AVAHO

Adding neoadjuvant atezolizumab to chemotherapy was associated with a significantly improved response in patients with early-stage triple-negative breast cancer, based on final data from a randomized trial.

The IMpassion031 trial showed significant improvement in pathological complete response (pCR) with the addition of atezolizumab to chemotherapy, as well as an acceptable safety profile, said Carlos H. Barrios, MD, of the Latin American Cooperative Oncology Group, Oncoclinicas, in Porto Allegre, Brazil, at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress. Those findings were published in the Lancet in 2020.

Heidi Splete/MDedge News

Dr. Barrios reported data from a final analysis of the IMpassion031 trial, with data on event-free survival (EFS), disease-free survival (DFS) and overall survival (OS) in the intent-to-treat (ITT) and PD-L1–positive populations.

In the study, patients with early triple-negative breast cancer (eTNBC) and a primary tumor greater than 2 cm were randomized to 840 mg of atezolizumab once every 2 weeks plus a neoadjuvant chemotherapy regimen of nab-paclitaxel 125 mg/m² once weekly for 12 weeks, followed by doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m² once every 2 weeks for 8 weeks. A total of 333 patients were randomized (165 atezolizumab and 168 placebo). Patients were stratified by stage II versus stage III, and by status of PD-L1, a protein that can predict treatment response (PD-L1 less than 1% vs. 1% or higher).

The primary endpoints (previously reported) were pathological complete response (pCR) in the ITT and PD-L1 populations. After a median follow-up of 39 months, the pCR was 58% in patients treated with atezolizumab versus 41% in those treated with neoadjuvant chemotherapy alone (P = .0044) in the ITT population, Dr. Barrios said. The added benefit from atezolizumab occurred regardless of the status of PD-L1.

Dr. Barrios reported the secondary outcomes of EFS, DFS, and OS in the intent-to-treat and PD-L1–positive populations. “This is a descriptive analysis, with no statistical comparison,” he emphasized.

The 2-year data on EFS, DFS, and OS consistently favored atezolizumab across key clinical subgroups, Dr. Barrios said. In the ITT population, 2-year EFS, DFS, and OS was 85%, 87%, and 95%, respectively, in the atezolizumab group and 80%, 83%, and 90%, respectively, in the placebo group. The results were similar, irrespective of PD-L1 status.

In the PD-L1–positive population, 2-year EFS, DFS, and OS was 89%, 91%, and 95%, respectively, in atezolizumab patients and 80%, 87%, and 91% in placebo patients.

Among patients without pCR at the time of surgery, 14 of 70 patients (20%) in the atezolizumab group and 33 of 99 patients (33%) in the placebo group received additional adjuvant systemic therapy. The most common adjunctive therapy was capecitabine.

As for safety, no new safety signals or treatment-related deaths were observed in the study. Overall, 70% of atezolizumab patients and 62% of placebo patients experienced grade 3 or 4 adverse events (AEs); 59% and 54% of which were treatment related. A total of 1% of patients in each group experienced grade 5 AEs. A total of 25% of atezolizumab patients and 20% of placebo patients experienced AEs leading to treatment discontinuation.

In a further exploratory analysis, pCR was highly predictive of long-term outcomes. Exploratory analysis of circulating tumor DNA (ctDNA) showed clearance in 89% of atezolizumab patients and 86% of placebo patients by the time of surgery.

Looking at the relationship between ctDNA, DFS, and OS, positive ctDNA was associated with a worse prognosis following surgery. As demonstrated in previous studies, pCR patients with negative ctDNA had the best DFS and OS. “In non-pCR patients with positive ctDNA, a numerical trend suggests improved overall survival with atezolizumab,” although the caveat is the very small numbers, Dr. Barrios said.

More research is needed, but in the final analysis, the significant pCR benefit seen with the addition of atezolizumab to chemotherapy for eTNBC translated into numerically improved EFS, DFS and OS, said Dr. Barrios. Additionally, “we should further analyze ctDNA to help select patients for further therapy.”

In a question-and-answer session, Dr. Barrios was asked how the results compared with other studies.

“We should not overinterpret the results,” he said. However, “what the IMpassion031 study shows is consistency; the results are aligned with previous studies addressing the same question of introducing immunotherapy,” in the patient population. Although the numbers in the IMpassion031 study did not reach statistical significance, it is important to recognize that they reflect previous research.

“In my opinion, looking at the whole field, immunotherapy is something we need to consider as part of the treatment of these patients,” said Dr. Barrios. However, more research is needed to better identify which patients do and do not need chemotherapy.
 

Phase 2 data show increased response with added atezolizumab for PD-L1–negative patients

In a second study known as ABSCG-52/ATHENE, researchers evaluated neoadjuvant atezolizumab in combination with dual HER2 blockade plus epirubicin for the treatment of patients with early HER2-positive breast cancer.

Heidi Splete/MDedge News

For most of these patients, the current standard of care is neoadjuvant dual HER2 blockade with trastuzumab (T) and pertuzumab (P) plus poly-chemotherapy, said Gabriel Rinnerthaler, MD, of the Salzburg (Austria) Cancer Research Institute, said in his presentation at the meeting. However, de-escalation of chemotherapy has been a major focus of research in recent years, and more research is needed on a combination of anthracyclines, such as epirubicin and idarubicin, and immune-checkpoint modulators.

In the phase 2 study, the researchers randomized patients with previously untreated, histologically confirmed HER2-positive early breast cancer (defined as a clinical prognostic stage cT1c–4a-d, N0-3, M0) in a 1:1 ratio to two 3-weekly cycles of a chemotherapy-free induction phase (part 1) with TP plus 1,200 mg atezolizumab (TP-A) or TP alone.

“We hypothesized that the additive effect of immune checkpoint inhibitors plus anti-HER2 therapy and chemotherapy would not be linear,” he said.

At the end of this period, all patients underwent four cycles of TP-A in combination with epirubicin (part 2). The primary endpoint was pCR (defined as absence of invasive cancer in the breast and axillary nodes, or ypT0/Tis ypN0) in the overall study population, and a pCR of 40% was considered a positive result.

A total of 29 patients were randomized to TP-A and 29 to TP alone in nine treatment centers in Austria. The study population ranged from 33 to 82 years, with a median age of 57 years. Most patients (72.4%) had hormone receptor (HR)–positive tumors; a total of 45 patients had stage IIA cancer, and 13 had stage IIB.

The primary endpoint of pCR occurred in 35 patients overall (60.3%). In a univariate analysis, the response rates were lower in HR-positive patients, in premenopausal patients, and in histologies other than NST (invasive carcinoma of no special type), Dr. Rinnerthaler said, but none of the differences were statistically significant, likely because of the small numbers in each group.

In an exploratory analysis of the ITT population with available PD-L1 data, the pCR was 69.2% for PD-L1–negative patients and 55.2% for PD-L1–positive patients.

“We observed the highest pCR rates in PD-L1–negative patients treated in the TP-A group and the lowest in PD-L1–positive patients treated with TP alone,” Dr. Rinnerthaler said.

No new safety concerns were observed during the study, Dr. Rinnerthaler noted. AEs of grade 3 or higher occurred in 17 patients (29.3%), including 9 in the TP-A group and 8 in the TP group. The most common AEs in both groups were nausea, diarrhea, and fatigue. No AEs of special interest of grade 3 or higher (defined as immune-related AEs, cardiac disorders, or infusion-related reactions) were observed.

The study findings were limited by the small sample size, but the resulting pCR rate of 60.3% was higher than the predefined threshold of 40% and supports additional research, said Dr. Rinnerthaler.

“For HER2-positive early breast cancer, a neoadjuvant chemotherapy de-escalation immunotherapy regimen with trastuzumab, pertuzumab, atezolizumab, and epirubicin is highly effective and safe and merits further investigation,” he concluded.

During a question-and-answer session, Dr. Rinnerthaler was asked why pCR increased in PD-L1 negative patients.

Previous data have shown that PD-L1 is up-regulated in certain tumors, and may serve as a surrogate for sensitivity, he said. In previous studies the additional effect of atezolizumab was seen in a PD-L1–negative group.

Dr. Rinnerthaler said he hopes to clarify this question when his research team reviews biopsy data from baseline and after the induction phase.
 

Defining response is key to de-escalation

In the IMpassion031 trial, “what we saw is a tendency to better outcomes for those patients who received atezolizumab,” said Matteo Lambertini, MD, of the University of Genova (Italy), who served as discussant for the two studies. The IMpassion031 study raises the question of where we are in the use of immuno-oncology for eTNBC. The study is now one of five neoadjuvant trials in this population.

Heidi Splete/MDedge News

Dr. Lambertini cited the KEYNOTE-522 study, which showed significant results in EFS. However, sample sizes and statistical design were different between these studies. “I think we need large studies of data in the adjuvant and postneoadjuvant setting for patients with triple-negative breast cancer.”

Postneoadjuvant considerations from the IMpassion031 trial showed good outcomes with no additional benefit of an immune checkpoint inhibitors.

For those patients with a pCR, it is definitely time to de-escalate treatment,” he said. In patients without pCR, escalation is needed, but an improved definition of pCR is also needed.

With regard to the ATHENE study, “it may be considered a positive study because the threshold of 40% was reached,” he said. The question is what is the optimum chemotherapy backbone. There appears to be no added benefit to adding an immune checkpoint inhibitor.

There are needs for defining the role of immunotherapy in HER2-positive breast cancer and more biomarker research to inform patient selection and study design, he said.

Finally, “I am not sure that the addition of an immune checkpoint inhibitor can be considered a de-escalation,” he noted.

IMpassion031 was supported by F. Hoffmann–La Roche. Dr. Barrio disclosed financial relationships with numerous companies. ABSCG-52/ATHENE was supported by the Austrian Breast and Colorectal Cancer Study Group and Roche Austria. Dr. Rinnerthaler disclosed relationships with multiple companies including Amgen, Daiichi Sankyo, Lilly, Gilead, MSD, Novartis, Pfizer, Roche, Seagen, and Pierre Fabre. Dr. Lambertini disclosed relationships with multiple companies including Roche, Novartis, AstraZeneca, Lilly, Exact Sciences, Pfizer, MSD, Seagen, Gilead, Takeda, Sandoz, Ipsen, Libbs, Knight, and Daiichi Sankyo.

Adding neoadjuvant atezolizumab to chemotherapy was associated with a significantly improved response in patients with early-stage triple-negative breast cancer, based on final data from a randomized trial.

The IMpassion031 trial showed significant improvement in pathological complete response (pCR) with the addition of atezolizumab to chemotherapy, as well as an acceptable safety profile, said Carlos H. Barrios, MD, of the Latin American Cooperative Oncology Group, Oncoclinicas, in Porto Allegre, Brazil, at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress. Those findings were published in the Lancet in 2020.

Heidi Splete/MDedge News

Dr. Barrios reported data from a final analysis of the IMpassion031 trial, with data on event-free survival (EFS), disease-free survival (DFS) and overall survival (OS) in the intent-to-treat (ITT) and PD-L1–positive populations.

In the study, patients with early triple-negative breast cancer (eTNBC) and a primary tumor greater than 2 cm were randomized to 840 mg of atezolizumab once every 2 weeks plus a neoadjuvant chemotherapy regimen of nab-paclitaxel 125 mg/m² once weekly for 12 weeks, followed by doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m² once every 2 weeks for 8 weeks. A total of 333 patients were randomized (165 atezolizumab and 168 placebo). Patients were stratified by stage II versus stage III, and by status of PD-L1, a protein that can predict treatment response (PD-L1 less than 1% vs. 1% or higher).

The primary endpoints (previously reported) were pathological complete response (pCR) in the ITT and PD-L1 populations. After a median follow-up of 39 months, the pCR was 58% in patients treated with atezolizumab versus 41% in those treated with neoadjuvant chemotherapy alone (P = .0044) in the ITT population, Dr. Barrios said. The added benefit from atezolizumab occurred regardless of the status of PD-L1.

Dr. Barrios reported the secondary outcomes of EFS, DFS, and OS in the intent-to-treat and PD-L1–positive populations. “This is a descriptive analysis, with no statistical comparison,” he emphasized.

The 2-year data on EFS, DFS, and OS consistently favored atezolizumab across key clinical subgroups, Dr. Barrios said. In the ITT population, 2-year EFS, DFS, and OS was 85%, 87%, and 95%, respectively, in the atezolizumab group and 80%, 83%, and 90%, respectively, in the placebo group. The results were similar, irrespective of PD-L1 status.

In the PD-L1–positive population, 2-year EFS, DFS, and OS was 89%, 91%, and 95%, respectively, in atezolizumab patients and 80%, 87%, and 91% in placebo patients.

Among patients without pCR at the time of surgery, 14 of 70 patients (20%) in the atezolizumab group and 33 of 99 patients (33%) in the placebo group received additional adjuvant systemic therapy. The most common adjunctive therapy was capecitabine.

As for safety, no new safety signals or treatment-related deaths were observed in the study. Overall, 70% of atezolizumab patients and 62% of placebo patients experienced grade 3 or 4 adverse events (AEs); 59% and 54% of which were treatment related. A total of 1% of patients in each group experienced grade 5 AEs. A total of 25% of atezolizumab patients and 20% of placebo patients experienced AEs leading to treatment discontinuation.

In a further exploratory analysis, pCR was highly predictive of long-term outcomes. Exploratory analysis of circulating tumor DNA (ctDNA) showed clearance in 89% of atezolizumab patients and 86% of placebo patients by the time of surgery.

Looking at the relationship between ctDNA, DFS, and OS, positive ctDNA was associated with a worse prognosis following surgery. As demonstrated in previous studies, pCR patients with negative ctDNA had the best DFS and OS. “In non-pCR patients with positive ctDNA, a numerical trend suggests improved overall survival with atezolizumab,” although the caveat is the very small numbers, Dr. Barrios said.

More research is needed, but in the final analysis, the significant pCR benefit seen with the addition of atezolizumab to chemotherapy for eTNBC translated into numerically improved EFS, DFS and OS, said Dr. Barrios. Additionally, “we should further analyze ctDNA to help select patients for further therapy.”

In a question-and-answer session, Dr. Barrios was asked how the results compared with other studies.

“We should not overinterpret the results,” he said. However, “what the IMpassion031 study shows is consistency; the results are aligned with previous studies addressing the same question of introducing immunotherapy,” in the patient population. Although the numbers in the IMpassion031 study did not reach statistical significance, it is important to recognize that they reflect previous research.

“In my opinion, looking at the whole field, immunotherapy is something we need to consider as part of the treatment of these patients,” said Dr. Barrios. However, more research is needed to better identify which patients do and do not need chemotherapy.
 

Phase 2 data show increased response with added atezolizumab for PD-L1–negative patients

In a second study known as ABSCG-52/ATHENE, researchers evaluated neoadjuvant atezolizumab in combination with dual HER2 blockade plus epirubicin for the treatment of patients with early HER2-positive breast cancer.

Heidi Splete/MDedge News

For most of these patients, the current standard of care is neoadjuvant dual HER2 blockade with trastuzumab (T) and pertuzumab (P) plus poly-chemotherapy, said Gabriel Rinnerthaler, MD, of the Salzburg (Austria) Cancer Research Institute, said in his presentation at the meeting. However, de-escalation of chemotherapy has been a major focus of research in recent years, and more research is needed on a combination of anthracyclines, such as epirubicin and idarubicin, and immune-checkpoint modulators.

In the phase 2 study, the researchers randomized patients with previously untreated, histologically confirmed HER2-positive early breast cancer (defined as a clinical prognostic stage cT1c–4a-d, N0-3, M0) in a 1:1 ratio to two 3-weekly cycles of a chemotherapy-free induction phase (part 1) with TP plus 1,200 mg atezolizumab (TP-A) or TP alone.

“We hypothesized that the additive effect of immune checkpoint inhibitors plus anti-HER2 therapy and chemotherapy would not be linear,” he said.

At the end of this period, all patients underwent four cycles of TP-A in combination with epirubicin (part 2). The primary endpoint was pCR (defined as absence of invasive cancer in the breast and axillary nodes, or ypT0/Tis ypN0) in the overall study population, and a pCR of 40% was considered a positive result.

A total of 29 patients were randomized to TP-A and 29 to TP alone in nine treatment centers in Austria. The study population ranged from 33 to 82 years, with a median age of 57 years. Most patients (72.4%) had hormone receptor (HR)–positive tumors; a total of 45 patients had stage IIA cancer, and 13 had stage IIB.

The primary endpoint of pCR occurred in 35 patients overall (60.3%). In a univariate analysis, the response rates were lower in HR-positive patients, in premenopausal patients, and in histologies other than NST (invasive carcinoma of no special type), Dr. Rinnerthaler said, but none of the differences were statistically significant, likely because of the small numbers in each group.

In an exploratory analysis of the ITT population with available PD-L1 data, the pCR was 69.2% for PD-L1–negative patients and 55.2% for PD-L1–positive patients.

“We observed the highest pCR rates in PD-L1–negative patients treated in the TP-A group and the lowest in PD-L1–positive patients treated with TP alone,” Dr. Rinnerthaler said.

No new safety concerns were observed during the study, Dr. Rinnerthaler noted. AEs of grade 3 or higher occurred in 17 patients (29.3%), including 9 in the TP-A group and 8 in the TP group. The most common AEs in both groups were nausea, diarrhea, and fatigue. No AEs of special interest of grade 3 or higher (defined as immune-related AEs, cardiac disorders, or infusion-related reactions) were observed.

The study findings were limited by the small sample size, but the resulting pCR rate of 60.3% was higher than the predefined threshold of 40% and supports additional research, said Dr. Rinnerthaler.

“For HER2-positive early breast cancer, a neoadjuvant chemotherapy de-escalation immunotherapy regimen with trastuzumab, pertuzumab, atezolizumab, and epirubicin is highly effective and safe and merits further investigation,” he concluded.

During a question-and-answer session, Dr. Rinnerthaler was asked why pCR increased in PD-L1 negative patients.

Previous data have shown that PD-L1 is up-regulated in certain tumors, and may serve as a surrogate for sensitivity, he said. In previous studies the additional effect of atezolizumab was seen in a PD-L1–negative group.

Dr. Rinnerthaler said he hopes to clarify this question when his research team reviews biopsy data from baseline and after the induction phase.
 

Defining response is key to de-escalation

In the IMpassion031 trial, “what we saw is a tendency to better outcomes for those patients who received atezolizumab,” said Matteo Lambertini, MD, of the University of Genova (Italy), who served as discussant for the two studies. The IMpassion031 study raises the question of where we are in the use of immuno-oncology for eTNBC. The study is now one of five neoadjuvant trials in this population.

Heidi Splete/MDedge News

Dr. Lambertini cited the KEYNOTE-522 study, which showed significant results in EFS. However, sample sizes and statistical design were different between these studies. “I think we need large studies of data in the adjuvant and postneoadjuvant setting for patients with triple-negative breast cancer.”

Postneoadjuvant considerations from the IMpassion031 trial showed good outcomes with no additional benefit of an immune checkpoint inhibitors.

For those patients with a pCR, it is definitely time to de-escalate treatment,” he said. In patients without pCR, escalation is needed, but an improved definition of pCR is also needed.

With regard to the ATHENE study, “it may be considered a positive study because the threshold of 40% was reached,” he said. The question is what is the optimum chemotherapy backbone. There appears to be no added benefit to adding an immune checkpoint inhibitor.

There are needs for defining the role of immunotherapy in HER2-positive breast cancer and more biomarker research to inform patient selection and study design, he said.

Finally, “I am not sure that the addition of an immune checkpoint inhibitor can be considered a de-escalation,” he noted.

IMpassion031 was supported by F. Hoffmann–La Roche. Dr. Barrio disclosed financial relationships with numerous companies. ABSCG-52/ATHENE was supported by the Austrian Breast and Colorectal Cancer Study Group and Roche Austria. Dr. Rinnerthaler disclosed relationships with multiple companies including Amgen, Daiichi Sankyo, Lilly, Gilead, MSD, Novartis, Pfizer, Roche, Seagen, and Pierre Fabre. Dr. Lambertini disclosed relationships with multiple companies including Roche, Novartis, AstraZeneca, Lilly, Exact Sciences, Pfizer, MSD, Seagen, Gilead, Takeda, Sandoz, Ipsen, Libbs, Knight, and Daiichi Sankyo.

Adding neoadjuvant atezolizumab to chemotherapy was associated with a significantly improved response in patients with early-stage triple-negative breast cancer, based on final data from a randomized trial.

The IMpassion031 trial showed significant improvement in pathological complete response (pCR) with the addition of atezolizumab to chemotherapy, as well as an acceptable safety profile, said Carlos H. Barrios, MD, of the Latin American Cooperative Oncology Group, Oncoclinicas, in Porto Allegre, Brazil, at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress. Those findings were published in the Lancet in 2020.

Heidi Splete/MDedge News

Dr. Barrios reported data from a final analysis of the IMpassion031 trial, with data on event-free survival (EFS), disease-free survival (DFS) and overall survival (OS) in the intent-to-treat (ITT) and PD-L1–positive populations.

In the study, patients with early triple-negative breast cancer (eTNBC) and a primary tumor greater than 2 cm were randomized to 840 mg of atezolizumab once every 2 weeks plus a neoadjuvant chemotherapy regimen of nab-paclitaxel 125 mg/m² once weekly for 12 weeks, followed by doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m² once every 2 weeks for 8 weeks. A total of 333 patients were randomized (165 atezolizumab and 168 placebo). Patients were stratified by stage II versus stage III, and by status of PD-L1, a protein that can predict treatment response (PD-L1 less than 1% vs. 1% or higher).

The primary endpoints (previously reported) were pathological complete response (pCR) in the ITT and PD-L1 populations. After a median follow-up of 39 months, the pCR was 58% in patients treated with atezolizumab versus 41% in those treated with neoadjuvant chemotherapy alone (P = .0044) in the ITT population, Dr. Barrios said. The added benefit from atezolizumab occurred regardless of the status of PD-L1.

Dr. Barrios reported the secondary outcomes of EFS, DFS, and OS in the intent-to-treat and PD-L1–positive populations. “This is a descriptive analysis, with no statistical comparison,” he emphasized.

The 2-year data on EFS, DFS, and OS consistently favored atezolizumab across key clinical subgroups, Dr. Barrios said. In the ITT population, 2-year EFS, DFS, and OS was 85%, 87%, and 95%, respectively, in the atezolizumab group and 80%, 83%, and 90%, respectively, in the placebo group. The results were similar, irrespective of PD-L1 status.

In the PD-L1–positive population, 2-year EFS, DFS, and OS was 89%, 91%, and 95%, respectively, in atezolizumab patients and 80%, 87%, and 91% in placebo patients.

Among patients without pCR at the time of surgery, 14 of 70 patients (20%) in the atezolizumab group and 33 of 99 patients (33%) in the placebo group received additional adjuvant systemic therapy. The most common adjunctive therapy was capecitabine.

As for safety, no new safety signals or treatment-related deaths were observed in the study. Overall, 70% of atezolizumab patients and 62% of placebo patients experienced grade 3 or 4 adverse events (AEs); 59% and 54% of which were treatment related. A total of 1% of patients in each group experienced grade 5 AEs. A total of 25% of atezolizumab patients and 20% of placebo patients experienced AEs leading to treatment discontinuation.

In a further exploratory analysis, pCR was highly predictive of long-term outcomes. Exploratory analysis of circulating tumor DNA (ctDNA) showed clearance in 89% of atezolizumab patients and 86% of placebo patients by the time of surgery.

Looking at the relationship between ctDNA, DFS, and OS, positive ctDNA was associated with a worse prognosis following surgery. As demonstrated in previous studies, pCR patients with negative ctDNA had the best DFS and OS. “In non-pCR patients with positive ctDNA, a numerical trend suggests improved overall survival with atezolizumab,” although the caveat is the very small numbers, Dr. Barrios said.

More research is needed, but in the final analysis, the significant pCR benefit seen with the addition of atezolizumab to chemotherapy for eTNBC translated into numerically improved EFS, DFS and OS, said Dr. Barrios. Additionally, “we should further analyze ctDNA to help select patients for further therapy.”

In a question-and-answer session, Dr. Barrios was asked how the results compared with other studies.

“We should not overinterpret the results,” he said. However, “what the IMpassion031 study shows is consistency; the results are aligned with previous studies addressing the same question of introducing immunotherapy,” in the patient population. Although the numbers in the IMpassion031 study did not reach statistical significance, it is important to recognize that they reflect previous research.

“In my opinion, looking at the whole field, immunotherapy is something we need to consider as part of the treatment of these patients,” said Dr. Barrios. However, more research is needed to better identify which patients do and do not need chemotherapy.
 

Phase 2 data show increased response with added atezolizumab for PD-L1–negative patients

In a second study known as ABSCG-52/ATHENE, researchers evaluated neoadjuvant atezolizumab in combination with dual HER2 blockade plus epirubicin for the treatment of patients with early HER2-positive breast cancer.

Heidi Splete/MDedge News

For most of these patients, the current standard of care is neoadjuvant dual HER2 blockade with trastuzumab (T) and pertuzumab (P) plus poly-chemotherapy, said Gabriel Rinnerthaler, MD, of the Salzburg (Austria) Cancer Research Institute, said in his presentation at the meeting. However, de-escalation of chemotherapy has been a major focus of research in recent years, and more research is needed on a combination of anthracyclines, such as epirubicin and idarubicin, and immune-checkpoint modulators.

In the phase 2 study, the researchers randomized patients with previously untreated, histologically confirmed HER2-positive early breast cancer (defined as a clinical prognostic stage cT1c–4a-d, N0-3, M0) in a 1:1 ratio to two 3-weekly cycles of a chemotherapy-free induction phase (part 1) with TP plus 1,200 mg atezolizumab (TP-A) or TP alone.

“We hypothesized that the additive effect of immune checkpoint inhibitors plus anti-HER2 therapy and chemotherapy would not be linear,” he said.

At the end of this period, all patients underwent four cycles of TP-A in combination with epirubicin (part 2). The primary endpoint was pCR (defined as absence of invasive cancer in the breast and axillary nodes, or ypT0/Tis ypN0) in the overall study population, and a pCR of 40% was considered a positive result.

A total of 29 patients were randomized to TP-A and 29 to TP alone in nine treatment centers in Austria. The study population ranged from 33 to 82 years, with a median age of 57 years. Most patients (72.4%) had hormone receptor (HR)–positive tumors; a total of 45 patients had stage IIA cancer, and 13 had stage IIB.

The primary endpoint of pCR occurred in 35 patients overall (60.3%). In a univariate analysis, the response rates were lower in HR-positive patients, in premenopausal patients, and in histologies other than NST (invasive carcinoma of no special type), Dr. Rinnerthaler said, but none of the differences were statistically significant, likely because of the small numbers in each group.

In an exploratory analysis of the ITT population with available PD-L1 data, the pCR was 69.2% for PD-L1–negative patients and 55.2% for PD-L1–positive patients.

“We observed the highest pCR rates in PD-L1–negative patients treated in the TP-A group and the lowest in PD-L1–positive patients treated with TP alone,” Dr. Rinnerthaler said.

No new safety concerns were observed during the study, Dr. Rinnerthaler noted. AEs of grade 3 or higher occurred in 17 patients (29.3%), including 9 in the TP-A group and 8 in the TP group. The most common AEs in both groups were nausea, diarrhea, and fatigue. No AEs of special interest of grade 3 or higher (defined as immune-related AEs, cardiac disorders, or infusion-related reactions) were observed.

The study findings were limited by the small sample size, but the resulting pCR rate of 60.3% was higher than the predefined threshold of 40% and supports additional research, said Dr. Rinnerthaler.

“For HER2-positive early breast cancer, a neoadjuvant chemotherapy de-escalation immunotherapy regimen with trastuzumab, pertuzumab, atezolizumab, and epirubicin is highly effective and safe and merits further investigation,” he concluded.

During a question-and-answer session, Dr. Rinnerthaler was asked why pCR increased in PD-L1 negative patients.

Previous data have shown that PD-L1 is up-regulated in certain tumors, and may serve as a surrogate for sensitivity, he said. In previous studies the additional effect of atezolizumab was seen in a PD-L1–negative group.

Dr. Rinnerthaler said he hopes to clarify this question when his research team reviews biopsy data from baseline and after the induction phase.
 

Defining response is key to de-escalation

In the IMpassion031 trial, “what we saw is a tendency to better outcomes for those patients who received atezolizumab,” said Matteo Lambertini, MD, of the University of Genova (Italy), who served as discussant for the two studies. The IMpassion031 study raises the question of where we are in the use of immuno-oncology for eTNBC. The study is now one of five neoadjuvant trials in this population.

Heidi Splete/MDedge News

Dr. Lambertini cited the KEYNOTE-522 study, which showed significant results in EFS. However, sample sizes and statistical design were different between these studies. “I think we need large studies of data in the adjuvant and postneoadjuvant setting for patients with triple-negative breast cancer.”

Postneoadjuvant considerations from the IMpassion031 trial showed good outcomes with no additional benefit of an immune checkpoint inhibitors.

For those patients with a pCR, it is definitely time to de-escalate treatment,” he said. In patients without pCR, escalation is needed, but an improved definition of pCR is also needed.

With regard to the ATHENE study, “it may be considered a positive study because the threshold of 40% was reached,” he said. The question is what is the optimum chemotherapy backbone. There appears to be no added benefit to adding an immune checkpoint inhibitor.

There are needs for defining the role of immunotherapy in HER2-positive breast cancer and more biomarker research to inform patient selection and study design, he said.

Finally, “I am not sure that the addition of an immune checkpoint inhibitor can be considered a de-escalation,” he noted.

IMpassion031 was supported by F. Hoffmann–La Roche. Dr. Barrio disclosed financial relationships with numerous companies. ABSCG-52/ATHENE was supported by the Austrian Breast and Colorectal Cancer Study Group and Roche Austria. Dr. Rinnerthaler disclosed relationships with multiple companies including Amgen, Daiichi Sankyo, Lilly, Gilead, MSD, Novartis, Pfizer, Roche, Seagen, and Pierre Fabre. Dr. Lambertini disclosed relationships with multiple companies including Roche, Novartis, AstraZeneca, Lilly, Exact Sciences, Pfizer, MSD, Seagen, Gilead, Takeda, Sandoz, Ipsen, Libbs, Knight, and Daiichi Sankyo.

It has been a troubling mystery—and yet, is an unsolved one: Last January, at least 9 service members who had worked at Malmstrom Air Force Base (AFB) in Montana were reported to have been diagnosed with non-Hodgkin lymphoma. Then more cancer cases were reported, not only at Malmstrom, but at Francis E. Warren AFB in Wyoming, Minot AFB in North Dakota, and Vandenberg AFB in California. The bases operate the silos that house nuclear warheads carried by Minuteman III intercontinental ballistic missiles (ICBMs).

In all, 36 cancer cases were reported among missileers: 10 developed non-Hodgkin lymphoma, 2 Hodgkin lymphoma, and 24 another form of cancer. Eight of the missileers, the majority of whom served at Malmstrom between 1997 and 2007, have died.

So far, though, the US Air Force (USAF) reports that it has found no current risk factors that could explain the unusual number of cases.

In February, Gen. Thomas Bussiere, commander of Air Force Global Strike Command, approved a study to conduct a formal assessment related to specific cancer concerns and examine the possibility of cancer clusters at ICBM bases. The Missile Community Cancer Study, conducted by the Air Force School of Aerospace Medicine, will look at all ICBM wings, all missileers, and those who maintain, guard, and support the bases. The review also incorporates active-duty medical data, the US Department of Veterans Affairs cancer registry data, mortality data, and public cancer registries.

Missileers may be exposed to a variety of chemicals and toxins. The potential hazardous materials exposure at the missile silos extends to all 3 missile bases, USAF says. The equipment in the launch control center and equipment buildings were identical. However, each of the ICBM bases has specific environmental and agricultural factors that will be considered as studies continue, according to the USAF. The land surrounding missile alert facilities, launch control centers, and launch facilities is not owned by the government; the study teams noted that locations could contain additional unknown agricultural hazards. Procedures for testing and cleaning the facilities vary across installations, creating inconsistencies, according to the USAF.

The study teams recently presented their initial findings. “[O]verall,” they said, “there were no factors identified that would be considered immediate concerns for acute cancer risks,” according to a report from the USAF 711^th Human Performance Wing, obtained by the Associated Press.

This isn’t the first time that concerns have been raised about possible cancer clusters at Malmstrom. In 2001, after cases of various cancers from missileers were reported—including cervical, thyroid, Hodgkin lymphoma, and non-Hodgkin lymphoma—the Air Force Institute for Operational Health conducted a site evaluation and sampling for possible chemical and biologic contaminants at their facilities. Results of all tests, the 2005 report said, did not demonstrate any levels above acceptable standards according to state and federal regulations. The survey concluded that launch control centers provide a safe and healthy working environment.

In 2005, following the release of the report, the USAF said “There is not sufficient evidence to consider the possibility of a cancer clustering to justify further investigation.” The research report noted, “[S]ometimes illnesses tend to occur by chance alone and it is not uncommon to see clustering or what has been referred to as ‘perceived clustering’ of conditions, especially when they occur in a close group of people or certain communities as in the military.”

On its website, though, the Air Force Medical Service now says that the findings from 2 decades ago may have changed.

The findings from the new study are not final. The USAF is continuing its investigation, including conducting an epidemiological study of cancers within the missile community. In the meantime, Air Force Global Strike Command Public Affairs says that, in response to the review panel’s recommendations, Gen. Bussiere has directed that facilities be deep cleaned regularly, signage denoting the presence of polychlorinated biphenyls be updated, and burning no longer allowed as a means of destroying classified materials inside the facilities.

Notably, the changes will also include improving communication and coordination between medical personnel and missile community members. Bussiere directed his staff to explore specifically assigning medical professionals to ICBM units, to have a better understanding of the environment and missions. He also ordered further engagement with personnel who work with known occupational hazards to collect more data and information. While awaiting the eventual replacement of the Minuteman III ICBM with the LGM-35A Sentinel, preventive maintenance and environmental upgrades will be prioritized and any upgrade or new piece of equipment will be “scrutinized for hazards.”

The USAF has also established a website to address the missileer community’s concerns.

It has been a troubling mystery—and yet, is an unsolved one: Last January, at least 9 service members who had worked at Malmstrom Air Force Base (AFB) in Montana were reported to have been diagnosed with non-Hodgkin lymphoma. Then more cancer cases were reported, not only at Malmstrom, but at Francis E. Warren AFB in Wyoming, Minot AFB in North Dakota, and Vandenberg AFB in California. The bases operate the silos that house nuclear warheads carried by Minuteman III intercontinental ballistic missiles (ICBMs).

In all, 36 cancer cases were reported among missileers: 10 developed non-Hodgkin lymphoma, 2 Hodgkin lymphoma, and 24 another form of cancer. Eight of the missileers, the majority of whom served at Malmstrom between 1997 and 2007, have died.

So far, though, the US Air Force (USAF) reports that it has found no current risk factors that could explain the unusual number of cases.

In February, Gen. Thomas Bussiere, commander of Air Force Global Strike Command, approved a study to conduct a formal assessment related to specific cancer concerns and examine the possibility of cancer clusters at ICBM bases. The Missile Community Cancer Study, conducted by the Air Force School of Aerospace Medicine, will look at all ICBM wings, all missileers, and those who maintain, guard, and support the bases. The review also incorporates active-duty medical data, the US Department of Veterans Affairs cancer registry data, mortality data, and public cancer registries.

Missileers may be exposed to a variety of chemicals and toxins. The potential hazardous materials exposure at the missile silos extends to all 3 missile bases, USAF says. The equipment in the launch control center and equipment buildings were identical. However, each of the ICBM bases has specific environmental and agricultural factors that will be considered as studies continue, according to the USAF. The land surrounding missile alert facilities, launch control centers, and launch facilities is not owned by the government; the study teams noted that locations could contain additional unknown agricultural hazards. Procedures for testing and cleaning the facilities vary across installations, creating inconsistencies, according to the USAF.

The study teams recently presented their initial findings. “[O]verall,” they said, “there were no factors identified that would be considered immediate concerns for acute cancer risks,” according to a report from the USAF 711^th Human Performance Wing, obtained by the Associated Press.

This isn’t the first time that concerns have been raised about possible cancer clusters at Malmstrom. In 2001, after cases of various cancers from missileers were reported—including cervical, thyroid, Hodgkin lymphoma, and non-Hodgkin lymphoma—the Air Force Institute for Operational Health conducted a site evaluation and sampling for possible chemical and biologic contaminants at their facilities. Results of all tests, the 2005 report said, did not demonstrate any levels above acceptable standards according to state and federal regulations. The survey concluded that launch control centers provide a safe and healthy working environment.

In 2005, following the release of the report, the USAF said “There is not sufficient evidence to consider the possibility of a cancer clustering to justify further investigation.” The research report noted, “[S]ometimes illnesses tend to occur by chance alone and it is not uncommon to see clustering or what has been referred to as ‘perceived clustering’ of conditions, especially when they occur in a close group of people or certain communities as in the military.”

On its website, though, the Air Force Medical Service now says that the findings from 2 decades ago may have changed.

The findings from the new study are not final. The USAF is continuing its investigation, including conducting an epidemiological study of cancers within the missile community. In the meantime, Air Force Global Strike Command Public Affairs says that, in response to the review panel’s recommendations, Gen. Bussiere has directed that facilities be deep cleaned regularly, signage denoting the presence of polychlorinated biphenyls be updated, and burning no longer allowed as a means of destroying classified materials inside the facilities.

Notably, the changes will also include improving communication and coordination between medical personnel and missile community members. Bussiere directed his staff to explore specifically assigning medical professionals to ICBM units, to have a better understanding of the environment and missions. He also ordered further engagement with personnel who work with known occupational hazards to collect more data and information. While awaiting the eventual replacement of the Minuteman III ICBM with the LGM-35A Sentinel, preventive maintenance and environmental upgrades will be prioritized and any upgrade or new piece of equipment will be “scrutinized for hazards.”

The USAF has also established a website to address the missileer community’s concerns.

It has been a troubling mystery—and yet, is an unsolved one: Last January, at least 9 service members who had worked at Malmstrom Air Force Base (AFB) in Montana were reported to have been diagnosed with non-Hodgkin lymphoma. Then more cancer cases were reported, not only at Malmstrom, but at Francis E. Warren AFB in Wyoming, Minot AFB in North Dakota, and Vandenberg AFB in California. The bases operate the silos that house nuclear warheads carried by Minuteman III intercontinental ballistic missiles (ICBMs).

In all, 36 cancer cases were reported among missileers: 10 developed non-Hodgkin lymphoma, 2 Hodgkin lymphoma, and 24 another form of cancer. Eight of the missileers, the majority of whom served at Malmstrom between 1997 and 2007, have died.

So far, though, the US Air Force (USAF) reports that it has found no current risk factors that could explain the unusual number of cases.

In February, Gen. Thomas Bussiere, commander of Air Force Global Strike Command, approved a study to conduct a formal assessment related to specific cancer concerns and examine the possibility of cancer clusters at ICBM bases. The Missile Community Cancer Study, conducted by the Air Force School of Aerospace Medicine, will look at all ICBM wings, all missileers, and those who maintain, guard, and support the bases. The review also incorporates active-duty medical data, the US Department of Veterans Affairs cancer registry data, mortality data, and public cancer registries.

Missileers may be exposed to a variety of chemicals and toxins. The potential hazardous materials exposure at the missile silos extends to all 3 missile bases, USAF says. The equipment in the launch control center and equipment buildings were identical. However, each of the ICBM bases has specific environmental and agricultural factors that will be considered as studies continue, according to the USAF. The land surrounding missile alert facilities, launch control centers, and launch facilities is not owned by the government; the study teams noted that locations could contain additional unknown agricultural hazards. Procedures for testing and cleaning the facilities vary across installations, creating inconsistencies, according to the USAF.

The study teams recently presented their initial findings. “[O]verall,” they said, “there were no factors identified that would be considered immediate concerns for acute cancer risks,” according to a report from the USAF 711^th Human Performance Wing, obtained by the Associated Press.

This isn’t the first time that concerns have been raised about possible cancer clusters at Malmstrom. In 2001, after cases of various cancers from missileers were reported—including cervical, thyroid, Hodgkin lymphoma, and non-Hodgkin lymphoma—the Air Force Institute for Operational Health conducted a site evaluation and sampling for possible chemical and biologic contaminants at their facilities. Results of all tests, the 2005 report said, did not demonstrate any levels above acceptable standards according to state and federal regulations. The survey concluded that launch control centers provide a safe and healthy working environment.

In 2005, following the release of the report, the USAF said “There is not sufficient evidence to consider the possibility of a cancer clustering to justify further investigation.” The research report noted, “[S]ometimes illnesses tend to occur by chance alone and it is not uncommon to see clustering or what has been referred to as ‘perceived clustering’ of conditions, especially when they occur in a close group of people or certain communities as in the military.”

On its website, though, the Air Force Medical Service now says that the findings from 2 decades ago may have changed.

The findings from the new study are not final. The USAF is continuing its investigation, including conducting an epidemiological study of cancers within the missile community. In the meantime, Air Force Global Strike Command Public Affairs says that, in response to the review panel’s recommendations, Gen. Bussiere has directed that facilities be deep cleaned regularly, signage denoting the presence of polychlorinated biphenyls be updated, and burning no longer allowed as a means of destroying classified materials inside the facilities.

Notably, the changes will also include improving communication and coordination between medical personnel and missile community members. Bussiere directed his staff to explore specifically assigning medical professionals to ICBM units, to have a better understanding of the environment and missions. He also ordered further engagement with personnel who work with known occupational hazards to collect more data and information. While awaiting the eventual replacement of the Minuteman III ICBM with the LGM-35A Sentinel, preventive maintenance and environmental upgrades will be prioritized and any upgrade or new piece of equipment will be “scrutinized for hazards.”

The USAF has also established a website to address the missileer community’s concerns.

In one of the first studies to examine this phenomenon, metabolically unhealthy obesity is associated with an increased risk, around 1.5-fold higher, of any obesity-related cancer, and an even higher risk, two- to threefold higher, for specific cancers, such as endometrial, liver, and renal cell cancers, compared with metabolically healthy normal weight.

Even in people with so-called “metabolically healthy” obesity, the risk for overall obesity-related cancer is increased, compared with normal-weight, metabolically healthy individuals; however, the associations here are weaker than in people with metabolically unhealthy obesity.

“The type of metabolic obesity phenotype is important when assessing obesity-related cancer risk,” lead researcher Ming Sun, PhD, from Lund University, Malmö, Sweden, said in an interview. “In general, metabolic aberrations further increased the obesity-induced cancer risk, suggesting that obesity and metabolic aberrations are useful targets for prevention.”

“This synergy means that when obesity and metabolic unhealth occur together, that’s particularly bad,” added Tanja Stocks, PhD, senior author, also of Lund University.

“But the data also highlight that even obesity and overweight alone comprise an increased risk of cancer,” Dr. Stocks noted.

Dr. Sun said the findings have important public health implications, suggesting that “a significant number of cancer cases could potentially be prevented by targeting the coexistence of metabolic problems and obesity, in particular for obesity-related cancers among men.”

The results will be presented as a poster by Dr. Sun at the European Congress on Obesity 2023, being held in Dublin, and have been published in the Journal of the National Cancer Institute.
 

Metabolically unhealthy obesity worst for cancer risks

Andrew G. Renehan, PhD, FRCS, professor of cancer studies and surgery, University of Manchester, England, welcomed the new work, saying it addresses the issue with very large study numbers. “[It] nicely demonstrates that there are clear examples where metabolically unhealthy overweight and obese phenotypes have increased cancer risk relative to [metabolically] healthy overweight and obese phenotypes,” he said.

“There is a clear need for clinically based research addressing these hypotheses ... but these studies will additionally need to factor in other dimensions such as the selection of treatment for metabolic aberrations, both medical and surgical, and the consequent metabolic control resulting from these interventions,” Dr. Renehan observed.

Vibhu Chittajallu, MD, a gastroenterologist based at University Hospitals Cleveland Medical Center, said it was beneficial to see another study further validating the association of obesity with the development of obesity-associated cancers.

“This is an interesting study [because it focuses] on the role of metabolic syndrome in obesity and how it affects the risk of development of obesity-associated cancers,” he said in an interview.

“I believe that the results of this study further strengthen the need for improved management of obesity and metabolic syndrome to reduce the risk of obesity-associated cancer formation that plays a role in preventable and premature deaths in adult patients with obesity.”
 

Synergy between metabolic aberrations and obesity, and cancer risk

Dr. Sun and colleagues note that obesity is an established risk factor for several cancers. It is often accompanied by metabolic aberrations, which have been a commonly proposed mechanism to link obesity with cancer. During the last decade, obesity with or without metabolic aberrations – commonly termed “metabolically unhealthy” or “healthy obesity” – has been extensively investigated in the cardiovascular field; however, studies regarding cancer are limited.

According to Dr. Sun, this new study is the first to look at the synergistic effect of unhealthy metabolism and body mass index – the latter was further categorized as normal weight (BMI < 25 kg/m2), overweight (BMI < 30) and obesity (BMI ≤ 30) – and the association with cancer risk, both overall and in relation to site-specific cancers.

Data were drawn from 797,193 European individuals (in Norway, Sweden, and Austria), of whom 23,630 developed an obesity-related cancer during the follow-up period. A metabolic score comprising mid-blood pressure, plasma glucose, and triglycerides was used to provide a measure of healthy or unhealthy metabolic status. Relative risks (hazard ratios) for overall and site-specific cancers were determined. Comparisons were made with metabolically healthy people of normal weight (effectively controls).

When different metabolic scores and BMIs were combined, participants fell into six categories: metabolically unhealthy obesity (6.8% of participants); metabolically healthy obesity (3.4%), metabolically unhealthy overweight (15.4%), metabolically healthy overweight (19.8%), metabolically unhealthy normal weight (12.5%), and metabolically healthy normal weight (42.0%).

Metabolically unhealthy women with obesity had a hazard ratio of 1.43 for overall obesity-related cancers, compared with metabolically healthy women of normal weight. Of particular note were risks of two cancer types in women with metabolically unhealthy obesity: renal cancer, with an HR of 2.43, and endometrial cancer, with an HR of 3.0, compared with controls.

Even in metabolically healthy women with obesity, compared with metabolically healthy women of normal weight, there was an increased risk of endometrial cancer, with an HR of 2.36.

“If you look at individual cancers, in particular endometrial cancer, this seems to be very much driven by obesity and not so much by the metabolic factor,” remarked Dr. Stocks.

In males, compared with metabolically healthy men of normal weight, metabolically unhealthy men with obesity had an overall obesity-related cancer risk HR of 1.91. Specifically, the risk of renal cell cancer was more than doubled, with an HR of 2.59. The HR for colon cancer was 1.85, and that for rectal cancer and pancreatic cancer was similar, both having HRs of 1.32.

Again, risk was lower in metabolically healthy men with obesity, although still higher than for metabolically healthy normal-weight men.

A version of this article first appeared on Medscape.com.

In one of the first studies to examine this phenomenon, metabolically unhealthy obesity is associated with an increased risk, around 1.5-fold higher, of any obesity-related cancer, and an even higher risk, two- to threefold higher, for specific cancers, such as endometrial, liver, and renal cell cancers, compared with metabolically healthy normal weight.

Even in people with so-called “metabolically healthy” obesity, the risk for overall obesity-related cancer is increased, compared with normal-weight, metabolically healthy individuals; however, the associations here are weaker than in people with metabolically unhealthy obesity.

“The type of metabolic obesity phenotype is important when assessing obesity-related cancer risk,” lead researcher Ming Sun, PhD, from Lund University, Malmö, Sweden, said in an interview. “In general, metabolic aberrations further increased the obesity-induced cancer risk, suggesting that obesity and metabolic aberrations are useful targets for prevention.”

“This synergy means that when obesity and metabolic unhealth occur together, that’s particularly bad,” added Tanja Stocks, PhD, senior author, also of Lund University.

“But the data also highlight that even obesity and overweight alone comprise an increased risk of cancer,” Dr. Stocks noted.

Dr. Sun said the findings have important public health implications, suggesting that “a significant number of cancer cases could potentially be prevented by targeting the coexistence of metabolic problems and obesity, in particular for obesity-related cancers among men.”

The results will be presented as a poster by Dr. Sun at the European Congress on Obesity 2023, being held in Dublin, and have been published in the Journal of the National Cancer Institute.
 

Metabolically unhealthy obesity worst for cancer risks

Andrew G. Renehan, PhD, FRCS, professor of cancer studies and surgery, University of Manchester, England, welcomed the new work, saying it addresses the issue with very large study numbers. “[It] nicely demonstrates that there are clear examples where metabolically unhealthy overweight and obese phenotypes have increased cancer risk relative to [metabolically] healthy overweight and obese phenotypes,” he said.

“There is a clear need for clinically based research addressing these hypotheses ... but these studies will additionally need to factor in other dimensions such as the selection of treatment for metabolic aberrations, both medical and surgical, and the consequent metabolic control resulting from these interventions,” Dr. Renehan observed.

Vibhu Chittajallu, MD, a gastroenterologist based at University Hospitals Cleveland Medical Center, said it was beneficial to see another study further validating the association of obesity with the development of obesity-associated cancers.

“This is an interesting study [because it focuses] on the role of metabolic syndrome in obesity and how it affects the risk of development of obesity-associated cancers,” he said in an interview.

“I believe that the results of this study further strengthen the need for improved management of obesity and metabolic syndrome to reduce the risk of obesity-associated cancer formation that plays a role in preventable and premature deaths in adult patients with obesity.”
 

Synergy between metabolic aberrations and obesity, and cancer risk

Dr. Sun and colleagues note that obesity is an established risk factor for several cancers. It is often accompanied by metabolic aberrations, which have been a commonly proposed mechanism to link obesity with cancer. During the last decade, obesity with or without metabolic aberrations – commonly termed “metabolically unhealthy” or “healthy obesity” – has been extensively investigated in the cardiovascular field; however, studies regarding cancer are limited.

According to Dr. Sun, this new study is the first to look at the synergistic effect of unhealthy metabolism and body mass index – the latter was further categorized as normal weight (BMI < 25 kg/m2), overweight (BMI < 30) and obesity (BMI ≤ 30) – and the association with cancer risk, both overall and in relation to site-specific cancers.

Data were drawn from 797,193 European individuals (in Norway, Sweden, and Austria), of whom 23,630 developed an obesity-related cancer during the follow-up period. A metabolic score comprising mid-blood pressure, plasma glucose, and triglycerides was used to provide a measure of healthy or unhealthy metabolic status. Relative risks (hazard ratios) for overall and site-specific cancers were determined. Comparisons were made with metabolically healthy people of normal weight (effectively controls).

When different metabolic scores and BMIs were combined, participants fell into six categories: metabolically unhealthy obesity (6.8% of participants); metabolically healthy obesity (3.4%), metabolically unhealthy overweight (15.4%), metabolically healthy overweight (19.8%), metabolically unhealthy normal weight (12.5%), and metabolically healthy normal weight (42.0%).

Metabolically unhealthy women with obesity had a hazard ratio of 1.43 for overall obesity-related cancers, compared with metabolically healthy women of normal weight. Of particular note were risks of two cancer types in women with metabolically unhealthy obesity: renal cancer, with an HR of 2.43, and endometrial cancer, with an HR of 3.0, compared with controls.

Even in metabolically healthy women with obesity, compared with metabolically healthy women of normal weight, there was an increased risk of endometrial cancer, with an HR of 2.36.

“If you look at individual cancers, in particular endometrial cancer, this seems to be very much driven by obesity and not so much by the metabolic factor,” remarked Dr. Stocks.

In males, compared with metabolically healthy men of normal weight, metabolically unhealthy men with obesity had an overall obesity-related cancer risk HR of 1.91. Specifically, the risk of renal cell cancer was more than doubled, with an HR of 2.59. The HR for colon cancer was 1.85, and that for rectal cancer and pancreatic cancer was similar, both having HRs of 1.32.

Again, risk was lower in metabolically healthy men with obesity, although still higher than for metabolically healthy normal-weight men.

A version of this article first appeared on Medscape.com.

In one of the first studies to examine this phenomenon, metabolically unhealthy obesity is associated with an increased risk, around 1.5-fold higher, of any obesity-related cancer, and an even higher risk, two- to threefold higher, for specific cancers, such as endometrial, liver, and renal cell cancers, compared with metabolically healthy normal weight.

Even in people with so-called “metabolically healthy” obesity, the risk for overall obesity-related cancer is increased, compared with normal-weight, metabolically healthy individuals; however, the associations here are weaker than in people with metabolically unhealthy obesity.

“The type of metabolic obesity phenotype is important when assessing obesity-related cancer risk,” lead researcher Ming Sun, PhD, from Lund University, Malmö, Sweden, said in an interview. “In general, metabolic aberrations further increased the obesity-induced cancer risk, suggesting that obesity and metabolic aberrations are useful targets for prevention.”

“This synergy means that when obesity and metabolic unhealth occur together, that’s particularly bad,” added Tanja Stocks, PhD, senior author, also of Lund University.

“But the data also highlight that even obesity and overweight alone comprise an increased risk of cancer,” Dr. Stocks noted.

Dr. Sun said the findings have important public health implications, suggesting that “a significant number of cancer cases could potentially be prevented by targeting the coexistence of metabolic problems and obesity, in particular for obesity-related cancers among men.”

The results will be presented as a poster by Dr. Sun at the European Congress on Obesity 2023, being held in Dublin, and have been published in the Journal of the National Cancer Institute.
 

Metabolically unhealthy obesity worst for cancer risks

Andrew G. Renehan, PhD, FRCS, professor of cancer studies and surgery, University of Manchester, England, welcomed the new work, saying it addresses the issue with very large study numbers. “[It] nicely demonstrates that there are clear examples where metabolically unhealthy overweight and obese phenotypes have increased cancer risk relative to [metabolically] healthy overweight and obese phenotypes,” he said.

“There is a clear need for clinically based research addressing these hypotheses ... but these studies will additionally need to factor in other dimensions such as the selection of treatment for metabolic aberrations, both medical and surgical, and the consequent metabolic control resulting from these interventions,” Dr. Renehan observed.

Vibhu Chittajallu, MD, a gastroenterologist based at University Hospitals Cleveland Medical Center, said it was beneficial to see another study further validating the association of obesity with the development of obesity-associated cancers.

“This is an interesting study [because it focuses] on the role of metabolic syndrome in obesity and how it affects the risk of development of obesity-associated cancers,” he said in an interview.

“I believe that the results of this study further strengthen the need for improved management of obesity and metabolic syndrome to reduce the risk of obesity-associated cancer formation that plays a role in preventable and premature deaths in adult patients with obesity.”
 

Synergy between metabolic aberrations and obesity, and cancer risk

Dr. Sun and colleagues note that obesity is an established risk factor for several cancers. It is often accompanied by metabolic aberrations, which have been a commonly proposed mechanism to link obesity with cancer. During the last decade, obesity with or without metabolic aberrations – commonly termed “metabolically unhealthy” or “healthy obesity” – has been extensively investigated in the cardiovascular field; however, studies regarding cancer are limited.

According to Dr. Sun, this new study is the first to look at the synergistic effect of unhealthy metabolism and body mass index – the latter was further categorized as normal weight (BMI < 25 kg/m2), overweight (BMI < 30) and obesity (BMI ≤ 30) – and the association with cancer risk, both overall and in relation to site-specific cancers.

Data were drawn from 797,193 European individuals (in Norway, Sweden, and Austria), of whom 23,630 developed an obesity-related cancer during the follow-up period. A metabolic score comprising mid-blood pressure, plasma glucose, and triglycerides was used to provide a measure of healthy or unhealthy metabolic status. Relative risks (hazard ratios) for overall and site-specific cancers were determined. Comparisons were made with metabolically healthy people of normal weight (effectively controls).

When different metabolic scores and BMIs were combined, participants fell into six categories: metabolically unhealthy obesity (6.8% of participants); metabolically healthy obesity (3.4%), metabolically unhealthy overweight (15.4%), metabolically healthy overweight (19.8%), metabolically unhealthy normal weight (12.5%), and metabolically healthy normal weight (42.0%).

Metabolically unhealthy women with obesity had a hazard ratio of 1.43 for overall obesity-related cancers, compared with metabolically healthy women of normal weight. Of particular note were risks of two cancer types in women with metabolically unhealthy obesity: renal cancer, with an HR of 2.43, and endometrial cancer, with an HR of 3.0, compared with controls.

Even in metabolically healthy women with obesity, compared with metabolically healthy women of normal weight, there was an increased risk of endometrial cancer, with an HR of 2.36.

“If you look at individual cancers, in particular endometrial cancer, this seems to be very much driven by obesity and not so much by the metabolic factor,” remarked Dr. Stocks.

In males, compared with metabolically healthy men of normal weight, metabolically unhealthy men with obesity had an overall obesity-related cancer risk HR of 1.91. Specifically, the risk of renal cell cancer was more than doubled, with an HR of 2.59. The HR for colon cancer was 1.85, and that for rectal cancer and pancreatic cancer was similar, both having HRs of 1.32.

Again, risk was lower in metabolically healthy men with obesity, although still higher than for metabolically healthy normal-weight men.

A version of this article first appeared on Medscape.com.

Bariatric surgery for obesity is associated with a reduced risk of developing breast cancer, new data suggest.

In a matched cohort study of more than 69,000 Canadian women, risk for incident breast cancer at 1 year was 40% higher among women who had not undergone bariatric surgery, compared with those who had. The risk remained elevated through 5 years of follow-up.

The findings were “definitely a bit surprising,” study author Aristithes G. Doumouras, MD, MPH, assistant professor of surgery at McMaster University, Hamilton, Ont., said in an interview. “The patients that underwent bariatric surgery had better cancer outcomes than patients who weighed less than they did, so it showed that there was more at play than just weight loss. This effect was durable [and] shows how powerful the surgery is, [as well as] the fact that we haven’t even explored all of its effects.”

The study was published online in JAMA Surgery.
 

Protective association

To determine whether there is a residual risk for breast cancer following bariatric surgery for obesity, the investigators analyzed clinical and administrative data collected between 2010 and 2016 in Ontario. They retrospectively matched women with obesity who underwent bariatric surgery with women without a history of bariatric surgery. Participants were matched by age and breast cancer screening status. Covariates included diabetes status, neighborhood income quintile, and measures of health care use. The population included 69,260 women (mean age, 45 years).

Among participants who underwent bariatric surgery for obesity, baseline body mass index was greater than 35 for those with related comorbid conditions, and BMI was greater than 40 for those without comorbid conditions. The investigators categorized nonsurgical control patients in accordance with the following four BMI categories: less than 25, 25-29, 30-34, and greater than or equal to 35. Each control group, as well as the surgical group, included 13,852 women.

Participants in the surgical group were followed for 5 years after bariatric surgery. Those in the nonsurgical group were followed for 5 years after the index date (that is, the date of BMI measurement).

In the overall population, 659 cases of breast cancer were diagnosed in the overall population (0.95%) during the study period. This total included 103 (0.74%) cancers in the surgical cohort; 128 (0.92%) in the group with BMI less than 25; 143 (1.03%) among those with BMI 25-29; 150 (1.08%) in the group with BMI 30-34; and 135 (0.97%) among those with BMI greater than or equal to 35.

Most cancers were stage I. There were 65 cases among those with BMI less than 25; 76 for those with BMI of 25-29; 65 for BMI of 30-34; 67 for BMI greater than or equal to 35, and 60 for the surgery group.

Most tumors were of medium grade and were estrogen receptor positive, progesterone receptor positive, and ERBB2 negative. No significant differences were observed across the groups for stage, grade, or hormone status.

There was an increased hazard for incident breast cancer in the nonsurgical group, compared with the postsurgical group after washout periods of 1 year (hazard ratio, 1.40), 2 years (HR, 1.31), and 5 years (HR, 1.38).

In a comparison of the postsurgical cohort with the nonsurgical cohort with BMI less than 25, the hazard of incident breast cancer was not significantly different for any of the washout periods, but there was a reduced hazard for incident breast cancer among postsurgical patients than among nonsurgical patients in all high BMI categories (BMI ≥ 25).

“Taken together, these results demonstrate that the protective association between substantial weight loss via bariatric surgery and breast cancer risk is sustained after 5 years following surgery and that it is associated with a baseline risk similar to that of women with BMI less than 25,” the investigators write.

Nevertheless, Dr. Doumouras said “the interaction between the surgery and individuals is poorly studied, and this level of personalized medicine is simply not there yet. We are working on developing a prospective cohort that has genetic, protein, and microbiome [data] to help answer these questions.”

There are not enough women in subpopulations such as BRCA carriers to study at this point, he added. “This is where more patients and time will really help the research process.”
 

A universal benefit?

“Although these findings are important overall for the general population at risk for breast cancer, we raise an important caveat: The benefit of surgical weight loss may not be universal,” write Justin B. Dimick, MD, MPH, surgical innovation editor for JAMA Surgery, and Melissa L. Pilewskie, MD, both of the University of Michigan, Ann Arbor, in an accompanying commentary.

“In addition to lifestyle factors, several nonmodifiable risk factors, such as a genetic predisposition, strong family history, personal history of a high-risk breast lesion, or history of chest wall radiation, impart significant elevation in risk, and the data remain mixed on the impact of weight loss for individuals in these high-risk cohorts,” they add.

“Further study to elucidate the underlying mechanism associated with obesity, weight loss, and breast cancer risk should help guide strategies for risk reduction that are specific to unique high-risk cohorts, because modifiable risk factors may not portend the same benefit among all groups.”

Commenting on the findings, Stephen Edge, MD, breast surgeon and vice president for system quality and outcomes at Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., said, “The importance of this study is that it shows that weight loss in midlife can reduce breast cancer risk back to or even below the risk of similar people who were not obese. This has major implications for counseling women.”

The investigators did not have information on the extent of weight loss with surgery or on which participants maintained the lower weight, Dr. Edge noted; “However, overall, most people who have weight reduction surgery have major weight loss.”

At this point, he said, “we can now tell women with obesity that in addition to the many other advantages of weight loss, their risk of getting breast cancer will also be reduced.”

The study was supported by the Ontario Bariatric Registry and ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ontario Ministry of Long-Term Care. Dr. Doumouras, Dr. Dimick, Dr. Pilewskie, and Dr. Edge reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Bariatric surgery for obesity is associated with a reduced risk of developing breast cancer, new data suggest.

In a matched cohort study of more than 69,000 Canadian women, risk for incident breast cancer at 1 year was 40% higher among women who had not undergone bariatric surgery, compared with those who had. The risk remained elevated through 5 years of follow-up.

The findings were “definitely a bit surprising,” study author Aristithes G. Doumouras, MD, MPH, assistant professor of surgery at McMaster University, Hamilton, Ont., said in an interview. “The patients that underwent bariatric surgery had better cancer outcomes than patients who weighed less than they did, so it showed that there was more at play than just weight loss. This effect was durable [and] shows how powerful the surgery is, [as well as] the fact that we haven’t even explored all of its effects.”

The study was published online in JAMA Surgery.
 

Protective association

To determine whether there is a residual risk for breast cancer following bariatric surgery for obesity, the investigators analyzed clinical and administrative data collected between 2010 and 2016 in Ontario. They retrospectively matched women with obesity who underwent bariatric surgery with women without a history of bariatric surgery. Participants were matched by age and breast cancer screening status. Covariates included diabetes status, neighborhood income quintile, and measures of health care use. The population included 69,260 women (mean age, 45 years).

Among participants who underwent bariatric surgery for obesity, baseline body mass index was greater than 35 for those with related comorbid conditions, and BMI was greater than 40 for those without comorbid conditions. The investigators categorized nonsurgical control patients in accordance with the following four BMI categories: less than 25, 25-29, 30-34, and greater than or equal to 35. Each control group, as well as the surgical group, included 13,852 women.

Participants in the surgical group were followed for 5 years after bariatric surgery. Those in the nonsurgical group were followed for 5 years after the index date (that is, the date of BMI measurement).

In the overall population, 659 cases of breast cancer were diagnosed in the overall population (0.95%) during the study period. This total included 103 (0.74%) cancers in the surgical cohort; 128 (0.92%) in the group with BMI less than 25; 143 (1.03%) among those with BMI 25-29; 150 (1.08%) in the group with BMI 30-34; and 135 (0.97%) among those with BMI greater than or equal to 35.

Most cancers were stage I. There were 65 cases among those with BMI less than 25; 76 for those with BMI of 25-29; 65 for BMI of 30-34; 67 for BMI greater than or equal to 35, and 60 for the surgery group.

Most tumors were of medium grade and were estrogen receptor positive, progesterone receptor positive, and ERBB2 negative. No significant differences were observed across the groups for stage, grade, or hormone status.

There was an increased hazard for incident breast cancer in the nonsurgical group, compared with the postsurgical group after washout periods of 1 year (hazard ratio, 1.40), 2 years (HR, 1.31), and 5 years (HR, 1.38).

In a comparison of the postsurgical cohort with the nonsurgical cohort with BMI less than 25, the hazard of incident breast cancer was not significantly different for any of the washout periods, but there was a reduced hazard for incident breast cancer among postsurgical patients than among nonsurgical patients in all high BMI categories (BMI ≥ 25).

“Taken together, these results demonstrate that the protective association between substantial weight loss via bariatric surgery and breast cancer risk is sustained after 5 years following surgery and that it is associated with a baseline risk similar to that of women with BMI less than 25,” the investigators write.

Nevertheless, Dr. Doumouras said “the interaction between the surgery and individuals is poorly studied, and this level of personalized medicine is simply not there yet. We are working on developing a prospective cohort that has genetic, protein, and microbiome [data] to help answer these questions.”

There are not enough women in subpopulations such as BRCA carriers to study at this point, he added. “This is where more patients and time will really help the research process.”
 

A universal benefit?

“Although these findings are important overall for the general population at risk for breast cancer, we raise an important caveat: The benefit of surgical weight loss may not be universal,” write Justin B. Dimick, MD, MPH, surgical innovation editor for JAMA Surgery, and Melissa L. Pilewskie, MD, both of the University of Michigan, Ann Arbor, in an accompanying commentary.

“In addition to lifestyle factors, several nonmodifiable risk factors, such as a genetic predisposition, strong family history, personal history of a high-risk breast lesion, or history of chest wall radiation, impart significant elevation in risk, and the data remain mixed on the impact of weight loss for individuals in these high-risk cohorts,” they add.

“Further study to elucidate the underlying mechanism associated with obesity, weight loss, and breast cancer risk should help guide strategies for risk reduction that are specific to unique high-risk cohorts, because modifiable risk factors may not portend the same benefit among all groups.”

Commenting on the findings, Stephen Edge, MD, breast surgeon and vice president for system quality and outcomes at Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., said, “The importance of this study is that it shows that weight loss in midlife can reduce breast cancer risk back to or even below the risk of similar people who were not obese. This has major implications for counseling women.”

The investigators did not have information on the extent of weight loss with surgery or on which participants maintained the lower weight, Dr. Edge noted; “However, overall, most people who have weight reduction surgery have major weight loss.”

At this point, he said, “we can now tell women with obesity that in addition to the many other advantages of weight loss, their risk of getting breast cancer will also be reduced.”

The study was supported by the Ontario Bariatric Registry and ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ontario Ministry of Long-Term Care. Dr. Doumouras, Dr. Dimick, Dr. Pilewskie, and Dr. Edge reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Bariatric surgery for obesity is associated with a reduced risk of developing breast cancer, new data suggest.

In a matched cohort study of more than 69,000 Canadian women, risk for incident breast cancer at 1 year was 40% higher among women who had not undergone bariatric surgery, compared with those who had. The risk remained elevated through 5 years of follow-up.

The findings were “definitely a bit surprising,” study author Aristithes G. Doumouras, MD, MPH, assistant professor of surgery at McMaster University, Hamilton, Ont., said in an interview. “The patients that underwent bariatric surgery had better cancer outcomes than patients who weighed less than they did, so it showed that there was more at play than just weight loss. This effect was durable [and] shows how powerful the surgery is, [as well as] the fact that we haven’t even explored all of its effects.”

The study was published online in JAMA Surgery.
 

Protective association

To determine whether there is a residual risk for breast cancer following bariatric surgery for obesity, the investigators analyzed clinical and administrative data collected between 2010 and 2016 in Ontario. They retrospectively matched women with obesity who underwent bariatric surgery with women without a history of bariatric surgery. Participants were matched by age and breast cancer screening status. Covariates included diabetes status, neighborhood income quintile, and measures of health care use. The population included 69,260 women (mean age, 45 years).

Among participants who underwent bariatric surgery for obesity, baseline body mass index was greater than 35 for those with related comorbid conditions, and BMI was greater than 40 for those without comorbid conditions. The investigators categorized nonsurgical control patients in accordance with the following four BMI categories: less than 25, 25-29, 30-34, and greater than or equal to 35. Each control group, as well as the surgical group, included 13,852 women.

Participants in the surgical group were followed for 5 years after bariatric surgery. Those in the nonsurgical group were followed for 5 years after the index date (that is, the date of BMI measurement).

In the overall population, 659 cases of breast cancer were diagnosed in the overall population (0.95%) during the study period. This total included 103 (0.74%) cancers in the surgical cohort; 128 (0.92%) in the group with BMI less than 25; 143 (1.03%) among those with BMI 25-29; 150 (1.08%) in the group with BMI 30-34; and 135 (0.97%) among those with BMI greater than or equal to 35.

Most cancers were stage I. There were 65 cases among those with BMI less than 25; 76 for those with BMI of 25-29; 65 for BMI of 30-34; 67 for BMI greater than or equal to 35, and 60 for the surgery group.

Most tumors were of medium grade and were estrogen receptor positive, progesterone receptor positive, and ERBB2 negative. No significant differences were observed across the groups for stage, grade, or hormone status.

There was an increased hazard for incident breast cancer in the nonsurgical group, compared with the postsurgical group after washout periods of 1 year (hazard ratio, 1.40), 2 years (HR, 1.31), and 5 years (HR, 1.38).

In a comparison of the postsurgical cohort with the nonsurgical cohort with BMI less than 25, the hazard of incident breast cancer was not significantly different for any of the washout periods, but there was a reduced hazard for incident breast cancer among postsurgical patients than among nonsurgical patients in all high BMI categories (BMI ≥ 25).

“Taken together, these results demonstrate that the protective association between substantial weight loss via bariatric surgery and breast cancer risk is sustained after 5 years following surgery and that it is associated with a baseline risk similar to that of women with BMI less than 25,” the investigators write.

Nevertheless, Dr. Doumouras said “the interaction between the surgery and individuals is poorly studied, and this level of personalized medicine is simply not there yet. We are working on developing a prospective cohort that has genetic, protein, and microbiome [data] to help answer these questions.”

There are not enough women in subpopulations such as BRCA carriers to study at this point, he added. “This is where more patients and time will really help the research process.”
 

A universal benefit?

“Although these findings are important overall for the general population at risk for breast cancer, we raise an important caveat: The benefit of surgical weight loss may not be universal,” write Justin B. Dimick, MD, MPH, surgical innovation editor for JAMA Surgery, and Melissa L. Pilewskie, MD, both of the University of Michigan, Ann Arbor, in an accompanying commentary.

“In addition to lifestyle factors, several nonmodifiable risk factors, such as a genetic predisposition, strong family history, personal history of a high-risk breast lesion, or history of chest wall radiation, impart significant elevation in risk, and the data remain mixed on the impact of weight loss for individuals in these high-risk cohorts,” they add.

“Further study to elucidate the underlying mechanism associated with obesity, weight loss, and breast cancer risk should help guide strategies for risk reduction that are specific to unique high-risk cohorts, because modifiable risk factors may not portend the same benefit among all groups.”

Commenting on the findings, Stephen Edge, MD, breast surgeon and vice president for system quality and outcomes at Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., said, “The importance of this study is that it shows that weight loss in midlife can reduce breast cancer risk back to or even below the risk of similar people who were not obese. This has major implications for counseling women.”

The investigators did not have information on the extent of weight loss with surgery or on which participants maintained the lower weight, Dr. Edge noted; “However, overall, most people who have weight reduction surgery have major weight loss.”

At this point, he said, “we can now tell women with obesity that in addition to the many other advantages of weight loss, their risk of getting breast cancer will also be reduced.”

The study was supported by the Ontario Bariatric Registry and ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ontario Ministry of Long-Term Care. Dr. Doumouras, Dr. Dimick, Dr. Pilewskie, and Dr. Edge reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A single dose of a new antibody-drug conjugate known as patritumab deruxtecan provoked a response in nearly one-third of patients with HR-positive/HER2-negative or triple-negative breast cancer, according to data presented from Abstract 1240 at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.

Heidi Splete/MDedge News

Patritumab deruxtecan (HER3-DXd) has previously demonstrated an acceptable safety profile and antitumor activity in phase I studies involving heavily pretreated patients with metastatic breast cancer and various levels of HER3 protein expression, said Mafalda Oliveira, MD, of the Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology in Barcelona.

Antibody-drug conjugates (ADCs) are a combination of a monoclonal antibody chemically linked to a drug, as defined by the National Cancer Institute. ADCs work by binding to receptors or proteins and selectively delivering cytotoxic drugs to the site of a tumor.

Dr. Oliveira presented results from part B the of SOLTI TOT-HER3 trial, a window-of-opportunity trial that evaluated the effect of a single dose of HER3-Dxd in patients with treatment-naive HR+/HER2– early breast cancer.

In such trials, patients receive one or more new compounds between the time of cancer diagnosis and standard treatment. Biological and clinical activity from part A of the SOLTI TOT-HER3 trial were presented at last year’s ESMO Breast Cancer Congress, Dr. Oliveira said.

In the current study, Dr. Oliveira and colleagues recruited 37 women with HR+/HER2– early breast cancer, including 20 who were hormone receptor–positive and 17 who had triple negative breast cancer (TNBC). The age of the participants ranged from 30 to 81 years, with a median age of 51 years; 54% were premenopausal. The mean tumor size was 21 mm, with a range of 10-81 mm.

Distinct from part A of the SOLTI TOT-HER3 trial, part B included a subset of patients with TNBC to assess preliminary efficacy in this subtype, Dr. Oliveira noted.

All patients in part B received a single dose of 5.6 mg/kg of HER3-DXd. The primary outcome was the variation in the tumor cellularity and tumor-infiltrating lymphocyte (CelTIL) score at baseline and after 21 days via breast ultrasound.

At day 21, the total CelTIL score increased by a significant mean difference of 9.4 points after a single dose; the mean differences for TNBC and HR+/HER2– patients, were 17.9 points and 2.2 points, respectively, Dr. Oliveira said. The overall response rate was 32% (35% in TNBC patients and 30% in HR+/HER2– patients) and was significantly associated with the absolute change in CelTIL (area under the curve = 0.693; P = .049). 

In a subtype analysis, a statistically significant change in CelTIL was observed between paired samples overall (P = .046) and in TNBC (P = .016), but not in HR+ (P = .793).

Baseline levels of ERBB3 (also known as human epidermal growth factor receptor type 3, or HER3) were not associated with changes in CelTIL or in overall response rate.

HER3-DXd induced high expression of immune-related genes (such as PD1, CD8, and CD19), and suppressed proliferation-related genes, she said.

A total of 31 patients (84%) reported any adverse events. Of these, the most common were nausea, fatigue, alopecia, diarrhea, constipation, and vomiting, and one patient experienced grade 3 treatment-related nausea. No interstitial lung disease events were reported during the study, and the incidence of hematological and hepatic toxicity was lower with the lower dose in part B, compared with the 6.5 mg/kg dose used in part A, Dr. Oliveira noted.

To further validate the findings of the current study and assess the activity of HER3-DXd in early breast cancer, Dr. Oliveira and colleagues are conducting a neoadjuvant phase II trial known as SOLTI-2103 VALENTINE. In this study, they are testing six cycles of HER3-DXd at a 5.6 mg/kg dose in HR+/HER2– breast cancer patients, she said.

During a question-and-answer session, Dr. Oliveira was asked whether CelTIL is the best endpoint for assessing HER3-DXd. Finding the best endpoint is always a challenge when conducting window-of-opportunity trials, she said. The CelTIL score has been correlated with pathologic complete response (pCR), as well as with disease-free survival and overall survival, she added.
 

ICARUS-BREAST01

In a presentation of Abstract 1890 during the same session, Barbari Pistilli, MD, of Gustave Roussy Cancer Center, Villejuif, France, shared data from a phase II study known as ICARUS-BREAST.

Heidi Splete/MDedge News

The study population included women with unresectable locally advanced breast cancer (ABC) who had undergone a median of two previous systemic therapies. In the current study, the patients underwent a median of eight cycles of HER3-DXd. The dosage was 5.6 mg/kg every 3 weeks until disease progression or unacceptable toxicity.

The primary outcome was overall response and disease progression after 3 months. Dr. Pistilli, who is also a coauthor of the research, provided data from 56 evaluable patients.

After 3 months, 16 patients (28.6%) showed a partial response, 30 patients showed stable disease (54%), and 10 (18%) showed disease progression. “No patients had a complete response,” Dr. Pistilli noted.

As for the safety profile, all patients reported at least one treatment-emergent event of any grade, but less than half (48.2%) were grade 3 or higher, and 12.5% led to treatment discontinuation. Fatigue and nausea were the most frequently reported adverse events overall, and occurred in 89.3% and 76.8% of patients, respectively. All grade and grade 3 or higher neutropenia occurred in four patients and six patients, respectively; all grade and grade 3 or higher thrombocytopenia occurred in four patients and two patients, respectively, Dr. Pistilli said.

Data on circulating tumor cells (CTCs) were available for 31 patients, and the researchers reviewed CTC counts after the first HER3-DXd cycle.

“We found that the median number of CTCs decreased by one to two cell cycles of HER3-DXd,” said Dr. Pistilli. She and her coauthors found no substantial impact of the treatment on HER3 negative CTC counts, and “more importantly, no increase of HER3 negative CTC counts at disease progression,” Dr. Pistilli continued.

In addition, patients with higher HER+ CTC counts at baseline or a greater decrease in HER3+ CTC counts after one cycle of HER3-DXd were more likely to have an early treatment response, but this association was not statistically significant.

Looking ahead, further analysis will be performed to evaluate the association between HER3+ CTC counts and dynamics and the main outcomes of overall response rate and progression-free survival to determine the potential of HER3+ CTC counts to identify patients who can benefit from HER3-DXd, said Dr. Pistilli. The ICARUS-BREAST01 study is ongoing, and further efficacy and biomarker analysis will be presented, she added.

In the question-and-answer session, Dr. Pistilli was asked why she chose CTC as a measure.

Dr. Pistilli responded that she and her coauthors wanted to understand whether CTC could serve as a biomarker to help in patient selection.

Also, when asked about which genes might be upregulated and downregulated in responders vs. nonresponders, she noted that some genes related to DNA repair were involved in patients who were responders, but more research is needed.
 

Early results merit further exploration

Although patritumab deruxtecan is early in development, “there is a clear signal to expand,” based on preliminary research, said Rebecca A. Dent, MD, who served as discussant for the two studies.

Heidi Splete/MDedge News

“There is no clear role for a specific subtype in both protein and gene expression,” noted Dr. Dent, who is a professor at Duke NUS Medical School, a collaboration between Duke University, Durham, N.C., and the National University of Singapore.

In the SOLTI TOT-HER3 trial, the small numbers make teasing out correlations a challenge, said Dr. Dent. However, changes were observed after just one cycle of the drug, and the upregulation of immune signature genes was reassuring, she said.

“A single dose of HER3-DXd induced an overall response of approximately 30% independently of hormone receptor status,” she emphasized, and the lower incidence of hematological and hepatic toxicity with the lower dose is good news as well. The findings were limited by the small sample size, but the results support moving forward with clinical development of HER3-DXd, she said.

The ICARUS-BREAST01 study researchers tried to show whether they could identify potential markers of early treatment response, and they examined CTCs and gene alterations, said Dr. Dent. “I think it is reassuring that despite these patients being heavily pretreated, HER-DXd seems to be active regardless of most frequent breast cancer genomic alterations,” she noted. Remaining questions include the need for more data on primary resistance.

“We are able to get these patients to respond, but what makes patients resistant to ADCs is just as important,” she said. “We see exciting data across all these subtypes,”

In Dr. Dent’s opinion, future research should focus on triple negative breast cancer, an opinion supported by the stronger response in this subset of patients in the SOLTI TOT-HER3 trial. “I think you need to bring triple negative to the table,” she said.

The SOLTI TOT-HER3 study was funded by Daiichi Sankyo. Dr. Oliveira disclosed relationships with companies including AstraZeneca, Ayala Pharmaceuticals, Boehringer-Ingelheim, Genentech, Gilead, GSK, Novartis, Roche, Seagen, Zenith Epigenetics, Daiichi Sankyo, iTEOS, MSD, Pierre-Fabre, Relay Therapeutics, and Eisai. ICARUS-BREAST01 was sponsored by the Gustave Roussy Cancer Center and supported by Daiichi Sankyo. Dr. Pistilli disclosed relationships with multiple companies including Daiichi-Sankyo, AstraZeneca, Gilead, Seagen, MSD, Novartis, Lilly, and Pierre Fabre. Dr. Dent disclosed financial relationships with companies including AstraZeneca, Roche, Eisai, Lilly, MSD, Novartis, and Pfizer.

A single dose of a new antibody-drug conjugate known as patritumab deruxtecan provoked a response in nearly one-third of patients with HR-positive/HER2-negative or triple-negative breast cancer, according to data presented from Abstract 1240 at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.

Heidi Splete/MDedge News

Patritumab deruxtecan (HER3-DXd) has previously demonstrated an acceptable safety profile and antitumor activity in phase I studies involving heavily pretreated patients with metastatic breast cancer and various levels of HER3 protein expression, said Mafalda Oliveira, MD, of the Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology in Barcelona.

Antibody-drug conjugates (ADCs) are a combination of a monoclonal antibody chemically linked to a drug, as defined by the National Cancer Institute. ADCs work by binding to receptors or proteins and selectively delivering cytotoxic drugs to the site of a tumor.

Dr. Oliveira presented results from part B the of SOLTI TOT-HER3 trial, a window-of-opportunity trial that evaluated the effect of a single dose of HER3-Dxd in patients with treatment-naive HR+/HER2– early breast cancer.

In such trials, patients receive one or more new compounds between the time of cancer diagnosis and standard treatment. Biological and clinical activity from part A of the SOLTI TOT-HER3 trial were presented at last year’s ESMO Breast Cancer Congress, Dr. Oliveira said.

In the current study, Dr. Oliveira and colleagues recruited 37 women with HR+/HER2– early breast cancer, including 20 who were hormone receptor–positive and 17 who had triple negative breast cancer (TNBC). The age of the participants ranged from 30 to 81 years, with a median age of 51 years; 54% were premenopausal. The mean tumor size was 21 mm, with a range of 10-81 mm.

Distinct from part A of the SOLTI TOT-HER3 trial, part B included a subset of patients with TNBC to assess preliminary efficacy in this subtype, Dr. Oliveira noted.

All patients in part B received a single dose of 5.6 mg/kg of HER3-DXd. The primary outcome was the variation in the tumor cellularity and tumor-infiltrating lymphocyte (CelTIL) score at baseline and after 21 days via breast ultrasound.

At day 21, the total CelTIL score increased by a significant mean difference of 9.4 points after a single dose; the mean differences for TNBC and HR+/HER2– patients, were 17.9 points and 2.2 points, respectively, Dr. Oliveira said. The overall response rate was 32% (35% in TNBC patients and 30% in HR+/HER2– patients) and was significantly associated with the absolute change in CelTIL (area under the curve = 0.693; P = .049). 

In a subtype analysis, a statistically significant change in CelTIL was observed between paired samples overall (P = .046) and in TNBC (P = .016), but not in HR+ (P = .793).

Baseline levels of ERBB3 (also known as human epidermal growth factor receptor type 3, or HER3) were not associated with changes in CelTIL or in overall response rate.

HER3-DXd induced high expression of immune-related genes (such as PD1, CD8, and CD19), and suppressed proliferation-related genes, she said.

A total of 31 patients (84%) reported any adverse events. Of these, the most common were nausea, fatigue, alopecia, diarrhea, constipation, and vomiting, and one patient experienced grade 3 treatment-related nausea. No interstitial lung disease events were reported during the study, and the incidence of hematological and hepatic toxicity was lower with the lower dose in part B, compared with the 6.5 mg/kg dose used in part A, Dr. Oliveira noted.

To further validate the findings of the current study and assess the activity of HER3-DXd in early breast cancer, Dr. Oliveira and colleagues are conducting a neoadjuvant phase II trial known as SOLTI-2103 VALENTINE. In this study, they are testing six cycles of HER3-DXd at a 5.6 mg/kg dose in HR+/HER2– breast cancer patients, she said.

During a question-and-answer session, Dr. Oliveira was asked whether CelTIL is the best endpoint for assessing HER3-DXd. Finding the best endpoint is always a challenge when conducting window-of-opportunity trials, she said. The CelTIL score has been correlated with pathologic complete response (pCR), as well as with disease-free survival and overall survival, she added.
 

ICARUS-BREAST01

In a presentation of Abstract 1890 during the same session, Barbari Pistilli, MD, of Gustave Roussy Cancer Center, Villejuif, France, shared data from a phase II study known as ICARUS-BREAST.

Heidi Splete/MDedge News

The study population included women with unresectable locally advanced breast cancer (ABC) who had undergone a median of two previous systemic therapies. In the current study, the patients underwent a median of eight cycles of HER3-DXd. The dosage was 5.6 mg/kg every 3 weeks until disease progression or unacceptable toxicity.

The primary outcome was overall response and disease progression after 3 months. Dr. Pistilli, who is also a coauthor of the research, provided data from 56 evaluable patients.

After 3 months, 16 patients (28.6%) showed a partial response, 30 patients showed stable disease (54%), and 10 (18%) showed disease progression. “No patients had a complete response,” Dr. Pistilli noted.

As for the safety profile, all patients reported at least one treatment-emergent event of any grade, but less than half (48.2%) were grade 3 or higher, and 12.5% led to treatment discontinuation. Fatigue and nausea were the most frequently reported adverse events overall, and occurred in 89.3% and 76.8% of patients, respectively. All grade and grade 3 or higher neutropenia occurred in four patients and six patients, respectively; all grade and grade 3 or higher thrombocytopenia occurred in four patients and two patients, respectively, Dr. Pistilli said.

Data on circulating tumor cells (CTCs) were available for 31 patients, and the researchers reviewed CTC counts after the first HER3-DXd cycle.

“We found that the median number of CTCs decreased by one to two cell cycles of HER3-DXd,” said Dr. Pistilli. She and her coauthors found no substantial impact of the treatment on HER3 negative CTC counts, and “more importantly, no increase of HER3 negative CTC counts at disease progression,” Dr. Pistilli continued.

In addition, patients with higher HER+ CTC counts at baseline or a greater decrease in HER3+ CTC counts after one cycle of HER3-DXd were more likely to have an early treatment response, but this association was not statistically significant.

Looking ahead, further analysis will be performed to evaluate the association between HER3+ CTC counts and dynamics and the main outcomes of overall response rate and progression-free survival to determine the potential of HER3+ CTC counts to identify patients who can benefit from HER3-DXd, said Dr. Pistilli. The ICARUS-BREAST01 study is ongoing, and further efficacy and biomarker analysis will be presented, she added.

In the question-and-answer session, Dr. Pistilli was asked why she chose CTC as a measure.

Dr. Pistilli responded that she and her coauthors wanted to understand whether CTC could serve as a biomarker to help in patient selection.

Also, when asked about which genes might be upregulated and downregulated in responders vs. nonresponders, she noted that some genes related to DNA repair were involved in patients who were responders, but more research is needed.
 

Early results merit further exploration

Although patritumab deruxtecan is early in development, “there is a clear signal to expand,” based on preliminary research, said Rebecca A. Dent, MD, who served as discussant for the two studies.

Heidi Splete/MDedge News

“There is no clear role for a specific subtype in both protein and gene expression,” noted Dr. Dent, who is a professor at Duke NUS Medical School, a collaboration between Duke University, Durham, N.C., and the National University of Singapore.

In the SOLTI TOT-HER3 trial, the small numbers make teasing out correlations a challenge, said Dr. Dent. However, changes were observed after just one cycle of the drug, and the upregulation of immune signature genes was reassuring, she said.

“A single dose of HER3-DXd induced an overall response of approximately 30% independently of hormone receptor status,” she emphasized, and the lower incidence of hematological and hepatic toxicity with the lower dose is good news as well. The findings were limited by the small sample size, but the results support moving forward with clinical development of HER3-DXd, she said.

The ICARUS-BREAST01 study researchers tried to show whether they could identify potential markers of early treatment response, and they examined CTCs and gene alterations, said Dr. Dent. “I think it is reassuring that despite these patients being heavily pretreated, HER-DXd seems to be active regardless of most frequent breast cancer genomic alterations,” she noted. Remaining questions include the need for more data on primary resistance.

“We are able to get these patients to respond, but what makes patients resistant to ADCs is just as important,” she said. “We see exciting data across all these subtypes,”

In Dr. Dent’s opinion, future research should focus on triple negative breast cancer, an opinion supported by the stronger response in this subset of patients in the SOLTI TOT-HER3 trial. “I think you need to bring triple negative to the table,” she said.

The SOLTI TOT-HER3 study was funded by Daiichi Sankyo. Dr. Oliveira disclosed relationships with companies including AstraZeneca, Ayala Pharmaceuticals, Boehringer-Ingelheim, Genentech, Gilead, GSK, Novartis, Roche, Seagen, Zenith Epigenetics, Daiichi Sankyo, iTEOS, MSD, Pierre-Fabre, Relay Therapeutics, and Eisai. ICARUS-BREAST01 was sponsored by the Gustave Roussy Cancer Center and supported by Daiichi Sankyo. Dr. Pistilli disclosed relationships with multiple companies including Daiichi-Sankyo, AstraZeneca, Gilead, Seagen, MSD, Novartis, Lilly, and Pierre Fabre. Dr. Dent disclosed financial relationships with companies including AstraZeneca, Roche, Eisai, Lilly, MSD, Novartis, and Pfizer.

A single dose of a new antibody-drug conjugate known as patritumab deruxtecan provoked a response in nearly one-third of patients with HR-positive/HER2-negative or triple-negative breast cancer, according to data presented from Abstract 1240 at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.

Heidi Splete/MDedge News

Patritumab deruxtecan (HER3-DXd) has previously demonstrated an acceptable safety profile and antitumor activity in phase I studies involving heavily pretreated patients with metastatic breast cancer and various levels of HER3 protein expression, said Mafalda Oliveira, MD, of the Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology in Barcelona.

Antibody-drug conjugates (ADCs) are a combination of a monoclonal antibody chemically linked to a drug, as defined by the National Cancer Institute. ADCs work by binding to receptors or proteins and selectively delivering cytotoxic drugs to the site of a tumor.

Dr. Oliveira presented results from part B the of SOLTI TOT-HER3 trial, a window-of-opportunity trial that evaluated the effect of a single dose of HER3-Dxd in patients with treatment-naive HR+/HER2– early breast cancer.

In such trials, patients receive one or more new compounds between the time of cancer diagnosis and standard treatment. Biological and clinical activity from part A of the SOLTI TOT-HER3 trial were presented at last year’s ESMO Breast Cancer Congress, Dr. Oliveira said.

In the current study, Dr. Oliveira and colleagues recruited 37 women with HR+/HER2– early breast cancer, including 20 who were hormone receptor–positive and 17 who had triple negative breast cancer (TNBC). The age of the participants ranged from 30 to 81 years, with a median age of 51 years; 54% were premenopausal. The mean tumor size was 21 mm, with a range of 10-81 mm.

Distinct from part A of the SOLTI TOT-HER3 trial, part B included a subset of patients with TNBC to assess preliminary efficacy in this subtype, Dr. Oliveira noted.

All patients in part B received a single dose of 5.6 mg/kg of HER3-DXd. The primary outcome was the variation in the tumor cellularity and tumor-infiltrating lymphocyte (CelTIL) score at baseline and after 21 days via breast ultrasound.

At day 21, the total CelTIL score increased by a significant mean difference of 9.4 points after a single dose; the mean differences for TNBC and HR+/HER2– patients, were 17.9 points and 2.2 points, respectively, Dr. Oliveira said. The overall response rate was 32% (35% in TNBC patients and 30% in HR+/HER2– patients) and was significantly associated with the absolute change in CelTIL (area under the curve = 0.693; P = .049). 

In a subtype analysis, a statistically significant change in CelTIL was observed between paired samples overall (P = .046) and in TNBC (P = .016), but not in HR+ (P = .793).

Baseline levels of ERBB3 (also known as human epidermal growth factor receptor type 3, or HER3) were not associated with changes in CelTIL or in overall response rate.

HER3-DXd induced high expression of immune-related genes (such as PD1, CD8, and CD19), and suppressed proliferation-related genes, she said.

A total of 31 patients (84%) reported any adverse events. Of these, the most common were nausea, fatigue, alopecia, diarrhea, constipation, and vomiting, and one patient experienced grade 3 treatment-related nausea. No interstitial lung disease events were reported during the study, and the incidence of hematological and hepatic toxicity was lower with the lower dose in part B, compared with the 6.5 mg/kg dose used in part A, Dr. Oliveira noted.

To further validate the findings of the current study and assess the activity of HER3-DXd in early breast cancer, Dr. Oliveira and colleagues are conducting a neoadjuvant phase II trial known as SOLTI-2103 VALENTINE. In this study, they are testing six cycles of HER3-DXd at a 5.6 mg/kg dose in HR+/HER2– breast cancer patients, she said.

During a question-and-answer session, Dr. Oliveira was asked whether CelTIL is the best endpoint for assessing HER3-DXd. Finding the best endpoint is always a challenge when conducting window-of-opportunity trials, she said. The CelTIL score has been correlated with pathologic complete response (pCR), as well as with disease-free survival and overall survival, she added.
 

ICARUS-BREAST01

In a presentation of Abstract 1890 during the same session, Barbari Pistilli, MD, of Gustave Roussy Cancer Center, Villejuif, France, shared data from a phase II study known as ICARUS-BREAST.

Heidi Splete/MDedge News

The study population included women with unresectable locally advanced breast cancer (ABC) who had undergone a median of two previous systemic therapies. In the current study, the patients underwent a median of eight cycles of HER3-DXd. The dosage was 5.6 mg/kg every 3 weeks until disease progression or unacceptable toxicity.

The primary outcome was overall response and disease progression after 3 months. Dr. Pistilli, who is also a coauthor of the research, provided data from 56 evaluable patients.

After 3 months, 16 patients (28.6%) showed a partial response, 30 patients showed stable disease (54%), and 10 (18%) showed disease progression. “No patients had a complete response,” Dr. Pistilli noted.

As for the safety profile, all patients reported at least one treatment-emergent event of any grade, but less than half (48.2%) were grade 3 or higher, and 12.5% led to treatment discontinuation. Fatigue and nausea were the most frequently reported adverse events overall, and occurred in 89.3% and 76.8% of patients, respectively. All grade and grade 3 or higher neutropenia occurred in four patients and six patients, respectively; all grade and grade 3 or higher thrombocytopenia occurred in four patients and two patients, respectively, Dr. Pistilli said.

Data on circulating tumor cells (CTCs) were available for 31 patients, and the researchers reviewed CTC counts after the first HER3-DXd cycle.

“We found that the median number of CTCs decreased by one to two cell cycles of HER3-DXd,” said Dr. Pistilli. She and her coauthors found no substantial impact of the treatment on HER3 negative CTC counts, and “more importantly, no increase of HER3 negative CTC counts at disease progression,” Dr. Pistilli continued.

In addition, patients with higher HER+ CTC counts at baseline or a greater decrease in HER3+ CTC counts after one cycle of HER3-DXd were more likely to have an early treatment response, but this association was not statistically significant.

Looking ahead, further analysis will be performed to evaluate the association between HER3+ CTC counts and dynamics and the main outcomes of overall response rate and progression-free survival to determine the potential of HER3+ CTC counts to identify patients who can benefit from HER3-DXd, said Dr. Pistilli. The ICARUS-BREAST01 study is ongoing, and further efficacy and biomarker analysis will be presented, she added.

In the question-and-answer session, Dr. Pistilli was asked why she chose CTC as a measure.

Dr. Pistilli responded that she and her coauthors wanted to understand whether CTC could serve as a biomarker to help in patient selection.

Also, when asked about which genes might be upregulated and downregulated in responders vs. nonresponders, she noted that some genes related to DNA repair were involved in patients who were responders, but more research is needed.
 

Early results merit further exploration

Although patritumab deruxtecan is early in development, “there is a clear signal to expand,” based on preliminary research, said Rebecca A. Dent, MD, who served as discussant for the two studies.

Heidi Splete/MDedge News

“There is no clear role for a specific subtype in both protein and gene expression,” noted Dr. Dent, who is a professor at Duke NUS Medical School, a collaboration between Duke University, Durham, N.C., and the National University of Singapore.

In the SOLTI TOT-HER3 trial, the small numbers make teasing out correlations a challenge, said Dr. Dent. However, changes were observed after just one cycle of the drug, and the upregulation of immune signature genes was reassuring, she said.

“A single dose of HER3-DXd induced an overall response of approximately 30% independently of hormone receptor status,” she emphasized, and the lower incidence of hematological and hepatic toxicity with the lower dose is good news as well. The findings were limited by the small sample size, but the results support moving forward with clinical development of HER3-DXd, she said.

The ICARUS-BREAST01 study researchers tried to show whether they could identify potential markers of early treatment response, and they examined CTCs and gene alterations, said Dr. Dent. “I think it is reassuring that despite these patients being heavily pretreated, HER-DXd seems to be active regardless of most frequent breast cancer genomic alterations,” she noted. Remaining questions include the need for more data on primary resistance.

“We are able to get these patients to respond, but what makes patients resistant to ADCs is just as important,” she said. “We see exciting data across all these subtypes,”

In Dr. Dent’s opinion, future research should focus on triple negative breast cancer, an opinion supported by the stronger response in this subset of patients in the SOLTI TOT-HER3 trial. “I think you need to bring triple negative to the table,” she said.

The SOLTI TOT-HER3 study was funded by Daiichi Sankyo. Dr. Oliveira disclosed relationships with companies including AstraZeneca, Ayala Pharmaceuticals, Boehringer-Ingelheim, Genentech, Gilead, GSK, Novartis, Roche, Seagen, Zenith Epigenetics, Daiichi Sankyo, iTEOS, MSD, Pierre-Fabre, Relay Therapeutics, and Eisai. ICARUS-BREAST01 was sponsored by the Gustave Roussy Cancer Center and supported by Daiichi Sankyo. Dr. Pistilli disclosed relationships with multiple companies including Daiichi-Sankyo, AstraZeneca, Gilead, Seagen, MSD, Novartis, Lilly, and Pierre Fabre. Dr. Dent disclosed financial relationships with companies including AstraZeneca, Roche, Eisai, Lilly, MSD, Novartis, and Pfizer.

Cooley JJ, Maguire FB, Morris CR, et al. Cervical cancer stage at diagnosis and survival among women ≥65 years in California. Cancer Epidemiol Biomarkers Prev. 2023;32:91-97. doi:10.1158/1055-9965.EPI-22-0793.

EXPERT COMMENTARY

Cervical cancer screening guidelines recommend screening cessation at age 65 once specific exit criteria are met. (According to the American Cancer Society, individuals aged >65 years who have no history of cervical intraepithelial neoplasia [CIN] grade 2 or more severe disease within the past 25 years, and who have documented adequate negative prior screening in the prior 10 years, discontinue all cervical cancer screening.)¹ We know, however, that about one-fifth of all cervical cancer cases are diagnosed among individuals aged 65 or older, and for Black women that proportion is even higher when data are appropriately adjusted to account for the increased rate of hysterectomy among Black versus White women.^2-4

Early-stage cervical cancer is largely a curable disease with very high 5-year overall survival rates. Unfortunately, more than half of all cervical cancer is diagnosed at a more advanced stage, and survival rates are much lower for this population.⁵

Cervical cancer incidence rates plummeted in the United States after the introduction of the Pap test for cervical cancer screening. However, the percentage of women who are not up to date with cervical cancer screening may now be increasing, from 14% in 2005 to 23% in 2019 according to one study from the US Preventive Services Task Force.⁶ When looking at cervical cancer screening rates by age, researchers from the Centers for Disease Control and Prevention estimate that the proportion of patients who have not been recently screened goes up as patients get older, with approximately 845,000 American women aged 61 to 65 not adequately screened in 2015 alone.⁷

Details of the study

Cooley and colleagues sought to better characterize the cohort of women diagnosed with cervical cancer at a later age, specifically the stage at diagnosis and survival.⁸ They used data from the California Cancer Registry (CCR), a large state-mandated, population-based data repository that is affiliated with the Surveillance, Epidemiology, and End Results (SEER) program.

The researchers identified 12,442 womenin the CCR who were newly diagnosed with cervical cancer from 2009 to 2018, 17.4% of whom were age 65 or older. They looked at cancer stage at diagnosis as it relates to relative survival rate (“the ratio of the observed survival rate among those who have cancer divided by the expected survival rate for people of the same sex, race/ethnicity, and age who do not have cancer”), Charlson comorbidity score, socioeconomic status, health insurance status, urbanicity, and race/ethnicity.

Results. In this study, 71% of women aged 65 or older presented with advanced-stage disease (FIGO [International Federation of Gynecology and Obstetrics] stage II–IV) as compared with only 48% in those aged 21 to 64. Five-year relative survival rates also were lower in the older cohort—23% to 37%, compared with 42% to 52% in the younger patients. In a sensitivity analysis, late-stage disease was associated with older age, increasing medical comorbidities, and nonadenocarcinoma histology.

Interestingly, older women of Hispanic ethnicity were less likely to be diagnosed with late-stage disease when compared with non-Hispanic White women.

Study strengths and limitations

Although this study’s conclusions—that patients with advanced-stage cancer are more likely to do poorly than those with early-stage cancer—may seem obvious to some even without the proven data, it is still important to highlight what a clinician may intuit with data to support that intuition. It is particularly important to emphasize this risk in older women in light of the aging population in the United States, with adults older than age 65 expected to account for more than 20% of the nation’s population by 2030.⁹

The study by Cooley and colleagues adds value to the existing literature due to its large study population, which included more than 12,000 patients diagnosed with cervical cancer.⁸ And although its results may not be completely generalizable as the data were gathered from only a California-specific population, the sample was diverse with significant portions of Hispanic and Black patients. This study supports previous data that showed high rates of advanced cervical cancer in women older than age 65, with resultant worse 5-year relative survival in this population of older women specifically.⁴ ●

Cooley JJ, Maguire FB, Morris CR, et al. Cervical cancer stage at diagnosis and survival among women ≥65 years in California. Cancer Epidemiol Biomarkers Prev. 2023;32:91-97. doi:10.1158/1055-9965.EPI-22-0793.

EXPERT COMMENTARY

Cervical cancer screening guidelines recommend screening cessation at age 65 once specific exit criteria are met. (According to the American Cancer Society, individuals aged >65 years who have no history of cervical intraepithelial neoplasia [CIN] grade 2 or more severe disease within the past 25 years, and who have documented adequate negative prior screening in the prior 10 years, discontinue all cervical cancer screening.)¹ We know, however, that about one-fifth of all cervical cancer cases are diagnosed among individuals aged 65 or older, and for Black women that proportion is even higher when data are appropriately adjusted to account for the increased rate of hysterectomy among Black versus White women.^2-4

Early-stage cervical cancer is largely a curable disease with very high 5-year overall survival rates. Unfortunately, more than half of all cervical cancer is diagnosed at a more advanced stage, and survival rates are much lower for this population.⁵

Cervical cancer incidence rates plummeted in the United States after the introduction of the Pap test for cervical cancer screening. However, the percentage of women who are not up to date with cervical cancer screening may now be increasing, from 14% in 2005 to 23% in 2019 according to one study from the US Preventive Services Task Force.⁶ When looking at cervical cancer screening rates by age, researchers from the Centers for Disease Control and Prevention estimate that the proportion of patients who have not been recently screened goes up as patients get older, with approximately 845,000 American women aged 61 to 65 not adequately screened in 2015 alone.⁷

Details of the study

Cooley and colleagues sought to better characterize the cohort of women diagnosed with cervical cancer at a later age, specifically the stage at diagnosis and survival.⁸ They used data from the California Cancer Registry (CCR), a large state-mandated, population-based data repository that is affiliated with the Surveillance, Epidemiology, and End Results (SEER) program.

The researchers identified 12,442 womenin the CCR who were newly diagnosed with cervical cancer from 2009 to 2018, 17.4% of whom were age 65 or older. They looked at cancer stage at diagnosis as it relates to relative survival rate (“the ratio of the observed survival rate among those who have cancer divided by the expected survival rate for people of the same sex, race/ethnicity, and age who do not have cancer”), Charlson comorbidity score, socioeconomic status, health insurance status, urbanicity, and race/ethnicity.

Results. In this study, 71% of women aged 65 or older presented with advanced-stage disease (FIGO [International Federation of Gynecology and Obstetrics] stage II–IV) as compared with only 48% in those aged 21 to 64. Five-year relative survival rates also were lower in the older cohort—23% to 37%, compared with 42% to 52% in the younger patients. In a sensitivity analysis, late-stage disease was associated with older age, increasing medical comorbidities, and nonadenocarcinoma histology.

Interestingly, older women of Hispanic ethnicity were less likely to be diagnosed with late-stage disease when compared with non-Hispanic White women.

Study strengths and limitations

Although this study’s conclusions—that patients with advanced-stage cancer are more likely to do poorly than those with early-stage cancer—may seem obvious to some even without the proven data, it is still important to highlight what a clinician may intuit with data to support that intuition. It is particularly important to emphasize this risk in older women in light of the aging population in the United States, with adults older than age 65 expected to account for more than 20% of the nation’s population by 2030.⁹

The study by Cooley and colleagues adds value to the existing literature due to its large study population, which included more than 12,000 patients diagnosed with cervical cancer.⁸ And although its results may not be completely generalizable as the data were gathered from only a California-specific population, the sample was diverse with significant portions of Hispanic and Black patients. This study supports previous data that showed high rates of advanced cervical cancer in women older than age 65, with resultant worse 5-year relative survival in this population of older women specifically.⁴ ●

Cooley JJ, Maguire FB, Morris CR, et al. Cervical cancer stage at diagnosis and survival among women ≥65 years in California. Cancer Epidemiol Biomarkers Prev. 2023;32:91-97. doi:10.1158/1055-9965.EPI-22-0793.

EXPERT COMMENTARY

Cervical cancer screening guidelines recommend screening cessation at age 65 once specific exit criteria are met. (According to the American Cancer Society, individuals aged >65 years who have no history of cervical intraepithelial neoplasia [CIN] grade 2 or more severe disease within the past 25 years, and who have documented adequate negative prior screening in the prior 10 years, discontinue all cervical cancer screening.)¹ We know, however, that about one-fifth of all cervical cancer cases are diagnosed among individuals aged 65 or older, and for Black women that proportion is even higher when data are appropriately adjusted to account for the increased rate of hysterectomy among Black versus White women.^2-4

Early-stage cervical cancer is largely a curable disease with very high 5-year overall survival rates. Unfortunately, more than half of all cervical cancer is diagnosed at a more advanced stage, and survival rates are much lower for this population.⁵

Cervical cancer incidence rates plummeted in the United States after the introduction of the Pap test for cervical cancer screening. However, the percentage of women who are not up to date with cervical cancer screening may now be increasing, from 14% in 2005 to 23% in 2019 according to one study from the US Preventive Services Task Force.⁶ When looking at cervical cancer screening rates by age, researchers from the Centers for Disease Control and Prevention estimate that the proportion of patients who have not been recently screened goes up as patients get older, with approximately 845,000 American women aged 61 to 65 not adequately screened in 2015 alone.⁷

Details of the study

Cooley and colleagues sought to better characterize the cohort of women diagnosed with cervical cancer at a later age, specifically the stage at diagnosis and survival.⁸ They used data from the California Cancer Registry (CCR), a large state-mandated, population-based data repository that is affiliated with the Surveillance, Epidemiology, and End Results (SEER) program.

The researchers identified 12,442 womenin the CCR who were newly diagnosed with cervical cancer from 2009 to 2018, 17.4% of whom were age 65 or older. They looked at cancer stage at diagnosis as it relates to relative survival rate (“the ratio of the observed survival rate among those who have cancer divided by the expected survival rate for people of the same sex, race/ethnicity, and age who do not have cancer”), Charlson comorbidity score, socioeconomic status, health insurance status, urbanicity, and race/ethnicity.

Results. In this study, 71% of women aged 65 or older presented with advanced-stage disease (FIGO [International Federation of Gynecology and Obstetrics] stage II–IV) as compared with only 48% in those aged 21 to 64. Five-year relative survival rates also were lower in the older cohort—23% to 37%, compared with 42% to 52% in the younger patients. In a sensitivity analysis, late-stage disease was associated with older age, increasing medical comorbidities, and nonadenocarcinoma histology.

Interestingly, older women of Hispanic ethnicity were less likely to be diagnosed with late-stage disease when compared with non-Hispanic White women.

Study strengths and limitations

Although this study’s conclusions—that patients with advanced-stage cancer are more likely to do poorly than those with early-stage cancer—may seem obvious to some even without the proven data, it is still important to highlight what a clinician may intuit with data to support that intuition. It is particularly important to emphasize this risk in older women in light of the aging population in the United States, with adults older than age 65 expected to account for more than 20% of the nation’s population by 2030.⁹

The study by Cooley and colleagues adds value to the existing literature due to its large study population, which included more than 12,000 patients diagnosed with cervical cancer.⁸ And although its results may not be completely generalizable as the data were gathered from only a California-specific population, the sample was diverse with significant portions of Hispanic and Black patients. This study supports previous data that showed high rates of advanced cervical cancer in women older than age 65, with resultant worse 5-year relative survival in this population of older women specifically.⁴ ●

As the number of cases of early-onset colorectal cancer (CRC) diagnosed before age 50 continues to rise, early detection has become increasingly important.

A new study has identified four signs and symptoms that can serve as red flags to facilitate earlier detection of early-onset CRC. The signs and symptoms are abdominal pain, rectal bleeding, diarrhea, and iron-deficiency anemia.

Two symptoms in particular – rectal bleeding and iron-deficiency anemia – point to the need for timely endoscopy and follow-up, the researchers say.

“Colorectal cancer is not simply a disease affecting older people; we want younger adults to be aware of and act on these potentially very telling signs and symptoms – particularly because people under 50 are considered to be at low risk, and they don’t receive routine colorectal cancer screening,” senior investigator Yin Cao, ScD, with Washington University School of Medicine, St. Louis, said in a news release.

“It’s also crucial to spread awareness among primary care doctors, gastroenterologists, and emergency medicine doctors,” Dr. Cao added. “To date, many early-onset colorectal cancers are detected in emergency rooms, and there often are significant diagnostic delays with this cancer.”

The study was published online  in the Journal of the National Cancer Institute.

Although previous research has identified rectal bleeding, iron-deficiency anemia, and rectal/abdominal pain as symptoms of early-onset CRC, most studies “have aggregated symptoms till the time of diagnosis,” which limits their use for early detection, the authors explain.

In the current study, the researchers analyzed data from more than 5,000 cases of early-onset CRC and from more than 22,000 control patients using the IBM MarketScan commercial database.

Dr. Cao and colleagues found that between 3 months and 2 years before diagnosis, abdominal pain, rectal bleeding, diarrhea, and iron-deficiency anemia each indicated an increased risk for early-onset CRC.

Among patients with early-onset CRC, 19.3% presented with one or more of the four red flags between 3 months and 2 years prior to the index date; 15.6% had one symptom, and 3.7% had two or more.

After multivariable adjustment, having one symptom almost doubled the risk for early-onset CRC (odds ratio, 1.94); having two symptoms increased risk by more than threefold (OR, 3.59); and having three or more boosted the risk by more than 6.5-fold (OR, 6.52).

Abdominal pain was associated with a 34% higher risk of early-onset CRC (11.6% among case patients vs. 7.7% among controls; OR, 1.34).

Although not as common, rectal bleeding was associated with the highest odds for early-onset CRC (7.2% case patients vs. 1.3% controls; OR, 5.13).

The other predictive signs and symptoms included diarrhea (2.8% case patients vs. 1.4% controls; OR, 1.43) and iron-deficiency anemia (2.3% case patients vs. 0.9% controls; OR, 2.07).

No differences were observed by gender for each sign or symptom.

Among patients with a red-flag symptom who presented between 3 months and 2 years before diagnosis, for those with early-onset CRC, the median diagnostic interval was 8.7 months.

The researchers suggest that clinicians prioritize prompt diagnostic workups for patients younger than 50 who present with rectal bleeding and/or iron-deficiency anemia and that they also keep abdominal pain and diarrhea in mind as early symptoms.

Dr. Cao noted that since most early-onset CRC cases “have been and will continue to be diagnosed after symptom presentation, it is crucial to recognize these red-flag signs and symptoms promptly and conduct a diagnostic workup as soon as possible.

“By doing so, we can diagnose the disease earlier, which in turn can reduce the need for more aggressive treatment and improve patients’ quality of life and survival rates,” said Dr. Cao.

The study was supported by grants from the National Institutes of Health. The authors declared no conflicts of interest.

A version of this article originally appeared on Medscape.com.

As the number of cases of early-onset colorectal cancer (CRC) diagnosed before age 50 continues to rise, early detection has become increasingly important.

A new study has identified four signs and symptoms that can serve as red flags to facilitate earlier detection of early-onset CRC. The signs and symptoms are abdominal pain, rectal bleeding, diarrhea, and iron-deficiency anemia.

Two symptoms in particular – rectal bleeding and iron-deficiency anemia – point to the need for timely endoscopy and follow-up, the researchers say.

“Colorectal cancer is not simply a disease affecting older people; we want younger adults to be aware of and act on these potentially very telling signs and symptoms – particularly because people under 50 are considered to be at low risk, and they don’t receive routine colorectal cancer screening,” senior investigator Yin Cao, ScD, with Washington University School of Medicine, St. Louis, said in a news release.

“It’s also crucial to spread awareness among primary care doctors, gastroenterologists, and emergency medicine doctors,” Dr. Cao added. “To date, many early-onset colorectal cancers are detected in emergency rooms, and there often are significant diagnostic delays with this cancer.”

The study was published online  in the Journal of the National Cancer Institute.

Although previous research has identified rectal bleeding, iron-deficiency anemia, and rectal/abdominal pain as symptoms of early-onset CRC, most studies “have aggregated symptoms till the time of diagnosis,” which limits their use for early detection, the authors explain.

In the current study, the researchers analyzed data from more than 5,000 cases of early-onset CRC and from more than 22,000 control patients using the IBM MarketScan commercial database.

Dr. Cao and colleagues found that between 3 months and 2 years before diagnosis, abdominal pain, rectal bleeding, diarrhea, and iron-deficiency anemia each indicated an increased risk for early-onset CRC.

Among patients with early-onset CRC, 19.3% presented with one or more of the four red flags between 3 months and 2 years prior to the index date; 15.6% had one symptom, and 3.7% had two or more.

After multivariable adjustment, having one symptom almost doubled the risk for early-onset CRC (odds ratio, 1.94); having two symptoms increased risk by more than threefold (OR, 3.59); and having three or more boosted the risk by more than 6.5-fold (OR, 6.52).

Abdominal pain was associated with a 34% higher risk of early-onset CRC (11.6% among case patients vs. 7.7% among controls; OR, 1.34).

Although not as common, rectal bleeding was associated with the highest odds for early-onset CRC (7.2% case patients vs. 1.3% controls; OR, 5.13).

The other predictive signs and symptoms included diarrhea (2.8% case patients vs. 1.4% controls; OR, 1.43) and iron-deficiency anemia (2.3% case patients vs. 0.9% controls; OR, 2.07).

No differences were observed by gender for each sign or symptom.

Among patients with a red-flag symptom who presented between 3 months and 2 years before diagnosis, for those with early-onset CRC, the median diagnostic interval was 8.7 months.

The researchers suggest that clinicians prioritize prompt diagnostic workups for patients younger than 50 who present with rectal bleeding and/or iron-deficiency anemia and that they also keep abdominal pain and diarrhea in mind as early symptoms.

Dr. Cao noted that since most early-onset CRC cases “have been and will continue to be diagnosed after symptom presentation, it is crucial to recognize these red-flag signs and symptoms promptly and conduct a diagnostic workup as soon as possible.

“By doing so, we can diagnose the disease earlier, which in turn can reduce the need for more aggressive treatment and improve patients’ quality of life and survival rates,” said Dr. Cao.

The study was supported by grants from the National Institutes of Health. The authors declared no conflicts of interest.

A version of this article originally appeared on Medscape.com.

As the number of cases of early-onset colorectal cancer (CRC) diagnosed before age 50 continues to rise, early detection has become increasingly important.

A new study has identified four signs and symptoms that can serve as red flags to facilitate earlier detection of early-onset CRC. The signs and symptoms are abdominal pain, rectal bleeding, diarrhea, and iron-deficiency anemia.

Two symptoms in particular – rectal bleeding and iron-deficiency anemia – point to the need for timely endoscopy and follow-up, the researchers say.

“Colorectal cancer is not simply a disease affecting older people; we want younger adults to be aware of and act on these potentially very telling signs and symptoms – particularly because people under 50 are considered to be at low risk, and they don’t receive routine colorectal cancer screening,” senior investigator Yin Cao, ScD, with Washington University School of Medicine, St. Louis, said in a news release.

“It’s also crucial to spread awareness among primary care doctors, gastroenterologists, and emergency medicine doctors,” Dr. Cao added. “To date, many early-onset colorectal cancers are detected in emergency rooms, and there often are significant diagnostic delays with this cancer.”

The study was published online  in the Journal of the National Cancer Institute.

Although previous research has identified rectal bleeding, iron-deficiency anemia, and rectal/abdominal pain as symptoms of early-onset CRC, most studies “have aggregated symptoms till the time of diagnosis,” which limits their use for early detection, the authors explain.

In the current study, the researchers analyzed data from more than 5,000 cases of early-onset CRC and from more than 22,000 control patients using the IBM MarketScan commercial database.

Dr. Cao and colleagues found that between 3 months and 2 years before diagnosis, abdominal pain, rectal bleeding, diarrhea, and iron-deficiency anemia each indicated an increased risk for early-onset CRC.

Among patients with early-onset CRC, 19.3% presented with one or more of the four red flags between 3 months and 2 years prior to the index date; 15.6% had one symptom, and 3.7% had two or more.

After multivariable adjustment, having one symptom almost doubled the risk for early-onset CRC (odds ratio, 1.94); having two symptoms increased risk by more than threefold (OR, 3.59); and having three or more boosted the risk by more than 6.5-fold (OR, 6.52).

Abdominal pain was associated with a 34% higher risk of early-onset CRC (11.6% among case patients vs. 7.7% among controls; OR, 1.34).

Although not as common, rectal bleeding was associated with the highest odds for early-onset CRC (7.2% case patients vs. 1.3% controls; OR, 5.13).

The other predictive signs and symptoms included diarrhea (2.8% case patients vs. 1.4% controls; OR, 1.43) and iron-deficiency anemia (2.3% case patients vs. 0.9% controls; OR, 2.07).

No differences were observed by gender for each sign or symptom.

Among patients with a red-flag symptom who presented between 3 months and 2 years before diagnosis, for those with early-onset CRC, the median diagnostic interval was 8.7 months.

The researchers suggest that clinicians prioritize prompt diagnostic workups for patients younger than 50 who present with rectal bleeding and/or iron-deficiency anemia and that they also keep abdominal pain and diarrhea in mind as early symptoms.

Dr. Cao noted that since most early-onset CRC cases “have been and will continue to be diagnosed after symptom presentation, it is crucial to recognize these red-flag signs and symptoms promptly and conduct a diagnostic workup as soon as possible.

“By doing so, we can diagnose the disease earlier, which in turn can reduce the need for more aggressive treatment and improve patients’ quality of life and survival rates,” said Dr. Cao.

The study was supported by grants from the National Institutes of Health. The authors declared no conflicts of interest.

A version of this article originally appeared on Medscape.com.

A safety analysis following a landmark randomized phase 3 trial confirms that vomiting and nausea are quite common in patients who take the drug trastuzumab deruxtecan (T-DXd; Enhertu) to treat HER2-low metastatic breast cancer. Interstitial lung disease (ILD) also remains a concern, and it’s not clear if retreatment after resolution is warranted.

In general, however, “T-DXd demonstrates a manageable safety profile consistent with prior reports. Results from this safety analysis continued to support its use as a new standard of care in patients with HER2-low metastatic breast cancer,” said report lead author Hope Rugo, MD, of the University of California, San Francisco, during a presentation at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.

T-DXd, an antibody-drug conjugate, received FDA approval in August 2022 for patients with HER2-low disease. The drug has been touted as “practice changing” and a “new standard of care.”

However, physicians have noted that the benefits of the drug come at the cost of significant adverse effects, including some that can cause hospitalization. There’s special concern about high-grade interstitial lung disease/pneumonitis, and an FDA boxed warning cautions clinicians about this possible side effect.

For the new analysis, researchers presented additional safety data from the industry-funded DESTINY-Breast04 trial, whose results was published in July 2022 in the New England Journal of Medicine. That study randomized 373 patients to T-DXd and 184 to physician’s choice of treatment. It found that, “among all patients, the median progression-free survival was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician’s choice group (hazard ratio for disease progression or death, 0.50; P < .001), and overall survival was 23.4 months and 16.8 months, respectively (hazard ratio for death, 0.64; P = .001).”

Exposure-adjusted incidence rates for any-grade treatment-emergent adverse events were lower for T-DXd versus physician’s choice of treatment (1.30 vs. 2.66). However, nausea and vomiting events were more than twice as common in patients who took T-DXd versus the physician’s choice (79.5% vs. 35.5%).

A total of 50.9% of patients in the T-DXd arm received antiemetic prophylaxis versus 37.2% in the physician’s choice arm. A single patient discontinued T-DXd treatment because of vomiting, and a single patient discontinued treatment because of nausea. No patients in the physician choice group discontinued treatment because of nausea or vomiting.

Neutropenia and febrile neutropenia were less frequent in the T-DXd arm versus physician’s choice (12.9% vs. 18.0% and 0.3% vs. 2.9%, respectively.)

ILD occurred in 45 patients (12.1%) of those in the T-DXd arm versus 1 (0.6%) in the physician choice arm. Ten patients of the patients in the T-DXd arm had not recovered by the data cutoff point.

Six patients with ILD were retreated following resolution; one discontinued because of an adverse event, two discontinued because of progressive disease, and three remained on the drug. “Given that there was only a small number of patients who were retreated with T-DXd, it’s difficult to make clinically meaningful conclusions on the effect of retreatment following grade IDL events that have resolved,” Dr. Rugo said.

In the big picture, “ILD pneumonitis remains an important identified risk and an adverse event of interest associated with T-DXd,” Dr. Rugo said. “It’s important that we adhere to management guidelines and updated toxicity management guidelines.”

In a discussion, Dr. Rugo said she prescribes three antiemetic drugs to help patients tolerate T-DXd therapy: “It makes a big difference. Anecdotally, it really has improved management of nausea. Start more and back down [as symptoms fade].”

Gustavo Werutsky, MD, PhD, of Moinhos de Vento Hospital, Porto Alegre, Brazil, the discussant for the presentation, also emphasized the importance of prevention and said he prescribes two or three prophylactic drugs. “In the beginning, we didn’t know these events were so important. A big part of the message is that patients from the beginning need to have a good prophylaxis for the nausea and vomiting.”

The researchers also presented a related report at the conference, an analysis of patient-reported outcomes from DESTINY-Breast02, a randomized phase 3 study of T-DXd (n = 406) versus physician’s choice of treatment (n = 202) in patients with HER2-positive metastatic breast cancer who were resistant/refractory to trastuzumab emtansine.

The analysis, led by Tanja Fehm, MD, of University Hospital Düsseldorf (Germany), found that the median time to definitive deterioration was longer with T-DXd versus the other arm per the EORTC QLQ-C30 global health status/quality of life score (14.1 vs. 5.9 months; HR, 0.56; 95% confidence interval, 0.44-0.71).

The studies were funded by Daiichi Sankyo and AstraZeneca, which make T-DXd. Dr. Hugo discloses relationships with Puma, NAPO, Blueprint, Scorpion Therapeutics, Merck, AstraZeneca, Gilead, Astellas, Daiichi Sankyo, F. Hoffmann–La Roche/Genentech, GlaxoSmithKline, Lilly, Novartis, OBI, Pfizer, Pionyr, Sermonix, Taiho Oncology, and Veru. Multiple other authors of both studies have various disclosures.

A safety analysis following a landmark randomized phase 3 trial confirms that vomiting and nausea are quite common in patients who take the drug trastuzumab deruxtecan (T-DXd; Enhertu) to treat HER2-low metastatic breast cancer. Interstitial lung disease (ILD) also remains a concern, and it’s not clear if retreatment after resolution is warranted.

In general, however, “T-DXd demonstrates a manageable safety profile consistent with prior reports. Results from this safety analysis continued to support its use as a new standard of care in patients with HER2-low metastatic breast cancer,” said report lead author Hope Rugo, MD, of the University of California, San Francisco, during a presentation at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.

T-DXd, an antibody-drug conjugate, received FDA approval in August 2022 for patients with HER2-low disease. The drug has been touted as “practice changing” and a “new standard of care.”

However, physicians have noted that the benefits of the drug come at the cost of significant adverse effects, including some that can cause hospitalization. There’s special concern about high-grade interstitial lung disease/pneumonitis, and an FDA boxed warning cautions clinicians about this possible side effect.

For the new analysis, researchers presented additional safety data from the industry-funded DESTINY-Breast04 trial, whose results was published in July 2022 in the New England Journal of Medicine. That study randomized 373 patients to T-DXd and 184 to physician’s choice of treatment. It found that, “among all patients, the median progression-free survival was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician’s choice group (hazard ratio for disease progression or death, 0.50; P < .001), and overall survival was 23.4 months and 16.8 months, respectively (hazard ratio for death, 0.64; P = .001).”

Exposure-adjusted incidence rates for any-grade treatment-emergent adverse events were lower for T-DXd versus physician’s choice of treatment (1.30 vs. 2.66). However, nausea and vomiting events were more than twice as common in patients who took T-DXd versus the physician’s choice (79.5% vs. 35.5%).

A total of 50.9% of patients in the T-DXd arm received antiemetic prophylaxis versus 37.2% in the physician’s choice arm. A single patient discontinued T-DXd treatment because of vomiting, and a single patient discontinued treatment because of nausea. No patients in the physician choice group discontinued treatment because of nausea or vomiting.

Neutropenia and febrile neutropenia were less frequent in the T-DXd arm versus physician’s choice (12.9% vs. 18.0% and 0.3% vs. 2.9%, respectively.)

ILD occurred in 45 patients (12.1%) of those in the T-DXd arm versus 1 (0.6%) in the physician choice arm. Ten patients of the patients in the T-DXd arm had not recovered by the data cutoff point.

Six patients with ILD were retreated following resolution; one discontinued because of an adverse event, two discontinued because of progressive disease, and three remained on the drug. “Given that there was only a small number of patients who were retreated with T-DXd, it’s difficult to make clinically meaningful conclusions on the effect of retreatment following grade IDL events that have resolved,” Dr. Rugo said.

In the big picture, “ILD pneumonitis remains an important identified risk and an adverse event of interest associated with T-DXd,” Dr. Rugo said. “It’s important that we adhere to management guidelines and updated toxicity management guidelines.”

In a discussion, Dr. Rugo said she prescribes three antiemetic drugs to help patients tolerate T-DXd therapy: “It makes a big difference. Anecdotally, it really has improved management of nausea. Start more and back down [as symptoms fade].”

Gustavo Werutsky, MD, PhD, of Moinhos de Vento Hospital, Porto Alegre, Brazil, the discussant for the presentation, also emphasized the importance of prevention and said he prescribes two or three prophylactic drugs. “In the beginning, we didn’t know these events were so important. A big part of the message is that patients from the beginning need to have a good prophylaxis for the nausea and vomiting.”

The researchers also presented a related report at the conference, an analysis of patient-reported outcomes from DESTINY-Breast02, a randomized phase 3 study of T-DXd (n = 406) versus physician’s choice of treatment (n = 202) in patients with HER2-positive metastatic breast cancer who were resistant/refractory to trastuzumab emtansine.

The analysis, led by Tanja Fehm, MD, of University Hospital Düsseldorf (Germany), found that the median time to definitive deterioration was longer with T-DXd versus the other arm per the EORTC QLQ-C30 global health status/quality of life score (14.1 vs. 5.9 months; HR, 0.56; 95% confidence interval, 0.44-0.71).

The studies were funded by Daiichi Sankyo and AstraZeneca, which make T-DXd. Dr. Hugo discloses relationships with Puma, NAPO, Blueprint, Scorpion Therapeutics, Merck, AstraZeneca, Gilead, Astellas, Daiichi Sankyo, F. Hoffmann–La Roche/Genentech, GlaxoSmithKline, Lilly, Novartis, OBI, Pfizer, Pionyr, Sermonix, Taiho Oncology, and Veru. Multiple other authors of both studies have various disclosures.

A safety analysis following a landmark randomized phase 3 trial confirms that vomiting and nausea are quite common in patients who take the drug trastuzumab deruxtecan (T-DXd; Enhertu) to treat HER2-low metastatic breast cancer. Interstitial lung disease (ILD) also remains a concern, and it’s not clear if retreatment after resolution is warranted.

In general, however, “T-DXd demonstrates a manageable safety profile consistent with prior reports. Results from this safety analysis continued to support its use as a new standard of care in patients with HER2-low metastatic breast cancer,” said report lead author Hope Rugo, MD, of the University of California, San Francisco, during a presentation at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.

T-DXd, an antibody-drug conjugate, received FDA approval in August 2022 for patients with HER2-low disease. The drug has been touted as “practice changing” and a “new standard of care.”

However, physicians have noted that the benefits of the drug come at the cost of significant adverse effects, including some that can cause hospitalization. There’s special concern about high-grade interstitial lung disease/pneumonitis, and an FDA boxed warning cautions clinicians about this possible side effect.

For the new analysis, researchers presented additional safety data from the industry-funded DESTINY-Breast04 trial, whose results was published in July 2022 in the New England Journal of Medicine. That study randomized 373 patients to T-DXd and 184 to physician’s choice of treatment. It found that, “among all patients, the median progression-free survival was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician’s choice group (hazard ratio for disease progression or death, 0.50; P < .001), and overall survival was 23.4 months and 16.8 months, respectively (hazard ratio for death, 0.64; P = .001).”

Exposure-adjusted incidence rates for any-grade treatment-emergent adverse events were lower for T-DXd versus physician’s choice of treatment (1.30 vs. 2.66). However, nausea and vomiting events were more than twice as common in patients who took T-DXd versus the physician’s choice (79.5% vs. 35.5%).

A total of 50.9% of patients in the T-DXd arm received antiemetic prophylaxis versus 37.2% in the physician’s choice arm. A single patient discontinued T-DXd treatment because of vomiting, and a single patient discontinued treatment because of nausea. No patients in the physician choice group discontinued treatment because of nausea or vomiting.

Neutropenia and febrile neutropenia were less frequent in the T-DXd arm versus physician’s choice (12.9% vs. 18.0% and 0.3% vs. 2.9%, respectively.)

ILD occurred in 45 patients (12.1%) of those in the T-DXd arm versus 1 (0.6%) in the physician choice arm. Ten patients of the patients in the T-DXd arm had not recovered by the data cutoff point.

Six patients with ILD were retreated following resolution; one discontinued because of an adverse event, two discontinued because of progressive disease, and three remained on the drug. “Given that there was only a small number of patients who were retreated with T-DXd, it’s difficult to make clinically meaningful conclusions on the effect of retreatment following grade IDL events that have resolved,” Dr. Rugo said.

In the big picture, “ILD pneumonitis remains an important identified risk and an adverse event of interest associated with T-DXd,” Dr. Rugo said. “It’s important that we adhere to management guidelines and updated toxicity management guidelines.”

In a discussion, Dr. Rugo said she prescribes three antiemetic drugs to help patients tolerate T-DXd therapy: “It makes a big difference. Anecdotally, it really has improved management of nausea. Start more and back down [as symptoms fade].”

Gustavo Werutsky, MD, PhD, of Moinhos de Vento Hospital, Porto Alegre, Brazil, the discussant for the presentation, also emphasized the importance of prevention and said he prescribes two or three prophylactic drugs. “In the beginning, we didn’t know these events were so important. A big part of the message is that patients from the beginning need to have a good prophylaxis for the nausea and vomiting.”

The researchers also presented a related report at the conference, an analysis of patient-reported outcomes from DESTINY-Breast02, a randomized phase 3 study of T-DXd (n = 406) versus physician’s choice of treatment (n = 202) in patients with HER2-positive metastatic breast cancer who were resistant/refractory to trastuzumab emtansine.

The analysis, led by Tanja Fehm, MD, of University Hospital Düsseldorf (Germany), found that the median time to definitive deterioration was longer with T-DXd versus the other arm per the EORTC QLQ-C30 global health status/quality of life score (14.1 vs. 5.9 months; HR, 0.56; 95% confidence interval, 0.44-0.71).

The studies were funded by Daiichi Sankyo and AstraZeneca, which make T-DXd. Dr. Hugo discloses relationships with Puma, NAPO, Blueprint, Scorpion Therapeutics, Merck, AstraZeneca, Gilead, Astellas, Daiichi Sankyo, F. Hoffmann–La Roche/Genentech, GlaxoSmithKline, Lilly, Novartis, OBI, Pfizer, Pionyr, Sermonix, Taiho Oncology, and Veru. Multiple other authors of both studies have various disclosures.

In postmenopausal women with hormone receptor–positive breast cancer, overweight and obesity were overall predictors of lower disease-free survival, but body mass index had no apparent association with the effect of extended endocrine therapy on disease-free survival, new data suggest.

Obesity is a well-known risk factor for breast cancer in postmenopausal women and has been associated with adverse prognosis, said Senna W.M. Lammers, MD, of Maastricht (the Netherlands) University during a presentation at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress. In addition, some studies suggest that patients with higher body mass index (BMI) experience reduced benefits from endocrine therapy, she said.

Dr. Lammers and colleagues conducted a study to determine the prognostic and predictive effect of BMI on disease-free survival in postmenopausal women with hormone receptor–positive (HR+) breast cancer who were treated with extended endocrine therapy.

The study population included participants in the randomized, phase III DATA trial, which evaluated the use of 6 years vs. 3 years of anastrozole in postmenopausal women with HR+ breast cancer who were disease-free after 2-3 years of adjuvant tamoxifen therapy.

Patients were categorized based on BMI as having normal weight (18.5-24.9 kg/m²), overweight (25-29.9 kg/m²), or obese (30 kg/m² or higher). The primary outcome was disease-free survival (DFS); the median follow-up period was 13.1 years.

DFS for patients with normal weight, overweight, and obesity was 66.2%, 59.5%, and 52.4%, with a P value of less than .001 for the trend, Dr. Lammers said. “These results were confirmed in multivariable analysis,” she said. Overall, patients with overweight and obesity had a worse DFS when compared with patients with normal weight (hazard ratio, 1.16; P = .10, for patients with overweight and HR, 1.26; P = .03 for patients with obesity).

“Next, we aimed to determine whether the prognostic effect of BMI differed by age,” Dr. Lammers said.

In women younger than 60 years, overweight and obesity were significantly associated with worse DFS (HR, 1.29; P = .05 and HR 1.83, P less than .001, respectively). However, this effect was not observed in women aged 60 years and older.

The researchers also examined the treatment effect of extended anastrozole on adapted DFS by weight, and found no significant differences among patients with normal weight, overweight, and obesity (HR, 1.00; HR, 0.74; and HR, 0.97, respectively), said Dr. Lammers.

In the question and answer session, Dr. Lammers was asked about possible explanations for the difference in DFS by age. Potential explanations include possible survival bias “as only the healthier [patients with obesity] survive to old age,” she said. Other potential explanations are biological, such as the potentially higher levels of bone density in older [patients with obesity], she said.

When asked about additional clinical implications, Dr. Lammers emphasized the importance of maintaining a healthy BMI for breast cancer patients of all ages. Other research areas might involve the use of lifestyle interventions, although these are challenging to implement, she noted.
 

Data draw attention to quality of life and lifestyle factors

The need to “look at drug development with new eyes” is particularly important when reviewing patient-reported outcomes, said Otto Metzger, MD, of the Dana Farber Cancer Institute, Boston, who served as the discussant for the session.

Dr. Metzger brought up the association between age and the effect of BMI on DFS, specifically.

Based on data from multiple studies and meta-analyses, “I do believe that obesity does play a role in prognosis,” he said, but the question is how long will researchers continue to simply record data without acting to add lifestyle interventions while also trying to develop new drugs, he said. Although convincing patients to make lifestyle changes remains a challenge, patients are often more motivated to make such changes after a cancer diagnosis, Dr. Metzger noted.

“I am a firm believer in the use of digital therapeutics in the context of clinical trials,” said Dr. Metzger. Digital technology offers great potential to educate patients on [adverse effects] and also to improve treatment adherence and quality of life, he concluded.

The study was supported by AstraZeneca, and Dr. Lammers disclosed financial relationships with AstraZeneca and Eli Lilly. Dr. Metzger disclosed receiving research funding to his institution from Pfizer, Genentech/Roche, and Sanofi, and serving as an adviser/consultant to AstraZeneca, Merck, Oncoclinicas, Resilience, and Roche.

In postmenopausal women with hormone receptor–positive breast cancer, overweight and obesity were overall predictors of lower disease-free survival, but body mass index had no apparent association with the effect of extended endocrine therapy on disease-free survival, new data suggest.

Obesity is a well-known risk factor for breast cancer in postmenopausal women and has been associated with adverse prognosis, said Senna W.M. Lammers, MD, of Maastricht (the Netherlands) University during a presentation at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress. In addition, some studies suggest that patients with higher body mass index (BMI) experience reduced benefits from endocrine therapy, she said.

Dr. Lammers and colleagues conducted a study to determine the prognostic and predictive effect of BMI on disease-free survival in postmenopausal women with hormone receptor–positive (HR+) breast cancer who were treated with extended endocrine therapy.

The study population included participants in the randomized, phase III DATA trial, which evaluated the use of 6 years vs. 3 years of anastrozole in postmenopausal women with HR+ breast cancer who were disease-free after 2-3 years of adjuvant tamoxifen therapy.

Patients were categorized based on BMI as having normal weight (18.5-24.9 kg/m²), overweight (25-29.9 kg/m²), or obese (30 kg/m² or higher). The primary outcome was disease-free survival (DFS); the median follow-up period was 13.1 years.

DFS for patients with normal weight, overweight, and obesity was 66.2%, 59.5%, and 52.4%, with a P value of less than .001 for the trend, Dr. Lammers said. “These results were confirmed in multivariable analysis,” she said. Overall, patients with overweight and obesity had a worse DFS when compared with patients with normal weight (hazard ratio, 1.16; P = .10, for patients with overweight and HR, 1.26; P = .03 for patients with obesity).

“Next, we aimed to determine whether the prognostic effect of BMI differed by age,” Dr. Lammers said.

In women younger than 60 years, overweight and obesity were significantly associated with worse DFS (HR, 1.29; P = .05 and HR 1.83, P less than .001, respectively). However, this effect was not observed in women aged 60 years and older.

The researchers also examined the treatment effect of extended anastrozole on adapted DFS by weight, and found no significant differences among patients with normal weight, overweight, and obesity (HR, 1.00; HR, 0.74; and HR, 0.97, respectively), said Dr. Lammers.

In the question and answer session, Dr. Lammers was asked about possible explanations for the difference in DFS by age. Potential explanations include possible survival bias “as only the healthier [patients with obesity] survive to old age,” she said. Other potential explanations are biological, such as the potentially higher levels of bone density in older [patients with obesity], she said.

When asked about additional clinical implications, Dr. Lammers emphasized the importance of maintaining a healthy BMI for breast cancer patients of all ages. Other research areas might involve the use of lifestyle interventions, although these are challenging to implement, she noted.
 

Data draw attention to quality of life and lifestyle factors

The need to “look at drug development with new eyes” is particularly important when reviewing patient-reported outcomes, said Otto Metzger, MD, of the Dana Farber Cancer Institute, Boston, who served as the discussant for the session.

Dr. Metzger brought up the association between age and the effect of BMI on DFS, specifically.

Based on data from multiple studies and meta-analyses, “I do believe that obesity does play a role in prognosis,” he said, but the question is how long will researchers continue to simply record data without acting to add lifestyle interventions while also trying to develop new drugs, he said. Although convincing patients to make lifestyle changes remains a challenge, patients are often more motivated to make such changes after a cancer diagnosis, Dr. Metzger noted.

“I am a firm believer in the use of digital therapeutics in the context of clinical trials,” said Dr. Metzger. Digital technology offers great potential to educate patients on [adverse effects] and also to improve treatment adherence and quality of life, he concluded.

The study was supported by AstraZeneca, and Dr. Lammers disclosed financial relationships with AstraZeneca and Eli Lilly. Dr. Metzger disclosed receiving research funding to his institution from Pfizer, Genentech/Roche, and Sanofi, and serving as an adviser/consultant to AstraZeneca, Merck, Oncoclinicas, Resilience, and Roche.

In postmenopausal women with hormone receptor–positive breast cancer, overweight and obesity were overall predictors of lower disease-free survival, but body mass index had no apparent association with the effect of extended endocrine therapy on disease-free survival, new data suggest.

Obesity is a well-known risk factor for breast cancer in postmenopausal women and has been associated with adverse prognosis, said Senna W.M. Lammers, MD, of Maastricht (the Netherlands) University during a presentation at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress. In addition, some studies suggest that patients with higher body mass index (BMI) experience reduced benefits from endocrine therapy, she said.

Dr. Lammers and colleagues conducted a study to determine the prognostic and predictive effect of BMI on disease-free survival in postmenopausal women with hormone receptor–positive (HR+) breast cancer who were treated with extended endocrine therapy.

The study population included participants in the randomized, phase III DATA trial, which evaluated the use of 6 years vs. 3 years of anastrozole in postmenopausal women with HR+ breast cancer who were disease-free after 2-3 years of adjuvant tamoxifen therapy.

Patients were categorized based on BMI as having normal weight (18.5-24.9 kg/m²), overweight (25-29.9 kg/m²), or obese (30 kg/m² or higher). The primary outcome was disease-free survival (DFS); the median follow-up period was 13.1 years.

DFS for patients with normal weight, overweight, and obesity was 66.2%, 59.5%, and 52.4%, with a P value of less than .001 for the trend, Dr. Lammers said. “These results were confirmed in multivariable analysis,” she said. Overall, patients with overweight and obesity had a worse DFS when compared with patients with normal weight (hazard ratio, 1.16; P = .10, for patients with overweight and HR, 1.26; P = .03 for patients with obesity).

“Next, we aimed to determine whether the prognostic effect of BMI differed by age,” Dr. Lammers said.

In women younger than 60 years, overweight and obesity were significantly associated with worse DFS (HR, 1.29; P = .05 and HR 1.83, P less than .001, respectively). However, this effect was not observed in women aged 60 years and older.

The researchers also examined the treatment effect of extended anastrozole on adapted DFS by weight, and found no significant differences among patients with normal weight, overweight, and obesity (HR, 1.00; HR, 0.74; and HR, 0.97, respectively), said Dr. Lammers.

In the question and answer session, Dr. Lammers was asked about possible explanations for the difference in DFS by age. Potential explanations include possible survival bias “as only the healthier [patients with obesity] survive to old age,” she said. Other potential explanations are biological, such as the potentially higher levels of bone density in older [patients with obesity], she said.

When asked about additional clinical implications, Dr. Lammers emphasized the importance of maintaining a healthy BMI for breast cancer patients of all ages. Other research areas might involve the use of lifestyle interventions, although these are challenging to implement, she noted.
 

Data draw attention to quality of life and lifestyle factors

The need to “look at drug development with new eyes” is particularly important when reviewing patient-reported outcomes, said Otto Metzger, MD, of the Dana Farber Cancer Institute, Boston, who served as the discussant for the session.

Dr. Metzger brought up the association between age and the effect of BMI on DFS, specifically.

Based on data from multiple studies and meta-analyses, “I do believe that obesity does play a role in prognosis,” he said, but the question is how long will researchers continue to simply record data without acting to add lifestyle interventions while also trying to develop new drugs, he said. Although convincing patients to make lifestyle changes remains a challenge, patients are often more motivated to make such changes after a cancer diagnosis, Dr. Metzger noted.

“I am a firm believer in the use of digital therapeutics in the context of clinical trials,” said Dr. Metzger. Digital technology offers great potential to educate patients on [adverse effects] and also to improve treatment adherence and quality of life, he concluded.

The study was supported by AstraZeneca, and Dr. Lammers disclosed financial relationships with AstraZeneca and Eli Lilly. Dr. Metzger disclosed receiving research funding to his institution from Pfizer, Genentech/Roche, and Sanofi, and serving as an adviser/consultant to AstraZeneca, Merck, Oncoclinicas, Resilience, and Roche.

Venetoclax combinations – especially a novel combination of venetoclax, ibrutinib, and obinutuzumab – outperform first-line chemoimmunotherapy for chronic lymphocytic leukemia in otherwise fit adults with few comorbidities, according to a phase 3 trial published in the New England Journal of Medicine.

The trial, dubbed GAIA–CLL13, “is a remarkable demonstration of the quality of fixed-duration therapies for younger, fit patients, and it challenges us to continue to work to develop therapeutic strategies that will ultimately cure patients with CLL,” two hematologic cancer specialists said in an accompanying editorial.

In short, “venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib were superior to chemoimmunotherapy with respect to both the minimal residual disease end point and progression-free survival, but venetoclax-rituximab was not,” Jennifer Woyach, MD, of Ohio State University, Columbus, and John Byrd, MD, University of Cincinnati, said in their commentary.

Noting that randomized trials involving venetoclax combinations in fit CLL patients “have been lacking,” the investigators compared 6 cycles of chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) with 12 cycles of venetoclax plus the anti-CD20 antibody rituximab, venetoclax plus the third generation anti-CD20 antibody obinutuzumab, and venetoclax combined with both obinutuzumab and the Bruton’s tyrosine kinase inhibitor ibrutinib in a novel triple-therapy regimen.

The 926 patients in the study were a mean of 61 years old and split about evenly among the four treatment arms. Ibrutinib was discontinued after two consecutive measurements if patients had undetectable minimal residual disease (uMRD). Subjects did not have TP53 aberrations, a marker of poor prognosis in CLL.

At 15 months, the percentage of patients with uMRD was significantly higher in the triple-therapy arm (92.2%) and the venetoclax-obinutuzumab group (86.5%) than in the chemoimmunotherapy group (52.0%), but there was no statistical difference with venetoclax-rituximab (57%, P = .32).

The three-year progression-free survival (PFS) was 90.5% in the triple-therapy arm versus 87.7% with venetoclax-obinutuzumab. The 3-year PFS with venetoclax-rituximab (80.8%) was again not statistically different than the 75.5% with chemoimmunotherapy (P = .18).
 

Not ready for prime time

The benefits of triple therapy and venetoclax-obinutuzumab held only in patients with unmutated IgVH. “The high efficacy of the fludarabine, cyclophosphamide, and rituximab regimen in young, fit patients with mutated IgVH may be difficult to improve on,” noted the investigators, led by Barbara Eichhorst, MD, a hematologic malignancy specialist at the University of Cologne (Germany).

Also, although triple-therapy results were impressive, some of the benefits “are neutralized by the need for dose reductions and early treatment discontinuation owing to adverse events,” they said.

For instance, triple therapy had the highest incidence of both grade 3 and 4 infections (21.2%) and atrial fibrillation (7.8%).

The editorialists noted that there has been “a flurry of interest” in trials combining ibrutinib and venetoclax – as was done in the triple-therapy arm – since both emerged as powerful tools against CLL in recent years. However, even with the study results, they said “the use of triplet therapy should be viewed as investigational.”

For one thing, rates of uMRD were not “dramatically different” between triple therapy and venetoclax-obinutuzumab, and longer follow-up is better gauge differences in PFS and long-term toxicities.

Also, ibrutinib is being eclipsed by the second-generation Bruton’s tyrosine kinase inhibitors acalabrutinib and zanubrutinib, because they have better safety profiles, and they are being assessed in CLL combination trials. For now, there are too many unknowns for routine use of triple therapy in fit CLL patients, they said.

The investigators and editorialists both noted that improved uMRD in the study translated into superior PFS, raising the possibility that uMRD might be a valid alternative endpoint to PFS in CLL trials.

With “median remissions in CLL lasting far in excess of 5 years, designing studies that take 8-10 years” to reach a PFS endpoint is simply too slow. Moving to an alternative endpoint such a uMRD would preserve “the momentum that has been generated” with recent advances, Dr. Woyach and Dr. Byrd said.

The work was funded by the companies that market venetoclax, ibrutinib, and obinutuzumab: AbbVie, Janssen, and Roche. Dr. Eichhorst is a consultant and/or speaker for the companies and also reported grants from them. Dr. Byrd is a consultant/adviser for Eilean Therapeutics, Kurome Therapeutics, Newave, and Orbimed. Dr. Woyach disclosed ties with AbbVie, AstraZeneca, Lilly, and other companies.

Venetoclax combinations – especially a novel combination of venetoclax, ibrutinib, and obinutuzumab – outperform first-line chemoimmunotherapy for chronic lymphocytic leukemia in otherwise fit adults with few comorbidities, according to a phase 3 trial published in the New England Journal of Medicine.

The trial, dubbed GAIA–CLL13, “is a remarkable demonstration of the quality of fixed-duration therapies for younger, fit patients, and it challenges us to continue to work to develop therapeutic strategies that will ultimately cure patients with CLL,” two hematologic cancer specialists said in an accompanying editorial.

In short, “venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib were superior to chemoimmunotherapy with respect to both the minimal residual disease end point and progression-free survival, but venetoclax-rituximab was not,” Jennifer Woyach, MD, of Ohio State University, Columbus, and John Byrd, MD, University of Cincinnati, said in their commentary.

Noting that randomized trials involving venetoclax combinations in fit CLL patients “have been lacking,” the investigators compared 6 cycles of chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) with 12 cycles of venetoclax plus the anti-CD20 antibody rituximab, venetoclax plus the third generation anti-CD20 antibody obinutuzumab, and venetoclax combined with both obinutuzumab and the Bruton’s tyrosine kinase inhibitor ibrutinib in a novel triple-therapy regimen.

The 926 patients in the study were a mean of 61 years old and split about evenly among the four treatment arms. Ibrutinib was discontinued after two consecutive measurements if patients had undetectable minimal residual disease (uMRD). Subjects did not have TP53 aberrations, a marker of poor prognosis in CLL.

At 15 months, the percentage of patients with uMRD was significantly higher in the triple-therapy arm (92.2%) and the venetoclax-obinutuzumab group (86.5%) than in the chemoimmunotherapy group (52.0%), but there was no statistical difference with venetoclax-rituximab (57%, P = .32).

The three-year progression-free survival (PFS) was 90.5% in the triple-therapy arm versus 87.7% with venetoclax-obinutuzumab. The 3-year PFS with venetoclax-rituximab (80.8%) was again not statistically different than the 75.5% with chemoimmunotherapy (P = .18).
 

Not ready for prime time

The benefits of triple therapy and venetoclax-obinutuzumab held only in patients with unmutated IgVH. “The high efficacy of the fludarabine, cyclophosphamide, and rituximab regimen in young, fit patients with mutated IgVH may be difficult to improve on,” noted the investigators, led by Barbara Eichhorst, MD, a hematologic malignancy specialist at the University of Cologne (Germany).

Also, although triple-therapy results were impressive, some of the benefits “are neutralized by the need for dose reductions and early treatment discontinuation owing to adverse events,” they said.

For instance, triple therapy had the highest incidence of both grade 3 and 4 infections (21.2%) and atrial fibrillation (7.8%).

The editorialists noted that there has been “a flurry of interest” in trials combining ibrutinib and venetoclax – as was done in the triple-therapy arm – since both emerged as powerful tools against CLL in recent years. However, even with the study results, they said “the use of triplet therapy should be viewed as investigational.”

For one thing, rates of uMRD were not “dramatically different” between triple therapy and venetoclax-obinutuzumab, and longer follow-up is better gauge differences in PFS and long-term toxicities.

Also, ibrutinib is being eclipsed by the second-generation Bruton’s tyrosine kinase inhibitors acalabrutinib and zanubrutinib, because they have better safety profiles, and they are being assessed in CLL combination trials. For now, there are too many unknowns for routine use of triple therapy in fit CLL patients, they said.

The investigators and editorialists both noted that improved uMRD in the study translated into superior PFS, raising the possibility that uMRD might be a valid alternative endpoint to PFS in CLL trials.

With “median remissions in CLL lasting far in excess of 5 years, designing studies that take 8-10 years” to reach a PFS endpoint is simply too slow. Moving to an alternative endpoint such a uMRD would preserve “the momentum that has been generated” with recent advances, Dr. Woyach and Dr. Byrd said.

The work was funded by the companies that market venetoclax, ibrutinib, and obinutuzumab: AbbVie, Janssen, and Roche. Dr. Eichhorst is a consultant and/or speaker for the companies and also reported grants from them. Dr. Byrd is a consultant/adviser for Eilean Therapeutics, Kurome Therapeutics, Newave, and Orbimed. Dr. Woyach disclosed ties with AbbVie, AstraZeneca, Lilly, and other companies.

Venetoclax combinations – especially a novel combination of venetoclax, ibrutinib, and obinutuzumab – outperform first-line chemoimmunotherapy for chronic lymphocytic leukemia in otherwise fit adults with few comorbidities, according to a phase 3 trial published in the New England Journal of Medicine.

The trial, dubbed GAIA–CLL13, “is a remarkable demonstration of the quality of fixed-duration therapies for younger, fit patients, and it challenges us to continue to work to develop therapeutic strategies that will ultimately cure patients with CLL,” two hematologic cancer specialists said in an accompanying editorial.

In short, “venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib were superior to chemoimmunotherapy with respect to both the minimal residual disease end point and progression-free survival, but venetoclax-rituximab was not,” Jennifer Woyach, MD, of Ohio State University, Columbus, and John Byrd, MD, University of Cincinnati, said in their commentary.

Noting that randomized trials involving venetoclax combinations in fit CLL patients “have been lacking,” the investigators compared 6 cycles of chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) with 12 cycles of venetoclax plus the anti-CD20 antibody rituximab, venetoclax plus the third generation anti-CD20 antibody obinutuzumab, and venetoclax combined with both obinutuzumab and the Bruton’s tyrosine kinase inhibitor ibrutinib in a novel triple-therapy regimen.

The 926 patients in the study were a mean of 61 years old and split about evenly among the four treatment arms. Ibrutinib was discontinued after two consecutive measurements if patients had undetectable minimal residual disease (uMRD). Subjects did not have TP53 aberrations, a marker of poor prognosis in CLL.

At 15 months, the percentage of patients with uMRD was significantly higher in the triple-therapy arm (92.2%) and the venetoclax-obinutuzumab group (86.5%) than in the chemoimmunotherapy group (52.0%), but there was no statistical difference with venetoclax-rituximab (57%, P = .32).

The three-year progression-free survival (PFS) was 90.5% in the triple-therapy arm versus 87.7% with venetoclax-obinutuzumab. The 3-year PFS with venetoclax-rituximab (80.8%) was again not statistically different than the 75.5% with chemoimmunotherapy (P = .18).
 

Not ready for prime time

The benefits of triple therapy and venetoclax-obinutuzumab held only in patients with unmutated IgVH. “The high efficacy of the fludarabine, cyclophosphamide, and rituximab regimen in young, fit patients with mutated IgVH may be difficult to improve on,” noted the investigators, led by Barbara Eichhorst, MD, a hematologic malignancy specialist at the University of Cologne (Germany).

Also, although triple-therapy results were impressive, some of the benefits “are neutralized by the need for dose reductions and early treatment discontinuation owing to adverse events,” they said.

For instance, triple therapy had the highest incidence of both grade 3 and 4 infections (21.2%) and atrial fibrillation (7.8%).

The editorialists noted that there has been “a flurry of interest” in trials combining ibrutinib and venetoclax – as was done in the triple-therapy arm – since both emerged as powerful tools against CLL in recent years. However, even with the study results, they said “the use of triplet therapy should be viewed as investigational.”

For one thing, rates of uMRD were not “dramatically different” between triple therapy and venetoclax-obinutuzumab, and longer follow-up is better gauge differences in PFS and long-term toxicities.

Also, ibrutinib is being eclipsed by the second-generation Bruton’s tyrosine kinase inhibitors acalabrutinib and zanubrutinib, because they have better safety profiles, and they are being assessed in CLL combination trials. For now, there are too many unknowns for routine use of triple therapy in fit CLL patients, they said.

The investigators and editorialists both noted that improved uMRD in the study translated into superior PFS, raising the possibility that uMRD might be a valid alternative endpoint to PFS in CLL trials.

With “median remissions in CLL lasting far in excess of 5 years, designing studies that take 8-10 years” to reach a PFS endpoint is simply too slow. Moving to an alternative endpoint such a uMRD would preserve “the momentum that has been generated” with recent advances, Dr. Woyach and Dr. Byrd said.

The work was funded by the companies that market venetoclax, ibrutinib, and obinutuzumab: AbbVie, Janssen, and Roche. Dr. Eichhorst is a consultant and/or speaker for the companies and also reported grants from them. Dr. Byrd is a consultant/adviser for Eilean Therapeutics, Kurome Therapeutics, Newave, and Orbimed. Dr. Woyach disclosed ties with AbbVie, AstraZeneca, Lilly, and other companies.