaneously published in the Journal of Clinical Oncology.
The monarchE trial compared 2 years of abemaciclib plus endocrine therapy vs endocrine therapy alone among 5,600 patients and found that the combination was associated with a 25% relative risk reduction in the primary endpoint – invasive disease-free survival (P =.0096; HR, 0.75; 95% CI, 0.60 - 0.93)
At 2 years, the rate of invasive disease-free survival was 92.2% in the abemaciclib arm vs 88.7% in the group that took endocrine therapy alone.
“This is the first time in more than 20 years that we have seen an advance in the adjuvant treatment of this form of breast cancer,” said lead investigator Stephen Johnston, MD, PhD, from the Royal Marsden Hospital NHS Foundation Trust in London, UK, in a meeting press release.
He told Medscape Medical News that the high-risk patients in their study “are predicted to relapse quite quickly” as a result of having a degree of endocrine resistance, “and by intervening early we are stopping these recurrences within the first 2 years.”
He continued: “The key issue ... is whether you need 2 years of treatment or perhaps even longer. One other trial is looking at 3 years with another drug, and we’ll just have to await further follow-up of the data to see if the [monarchE] curves continue to separate while on treatment.”
According to Giuseppe Curigliano, MD, PhD, head of the Division of Early Drug Development at the European Institute of Oncology, Milan, Italy, “This is a very important trial and the findings will change practice. Once approved for high risk HR+ HER2-negative early breast cancer, the new standard of care for these patients will be to add two years of abemaciclib to endocrine therapy.”
Curigliano, who was not involved with the study, further commented during a meeting press conference that a randomized trial will be needed to answer a new important question: Can these high-risk patients treated with a CDK4/6 inhibitor be spared chemotherapy?
Investigator Johnston pointed out that many patients diagnosed with HR+, HER2 breast cancer will not experience recurrence with standard-of-care therapies.
But he also explained “that up to 20% may develop recurrence or distant relapse in the first 10 years” and that the risk of recurrence is “much greater” for patients who have high-risk clinical or pathological features, “especially during the first few years on their adjuvant endocrine therapy.”
Study details
Abemaciclib was approved by the US Food and Drug Administration in 2017 and is approved in combination with the endocrine therapy fulvestrant for the treatment of HR+, HER2-negative advanced or metastatic breast cancer that has progressed after endocrine therapy.
The approval was, in part, based on data from the MONARCH-2 trial, which showed consistent overall survival benefits with the combination.
MonarchE, on the other hand, examined the impact of abemaciclib in the first-line adjuvant setting, enrolling patients with HR+, HER2-negative, node-positive early breast cancer who had a tumor size of ≥5 cm, histologic grade 3 disease, and/or Ki67 index of ≥20%.
They were randomly assigned in a 1:1 fashion to abemaciclib 150 mg twice daily for up to 2 years plus standard of care endocrine therapy or standard of care endocrine therapy alone.
The choice of endocrine therapy was left to the physician and was continued for 5-10 years, as clinically indicated.
The trial included 5,637 patients. An efficacy interim analysis was planned for when 75% of the estimated invasive disease-free survival events had occurred, which equated to 323 events in the intention-to-treat population.
This occurred after approximately 15.5 months of follow-up in each arm, when 12.5% of patients had completed the 2-year treatment period, leaving 70% still in treatment.
The intention-to-treat population included 2,808 patients from the abemaciclib plus endocrine therapy group and 2,829 in the group taking endocrine therapy alone.
The two groups were well balanced in terms of their baseline characteristics. The vast majority (approximately 85%) of patients were younger than 65 years, and 56.5% were postmenopausal.
Also, 37% had previously received neoadjuvant chemotherapy, and approximately 58% had adjuvant chemotherapy.
Distant relapse-free survival was significantly reduced with abemaciclib plus endocrine therapy vs endocrine therapy alone, at a hazard ratio of 0.72 (P = .0085), and a 2-year rate of 93.6% and 90.3%, respectively.
Johnston highlighted that not only was the number of patients with distant recurrences reduced with the combination therapy, at 92 vs 142 with endocrine therapy alone, but also the reductions were in key locations.
The number of patients with recurrences in the bone were 32 with abemaciclib and 81 with endocrine therapy alone; 29 patients with abemaciclib and 42 with endocrine therapy alone had recurrences in the liver.
The results show that the most frequent adverse events in the abemaciclib arm were diarrhea (82%), neutropenia (45%), and fatigue (38%), whereas arthralgia (31%), hot flush (21%), and fatigue (15%) were seen most often in the control group.
Venous thromboembolic events were recorded in 2.3% of patients in the abemaciclib group versus 0.5% of those on endocrine therapy alone; interstitial lung disease was seen in 2.7% and 1.2%, respectively.
Despite the protocol allowing dose reductions from 150 mg to 100 mg twice daily if required, 463 (16.6%) patients discontinued abemaciclib as a result of adverse events. Of those, 306 continued on endocrine therapy.
“Adherence to treatment will be an important issue to be considered in the real-life population of patients when this treatment is approved and used in clinical practice,” Johnston said.
Nevertheless, diarrhea frequency and severity decreased significantly over time, and only 4.8% of the abemaciclib group discontinued use as a result of this adverse event.
Questions remain
George W. Sledge Jr, MD, professor of medicine (oncology) at Stanford University Medical Center, Palo Alto, California, was the invited discussant after the presentation.
He said that “positive trials raise as many questions as they answer, and monarchE is no exception.”
For example, there is the conundrum posed by the negative results of the very similar PALLAS trial, which looked at the addition of palbociclib to adjuvant endocrine therapy for HR+, HER2-negative early breast cancer and was also presented at the ESMO meeting.
Returning to monarchE, Sledge asked what the ultimate increase in invasive disease- and distant relapse-free survival will be with the drug combination, noting that the trial has “very, very short follow-up.”
“Second, will the improvements seen in disease-free survival lead to what we really care about: improved overall survival? Again, time will tell, but health care systems and patients care deeply about the answer to this question.”
Sledge continued: “How about late recurrence? Do CDK4/6 inhibitors kill off dormant or slow-growing micro-mets that lead to recurrences 5 or more years out?”
He also asked what the optimum duration of therapy would be: “Is it more than we need, or not enough?”
Sledge wondered whether it is possible to determine who benefits “and why the drug fails some patients.”
Finally, Sledge said, “These drugs are expensive. ... 2 years of adjuvant therapy is simply out of reach for the majority of patients around the globe who might be candidates for adjuvant CDK4/6 inhibitor therapy.”
And he observed an important truism: “A patient cannot benefit from a drug she cannot take.”
The study was funded by Eli Lilly. Johnston, Sledge, and Curigliano have financial ties to Eli Lilly and multiple other drug companies.
This article first appeared on Medscape.com.
The research was presented Sept. 19 at the ESMO Virtual Congress 2020 and simultaneously published in the Journal of Clinical Oncology.
The monarchE trial compared 2 years of abemaciclib plus endocrine therapy vs endocrine therapy alone among 5,600 patients and found that the combination was associated with a 25% relative risk reduction in the primary endpoint – invasive disease-free survival (P =.0096; HR, 0.75; 95% CI, 0.60 - 0.93)
At 2 years, the rate of invasive disease-free survival was 92.2% in the abemaciclib arm vs 88.7% in the group that took endocrine therapy alone.
“This is the first time in more than 20 years that we have seen an advance in the adjuvant treatment of this form of breast cancer,” said lead investigator Stephen Johnston, MD, PhD, from the Royal Marsden Hospital NHS Foundation Trust in London, UK, in a meeting press release.
He told Medscape Medical News that the high-risk patients in their study “are predicted to relapse quite quickly” as a result of having a degree of endocrine resistance, “and by intervening early we are stopping these recurrences within the first 2 years.”
He continued: “The key issue ... is whether you need 2 years of treatment or perhaps even longer. One other trial is looking at 3 years with another drug, and we’ll just have to await further follow-up of the data to see if the [monarchE] curves continue to separate while on treatment.”
According to Giuseppe Curigliano, MD, PhD, head of the Division of Early Drug Development at the European Institute of Oncology, Milan, Italy, “This is a very important trial and the findings will change practice. Once approved for high risk HR+ HER2-negative early breast cancer, the new standard of care for these patients will be to add two years of abemaciclib to endocrine therapy.”
Curigliano, who was not involved with the study, further commented during a meeting press conference that a randomized trial will be needed to answer a new important question: Can these high-risk patients treated with a CDK4/6 inhibitor be spared chemotherapy?
Investigator Johnston pointed out that many patients diagnosed with HR+, HER2 breast cancer will not experience recurrence with standard-of-care therapies.
But he also explained “that up to 20% may develop recurrence or distant relapse in the first 10 years” and that the risk of recurrence is “much greater” for patients who have high-risk clinical or pathological features, “especially during the first few years on their adjuvant endocrine therapy.”
Study details
Abemaciclib was approved by the US Food and Drug Administration in 2017 and is approved in combination with the endocrine therapy fulvestrant for the treatment of HR+, HER2-negative advanced or metastatic breast cancer that has progressed after endocrine therapy.
The approval was, in part, based on data from the MONARCH-2 trial, which showed consistent overall survival benefits with the combination.
MonarchE, on the other hand, examined the impact of abemaciclib in the first-line adjuvant setting, enrolling patients with HR+, HER2-negative, node-positive early breast cancer who had a tumor size of ≥5 cm, histologic grade 3 disease, and/or Ki67 index of ≥20%.
They were randomly assigned in a 1:1 fashion to abemaciclib 150 mg twice daily for up to 2 years plus standard of care endocrine therapy or standard of care endocrine therapy alone.
The choice of endocrine therapy was left to the physician and was continued for 5-10 years, as clinically indicated.
The trial included 5,637 patients. An efficacy interim analysis was planned for when 75% of the estimated invasive disease-free survival events had occurred, which equated to 323 events in the intention-to-treat population.
This occurred after approximately 15.5 months of follow-up in each arm, when 12.5% of patients had completed the 2-year treatment period, leaving 70% still in treatment.
The intention-to-treat population included 2,808 patients from the abemaciclib plus endocrine therapy group and 2,829 in the group taking endocrine therapy alone.
The two groups were well balanced in terms of their baseline characteristics. The vast majority (approximately 85%) of patients were younger than 65 years, and 56.5% were postmenopausal.
Also, 37% had previously received neoadjuvant chemotherapy, and approximately 58% had adjuvant chemotherapy.
Distant relapse-free survival was significantly reduced with abemaciclib plus endocrine therapy vs endocrine therapy alone, at a hazard ratio of 0.72 (P = .0085), and a 2-year rate of 93.6% and 90.3%, respectively.
Johnston highlighted that not only was the number of patients with distant recurrences reduced with the combination therapy, at 92 vs 142 with endocrine therapy alone, but also the reductions were in key locations.
The number of patients with recurrences in the bone were 32 with abemaciclib and 81 with endocrine therapy alone; 29 patients with abemaciclib and 42 with endocrine therapy alone had recurrences in the liver.
The results show that the most frequent adverse events in the abemaciclib arm were diarrhea (82%), neutropenia (45%), and fatigue (38%), whereas arthralgia (31%), hot flush (21%), and fatigue (15%) were seen most often in the control group.
Venous thromboembolic events were recorded in 2.3% of patients in the abemaciclib group versus 0.5% of those on endocrine therapy alone; interstitial lung disease was seen in 2.7% and 1.2%, respectively.
Despite the protocol allowing dose reductions from 150 mg to 100 mg twice daily if required, 463 (16.6%) patients discontinued abemaciclib as a result of adverse events. Of those, 306 continued on endocrine therapy.
“Adherence to treatment will be an important issue to be considered in the real-life population of patients when this treatment is approved and used in clinical practice,” Johnston said.
Nevertheless, diarrhea frequency and severity decreased significantly over time, and only 4.8% of the abemaciclib group discontinued use as a result of this adverse event.
Questions remain
George W. Sledge Jr, MD, professor of medicine (oncology) at Stanford University Medical Center, Palo Alto, California, was the invited discussant after the presentation.
He said that “positive trials raise as many questions as they answer, and monarchE is no exception.”
For example, there is the conundrum posed by the negative results of the very similar PALLAS trial, which looked at the addition of palbociclib to adjuvant endocrine therapy for HR+, HER2-negative early breast cancer and was also presented at the ESMO meeting.
Returning to monarchE, Sledge asked what the ultimate increase in invasive disease- and distant relapse-free survival will be with the drug combination, noting that the trial has “very, very short follow-up.”
“Second, will the improvements seen in disease-free survival lead to what we really care about: improved overall survival? Again, time will tell, but health care systems and patients care deeply about the answer to this question.”
Sledge continued: “How about late recurrence? Do CDK4/6 inhibitors kill off dormant or slow-growing micro-mets that lead to recurrences 5 or more years out?”
He also asked what the optimum duration of therapy would be: “Is it more than we need, or not enough?”
Sledge wondered whether it is possible to determine who benefits “and why the drug fails some patients.”
Finally, Sledge said, “These drugs are expensive. ... 2 years of adjuvant therapy is simply out of reach for the majority of patients around the globe who might be candidates for adjuvant CDK4/6 inhibitor therapy.”
And he observed an important truism: “A patient cannot benefit from a drug she cannot take.”
The study was funded by Eli Lilly. Johnston, Sledge, and Curigliano have financial ties to Eli Lilly and multiple other drug companies.
This article first appeared on Medscape.com.
FROM ESMO 2020
First-in-class ADC ups survival in mTNBC
The first-in-class drug is directed at trophoblast cell surface antigen 2 (Trop-2), which is highly expressed in breast cancer. Research on the drug was presented at the European Society for Medical Oncology Virtual Congress 2020.
ASCENT randomly assigned more than 500 patients who had metastatic TNBC and who had experienced disease progression after a median of four lines of therapy to receive either SG or physician’s choice of chemotherapy. SG significantly improved median progression-free survival (5.6 vs 1.7 months; hazard ratio [HR], 0.41; P < .0001) and median overall survival (12.1 vs 6.7 months; HR, 0.48; P < .0001).
The response rate was 35% for SG vs 5% for chemotherapy (P < .0001).
The study was presented by Aditya Bardia, MD, MPH, a medical oncologist at Massachusetts General Hospital, Boston, Massachusetts.
He said that because the safety profile of SG is consistent with previous reports and the treatment discontinuation rate was low, the clinical benefit “confirms the use of sacituzumab govitecan” in metastatic TNBC. This was a reference to the fact that the drug previously received accelerated approval on the basis of early data.
Bardia added that ongoing studies are evaluating the use of SG in earlier lines of therapy, including neoadjuvant settings in combination with other targeted agents, as well as in hormone receptor–positive metastatic breast cancer. One such study is the phase 3 TROPiCS-02 study, which is actively accruing patients.
Invited discussant Fatima Cardoso, MD, director of the Breast Unit at Champalimaud Clinical Center, Lisbon, Portugal, said the treatment algorithm for the management of TNBC will need to be updated in light of these results.
“In my opinion, we should now add sacituzumab govitecan as a new treatment option for patients treated with two or more lines of therapy,” she said.
She noted that the study design raised some questions over the way such trials should be conducted and the future sequencing of treatments.
Objections to study design and execution
Discussant Cardoso said the choice of progression-free survival as the primary endpoint for the trial was not ideal.
“In the metastatic setting, and particularly for triple-negative breast cancer, where the median survival is quite low and where each line of treatment, particularly after the second line, has a short duration, the primary endpoint should have been overall survival,” she commented.
“Luckily, we saw some results, but we could have missed it,” Cardoso said. She made “a plea to make sure that overall survival is at least the co–primary endpoint” in the future.
Cardoso also said it was not clear to her why the trial had to be stopped. “For the current patients, if there is no crossover, there is no benefit in stopping the trial,” she said.
She went on: “For future patients, it’s better to have the final results sufficiently powered.” She noted that the benefit seen in ASCENT was “moderate” and “so not a substantial breakthrough.” She added that it was “important not to stop trials too early.”
On the positive side, Cardoso said the median number of previous lines of therapy was “quite remarkable for this subtype, and it is important then for us to discuss sequencing,” particularly given that so many patients received checkpoint inhibitors before entering the trial.
Safety and a focus on diarrhea
Investigator Bardia explained that SG is an antibody-drug conjugate directed at Trop-2, which is highly expressed in breast cancer.
The antibody is linked to SN-38, the active metabolite of irinotecan, via a hydrolyzable linker that makes internalization and enzymatic cleavage by tumor cells unnecessary.
Hydrolysis of the linker releases SN-38 both within the tumor cell and extracellularly to induce a so-called bystander effect, in which neighboring tumors cells may be killed even if they do not express Trop-2.
On the basis of positive results from phase 1/2 trial data, SG was granted accelerated approval by the US Food and Drug Administration for patients with metastatic TNBC who experience disease progression after at least two prior therapies.
ASCENT was therefore a phase 3 confirmatory study. Patients with metastatic TNBC who had received at least two prior chemotherapy regimens were randomly assigned in a 1:1 ratio to receive intravenous SG on days 1 and 8 of a 21-day cycle or to receive physician’s choice of treatment.
Physicians could choose eribulin, vinorelbine, gemcitabine, or capecitabine.
The patients continued receiving treatment until disease progression or unacceptable toxicity occurred. On the unanimous recommendation of the data safety monitoring committee, the trial was ended early because of “compelling evidence of efficacy.”
In all, 267 patients were randomly assigned to receive SG. Of those patients, 15 remain on treatment. Treatment was discontinued for 199 patients who experienced disease progression. In the control arm, 262 patients were included, none of whom are still on treatment; 166 discontinued because of disease progression.
The current analysis is limited to 235 patients in the SG group and, in the control arm, 233 patients who did not have brain metastases. Patients with brain metastases will be the subject of a later analysis.
All but one patient in both treatment groups were women. The median age was approximately 54 years. The median number of prior treatment regimens was four. All patients had previously received chemotherapy, and between 26% and 29% have taken checkpoint inhibitors.
By the data cutoff of March 11, 2020, patients had received a median of seven treatment cycles with SG. Progression-free survival was adjudicated by blind, independent central review. The median duration of response was of borderline significance, at 6.3 months vs 3.6 months (P = .057).
Bardia showed that the results were consistent among all subgroups, including subgroups determined on the basis of age, number of prior therapies, whether patients had received prior immune checkpoint therapy, and the presence of liver metastases.
With respect to safety, the important grade 3 or higher treatment-related adverse events were neutropenia (seen in 51% of SG patients vs 33% of patients in the control arm), diarrhea (10% vs <1%), leukopenia (10% vs 5%), anemia (8% vs 5%), and febrile neutropenia (6% vs 2%).
Despite the fact that the adverse event rate was higher with SG than with physician’s choice of chemotherapy, the percentage of such events that led to treatment discontinuation was numerically lower, at 4.7% vs 5.4%.
Cardoso highlighted the “substantial percentage” of patients with diarrhea and nausea in the trial and noted that “all grades” of these adverse events “affect quality of life.”
The focus therefore should be on patient education, prophylaxis, and “the early management of side effects,” she said.
This point was taken up in the postpresentation debate. Bardia said the high rate of diarrhea “likely relates to the toxic payload, which is SN-38, which is known to cause diarrhea.
“Loperamide or immodium prophylaxis can be used in patients who receive this drug, and in general, our experience with the use of sacituzumab govitecan is you can control the diarrhea,” Bardia said.
He added: “There is also a different side effect that occurs during the infusion of SG, which is abdominal cramping and diarrhea, and that’s more of a cholinergic reaction. For that, atropine is the best medication to use.”
The study was funded by Immunomedics Inc. Bardia has disclosed financial ties with Immunomedics and multiple other pharmaceutical companies. Cardoso has disclosed financial ties to multiple drug companies.
This article first appeared on Medscape.com.
The first-in-class drug is directed at trophoblast cell surface antigen 2 (Trop-2), which is highly expressed in breast cancer. Research on the drug was presented at the European Society for Medical Oncology Virtual Congress 2020.
ASCENT randomly assigned more than 500 patients who had metastatic TNBC and who had experienced disease progression after a median of four lines of therapy to receive either SG or physician’s choice of chemotherapy. SG significantly improved median progression-free survival (5.6 vs 1.7 months; hazard ratio [HR], 0.41; P < .0001) and median overall survival (12.1 vs 6.7 months; HR, 0.48; P < .0001).
The response rate was 35% for SG vs 5% for chemotherapy (P < .0001).
The study was presented by Aditya Bardia, MD, MPH, a medical oncologist at Massachusetts General Hospital, Boston, Massachusetts.
He said that because the safety profile of SG is consistent with previous reports and the treatment discontinuation rate was low, the clinical benefit “confirms the use of sacituzumab govitecan” in metastatic TNBC. This was a reference to the fact that the drug previously received accelerated approval on the basis of early data.
Bardia added that ongoing studies are evaluating the use of SG in earlier lines of therapy, including neoadjuvant settings in combination with other targeted agents, as well as in hormone receptor–positive metastatic breast cancer. One such study is the phase 3 TROPiCS-02 study, which is actively accruing patients.
Invited discussant Fatima Cardoso, MD, director of the Breast Unit at Champalimaud Clinical Center, Lisbon, Portugal, said the treatment algorithm for the management of TNBC will need to be updated in light of these results.
“In my opinion, we should now add sacituzumab govitecan as a new treatment option for patients treated with two or more lines of therapy,” she said.
She noted that the study design raised some questions over the way such trials should be conducted and the future sequencing of treatments.
Objections to study design and execution
Discussant Cardoso said the choice of progression-free survival as the primary endpoint for the trial was not ideal.
“In the metastatic setting, and particularly for triple-negative breast cancer, where the median survival is quite low and where each line of treatment, particularly after the second line, has a short duration, the primary endpoint should have been overall survival,” she commented.
“Luckily, we saw some results, but we could have missed it,” Cardoso said. She made “a plea to make sure that overall survival is at least the co–primary endpoint” in the future.
Cardoso also said it was not clear to her why the trial had to be stopped. “For the current patients, if there is no crossover, there is no benefit in stopping the trial,” she said.
She went on: “For future patients, it’s better to have the final results sufficiently powered.” She noted that the benefit seen in ASCENT was “moderate” and “so not a substantial breakthrough.” She added that it was “important not to stop trials too early.”
On the positive side, Cardoso said the median number of previous lines of therapy was “quite remarkable for this subtype, and it is important then for us to discuss sequencing,” particularly given that so many patients received checkpoint inhibitors before entering the trial.
Safety and a focus on diarrhea
Investigator Bardia explained that SG is an antibody-drug conjugate directed at Trop-2, which is highly expressed in breast cancer.
The antibody is linked to SN-38, the active metabolite of irinotecan, via a hydrolyzable linker that makes internalization and enzymatic cleavage by tumor cells unnecessary.
Hydrolysis of the linker releases SN-38 both within the tumor cell and extracellularly to induce a so-called bystander effect, in which neighboring tumors cells may be killed even if they do not express Trop-2.
On the basis of positive results from phase 1/2 trial data, SG was granted accelerated approval by the US Food and Drug Administration for patients with metastatic TNBC who experience disease progression after at least two prior therapies.
ASCENT was therefore a phase 3 confirmatory study. Patients with metastatic TNBC who had received at least two prior chemotherapy regimens were randomly assigned in a 1:1 ratio to receive intravenous SG on days 1 and 8 of a 21-day cycle or to receive physician’s choice of treatment.
Physicians could choose eribulin, vinorelbine, gemcitabine, or capecitabine.
The patients continued receiving treatment until disease progression or unacceptable toxicity occurred. On the unanimous recommendation of the data safety monitoring committee, the trial was ended early because of “compelling evidence of efficacy.”
In all, 267 patients were randomly assigned to receive SG. Of those patients, 15 remain on treatment. Treatment was discontinued for 199 patients who experienced disease progression. In the control arm, 262 patients were included, none of whom are still on treatment; 166 discontinued because of disease progression.
The current analysis is limited to 235 patients in the SG group and, in the control arm, 233 patients who did not have brain metastases. Patients with brain metastases will be the subject of a later analysis.
All but one patient in both treatment groups were women. The median age was approximately 54 years. The median number of prior treatment regimens was four. All patients had previously received chemotherapy, and between 26% and 29% have taken checkpoint inhibitors.
By the data cutoff of March 11, 2020, patients had received a median of seven treatment cycles with SG. Progression-free survival was adjudicated by blind, independent central review. The median duration of response was of borderline significance, at 6.3 months vs 3.6 months (P = .057).
Bardia showed that the results were consistent among all subgroups, including subgroups determined on the basis of age, number of prior therapies, whether patients had received prior immune checkpoint therapy, and the presence of liver metastases.
With respect to safety, the important grade 3 or higher treatment-related adverse events were neutropenia (seen in 51% of SG patients vs 33% of patients in the control arm), diarrhea (10% vs <1%), leukopenia (10% vs 5%), anemia (8% vs 5%), and febrile neutropenia (6% vs 2%).
Despite the fact that the adverse event rate was higher with SG than with physician’s choice of chemotherapy, the percentage of such events that led to treatment discontinuation was numerically lower, at 4.7% vs 5.4%.
Cardoso highlighted the “substantial percentage” of patients with diarrhea and nausea in the trial and noted that “all grades” of these adverse events “affect quality of life.”
The focus therefore should be on patient education, prophylaxis, and “the early management of side effects,” she said.
This point was taken up in the postpresentation debate. Bardia said the high rate of diarrhea “likely relates to the toxic payload, which is SN-38, which is known to cause diarrhea.
“Loperamide or immodium prophylaxis can be used in patients who receive this drug, and in general, our experience with the use of sacituzumab govitecan is you can control the diarrhea,” Bardia said.
He added: “There is also a different side effect that occurs during the infusion of SG, which is abdominal cramping and diarrhea, and that’s more of a cholinergic reaction. For that, atropine is the best medication to use.”
The study was funded by Immunomedics Inc. Bardia has disclosed financial ties with Immunomedics and multiple other pharmaceutical companies. Cardoso has disclosed financial ties to multiple drug companies.
This article first appeared on Medscape.com.
The first-in-class drug is directed at trophoblast cell surface antigen 2 (Trop-2), which is highly expressed in breast cancer. Research on the drug was presented at the European Society for Medical Oncology Virtual Congress 2020.
ASCENT randomly assigned more than 500 patients who had metastatic TNBC and who had experienced disease progression after a median of four lines of therapy to receive either SG or physician’s choice of chemotherapy. SG significantly improved median progression-free survival (5.6 vs 1.7 months; hazard ratio [HR], 0.41; P < .0001) and median overall survival (12.1 vs 6.7 months; HR, 0.48; P < .0001).
The response rate was 35% for SG vs 5% for chemotherapy (P < .0001).
The study was presented by Aditya Bardia, MD, MPH, a medical oncologist at Massachusetts General Hospital, Boston, Massachusetts.
He said that because the safety profile of SG is consistent with previous reports and the treatment discontinuation rate was low, the clinical benefit “confirms the use of sacituzumab govitecan” in metastatic TNBC. This was a reference to the fact that the drug previously received accelerated approval on the basis of early data.
Bardia added that ongoing studies are evaluating the use of SG in earlier lines of therapy, including neoadjuvant settings in combination with other targeted agents, as well as in hormone receptor–positive metastatic breast cancer. One such study is the phase 3 TROPiCS-02 study, which is actively accruing patients.
Invited discussant Fatima Cardoso, MD, director of the Breast Unit at Champalimaud Clinical Center, Lisbon, Portugal, said the treatment algorithm for the management of TNBC will need to be updated in light of these results.
“In my opinion, we should now add sacituzumab govitecan as a new treatment option for patients treated with two or more lines of therapy,” she said.
She noted that the study design raised some questions over the way such trials should be conducted and the future sequencing of treatments.
Objections to study design and execution
Discussant Cardoso said the choice of progression-free survival as the primary endpoint for the trial was not ideal.
“In the metastatic setting, and particularly for triple-negative breast cancer, where the median survival is quite low and where each line of treatment, particularly after the second line, has a short duration, the primary endpoint should have been overall survival,” she commented.
“Luckily, we saw some results, but we could have missed it,” Cardoso said. She made “a plea to make sure that overall survival is at least the co–primary endpoint” in the future.
Cardoso also said it was not clear to her why the trial had to be stopped. “For the current patients, if there is no crossover, there is no benefit in stopping the trial,” she said.
She went on: “For future patients, it’s better to have the final results sufficiently powered.” She noted that the benefit seen in ASCENT was “moderate” and “so not a substantial breakthrough.” She added that it was “important not to stop trials too early.”
On the positive side, Cardoso said the median number of previous lines of therapy was “quite remarkable for this subtype, and it is important then for us to discuss sequencing,” particularly given that so many patients received checkpoint inhibitors before entering the trial.
Safety and a focus on diarrhea
Investigator Bardia explained that SG is an antibody-drug conjugate directed at Trop-2, which is highly expressed in breast cancer.
The antibody is linked to SN-38, the active metabolite of irinotecan, via a hydrolyzable linker that makes internalization and enzymatic cleavage by tumor cells unnecessary.
Hydrolysis of the linker releases SN-38 both within the tumor cell and extracellularly to induce a so-called bystander effect, in which neighboring tumors cells may be killed even if they do not express Trop-2.
On the basis of positive results from phase 1/2 trial data, SG was granted accelerated approval by the US Food and Drug Administration for patients with metastatic TNBC who experience disease progression after at least two prior therapies.
ASCENT was therefore a phase 3 confirmatory study. Patients with metastatic TNBC who had received at least two prior chemotherapy regimens were randomly assigned in a 1:1 ratio to receive intravenous SG on days 1 and 8 of a 21-day cycle or to receive physician’s choice of treatment.
Physicians could choose eribulin, vinorelbine, gemcitabine, or capecitabine.
The patients continued receiving treatment until disease progression or unacceptable toxicity occurred. On the unanimous recommendation of the data safety monitoring committee, the trial was ended early because of “compelling evidence of efficacy.”
In all, 267 patients were randomly assigned to receive SG. Of those patients, 15 remain on treatment. Treatment was discontinued for 199 patients who experienced disease progression. In the control arm, 262 patients were included, none of whom are still on treatment; 166 discontinued because of disease progression.
The current analysis is limited to 235 patients in the SG group and, in the control arm, 233 patients who did not have brain metastases. Patients with brain metastases will be the subject of a later analysis.
All but one patient in both treatment groups were women. The median age was approximately 54 years. The median number of prior treatment regimens was four. All patients had previously received chemotherapy, and between 26% and 29% have taken checkpoint inhibitors.
By the data cutoff of March 11, 2020, patients had received a median of seven treatment cycles with SG. Progression-free survival was adjudicated by blind, independent central review. The median duration of response was of borderline significance, at 6.3 months vs 3.6 months (P = .057).
Bardia showed that the results were consistent among all subgroups, including subgroups determined on the basis of age, number of prior therapies, whether patients had received prior immune checkpoint therapy, and the presence of liver metastases.
With respect to safety, the important grade 3 or higher treatment-related adverse events were neutropenia (seen in 51% of SG patients vs 33% of patients in the control arm), diarrhea (10% vs <1%), leukopenia (10% vs 5%), anemia (8% vs 5%), and febrile neutropenia (6% vs 2%).
Despite the fact that the adverse event rate was higher with SG than with physician’s choice of chemotherapy, the percentage of such events that led to treatment discontinuation was numerically lower, at 4.7% vs 5.4%.
Cardoso highlighted the “substantial percentage” of patients with diarrhea and nausea in the trial and noted that “all grades” of these adverse events “affect quality of life.”
The focus therefore should be on patient education, prophylaxis, and “the early management of side effects,” she said.
This point was taken up in the postpresentation debate. Bardia said the high rate of diarrhea “likely relates to the toxic payload, which is SN-38, which is known to cause diarrhea.
“Loperamide or immodium prophylaxis can be used in patients who receive this drug, and in general, our experience with the use of sacituzumab govitecan is you can control the diarrhea,” Bardia said.
He added: “There is also a different side effect that occurs during the infusion of SG, which is abdominal cramping and diarrhea, and that’s more of a cholinergic reaction. For that, atropine is the best medication to use.”
The study was funded by Immunomedics Inc. Bardia has disclosed financial ties with Immunomedics and multiple other pharmaceutical companies. Cardoso has disclosed financial ties to multiple drug companies.
This article first appeared on Medscape.com.
FROM ESMO 2020
Pembrolizumab combo flops in pretreated HR-positive, ERBB2-negative breast cancer
Key clinical point: Pembrolizumab plus eribulin did not outperform eribulin alone among patients with heavily pretreated, HR-positive, ERBB2-negative metastatic breast cancer.
Major finding: After a median of 10.5 months of follow-up, combination therapy did not improve PFS or OS in the intention-to-treat population or in the subgroup of PD-L1 positive patients.
Study details: Multicenter randomized trial of 88 patients with HR-positive, ERBB2-negative metastatic breast cancer who had received >2 lines of hormonal therapy and 0-2 lines of chemotherapy.
Disclosures: Merck & Co providing study funding and pembrolizumab. Eisai provided eribulin. Several investigators disclosed ties to Merck, Eisai, and other pharmaceutical companies.
Citation: Tolaney SM et al. Jama Oncol. 2020 Sep 3. doi: 10.1001/jamaoncol.2020.3524
Key clinical point: Pembrolizumab plus eribulin did not outperform eribulin alone among patients with heavily pretreated, HR-positive, ERBB2-negative metastatic breast cancer.
Major finding: After a median of 10.5 months of follow-up, combination therapy did not improve PFS or OS in the intention-to-treat population or in the subgroup of PD-L1 positive patients.
Study details: Multicenter randomized trial of 88 patients with HR-positive, ERBB2-negative metastatic breast cancer who had received >2 lines of hormonal therapy and 0-2 lines of chemotherapy.
Disclosures: Merck & Co providing study funding and pembrolizumab. Eisai provided eribulin. Several investigators disclosed ties to Merck, Eisai, and other pharmaceutical companies.
Citation: Tolaney SM et al. Jama Oncol. 2020 Sep 3. doi: 10.1001/jamaoncol.2020.3524
Key clinical point: Pembrolizumab plus eribulin did not outperform eribulin alone among patients with heavily pretreated, HR-positive, ERBB2-negative metastatic breast cancer.
Major finding: After a median of 10.5 months of follow-up, combination therapy did not improve PFS or OS in the intention-to-treat population or in the subgroup of PD-L1 positive patients.
Study details: Multicenter randomized trial of 88 patients with HR-positive, ERBB2-negative metastatic breast cancer who had received >2 lines of hormonal therapy and 0-2 lines of chemotherapy.
Disclosures: Merck & Co providing study funding and pembrolizumab. Eisai provided eribulin. Several investigators disclosed ties to Merck, Eisai, and other pharmaceutical companies.
Citation: Tolaney SM et al. Jama Oncol. 2020 Sep 3. doi: 10.1001/jamaoncol.2020.3524
Breast Cancer: 9/22/20
Efficacy of immunotherapy also depends on breast cancer subtype. Triple-negative and HER2-positive tumors have higher TMB and TILs compared to luminal subtype. A phase 2 study in 88 patients with metastatic HR-positive, ERBB2-negative breast cancer demonstrated no difference in PFS or ORR with pembrolizumab/eribulin versus eribulin alone, including the PD-L1 positive population. There was a trend towards greater immunotherapy benefit in the high TMB subgroup which is encouraging. Future research with novel agents that may augment immune response and/or alter tumor microenvironment are intriguing concepts.
First-line endocrine therapy plus CDK 4/6 inhibitor is considered standard of care for HR-positive metastatic breast cancer. A retrospective chart review evaluating everolimus plus endocrine therapy post-CDK 4/6 inhibitor demonstrated PFS of 4.2 months and ORR of 17%. Although benefit appears modest, mTOR inhibitor combinations remain a valuable treatment option for select patients. Chemotherapy is often reserved for rapidly progressive disease or visceral crisis, however, it is crucial to evaluate for endocrine resistance. Furthermore, additional research is warranted to determine interactions between PI3K/Akt/mTOR and downstream Cyclin D/CDK 4/6/Rb pathways and implications on treatment sequencing.
Trastuzumab therapy for 1 year is standard of care for early-stage HER2-positive breast cancer. A meta-analysis of 5 trials with 11,376 patients showed noninferiority of shorter duration trastuzumab compared to 1 year for DFS and OS and lower congestive heart failure rates with the former. Trastuzumab is well-tolerated, and although cardiac toxicity is often reversible, it can carry more severe consequences in patients with cardiac conditions. Shorter duration may be an option in patients with clinically lower risk disease (ER-positive, node-negative tumors) and significant cardiac risk factors, and represents a method of therapy de-escalation for the appropriate patient.
The COVID-19 pandemic has impacted oncology healthcare delivery models and cancer patients have poorer outcomes from COVID-19. A survey study of Brazilian breast cancer specialists demonstrated changing practices for early-stage breast cancer as the pandemic progressed. For HR-positive tumors with low ki-67, 48% would recommend NET for postmenopausal women, while 34% would recommend NET for those with high ki-67. There is limited data regarding NET for pre-menopausal women. Genomic assays may have an evolving role to identify patients who may be appropriate candidates for neoadjuvant therapy versus upfront surgery. Strategies to decrease treatment complications and effectively utilize resources are essential during the COVID-19 pandemic.
Erin Roesch, MD
The Cleveland Clinic
References:
Zhu L, Narloch, JL, Onkar S, et al. Metastatic breast cancers have reduced immune cell recruitment but harbor increased macrophages relative to their matched primary tumors. J Immunother Cancer 2019; 7:265.
Nanda R, Liu MC, Yau C, et al. Effect of pembrolizumab plus neoadjuvant chemotherapy on pathologic complete response in women with early-stage breast cancer: An analysis of the ongoing phase 2 adaptively randomized I-SPY2 trial. JAMA Oncol. 2020; 6(5):676–684.
Schmid P, Adams S, Rugo HS, et al. IMpassion130: updated overall survival (OS) from a global, randomized, double-blind, placebo-controlled, Phase III study of atezolizumab (atezo) + nab-paclitaxel (nP) in previously untreated locally advanced or metastatic triple-negative breast cancer (mTNBC). J Clin Oncol 2019; 37S:ASCO #1003.
Cortes J, Cescon DW, Rugo HS, et al. KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. J Clin Oncol 2020;38S:ASCO #1000.
Martinello R, Becco P, Vici P, et al. Trastuzumab-related cardiotoxicity in patients with nonlimiting cardiac comorbidity. Breast J 2019; 25(3):444-449.
Liang W, Guan W, Chen R, et al. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. Lancet Oncol 2020; 21(3):335-337.
Efficacy of immunotherapy also depends on breast cancer subtype. Triple-negative and HER2-positive tumors have higher TMB and TILs compared to luminal subtype. A phase 2 study in 88 patients with metastatic HR-positive, ERBB2-negative breast cancer demonstrated no difference in PFS or ORR with pembrolizumab/eribulin versus eribulin alone, including the PD-L1 positive population. There was a trend towards greater immunotherapy benefit in the high TMB subgroup which is encouraging. Future research with novel agents that may augment immune response and/or alter tumor microenvironment are intriguing concepts.
First-line endocrine therapy plus CDK 4/6 inhibitor is considered standard of care for HR-positive metastatic breast cancer. A retrospective chart review evaluating everolimus plus endocrine therapy post-CDK 4/6 inhibitor demonstrated PFS of 4.2 months and ORR of 17%. Although benefit appears modest, mTOR inhibitor combinations remain a valuable treatment option for select patients. Chemotherapy is often reserved for rapidly progressive disease or visceral crisis, however, it is crucial to evaluate for endocrine resistance. Furthermore, additional research is warranted to determine interactions between PI3K/Akt/mTOR and downstream Cyclin D/CDK 4/6/Rb pathways and implications on treatment sequencing.
Trastuzumab therapy for 1 year is standard of care for early-stage HER2-positive breast cancer. A meta-analysis of 5 trials with 11,376 patients showed noninferiority of shorter duration trastuzumab compared to 1 year for DFS and OS and lower congestive heart failure rates with the former. Trastuzumab is well-tolerated, and although cardiac toxicity is often reversible, it can carry more severe consequences in patients with cardiac conditions. Shorter duration may be an option in patients with clinically lower risk disease (ER-positive, node-negative tumors) and significant cardiac risk factors, and represents a method of therapy de-escalation for the appropriate patient.
The COVID-19 pandemic has impacted oncology healthcare delivery models and cancer patients have poorer outcomes from COVID-19. A survey study of Brazilian breast cancer specialists demonstrated changing practices for early-stage breast cancer as the pandemic progressed. For HR-positive tumors with low ki-67, 48% would recommend NET for postmenopausal women, while 34% would recommend NET for those with high ki-67. There is limited data regarding NET for pre-menopausal women. Genomic assays may have an evolving role to identify patients who may be appropriate candidates for neoadjuvant therapy versus upfront surgery. Strategies to decrease treatment complications and effectively utilize resources are essential during the COVID-19 pandemic.
Erin Roesch, MD
The Cleveland Clinic
References:
Zhu L, Narloch, JL, Onkar S, et al. Metastatic breast cancers have reduced immune cell recruitment but harbor increased macrophages relative to their matched primary tumors. J Immunother Cancer 2019; 7:265.
Nanda R, Liu MC, Yau C, et al. Effect of pembrolizumab plus neoadjuvant chemotherapy on pathologic complete response in women with early-stage breast cancer: An analysis of the ongoing phase 2 adaptively randomized I-SPY2 trial. JAMA Oncol. 2020; 6(5):676–684.
Schmid P, Adams S, Rugo HS, et al. IMpassion130: updated overall survival (OS) from a global, randomized, double-blind, placebo-controlled, Phase III study of atezolizumab (atezo) + nab-paclitaxel (nP) in previously untreated locally advanced or metastatic triple-negative breast cancer (mTNBC). J Clin Oncol 2019; 37S:ASCO #1003.
Cortes J, Cescon DW, Rugo HS, et al. KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. J Clin Oncol 2020;38S:ASCO #1000.
Martinello R, Becco P, Vici P, et al. Trastuzumab-related cardiotoxicity in patients with nonlimiting cardiac comorbidity. Breast J 2019; 25(3):444-449.
Liang W, Guan W, Chen R, et al. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. Lancet Oncol 2020; 21(3):335-337.
Efficacy of immunotherapy also depends on breast cancer subtype. Triple-negative and HER2-positive tumors have higher TMB and TILs compared to luminal subtype. A phase 2 study in 88 patients with metastatic HR-positive, ERBB2-negative breast cancer demonstrated no difference in PFS or ORR with pembrolizumab/eribulin versus eribulin alone, including the PD-L1 positive population. There was a trend towards greater immunotherapy benefit in the high TMB subgroup which is encouraging. Future research with novel agents that may augment immune response and/or alter tumor microenvironment are intriguing concepts.
First-line endocrine therapy plus CDK 4/6 inhibitor is considered standard of care for HR-positive metastatic breast cancer. A retrospective chart review evaluating everolimus plus endocrine therapy post-CDK 4/6 inhibitor demonstrated PFS of 4.2 months and ORR of 17%. Although benefit appears modest, mTOR inhibitor combinations remain a valuable treatment option for select patients. Chemotherapy is often reserved for rapidly progressive disease or visceral crisis, however, it is crucial to evaluate for endocrine resistance. Furthermore, additional research is warranted to determine interactions between PI3K/Akt/mTOR and downstream Cyclin D/CDK 4/6/Rb pathways and implications on treatment sequencing.
Trastuzumab therapy for 1 year is standard of care for early-stage HER2-positive breast cancer. A meta-analysis of 5 trials with 11,376 patients showed noninferiority of shorter duration trastuzumab compared to 1 year for DFS and OS and lower congestive heart failure rates with the former. Trastuzumab is well-tolerated, and although cardiac toxicity is often reversible, it can carry more severe consequences in patients with cardiac conditions. Shorter duration may be an option in patients with clinically lower risk disease (ER-positive, node-negative tumors) and significant cardiac risk factors, and represents a method of therapy de-escalation for the appropriate patient.
The COVID-19 pandemic has impacted oncology healthcare delivery models and cancer patients have poorer outcomes from COVID-19. A survey study of Brazilian breast cancer specialists demonstrated changing practices for early-stage breast cancer as the pandemic progressed. For HR-positive tumors with low ki-67, 48% would recommend NET for postmenopausal women, while 34% would recommend NET for those with high ki-67. There is limited data regarding NET for pre-menopausal women. Genomic assays may have an evolving role to identify patients who may be appropriate candidates for neoadjuvant therapy versus upfront surgery. Strategies to decrease treatment complications and effectively utilize resources are essential during the COVID-19 pandemic.
Erin Roesch, MD
The Cleveland Clinic
References:
Zhu L, Narloch, JL, Onkar S, et al. Metastatic breast cancers have reduced immune cell recruitment but harbor increased macrophages relative to their matched primary tumors. J Immunother Cancer 2019; 7:265.
Nanda R, Liu MC, Yau C, et al. Effect of pembrolizumab plus neoadjuvant chemotherapy on pathologic complete response in women with early-stage breast cancer: An analysis of the ongoing phase 2 adaptively randomized I-SPY2 trial. JAMA Oncol. 2020; 6(5):676–684.
Schmid P, Adams S, Rugo HS, et al. IMpassion130: updated overall survival (OS) from a global, randomized, double-blind, placebo-controlled, Phase III study of atezolizumab (atezo) + nab-paclitaxel (nP) in previously untreated locally advanced or metastatic triple-negative breast cancer (mTNBC). J Clin Oncol 2019; 37S:ASCO #1003.
Cortes J, Cescon DW, Rugo HS, et al. KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. J Clin Oncol 2020;38S:ASCO #1000.
Martinello R, Becco P, Vici P, et al. Trastuzumab-related cardiotoxicity in patients with nonlimiting cardiac comorbidity. Breast J 2019; 25(3):444-449.
Liang W, Guan W, Chen R, et al. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. Lancet Oncol 2020; 21(3):335-337.
Sarcoidosis can co-occur in older patients with breast cancer
Key clinical point: Sarcoidosis can develop after breast cancer and requires histologic confirmation.
Major finding: Twenty of 429 (4.9%) women with sarcoidosis had breast cancer, which usually was diagnosed first. Sarcoidosis was diagnosed at a median age of 53.9 years, most often involved the lungs and central lymph nodes, and was asymptomatic in half of cases.
Study details: Single-center retrospective study of 1,000 sarcoidosis cases.
Disclosures: The study was not funded. The investigators reported having no conflicts.
Citation: Papanikolaou IC et al. Resp Med Case Rep. 2020 Aug 13. doi: 10.1016/j.rmcr.2020.101190
Key clinical point: Sarcoidosis can develop after breast cancer and requires histologic confirmation.
Major finding: Twenty of 429 (4.9%) women with sarcoidosis had breast cancer, which usually was diagnosed first. Sarcoidosis was diagnosed at a median age of 53.9 years, most often involved the lungs and central lymph nodes, and was asymptomatic in half of cases.
Study details: Single-center retrospective study of 1,000 sarcoidosis cases.
Disclosures: The study was not funded. The investigators reported having no conflicts.
Citation: Papanikolaou IC et al. Resp Med Case Rep. 2020 Aug 13. doi: 10.1016/j.rmcr.2020.101190
Key clinical point: Sarcoidosis can develop after breast cancer and requires histologic confirmation.
Major finding: Twenty of 429 (4.9%) women with sarcoidosis had breast cancer, which usually was diagnosed first. Sarcoidosis was diagnosed at a median age of 53.9 years, most often involved the lungs and central lymph nodes, and was asymptomatic in half of cases.
Study details: Single-center retrospective study of 1,000 sarcoidosis cases.
Disclosures: The study was not funded. The investigators reported having no conflicts.
Citation: Papanikolaou IC et al. Resp Med Case Rep. 2020 Aug 13. doi: 10.1016/j.rmcr.2020.101190
Everolimus after palbociclib of modest value in metastatic HR+ HER2- breast cancer
Key clinical point: The mTOR inhibitor everolimus performed modestly when sequenced after palbociclib in metastatic HR+ HER2- breast cancer.
Major finding: Median PFS on everolimus was 4.2 months. ORR was 17.1% (all partial responses).
Study details: Two-center retrospective chart review of 41 patients who received everolimus combinations after their metastatic HR+ HER2- breast cancer progressed on palbociclib.
Disclosures: The National Cancer Institute provided funding. Four of the investigators disclosed ties to Novartis, Pfizer, and other pharmaceutical companies.
Citation: Dhakal A et al. Breast Cancer (Auckl). 2020 Jul 23. doi: 10.1177/1178223420944864
Key clinical point: The mTOR inhibitor everolimus performed modestly when sequenced after palbociclib in metastatic HR+ HER2- breast cancer.
Major finding: Median PFS on everolimus was 4.2 months. ORR was 17.1% (all partial responses).
Study details: Two-center retrospective chart review of 41 patients who received everolimus combinations after their metastatic HR+ HER2- breast cancer progressed on palbociclib.
Disclosures: The National Cancer Institute provided funding. Four of the investigators disclosed ties to Novartis, Pfizer, and other pharmaceutical companies.
Citation: Dhakal A et al. Breast Cancer (Auckl). 2020 Jul 23. doi: 10.1177/1178223420944864
Key clinical point: The mTOR inhibitor everolimus performed modestly when sequenced after palbociclib in metastatic HR+ HER2- breast cancer.
Major finding: Median PFS on everolimus was 4.2 months. ORR was 17.1% (all partial responses).
Study details: Two-center retrospective chart review of 41 patients who received everolimus combinations after their metastatic HR+ HER2- breast cancer progressed on palbociclib.
Disclosures: The National Cancer Institute provided funding. Four of the investigators disclosed ties to Novartis, Pfizer, and other pharmaceutical companies.
Citation: Dhakal A et al. Breast Cancer (Auckl). 2020 Jul 23. doi: 10.1177/1178223420944864
COVID-19 changed early breast cancer management
Key clinical point: In Brazil, the COVID-19 pandemic changed how specialists managed early breast cancer, especially HR-positive tumors.
Major finding: Nearly 70% of breast cancer specialists reported changing their management of early breast cancer. For more proliferative HR-positive tumors (Ki-67 >30%), 34% recommended neoadjuvant endocrine therapy (NET) for postmenopausal patients, while 10.9% recommended NET for premenopausal patients.
Study details: Survey of 503 breast cancer specialists in Brazil.
Disclosures: The study was not funded. The researchers reported having no conflicts.
Citation: Cavalcante FP et al. Breast Cancer Res Treat. 2020 Aug 16. doi: 10.1007/s10549-020-05877-y
Key clinical point: In Brazil, the COVID-19 pandemic changed how specialists managed early breast cancer, especially HR-positive tumors.
Major finding: Nearly 70% of breast cancer specialists reported changing their management of early breast cancer. For more proliferative HR-positive tumors (Ki-67 >30%), 34% recommended neoadjuvant endocrine therapy (NET) for postmenopausal patients, while 10.9% recommended NET for premenopausal patients.
Study details: Survey of 503 breast cancer specialists in Brazil.
Disclosures: The study was not funded. The researchers reported having no conflicts.
Citation: Cavalcante FP et al. Breast Cancer Res Treat. 2020 Aug 16. doi: 10.1007/s10549-020-05877-y
Key clinical point: In Brazil, the COVID-19 pandemic changed how specialists managed early breast cancer, especially HR-positive tumors.
Major finding: Nearly 70% of breast cancer specialists reported changing their management of early breast cancer. For more proliferative HR-positive tumors (Ki-67 >30%), 34% recommended neoadjuvant endocrine therapy (NET) for postmenopausal patients, while 10.9% recommended NET for premenopausal patients.
Study details: Survey of 503 breast cancer specialists in Brazil.
Disclosures: The study was not funded. The researchers reported having no conflicts.
Citation: Cavalcante FP et al. Breast Cancer Res Treat. 2020 Aug 16. doi: 10.1007/s10549-020-05877-y
Shorter-duration trastuzumab noninferior in early breast cancer
Key clinical point: For patients with early breast cancer, ≤ 6 months of adjuvant trastuzumab was noninferior to a 1-year course and appeared to be less cardiotoxic.
Major finding: 5-year DFS rates were 85.4% vs. 87.1%, respectively. Rates of congestive heart failure were 3.9% vs. 6.9%, respectively.
Study details: Meta-analysis of 5 randomized trials (11,376 patients).
Disclosures: Funding sources were not reported. Two coinvestigators disclosed ties to Roche, Eisai, Novartis, Sanofi, Kendle India, and several other pharmaceutical companies.
Citation: Gulia S et al. 2020 Aug 24. JAMA Netw Open. doi: 10.1001/jamanetworkopen.2020.11777
Key clinical point: For patients with early breast cancer, ≤ 6 months of adjuvant trastuzumab was noninferior to a 1-year course and appeared to be less cardiotoxic.
Major finding: 5-year DFS rates were 85.4% vs. 87.1%, respectively. Rates of congestive heart failure were 3.9% vs. 6.9%, respectively.
Study details: Meta-analysis of 5 randomized trials (11,376 patients).
Disclosures: Funding sources were not reported. Two coinvestigators disclosed ties to Roche, Eisai, Novartis, Sanofi, Kendle India, and several other pharmaceutical companies.
Citation: Gulia S et al. 2020 Aug 24. JAMA Netw Open. doi: 10.1001/jamanetworkopen.2020.11777
Key clinical point: For patients with early breast cancer, ≤ 6 months of adjuvant trastuzumab was noninferior to a 1-year course and appeared to be less cardiotoxic.
Major finding: 5-year DFS rates were 85.4% vs. 87.1%, respectively. Rates of congestive heart failure were 3.9% vs. 6.9%, respectively.
Study details: Meta-analysis of 5 randomized trials (11,376 patients).
Disclosures: Funding sources were not reported. Two coinvestigators disclosed ties to Roche, Eisai, Novartis, Sanofi, Kendle India, and several other pharmaceutical companies.
Citation: Gulia S et al. 2020 Aug 24. JAMA Netw Open. doi: 10.1001/jamanetworkopen.2020.11777
Checkpoint inhibitors of limited benefit in metastatic breast cancer
Key clinical point: Despite showing efficacy in specific subgroups, immune checkpoint inhibitors (ICIs) are unlikely to benefit most women with metastatic breast cancer.
Major finding: Objective response rates were 19% overall, 27% in PD-L1 positive patients, 18% in PD-L1 negative patients, 28% in HER2-positive breast cancer, 23% in triple-negative breast cancer, 35% when used in the first line, 26% when combined with systemic therapy, and 9% when used as monotherapy.
Study details: Meta-analysis of 27 studies of metastatic breast cancer (1,746 patients).
Disclosures: The study was funded by the National Natural Science Foundation of China. The investigators reported having no conflicts.
Citation: Zou Y et al. Ther Adv Med Oncol. 2020 Aug 17. doi: 10.1177/1758835920940928
Key clinical point: Despite showing efficacy in specific subgroups, immune checkpoint inhibitors (ICIs) are unlikely to benefit most women with metastatic breast cancer.
Major finding: Objective response rates were 19% overall, 27% in PD-L1 positive patients, 18% in PD-L1 negative patients, 28% in HER2-positive breast cancer, 23% in triple-negative breast cancer, 35% when used in the first line, 26% when combined with systemic therapy, and 9% when used as monotherapy.
Study details: Meta-analysis of 27 studies of metastatic breast cancer (1,746 patients).
Disclosures: The study was funded by the National Natural Science Foundation of China. The investigators reported having no conflicts.
Citation: Zou Y et al. Ther Adv Med Oncol. 2020 Aug 17. doi: 10.1177/1758835920940928
Key clinical point: Despite showing efficacy in specific subgroups, immune checkpoint inhibitors (ICIs) are unlikely to benefit most women with metastatic breast cancer.
Major finding: Objective response rates were 19% overall, 27% in PD-L1 positive patients, 18% in PD-L1 negative patients, 28% in HER2-positive breast cancer, 23% in triple-negative breast cancer, 35% when used in the first line, 26% when combined with systemic therapy, and 9% when used as monotherapy.
Study details: Meta-analysis of 27 studies of metastatic breast cancer (1,746 patients).
Disclosures: The study was funded by the National Natural Science Foundation of China. The investigators reported having no conflicts.
Citation: Zou Y et al. Ther Adv Med Oncol. 2020 Aug 17. doi: 10.1177/1758835920940928
Study eyes breast cancer mortality in older women
Key clinical point: Later uptake and less extensive use of screening mammography might explain a relatively high rate of deaths from breast cancer among older women in Germany.
Major finding: Women aged ≥ 70 years in Germany had a 19% lower incidence but a 45% higher rate of mortality from breast cancer compared with their peers in the United States.
Study details: Population-based study of the Surveillance, Epidemiology, and End Results (SEER) 9 registry in the United States, and the Saarland Cancer Registry and the German Centre for Cancer Registry Data in Germany.
Disclosures: German Cancer Aid funded the study. The investigators reported having no conflicts.
Citation: Jansen L et al. Cancers (Basel). 2020 Aug 26. doi: 10.3390/cancers12092419
Key clinical point: Later uptake and less extensive use of screening mammography might explain a relatively high rate of deaths from breast cancer among older women in Germany.
Major finding: Women aged ≥ 70 years in Germany had a 19% lower incidence but a 45% higher rate of mortality from breast cancer compared with their peers in the United States.
Study details: Population-based study of the Surveillance, Epidemiology, and End Results (SEER) 9 registry in the United States, and the Saarland Cancer Registry and the German Centre for Cancer Registry Data in Germany.
Disclosures: German Cancer Aid funded the study. The investigators reported having no conflicts.
Citation: Jansen L et al. Cancers (Basel). 2020 Aug 26. doi: 10.3390/cancers12092419
Key clinical point: Later uptake and less extensive use of screening mammography might explain a relatively high rate of deaths from breast cancer among older women in Germany.
Major finding: Women aged ≥ 70 years in Germany had a 19% lower incidence but a 45% higher rate of mortality from breast cancer compared with their peers in the United States.
Study details: Population-based study of the Surveillance, Epidemiology, and End Results (SEER) 9 registry in the United States, and the Saarland Cancer Registry and the German Centre for Cancer Registry Data in Germany.
Disclosures: German Cancer Aid funded the study. The investigators reported having no conflicts.
Citation: Jansen L et al. Cancers (Basel). 2020 Aug 26. doi: 10.3390/cancers12092419