Claudine Isaacs, MD is Professor of Medicine and Oncology and Associate Director for Clinical Research at the Lombardi Comprehensive Cancer Center.

Issacs

"It's really important for us to try [to] figure out who we think we should be [receiving first-line T-DXd plus pertuzumab] because this treatment is certainly associated with greater potential toxicity. We need to balance the risks and benefits and try to sort out amongst ourselves where we think this really fits in today's paradigm of treatment."

Claudine Isaacs, MD, professor of medicine and oncology and co-director of the Breast Cancer Program at Georgetown Lombardi Comprehensive Cancer Center, emphasized the importance of establishing consensus on how to integrate data from the phase 3 DESTINY-Breast09 trial (NCT04784715) into clinical practice for patients with HER2-positive metastatic breast cancer.

DESTINY-Breast09 evaluated fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) plus pertuzumab (Perjeta) vs a taxane, trastuzumab (Herceptin), and pertuzumab (THP) in the first-line setting for patients with advanced HER2-positive breast cancer. Data demonstrated a progression-free survival (PFS) benefit favoring the T-DXd–based regimen (HR, 0.56; 95% CI, 0.44-0.71; 

 <.00001). Patients treated with T-DXd plus pertuzumab (n = 383) experienced a median PFS of 40.7 months (95% CI, 36.5-not calculable [NC]) per blinded independent central review compared with 26.9 months (95% CI, 21.8-NC) among those who received THP (n = 387).

Although these results suggest that this antibody-drug conjugate–based treatment may improve frontline outcomes, Isaacs noted that the regimen’s toxicity profile, particularly the risk of interstitial lung disease (ILD), may complicate broad application. In DESTINY-Breast09, treatment-emergent adverse effects led to any dose interruptions and any dose reductions in 68.8% and 45.9% of patients, respectively, in the T-DXd/pertuzumab arm. These respective rates were 49.0% and 19.9% in the THP arm. However, the rates of TEAEs leading to any treatment discontinuation were 20.7% in the experimental arm vs 28.3% in the control arm.

According to Isaacs, despite the efficacy observed, the clinical community must carefully determine in which patients this approach offers a favorable risk-benefit ratio. T-DXd carries greater potential toxicity relative to existing standards, and its introduction earlier in the treatment paradigm requires further consensus on optimal patient selection. Patients with preexisting pulmonary risk or limited ability to undergo regular monitoring may not be ideal candidates for frontline T-DXd–based therapy.

Videos

Claudine Isaacs, MD, discusses how to integrate data from the phase 3 DESTINY-Breast09 trial into the HER2-positive metastatic breast cancer paradigm. 

Dr Isaacs on Establishing Consensus on DESTINY-Breast09 Data in HER2+ Metastatic Breast Cancer

Claudine Isaacs, MD, professor, medical director, Fisher Center for Familial Cancer Research, co-director, Breast Cancer Program, Lombardi Comprehensive Cancer Center at Georgetown University, discusses the rapidly evolving HER2-positive breast cancer armamentarium.

In recent years, significant advances ​have been made across breast cancer subtypes, says Isaacs. ​The field of HER2-positive breast cancer, in particular, has gained a number of regulatory approvals.

For example, the ​phase 2 HER2CLIMB trial randomized patients with HER2-positive metastatic breast cancer who were previously treated with trastuzumab (Herceptin), pertuzumab (Perjeta), and ​ado-trastuzumab emtansine (T-DM1; Kadcyla) to receive tucatinib (Tukysa) or placebo, in combination with trastuzumab and capecitabine.

Data from HER2CLIMB showed prolong​ed progression-free survival ​and overall survival ​with the tucatinib-based regimen versus placebo, says Isaacs.

​These findings led to the April 2020 approval of tucatinib ​in combination with trastuzumab/capecitabine for the treatment of patients with unresectable locally advanced or metastatic HER2-positive breast cancer, Isaacs concludes.

Claudine Isaacs, MD, discusses the rapidly evolving HER2-positive breast cancer armamentarium.

 Dr. Isaacs on the Evolving Treatment Landscape in HER2+ Breast Cancer 

Claudine Isaacs, MD, professor, medical director, Fisher Center for Familial Cancer Research, co-director, Breast Cancer Program, Georgetown University/Lombardi Cancer Center, discusses antibody drug conjugates (ADCs) in the treatment of patients with triple-negative breast cancer (TNBC).

Isaacs predicts that a breakthrough is imminent in the treatment of TNBC, with positive data from phase II trials now being studied in phase III trials. ADCs target an antigen that is present in a fair proportion of patients with TNBC, and results are indicating benefit in heavily pre-treated patients with metastatic disease.

The ADC sacituzumab govitecan (IMMU-132) targets TROP-2, which is an antigen present in a significant proportion of patients with TNBC. In a recent study of 110 patients, treatment with sacituzumab govitecan elicited an objective response rate of 34% in patients with heavily pretreated metastatic TNBC.

Claudine Isaacs, MD, professor, medical director, Fisher Center for Familial Cancer Research, co-director, Breast Cancer Program, Georgetown University/Lombardi Cancer Center, discusses antibody drug conjugates in the treatment of patients with triple-negative breast cancer.
 

Dr. Isaacs Discusses Antibody Drug Conjugates in TNBC

Claudine Isaacs, MD, professor, medical director, Fisher Center for Familial Cancer Research, co-director, Breast Cancer Program, Georgetown University/Lombardi Cancer Center, discusses the future of treatment for patients with HER2-positive breast cancer.

There are a number of new drugs on the horizon for the treatment of patients with HER2-positive breast cancer. The landscape has undergone a dramatic change in the past few years with the data with pertuzumab (Perjeta) in first-line, the CLEOPATRA study, and the data on ado-trastuzumab emtansine (T-DM1; Kadcyla) in the second-line setting, says Isaacs.

Patients were doing well for so long, that clinical trial accruement was somewhat of a challenge, Isaacs says. However, there are a lot of exciting agents and combinations on the horizon, such as tucatinib (ONT-380), which may have the ability to penetrate the blood-brain barrier in patients with HER2-positive breast cancer. Additionally, there is interest in looking at immunotherapy with HER2-targeted therapies, as well as CDK4/6 inhibitors in combination with HER2-targeted therapies.

Claudine Isaacs, MD, professor, medical director, Fisher Center for Familial Cancer Research, co-director, Breast Cancer Program, Georgetown University/Lombardi Cancer Center, discusses the future of treatment for patients with HER2-positive breast cancer.
 

Dr. Isaacs Discusses the Future of Treatment for HER2+ Breast Cancer

Claudine Isaacs, MD, professor, medical director, Fisher Center for Familial Cancer Research, co-director, Breast Cancer Program, Georgetown University/Lombardi Cancer Center, discusses sacituzumab govitecan (IMMU-132) for the treatment of patients with triple-negative breast cancer (TNBC). 

Sacituzumab govitecan targets TROP-2, which is an antigen present in a significant proportion of patients with TNBC. It is bound to a fairly toxic chemotherapy, Isaacs says, which is the active metabolite of irinotecan, SN-38. This is linked with a humanized IgG antibody targeted against TROP-2, a cell-surface glycoprotein that is expressed in more than 90% of TNBC.

In a recent study, treatment with sacituzumab govitecan elicited an objective response rate (ORR) of 34% in patients with heavily pretreated metastatic TNBC. In this 110-patient single-arm trial, the ORR was accompanied by stable disease for ≥6 months in 11% of patients, for an overall disease control rate of 45%.

In February 2016, the FDA granted a breakthrough therapy designation to sacituzumab govitecan as a treatment for TNBC following at least 2 treatments for metastatic disease. Discussion regarding a biologics license application are currently ongoing.

Claudine Isaacs, MD, professor, medical director, Fisher Center for Familial Cancer Research, co-director, Breast Cancer Program, Georgetown University/Lombardi Cancer Center, discusses sacituzumab govitecan (IMMU-132) for the treatment of patients with triple-negative breast cancer. 
 

Dr. Isaacs Discusses Sacituzumab Govitecan in TNBC

Claudine Isaacs, MD, professor, medical director, Fisher Center for Familial Cancer Research, co-director, Breast Cancer Program, Georgetown University/Lombardi Cancer Center, discusses the role of neratinib (Nerlynx) in the treatment landscape of HER2-positive breast cancer.

In July 2017, the FDA approved neratinib for the extended adjuvant treatment of patients with early stage, HER2-positive breast cancer following postoperative trastuzumab (Herceptin). The approval followed a 12-4 recommendation from the FDA’s Oncologic Drugs Advisory Committee, which was based on data from the phase III ExteNET trial and the phase II CONTROL trial.

The invasive disease-free survival rate in ExteNET at 2 years was 94.2% with neratinib versus 91.9% with placebo. The results indicated that the benefit may vary based on hormone receptor status. An exploratory subgroup analysis indicated that neratinib lowered the risk of recurrence by 51% (HR, 0.49; 95% CI, 0.31-0.75) in HR-positive patients, compared with 7% in HR-negative patients (HR, 0.93; 95% CI, 0.60-1.43).

Although the data with neratinib was impressive, Isaacs says that clinicians are not sure how to position the agent in the treatment regimen.

Claudine Isaacs, MD, professor, medical director, Fisher Center for Familial Cancer Research, co-director, Breast Cancer Program, Georgetown University/Lombardi Cancer Center, discusses the role of neratinib (Nerlynx) in the treatment landscape of HER2-positive breast cancer.
 

Dr. Isaacs Discusses the Role of Neratinib in HER2+ Breast Cancer

Claudine Isaacs, MD, professor, medical director, Fisher Center for Familial Cancer Research, co-director, Breast Cancer Program, Georgetown University/Lombardi Cancer Center, discusses the importance of genetic counseling and the role of the genetic counselor.

Isaacs says in her mind, genetic counseling has always been an important part of genetic testing. Genetic counselors spend time with patients in order to obtain thorough family history and identify a hereditary predisposition for cancer.

Genetic counselors also discuss the implications of genetic tests with patients and family members and may have greater knowledge about the different tests available, Isaacs says. Genetic counselors are also on the forefront of any updates on reclassifications of genetic tests.

Claudine Isaacs, MD, professor, medical director, Fisher Center for Familial Cancer Research, co-director, Breast Cancer Program, Georgetown University/Lombardi Cancer Center, discusses the importance of genetic counseling and the role of the genetic counselor

Claudine Isaacs, MD

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