Ajay Dhakal, MBBS, assistant professor, Department of Medicine, Hematology/Oncology, the University of Rochester Medical Center, discusses the two key trials supporting the use of pertuzumab (Perjeta) as a standard-of-care regimen in HER2-positive breast cancer. 

In 2012, the dual anti-HER2 combination of pertuzumab plus trastuzumab (Herceptin) and chemotherapy gained FDA approval for the treatment of patients with metastatic HER2-positive breast cancer according to results from the phase 3 CLEOPATRA trial (NCT00567190), Dhakal begins. In the trial, pertuzumab in combination with trastuzumab (Herceptin) and docetaxel was compared with a placebo regimen in patients who previously received no more than one prior hormonal treatment. The regimen demonstrated a significant improvement in progression-free survival and overall survival in this patient population and helped establish pertuzumab as a standard frontline treatment for patients with metastatic HER2-positive breast cancer, Dhakal states.

Although pertuzumab was proven effective in the metastatic setting, its use in the adjuvant setting required further exploration, Dhakal continues. The phase 3 APHINITY trial (NCT01358877) compared pertuzumab in combination with standard-of-care (SOC) trastuzumab and chemotherapy vs trastuzumab and chemotherapy alone in the adjuvant setting. The regimen was evaluated in patients with node-positive or high-risk node-negative HER2-positive, operable breast cancer.

Results showed that the addition of pertuzumab to trastuzumab and chemotherapy significantly improved 3-year invasive disease-free survival in patients with node-positive HER2-positive breast cancer, Dhakal says. However, no statistically significant benefit was observed with the regimen in node-negative patients, he notes. Based on these results, pertuzumab plus trastuzumab and chemotherapy was subsequently approved for use in the adjuvant setting in 2017. This regimen has been incorporated into the adjuvant setting as a SOC for node-positive patients, Dhakal concludes.

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Ajay Dhakal, MBBS, discusses the two key trials supporting the use of pertuzumab as a standard-of-care regimen in HER2-positive breast cancer. 

Dr. Dhakal on the Evolution of Pertuzumab Regimens in HER2+ Breast Cancer

Ajay Dhakal, MBBS, assistant professor, Department of Medicine, Hematology/Oncology, the University of Rochester Medical Center, discusses the evolution and implementation of the antibody-drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (Enhertu) across the landscape of HER2-positive breast cancer landscape.

The recent success of trastuzumab deruxtecan in clinical trials, plus its FDA approvals in breast, lung, and gastric cancers, have made it the most notable ADC currently in the cancer treatment landscape, Dhakal notes. Within the breast cancer space, another indication was added with the

FDA approval of the ADC for the treatment of patients with unresectable or metastatic HER2-low breast cancer

The design of trastuzumab deruxtecan has led the way in the development of next-generation ADCs due to trastuzumab deruxtecan’s fundamental differences when compared with ado-trastuzumab emtansine (T-DM1; Kadcyla). Trastuzumab deruxtecan has a higher drug-to-antibody ratio compared with T-DM1, and trastuzumab deruxtecan has a unique cleavable linker. Once the ADC enters the cell, the cleavable linker does not have to wait for the cells to come in and dissolve the linker; instead, the linker easily detaches from the ADC, creating a bystander effect, Dhakal adds.

Trastuzumab deruxtecan’s superiority over T-DM1 in the second-line setting of HER2-positive metastatic breast cancer was demonstrated in the phase 3 DESTINY-Breast03 trial (NCT03529110). The multicenter, randomized, open-label study compared the antitumor activity, safety, and efficacy of trastuzumab deruxtecan vs T-DM1 in unresectable, metastatic HER2-positive breast cancers.

Trastuzumab deruxtecan significantly improved progression-free survival (PFS) vs T-DM1, with patients in the experimental arm experiencing a median PFS that was not yet reached, compared with 6.8 months in the control arm. These data led to the regular 

FDA approval of trastuzumab deruxtecan for adult patients with unresectable or metastatic HER2-positive breast cancer

 who have previously received an anti–HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting, Dhakal concludes.

Ajay Dhakal, MBBS, discusses the evolution and implementation of the antibody-drug conjugate trastuzumab deruxtecan across the landscape of HER2-positive breast cancer landscape.


Ajay Dhakal, MBBS

Articles

Dr. Dhakal on the Evolution of Pertuzumab Regimens in HER2+ Breast Cancer

Dr. Dhakal on the Implementation of Trastuzumab Deruxtecan Across the HER2+ Breast Cancer Landscape