Sara M. Tolaney, MD, MPH

Sara M. Tolaney, MD, MPH, associate director of the Susan F. Smith Center for Women’s Cancers; director of Clinical Trials, Breast Oncology; and senior physician at Dana-Farber Cancer Institute, as well as an assistant professor of medicine at Harvard Medical School, discusses appropriately de-escalating treatment to reduce toxicities in stage I HER2-positive breast cancer.

One of the questions that arises with the use of HER2-targeted therapies is: Can therapy be appropriately de-escalated for patients who may be at lower clinical risk? Some pivotal trials focus on de-escalation strategies, specifically in patients with stage I HER2-positive disease. Previous data from the phase 2 APT trial suggest that patients with stage I HER2-positive cancers can have good outcomes with paclitaxel and trastuzumab (Herceptin). However, that is still a chemotherapy-based regimen that is associated with risks of neuropathy and alopecia. There has been interest in determining whether toxicities can be further reduced, adds Tolaney.

19th Annual International Congress on the Future of Breast Cancer® East

 is the ATEMPT trial, which looked at administering 1 year of T-DM1 to patients with stage I HER2-positive disease. Patients were randomized to either T-DM1 or to the paclitaxel/trastuzumab regimen, as was administered in the APT trial. The ATEMPT trial did demonstrate that 1 year of T-DM1 was associated with a 3-year disease-free survival rate of 97.7%. The trial was then randomized to compare toxicities between the 2 arms. Higher rates of neutropenia, infusion reactions, alopecia, and neuropathy were seen with trastuzumab and paclitaxel, whereas with T-DM1, there were higher rates of thrombocytopenia and liver function abnormalities, concludes Tolaney.

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Sara M. Tolaney, MD, MPH, discusses appropriately deescalating treatment to reduce toxicities in stage I HER2-positive breast cancer.

Dr. Tolaney on Deescalating Therapy in Stage I HER2+ Breast Cancer

Sara M. Tolaney, MD, MPH, associate director of the Susan F. Smith Center for Women’s Cancers; director of Clinical Trials, Breast Oncology; senior physician at Dana-Farber Cancer Institute; and assistant professor of medicine at Harvard Medical School, discusses the unmet need with regard to effectively preventing central nervous system (CNS) recurrence in HER2-positive breast cancer.

In the early disease setting, the field continues to do a better job of curing patients with HER2-positive disease, with the addition of pertuzumab (Perjeta), T-DM1 (ado-trastuzumab emtansine; Kadcyla), and sometimes neratinib (Nerlyx), says Tolaney. However, despite these advances, some patients still recur after these treatments. Interestingly, in the phase 3 KATHERINE study, 5% of disease-free survival events observed were CNS recurrences, notes Tolaney. In fact, no benefit with T-DM1 over trastuzumab was observed with regard to preventing those recurrences.

The field is left with the unmet need of trying to decrease CNS recurrences, and it begs the question of how that need can be addressed. Some have hypothesized that using a TKI, such as tucatinib (Tukysa), could potentially address this need, based on the activity observed with the agent in the metastatic setting, says Tolaney.

To this end, an arm in the COMPASS trial is enrolling patients with residual disease after preoperative HER2-directed therapy and randomizing them to receive T-DM1 or T-DM1 with tuctanib. It will be interesting to know whether the addition of tucatinib will help improve overall events and decrease rates of CNS recurrence in patients with HER2-positive disease, concludes Tolaney.

Sara M. Tolaney, MD, MPH, discusses the unmet need with regard to effectively preventing central nervous system recurrence in HER2-positive breast cancer.

Dr. Tolaney on CNS Recurrence in HER2+ Breast Cancer

Sara M. Tolaney, MD, MPH, associate director of the Susan F. Smith Center for Women’s Cancers; director of Clinical Trials, Breast Oncology; senior physician at Dana-Farber Cancer Institute; and assistant professor of medicine at Harvard Medical School, discusses the unmet need with regard to effectively preventing central nervous system (CNS) recurrence in HER2-positive breast cancer.

In the early disease setting, the field continues to do a better job of curing patients with HER2-positive disease, with the addition of pertuzumab (Perjeta), T-DM1 (ado-trastuzumab emtansine; Kadcyla), and sometimes neratinib (Nerlyx), says Tolaney. However, despite these advances, some patients still recur after these treatments. Interestingly, in the phase 3 KATHERINE study, 5% of disease-free survival events observed were CNS recurrences, notes Tolaney. In fact, no benefit with T-DM1 over trastuzumab was observed with regard to preventing those recurrences.

The field is left with the unmet need of trying to decrease CNS recurrences, and it begs the question of how that need can be addressed. Some have hypothesized that using a TKI, such as tucatinib (Tukysa), could potentially address this need, based on the activity observed with the agent in the metastatic setting, says Tolaney.

To this end, an arm in the COMPASS trial is enrolling patients with residual disease after preoperative HER2-directed therapy and randomizing them to receive T-DM1 or T-DM1 with tuctanib. It will be interesting to know whether the addition of tucatinib will help improve overall events and decrease rates of CNS recurrence in patients with HER2-positive disease, concludes Tolaney.

Sara M. Tolaney, MD, MPH, discusses the unmet need with regard to effectively preventing central nervous system recurrence in HER2-positive breast cancer.

Sara M. Tolaney, MD, MPH, associate director of the Susan F. Smith’s Center for Women’s Cancers, director of Clinical Trials, Breast Oncology, senior physician at Dana-Farber Cancer Institute, and assistant professor of medicine at Harvard Medical School, discusses sequencing strategies in metastatic HER2-positive breast cancer.

On December 20 2019, the FDA granted an accelerated approval to fam-trastuzumab deruxtecan-nxki (DS-8201; Enhertu) for patients with unresectable or metastatic HER2-positive breast cancer who have received at least 2 prior anti—HER2-based regimens in the metastatic setting.

More recently, on April 17 2020, the FDA approved tucatinib (Tukysa) in combination with trastuzumab (Herceptin) and capecitabine (Xeloda) for the same patient population who have received at least 1 prior anti—HER2-based therapy in the metastatic setting. The approval, which is based on data from the phase 2 HER2CLIMB trial, is also indicated for patients with brain metastases.

Both regimens can be considered for patients who received prior docetaxel, trastuzumab, and pertuzumab (Perjeta) in the frontline setting and ado-trastuzumab emtansine (T-DM1; Kadcyla) in the second-line setting, says Tolaney.

Patients with brain metastases should receive the tucatinib-based regimen, explains Tolaney. Unlike the phase 2 HER2CLIMB trial which included patients with progressive or untreated brain metastases, the phase 2 DESTINY-Breast01 trial with trastuzumab deruxtecan limited enrollment to a small number of patients with stable and treated brain metastases, explains Tolaney.

If patients progress on either third-line option, the alternative regimen can be implemented as a fourth-line therapy, concludes Tolaney.

Sara M. Tolaney, MD, MPH, discusses sequencing strategies in metastatic HER2-positive breast cancer.

Author | Sara M. Tolaney, MD, MPH

Articles

Dr. Tolaney on Deescalating Therapy in Stage I HER2+ Breast Cancer

Dr. Tolaney on CNS Recurrence in HER2+ Breast Cancer

Dr. Tolaney on CNS Recurrence in HER2+ Breast Cancer

Dr. Tolaney on Sequencing Strategies in Metastatic HER2+ Breast Cancer