Dr Bazhenova on the Optimal Positioning of ADCs in Lung Cancer

“I think what we are waiting to see is what’s going to happen in first line. We know the sac-TMT trial in first-line PD-L1 ≥1 [NSCLC] is positive. There are many other studies going on in the first line, and will they meet the required threshold? It remains to be seen.”

Lyudmila A. Bazhenova, MD, professor of medicine and at the UC San Diego Moores Cancer Center, UC San Diego Health, discussed the current state and future direction of antibody-drug conjugate (ADC) development in lung cancer, a topic covered in the Bridging the Gaps in Lung Cancer meeting.

Bazhenova noted that despite 3 ADCs already approved in lung cancer: datopotamab deruxtecan-dlnk (Datroway), fam-trastuzumab deruxtecan-nxki (Enhertu), and telisotuzumab vedotin-tllv (Emrelis), the field remains in its early stages, as these approvals were based on single-arm studies. She pointed out that among 5 subsequent randomized phase 3 trials, 4 evaluating agents against docetaxel in the second-line setting were negative, as was a phase 3 trial of a HER3-directed ADC in EGFR-mutant, TKI-resistant disease. By contrast, she noted that trials of sacituzumab tirumotecan (sac-TMT), a TROP2-directed ADC with a different payload and linker, have consistently returned positive results across multiple settings, including first-line, second-line post–EGFR TKI, and head-to-head against docetaxel.

Bazhenova suggested that these differing outcomes may reflect meaningful distinctions in ADC design, proposing that sac-TMT’s stronger payload and improved linker characteristics could help explain its more favorable trial results. She said the field is now awaiting first-line data more broadly, noting that while the sac-TMT trial in PD-L1–high patients was positive, several other first-line studies are ongoing and it remains unclear whether they will meet efficacy thresholds.

Bazhenova also raised tolerability as a key consideration, even for regimens that succeed on efficacy. She noted that carboplatin-pemetrexed is a relatively well-tolerated regimen, and that adding an ADC will likely increase toxicity, meaning it remains to be seen how these tradeoffs will be weighed in clinical practice.