Cross Currents: ADCs After EGFR TKI Progression in EGFR-Mutated NSCLC

"Because the toxicity exists, I see the ADC as a delivery system of the chemotherapy. So it’s not chemo-free."

In a 3-part video series recorded at the 2026 ESMO Congress, Li Zhang, MD, a professor in the Department of Medical Oncology and deputy director of the Lung Cancer Research Center at Sun Yat-sen University Cancer Center, discussed the role of antibody-drug conjugates (ADCs) for patients with EGFR-mutated non–small cell lung cancer (NSCLC) whose disease has progressed on EGFR tyrosine kinase inhibitors (TKIs), focusing on sacituzumab tirumotecan (sac-TMT) and izalontamab brengitecan (iza-bren).

The discussion is part of Cross Currents: Where East Meets West in Cancer Care, a video series produced through a collaboration between OncLive and China-based digital health platform DXY. In Cross Currents, oncologists from the United States and China compare clinical practice in their regions and discuss key data from major meetings.

At the 2026 ESMO Congress, Zhang and colleagues presented results from 2 phase 3 trials in this setting. In OptiTROP-Lung04, sac-TMT, a TROP2-directed ADC, improved overall survival (OS) versus pemetrexed plus platinum chemotherapy in 376 patients whose disease progressed after EGFR TKI therapy. At a median follow-up of 32.3 months, the median OS was 25.9 versus 17.4 months (HR, 0.69; 95% CI, 0.54-0.89; 1-sided P = .0021).

In PANKU-Lung01 (NCT06382116), for which Zhang was the presenting author, iza-bren, a bispecific EGFR × HER3 ADC, improved median progression-free survival (PFS) by blinded independent central review versus platinum-based chemotherapy in 432 patients whose disease progressed on a third-generation EGFR TKI (11.1 vs 5.7 months; HR, 0.40; 95% CI, 0.31-0.51; 1-sided P < .0001).

In the PANKU-Lung01 analysis, the objective response rate (ORR) was 60.2% versus 34.5%, the median duration of response was 10.4 versus 5.7 months, and OS data were immature. Grade 3 or higher treatment-related adverse effects (TRAEs) occurred in 78.7% versus 62.1% of patients.

In part 1, Zhang walked through both trials. He described OptiTROP-Lung04 as the first randomized phase 3 trial to show an OS benefit with a TROP2-directed ADC, and noted that sac-TMT is already approved in China for this indication, with global studies under way. For PANKU-Lung01, he said early OS trends favor iza-bren and that follow-up is continuing.

In part 2, Zhang cautioned against comparing the 2 trials directly because their populations differed. OptiTROP-Lung04 enrolled more patients with brain metastases and allowed some patients whose disease had progressed on first- or second-generation EGFR TKIs, whereas all patients in PANKU-Lung01 had progressed on a third-generation TKI.

The toxicity profiles also differ: stomatitis is the most common adverse effect with sac-TMT, whereas iza-bren is associated primarily with hematologic toxicity, including neutropenia, thrombocytopenia, and anemia. Zhang said treatment selection may come down to the patient: those concerned about the effect of stomatitis on quality of life may prefer iza-bren, whereas sac-TMT, with relatively lower hematologic toxicity, may suit patients who have already received chemotherapy. He noted that iza-bren has been submitted for approval but is not yet available in China.

In part 3, Zhang looked ahead to first-line use. Both agents are being studied in combination with EGFR TKIs as potential alternatives to TKI plus chemotherapy, and he said results from a trial pairing a TKI with sac-TMT are expected within the next year. He also pointed to ADC-plus-immunotherapy combinations as an emerging option for patients without driver alterations.

For oncologists new to ADCs, he offered several lessons: ADCs function as delivery systems for chemotherapy rather than chemotherapy-free treatment; because most current agents carry topoisomerase I inhibitor payloads, switching to an ADC with a different target but the same payload class may not be effective; and toxicity can exceed that of standard chemotherapy.

Zhang also described practical differences between the 2 countries. Blood transfusions are harder to obtain in China, so anemia is often managed with erythropoietin alone, whereas several treatments for thrombocytopenia, including thrombopoietin and interleukin-11, are available in China but are harder to access in the United States. Most patients in China also receive ADCs as inpatients because of reimbursement requirements, compared with outpatient treatment in the United States.

He said these differences reflect practice patterns rather than differences in efficacy or toxicity, and he closed by noting that many China-developed ADCs, including sac-TMT and iza-bren, are now partnered with international pharmaceutical companies and are being evaluated in global registration trials.