Adjuvant trastuzumab for breast cancer: 6 months may suffice

Shortening the duration of adjuvant trastuzumab (Herceptin) therapy for early-stage HER2+ breast cancer from the current standard of 12 months to 6 months yields similar efficacy but halves the incidence of cardiac toxicity, the PERSEPHONE trial found.

“In 2005, trastuzumab was licensed with a standard of three weekly injections for 12 months, and this was the duration used empirically in pivotal registration studies,” lead study author Helena Earl, MD, professor of clinical cancer medicine at the University of Cambridge, England, said in a press briefing leading up to the annual meeting of the American Society of Clinical Oncology.

However, cardiac toxicity has been particularly problematic with this regimen. Furthermore, the Fin-HER trial, while small, suggested that only 9 weeks of adjuvant trastuzumab was possibly as efficacious (N Engl J Med. 2006 Feb;354[8]:809-20).

Dr. Earl and her coinvestigators enrolled in their phase 3 noninferiority, randomized, controlled trial 4,089 women with early-stage HER2+ breast cancer, randomizing them to either 6 months or 12 months of trastuzumab, mapped onto standard U.K. real-world practice.

The main findings showed that the 4-year rate of disease-free survival, the trial’s primary endpoint, was nearly 90% in both groups, with the absolute difference of just 0.4% falling well within the predefined 3% margin for noninferiority.

Moreover, the rate of stopping trastuzumab because of cardiotoxicity was half as high with the shorter-duration therapy; patients in that arm had more rapid recovery of cardiac function, too.

“The PERSEPHONE trial’s first results demonstrate that 6 months of adjuvant trastuzumab is noninferior to 12 months; 6 months, compared with 12 months, of treatment reduces cardiac and other toxicities and costs both to patients and health care systems,” Dr. Earl summarized. “We are confident [these results] will mark the first steps towards reduction of treatment duration for many women with HER2+ breast cancer.”

The investigators are still analyzing quality of life, patient-reported outcomes, and health economic data, she said. In addition, they are performing translational studies to look for biomarkers that may identify subgroups who fare better with one or the other duration of trastuzumab.

 

Will the standard change?

At present, the PERSEPHONE findings are not sufficient to change the existing standard of care of 12 months of adjuvant trastuzumab, according to Dr. Earl. “We need to be very careful and cautious about coming out at this point and saying, ‘Yes, 6 months is enough,’ ” she maintained. “At the moment, I do think we need to wait for longer follow-up and we need to take a real close look at the data. Changing from an established treatment that works is always going to be a very complex and very challenging thing to do.”

“Personally, I find the results quite compelling, and I think that it is likely that they will signal a shift even in the U.S. oncology community toward shorter duration of Herceptin adjuvant therapy,” commented Richard L. Schilsky, MD, FACP, FASCO, chief medical officer of ASCO and press briefing moderator. However, “we don’t have data yet on overall survival. Survival in this study is still relatively short for a breast cancer population, although patients with HER2+ disease oftentimes have a somewhat more aggressive course,” he noted. In addition, the ongoing translational studies will be critical to any decisions about changing the standard of care because some subgroups of patients will probably not fare as well with the shorter-duration therapy.

 

U.S. payers are unlikely to start covering only 6 months of trastuzumab unless the drug’s label is changed based on new data or clinical practice guidelines begin to endorse that shorter duration, according to Dr. Schilsky. “Until one of those things occurs, there is not really a rationale for a payer to mandate that a physician undertake a course of treatment that they may not think is in the patient’s best interest,” he elaborated.

As roughly 12% to 15% of women with early breast cancer have HER2+ disease, the PERSEPHONE findings could have considerable implications for treatment costs, noted Bruce E. Johnson, MD, FASCO, president of ASCO.

However, longer follow-up will be needed before any change to the standard is made, he agreed. “One has to be circumspect about how long you wait and how much more data one has before making a definitive statement. With 8% deaths and 12% recurrences, it may be a bit early to make a definite change in practice.”

While important, the more favorable safety of the 6-month therapy is not sufficient, according to Dr. Johnson, who is also a professor of medicine at the Dana-Farber Cancer Institute and a leader of the Dana-Farber/Harvard Cancer Center Lung Cancer Program, both in Boston. “In my opinion, the efficacy drives most of the therapeutic decision making. We are encouraged by this, and 5-year follow-up is certainly a reasonable initial step. But to be sure of the efficacy, you probably need a bit more time and a few more events,” he explained.

 

Study details

Patients enrolled in PERSEPHONE had stage Ia to IIIa breast cancer. They were randomized evenly to either 6 months (9 cycles) or 12 months (18 cycles) of adjuvant trastuzumab, given with or after completion of chemotherapy.

Main results showed that the 4-year rate of disease-free survival was 89.8% with 12 months of trastuzumab and 89.4% with 6 months of trastuzumab (hazard ratio, 1.07; P for noninferiority = .01), Dr. Earl reported.

Cardiotoxicity data for the trial population, previously reported (Br J Cancer. 2016 Dec 6;115[12]:1462-70), showed that the rate of stopping trastuzumab because of this adverse effect was 8% with the standard-duration therapy and 4% with the shorter-duration therapy (P less than .0001). Patients saw recovery of cardiac function after stopping the drug (P less than .0001), with more rapid recovery in the shorter-duration group (P = .02).

 

The group given 6 months of trastuzumab also had lower rates of grade 3 or 4 cough, fatigue, pain, chills, and palpitations, problems which patients reported were having an impact on their lives, Dr. Earl noted. “Perhaps more importantly, patients given 6 months of treatment will be able to return more quickly to their normal lives once their treatment is completed.”

Dr. Earl disclosed that she has a consulting or advisory role with Celgene, Pfizer, Roche, and AstraZeneca; receives travel, accommodations, or expenses, and receives honoraria from Pfizer, Daiichi Sankyo, Amgen, and AstraZeneca; and receives research funding from Roche and Sanofi Pasteur. The study was funded by the National Institute for Health Research in the United Kingdom.

SOURCE: Earl H et al. ASCO 2018, Abstract 506.

Shortening the duration of adjuvant trastuzumab (Herceptin) therapy for early-stage HER2+ breast cancer from the current standard of 12 months to 6 months yields similar efficacy but halves the incidence of cardiac toxicity, the PERSEPHONE trial found.

“In 2005, trastuzumab was licensed with a standard of three weekly injections for 12 months, and this was the duration used empirically in pivotal registration studies,” lead study author Helena Earl, MD, professor of clinical cancer medicine at the University of Cambridge, England, said in a press briefing leading up to the annual meeting of the American Society of Clinical Oncology.

However, cardiac toxicity has been particularly problematic with this regimen. Furthermore, the Fin-HER trial, while small, suggested that only 9 weeks of adjuvant trastuzumab was possibly as efficacious (N Engl J Med. 2006 Feb;354[8]:809-20).

Dr. Earl and her coinvestigators enrolled in their phase 3 noninferiority, randomized, controlled trial 4,089 women with early-stage HER2+ breast cancer, randomizing them to either 6 months or 12 months of trastuzumab, mapped onto standard U.K. real-world practice.

The main findings showed that the 4-year rate of disease-free survival, the trial’s primary endpoint, was nearly 90% in both groups, with the absolute difference of just 0.4% falling well within the predefined 3% margin for noninferiority.

Moreover, the rate of stopping trastuzumab because of cardiotoxicity was half as high with the shorter-duration therapy; patients in that arm had more rapid recovery of cardiac function, too.

“The PERSEPHONE trial’s first results demonstrate that 6 months of adjuvant trastuzumab is noninferior to 12 months; 6 months, compared with 12 months, of treatment reduces cardiac and other toxicities and costs both to patients and health care systems,” Dr. Earl summarized. “We are confident [these results] will mark the first steps towards reduction of treatment duration for many women with HER2+ breast cancer.”

The investigators are still analyzing quality of life, patient-reported outcomes, and health economic data, she said. In addition, they are performing translational studies to look for biomarkers that may identify subgroups who fare better with one or the other duration of trastuzumab.

 

Will the standard change?

At present, the PERSEPHONE findings are not sufficient to change the existing standard of care of 12 months of adjuvant trastuzumab, according to Dr. Earl. “We need to be very careful and cautious about coming out at this point and saying, ‘Yes, 6 months is enough,’ ” she maintained. “At the moment, I do think we need to wait for longer follow-up and we need to take a real close look at the data. Changing from an established treatment that works is always going to be a very complex and very challenging thing to do.”

“Personally, I find the results quite compelling, and I think that it is likely that they will signal a shift even in the U.S. oncology community toward shorter duration of Herceptin adjuvant therapy,” commented Richard L. Schilsky, MD, FACP, FASCO, chief medical officer of ASCO and press briefing moderator. However, “we don’t have data yet on overall survival. Survival in this study is still relatively short for a breast cancer population, although patients with HER2+ disease oftentimes have a somewhat more aggressive course,” he noted. In addition, the ongoing translational studies will be critical to any decisions about changing the standard of care because some subgroups of patients will probably not fare as well with the shorter-duration therapy.

 

U.S. payers are unlikely to start covering only 6 months of trastuzumab unless the drug’s label is changed based on new data or clinical practice guidelines begin to endorse that shorter duration, according to Dr. Schilsky. “Until one of those things occurs, there is not really a rationale for a payer to mandate that a physician undertake a course of treatment that they may not think is in the patient’s best interest,” he elaborated.

As roughly 12% to 15% of women with early breast cancer have HER2+ disease, the PERSEPHONE findings could have considerable implications for treatment costs, noted Bruce E. Johnson, MD, FASCO, president of ASCO.

However, longer follow-up will be needed before any change to the standard is made, he agreed. “One has to be circumspect about how long you wait and how much more data one has before making a definitive statement. With 8% deaths and 12% recurrences, it may be a bit early to make a definite change in practice.”

While important, the more favorable safety of the 6-month therapy is not sufficient, according to Dr. Johnson, who is also a professor of medicine at the Dana-Farber Cancer Institute and a leader of the Dana-Farber/Harvard Cancer Center Lung Cancer Program, both in Boston. “In my opinion, the efficacy drives most of the therapeutic decision making. We are encouraged by this, and 5-year follow-up is certainly a reasonable initial step. But to be sure of the efficacy, you probably need a bit more time and a few more events,” he explained.

 

Study details

Patients enrolled in PERSEPHONE had stage Ia to IIIa breast cancer. They were randomized evenly to either 6 months (9 cycles) or 12 months (18 cycles) of adjuvant trastuzumab, given with or after completion of chemotherapy.

Main results showed that the 4-year rate of disease-free survival was 89.8% with 12 months of trastuzumab and 89.4% with 6 months of trastuzumab (hazard ratio, 1.07; P for noninferiority = .01), Dr. Earl reported.

Cardiotoxicity data for the trial population, previously reported (Br J Cancer. 2016 Dec 6;115[12]:1462-70), showed that the rate of stopping trastuzumab because of this adverse effect was 8% with the standard-duration therapy and 4% with the shorter-duration therapy (P less than .0001). Patients saw recovery of cardiac function after stopping the drug (P less than .0001), with more rapid recovery in the shorter-duration group (P = .02).

 

The group given 6 months of trastuzumab also had lower rates of grade 3 or 4 cough, fatigue, pain, chills, and palpitations, problems which patients reported were having an impact on their lives, Dr. Earl noted. “Perhaps more importantly, patients given 6 months of treatment will be able to return more quickly to their normal lives once their treatment is completed.”

Dr. Earl disclosed that she has a consulting or advisory role with Celgene, Pfizer, Roche, and AstraZeneca; receives travel, accommodations, or expenses, and receives honoraria from Pfizer, Daiichi Sankyo, Amgen, and AstraZeneca; and receives research funding from Roche and Sanofi Pasteur. The study was funded by the National Institute for Health Research in the United Kingdom.

SOURCE: Earl H et al. ASCO 2018, Abstract 506.

Shortening the duration of adjuvant trastuzumab (Herceptin) therapy for early-stage HER2+ breast cancer from the current standard of 12 months to 6 months yields similar efficacy but halves the incidence of cardiac toxicity, the PERSEPHONE trial found.

“In 2005, trastuzumab was licensed with a standard of three weekly injections for 12 months, and this was the duration used empirically in pivotal registration studies,” lead study author Helena Earl, MD, professor of clinical cancer medicine at the University of Cambridge, England, said in a press briefing leading up to the annual meeting of the American Society of Clinical Oncology.

However, cardiac toxicity has been particularly problematic with this regimen. Furthermore, the Fin-HER trial, while small, suggested that only 9 weeks of adjuvant trastuzumab was possibly as efficacious (N Engl J Med. 2006 Feb;354[8]:809-20).

Dr. Earl and her coinvestigators enrolled in their phase 3 noninferiority, randomized, controlled trial 4,089 women with early-stage HER2+ breast cancer, randomizing them to either 6 months or 12 months of trastuzumab, mapped onto standard U.K. real-world practice.

The main findings showed that the 4-year rate of disease-free survival, the trial’s primary endpoint, was nearly 90% in both groups, with the absolute difference of just 0.4% falling well within the predefined 3% margin for noninferiority.

Moreover, the rate of stopping trastuzumab because of cardiotoxicity was half as high with the shorter-duration therapy; patients in that arm had more rapid recovery of cardiac function, too.

“The PERSEPHONE trial’s first results demonstrate that 6 months of adjuvant trastuzumab is noninferior to 12 months; 6 months, compared with 12 months, of treatment reduces cardiac and other toxicities and costs both to patients and health care systems,” Dr. Earl summarized. “We are confident [these results] will mark the first steps towards reduction of treatment duration for many women with HER2+ breast cancer.”

The investigators are still analyzing quality of life, patient-reported outcomes, and health economic data, she said. In addition, they are performing translational studies to look for biomarkers that may identify subgroups who fare better with one or the other duration of trastuzumab.

 

Will the standard change?

At present, the PERSEPHONE findings are not sufficient to change the existing standard of care of 12 months of adjuvant trastuzumab, according to Dr. Earl. “We need to be very careful and cautious about coming out at this point and saying, ‘Yes, 6 months is enough,’ ” she maintained. “At the moment, I do think we need to wait for longer follow-up and we need to take a real close look at the data. Changing from an established treatment that works is always going to be a very complex and very challenging thing to do.”

“Personally, I find the results quite compelling, and I think that it is likely that they will signal a shift even in the U.S. oncology community toward shorter duration of Herceptin adjuvant therapy,” commented Richard L. Schilsky, MD, FACP, FASCO, chief medical officer of ASCO and press briefing moderator. However, “we don’t have data yet on overall survival. Survival in this study is still relatively short for a breast cancer population, although patients with HER2+ disease oftentimes have a somewhat more aggressive course,” he noted. In addition, the ongoing translational studies will be critical to any decisions about changing the standard of care because some subgroups of patients will probably not fare as well with the shorter-duration therapy.

 

U.S. payers are unlikely to start covering only 6 months of trastuzumab unless the drug’s label is changed based on new data or clinical practice guidelines begin to endorse that shorter duration, according to Dr. Schilsky. “Until one of those things occurs, there is not really a rationale for a payer to mandate that a physician undertake a course of treatment that they may not think is in the patient’s best interest,” he elaborated.

As roughly 12% to 15% of women with early breast cancer have HER2+ disease, the PERSEPHONE findings could have considerable implications for treatment costs, noted Bruce E. Johnson, MD, FASCO, president of ASCO.

However, longer follow-up will be needed before any change to the standard is made, he agreed. “One has to be circumspect about how long you wait and how much more data one has before making a definitive statement. With 8% deaths and 12% recurrences, it may be a bit early to make a definite change in practice.”

While important, the more favorable safety of the 6-month therapy is not sufficient, according to Dr. Johnson, who is also a professor of medicine at the Dana-Farber Cancer Institute and a leader of the Dana-Farber/Harvard Cancer Center Lung Cancer Program, both in Boston. “In my opinion, the efficacy drives most of the therapeutic decision making. We are encouraged by this, and 5-year follow-up is certainly a reasonable initial step. But to be sure of the efficacy, you probably need a bit more time and a few more events,” he explained.

 

Study details

Patients enrolled in PERSEPHONE had stage Ia to IIIa breast cancer. They were randomized evenly to either 6 months (9 cycles) or 12 months (18 cycles) of adjuvant trastuzumab, given with or after completion of chemotherapy.

Main results showed that the 4-year rate of disease-free survival was 89.8% with 12 months of trastuzumab and 89.4% with 6 months of trastuzumab (hazard ratio, 1.07; P for noninferiority = .01), Dr. Earl reported.

Cardiotoxicity data for the trial population, previously reported (Br J Cancer. 2016 Dec 6;115[12]:1462-70), showed that the rate of stopping trastuzumab because of this adverse effect was 8% with the standard-duration therapy and 4% with the shorter-duration therapy (P less than .0001). Patients saw recovery of cardiac function after stopping the drug (P less than .0001), with more rapid recovery in the shorter-duration group (P = .02).

 

The group given 6 months of trastuzumab also had lower rates of grade 3 or 4 cough, fatigue, pain, chills, and palpitations, problems which patients reported were having an impact on their lives, Dr. Earl noted. “Perhaps more importantly, patients given 6 months of treatment will be able to return more quickly to their normal lives once their treatment is completed.”

Dr. Earl disclosed that she has a consulting or advisory role with Celgene, Pfizer, Roche, and AstraZeneca; receives travel, accommodations, or expenses, and receives honoraria from Pfizer, Daiichi Sankyo, Amgen, and AstraZeneca; and receives research funding from Roche and Sanofi Pasteur. The study was funded by the National Institute for Health Research in the United Kingdom.

SOURCE: Earl H et al. ASCO 2018, Abstract 506.