Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer

Author(s): Javier Cortés, M.D., Ph.D., Sung-Bae Kim, M.D., Ph.D., Wei-Pang Chung, M.D., Seock-Ah Im, M.D., Ph.D., Yeon Hee Park, M.D., Ph.D., Roberto Hegg, M.D., Ph.D., Min Hwan Kim, M.D., Ph.D., Ling-Ming Tseng, M.D., Vanessa Petry, M.D., Chi-Feng Chung, M.D., Hiroji Iwata, M.D., Ph.D., Erika Hamilton, M.D., et al., for the DESTINY-Breast03 Trial Investigators*

Source: N Engl J Med 2022; 386:1143-1154 DOI: 10.1056/NEJMoa2115022

Dr. Lucio Gordan's Thoughts

Very robust improvement of response rate, progression-free survival and decreased risk of death with trastuzumab deruxtecan versus trastuzumab emtansine. Early detection, knowledge about management and pre-treatment risk assessment of pulmonary toxicities are of paramount importance.

ABSTRACT

BACKGROUND

Trastuzumab emtansine is the current standard treatment for patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer whose disease progresses after treatment with a combination of anti-HER2 antibodies and a taxane.

METHODS

We conducted a phase 3, multicenter, open-label, randomized trial to compare the efficacy and safety of trastuzumab deruxtecan (a HER2 antibody–drug conjugate) with those of trastuzumab emtansine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. The primary end point was progression-free survival (as determined by blinded independent central review); secondary end points included overall survival, objective response, and safety.

RESULTS

Among 524 randomly assigned patients, the percentage of those who were alive without disease progression at 12 months was 75.8% (95% confidence interval [CI], 69.8 to 80.7) with trastuzumab deruxtecan and 34.1% (95% CI, 27.7 to 40.5) with trastuzumab emtansine (hazard ratio for progression or death from any cause, 0.28; 95% CI, 0.22 to 0.37; P<0.001). The percentage of patients who were alive at 12 months was 94.1% (95% CI, 90.3 to 96.4) with trastuzumab deruxtecan and 85.9% (95% CI, 80.9 to 89.7) with trastuzumab emtansine (hazard ratio for death, 0.55; 95% CI, 0.36 to 0.86; prespecified significance boundary not reached). An overall response (a complete or partial response) occurred in 79.7% (95% CI, 74.3 to 84.4) of the patients who received trastuzumab deruxtecan and in 34.2% (95% CI, 28.5 to 40.3) of those who received trastuzumab emtansine. The incidence of drug-related adverse events of any grade was 98.1% with trastuzumab deruxtecan and 86.6% with trastuzumab emtansine, and the incidence of drug-related adverse events of grade 3 or 4 was 45.1% and 39.8%, respectively. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 10.5% of the patients in the trastuzumab deruxtecan group and in 1.9% of those in the trastuzumab emtansine group; none of these events were of grade 4 or 5.

CONCLUSIONS

Among patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane, the risk of disease progression or death was lower among those who received trastuzumab deruxtecan than among those who received trastuzumab emtansine. Treatment with trastuzumab deruxtecan was associated with interstitial lung disease and pneumonitis. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast03 ClinicalTrials.gov number.

Author Affiliations

From the International Breast Cancer Center, Quirónsalud Group, Barcelona, the Scientific Department, Medica Scientia Innovation Research, Valencia, and the Department of Medicine, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, Madrid — all in Spain (J. Cortés); Asan Medical Center, University of Ulsan College of Medicine, Ulsan (S.-B.K.), Seoul National University Hospital, Cancer Research Institute (S.-A.I.), and Seoul National University Bundang Hospital (J.H.K.), Seoul National University College of Medicine, and Samsung Medical Center (Y.H.P.), Seoul, and Severance Hospital, Yonsei University, Yonsei (M.H.K.) — all in South Korea; the Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan (W.-P.C.), and the Department of Surgery, Taipei Veterans General Hospital, College of Medicine, National Yang-Ming Chiao Tung University (L.-M.T.), Koo Foundation Sun Yat-Sen Cancer Center (C.-F.C.), and National Taiwan University Hospital and National Taiwan University College of Medicine (C.-S.H.), Taipei — all in Taiwan; Clínica de Pesquisas e Centro de Estudos em Oncologia Ginecológica e Mamária (R.H.) and Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira (V.P.), São Paulo, and Hospital Nossa Senhora da Conceição, Porto Alegre (J.L.P.) — all in Brazil; Aichi Cancer Center Hospital, Aichi, Japan (H.I.); Sarah Cannon Research Institute, Tennessee Oncology, Nashville (E.H.); the Department of Oncology and Hematology–Oncology, University of Milan, and the Division of Early Drug Development, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico — both in Milan (G.C.); the Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (B.X.); the University of Hong Kong, Hong Kong (J.W.Y.C.); Daiichi Sankyo, Basking Ridge, NJ (C.L., Y.L., J. Cathcart, E.B.); AstraZeneca, Gaithersburg, MD (S.V.); and the David Geffen School of Medicine and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles (S.A.H.).

Utility of the 70-Gene MammaPrint Assay for Prediction of Benefit From Extended Letrozole Therapy in the NRG Oncology/NSABP B-42 Trial

MammaPrint did not predict distant recurrence, but it did predict patients who may benefit from extended hormonal therapy. We do have breast index, so now we have options. Breast index can predict the possibility of recurrence though by helping to determine the level of risk.

Inavolisib-Based Therapy in PIK3CA-Mutated Advanced Breast Cancer

Adding Inavolisib to CKD4/6 inhibitor and AI improved progression-free survival (almost doubled 15 vs 7m) but toxicity was higher still in the single digits (hyperglycemia, diarrhea, stomatitis… all less than 6% G3/4).

Tailored Dose-Dense Versus Standard Adjuvant Chemotherapy for High-Risk Early Breast Cancer: End-of-Study Results of the Randomized PANTHER Trial

Well done study showing a 20% decrease in recurrence risk when using dose dense therapy [EC]/D compared to conventional dose [FEC]/D. Sometimes it is worth it to push.

Final Results of RIGHT Choice: Ribociclib Plus Endocrine Therapy Versus Combination Chemotherapy in Premenopausal Women With Clinically Aggressive Hormone Receptor–Positive/Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer

Myth busted. In aggressive breast cancer, no need to start chemotherapy now, ET and CKD4/6 inhibitors are better tolerated with significant progression-free survival (PFS) benefit and same response rate.

Phase III Randomized, Placebo-Controlled Clinical Trial of Donepezil for Treatment of Cognitive Impairment in Breast Cancer Survivors After Adjuvant Chemotherapy (WF-97116)

It seems donepezil did not show any cognitive benefit when added to standard adjuvant chemotherapy for breast cancer. Unfortunately, adequate treatment for ‘chemo-brain’ remains elusive. There is data that a lipid structure, S1P, may be linked to this process and may be ‘druggable’ with some of the MS agents.