Trastuzumab Deruxtecan Is Effective in HER2-Low Breast Cancer

Published OnlineFirst February 28, 2020; DOI: 10.1158/2159-8290.CD-RW2020-030

RESEARCH WATCH

Clinical Trials

Major Finding: The anti-HER2–drug con- Concept: Prior work hinted that T-DXd Impact: Studies to find predictors of jugate trastuzumab deruxtecan (T-DXd) may be effective even in HER2-low dis- serious side effects and a phase III was effective in HER2-low breast cancer. ease due to a bystander effect. clinical trial are now under way.

TRASTUZUMAB DERUXTECAN IS EFFECTIVE IN HER2-LOW BREAST CANCER Trastuzumab deruxtecan (T-DXd), a drug–antibody con- anemia—occurred in 53 patients (98%) and led to treatment dis- jugate that combines the HER2 antibody trastuzumab with continuation in 11 patients (20%). Notably, three patients (all the topoisomerase I inhibitor deruxtecan, is approved to in the cohort receiving the higher dose) died of effects deemed treat patients with HER2-positive breast cancer who have not to be due to study treatment, two of pneumonitis and one of responded to other HER2-targeted therapies. Counterintui- interstitial lung disease (ILD). Due to the greater potential for tively, preclinical studies have indicated that T-DXd may also adverse effects with the higher dose, the lower dose was recom- be effective against breast cancers with low overall HER2 expres- mended for further study, and predictors of drug-related ILD sion, possibly because the high payload of cell membrane–per- are currently being evaluated in other studies. Some limitations meable deruxtecan can affect low-HER2 cells neighboring those of this study include its small size, lack of randomization, and with higher HER2 expression, reﬂ ecting a bystander effect. In a lack of prospective evaluation of HER2 status. The results of ﬁ rst-in-human, nonrandomized, open-label, phase Ib clinical this early study demonstrate the potential value of T-DXd trial, Modi and colleagues investigated the use of T-DXd at two treatment in a patient population with poor prognosis and dose levels in 54 patients with advanced HER2-low breast can- few treatment options remaining, and a randomized, phase III cer. Patients had been heavily pretreated, with a median number clinical trial of T-DXd in patients with advanced HER2-negative of prior therapies of 7.5, and 10 patients (19%) had already breast cancer is now being conducted. ■ received HER2-targeted therapies. According to an independ- ent central review, all responses were partial, and the objective Modi S, Park H, Murthy RK, Iwata H, Tamura K, Tsurutani J, response rate was 37%, with the median duration of response et al. Antitumor activity and safety of trastuzumab deruxtecan in being 10.4 months. Treatment-emergent adverse events—most patients with HER2-low–expressing advanced breast cancer: Results commonly gastrointestinal disturbances, fatigue, alopecia, and from a phase Ib study. J Clin Oncol 2020 Feb 14 [Epub ahead of print].

Structural Biology

Major Finding: The structure of CD20 Concept: Cryo-electron microscopy Impact: This structure provides a with the antibody drug rituximab showed revealed a previously unrecognized sec- basis for further exploration of how the binding mode and 2:2 stoichiometry. ond epitope and Fab–Fab interactions. CD20 antibodies deplete B cells.

STRUCTURE OF CD20 BOUND TO RITUXIMAB REVEALS MECHANISTIC INFORMATION Multiple monoclonal antibodies targeting CD20, by light-chain residues and, based on the contact an integral membrane protein specifi c to B cells, surface area, likely contributed substantially to the are approved for the treatment of B-cell malignan- affi nity of rituximab for CD20. Fab–Fab interac- cies and autoimmune disorders. These therapies tions between the two rituximab molecules in each are effective because they result in B-cell deple- complex were facilitated by proximity between the tion, but there appear to be several mechanisms primary epitopes of each CD20 molecule, further of action, and a lack of high-resolution structural strengthening the tetrameric structure. Combined data on CD20 has hindered understanding of how with the results of some biochemical experiments, anti-CD20 therapies work at the molecular level. Rougé and these structural details explain why rituximab has such high colleagues used cryo-electron microscopy to determine the affi nity (in the nanomolar range) for CD20 despite its low structure of CD20 bound to the therapeutic antibody rituxi- affi nity for the primary epitope found on ECL2. Interestingly, mab at a resolution of 3.3 Å. Inspection of the structure molecular modeling of an assembly of CD20 and rituximab revealed that rituximab-bound CD20 existed as a dimer, molecules based on the structure revealed by this study sug- with each dimer being bound by two antigen-binding frag- gested how rituximab facilitates cell-surface CD20 clustering ments (Fab) from two separate rituximab molecules. Further and complement recruitment. In summary, this study pro- analysis of the structure showed that CD20 had a unique fold vides an unprecedented view into the structure of the thera- characterized by four tightly packed antiparallel transmem- peutic target CD20 and imparts hints about the mechanism brane helices and two extracellular loops (ECL), one of which of action of rituximab. ■ (ECL2) contained a highly solvent-accessible region that bears the epitope recognized by most CD20 antibodies. In addition Rougé L, Chiang N, Steffek M, Kugel C, Croll TI, Tam C, et al. to this known epitope on ECL2, the structure also contained Structure of CD20 in complex with the therapeutic monoclonal anti- a secondary epitope on ECL1, which was mainly recognized body rituximab. Science 2020 Feb 20 [Epub ahead of print].

488 | CANCER DISCOVERYAPRIL 2020 AACRJournals.org

Trastuzumab Deruxtecan Is Effective in HER2-Low Breast Cancer

Cancer Discov 2020;10:488. Published OnlineFirst February 28, 2020.

Updated version Access the most recent version of this article at: doi:10.1158/2159-8290.CD-RW2020-030

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