Alexander Spira, MD, PhD, US Oncology Research, Virginia Cancer Specialists, Fairfax, Virginia, USA
Which advantages do antibody-drug conjugates (ADCs) offer over other treatment approaches?
Antibody-drug conjugates have opened up an entirely new paradigm. Targeted therapy requires specific mutations, and immunotherapy only works if the tumor expresses neoantigens or is essentially able to respond to these agents. As we know, these two approaches do not work forever, not every patient responds to them, and certainly not every patient has a targetable mutation. It is therefore nice to have something new and different. An ADC consists of an antibody, a linker that sits next to it, and the drug, which is usually chemotherapy-based. Therefore, in theory, they should show enhanced efficacy compared to mere antibodies such as trastuzumab or rituximab.
What may be shortcomings such as particular adverse events in comparison to other drug classes?
With ADCs, we need to get used to a new toxicity profile. ADCs are designed to be very specific. The chemotherapy part is internalized into the tumor cell, but systemic toxicity can emerge if leakage or spillage occurs. These toxicities typically include cytopenias and diarrhea. Moreover, specific events such as ocular toxicity are not uncommon depending on the type of antibody or linker. Several clinical trials are elucidating that. Also, many ADCs involve some pulmonary toxicity as this is a class effect. Pulmonary adverse events are rare but can be devastating.
Which emerging ADCs do you consider particularly promising for future routine use?
From my perspective, there are three drugs on which to put the focus that were also discussed at WCLC 2020. The Trop-2-directed ADC datopotamab deruxtecan is a very exciting and promising agent, because the transmembrane glycoprotein Trop-2 is a relatively new target. In the phase I TROPION-PanTumor01 study, datopotamab deruxtecan has shown highly encouraging antitumor activity with disease control rates of up to 80 % and a manageable safety profile in heavily pretreated NSCLC patients . Based on these insights, the randomized, phase III TROPION-Lung01 study is currently comparing datopotamab deruxtecan with docetaxel in patients with stage IIIB/IV NSCLC who have previously been treated with immunotherapy and platinum-based chemotherapy. Another Trop-2-directed ADC, sacituzumab govitecan, has already received FDA approval for the treatment of triple-negative breast cancer.
Moreover, the HER2-directed ADC trastuzumab deruxtecan has shown activity in HER2-overexpressing and HER2-mutated lung cancer in the phase II DESTINY-Lung01 trial [2, 3]. We are looking forward to the FDA approval of trastuzumab deruxtecan in this indication. Lastly, phase I data obtained in an EGFR-mutated population demonstrated antitumor activity of the HER3-directed ADC patritumab deruxtecan . These were patients who had received at least one EGFR inhibitor and at least one platinum-based chemotherapy regimen. Patritumab deruxtecan is currently being evaluated in the phase II HERTHENA-Lung01 trial after failure of EGFR TKI treatment and platinum-based chemotherapy. From my point of view, these are the three ADCs that might become game changers in the future.
Where do you see the ADC approach three years from now?
I think the ADCs I mentioned will receive FDA approval in the next months or years, as well as many others. Numerous ADCs are being developed in multiple tumor types. We are excited about this new technology as it is almost unlimited. Any antigen on the tumor surface can be targeted as long as it is not overly expressed on normal cells. In the management of breast cancer, the ADC technology has enabled the reinvention of an established HER2-targeted treatment. I was recently involved with phase I assessments in the field of leukemia and lymphoma, where we expect FDA approvals in the near future. Many tumor-specific antigens can be used for the design of ADCs against leukemia and lymphoma, but this also applies to solid tumors. The possibilities are almost endless.