Dr Rotow on the Investigation of ABBV-637 Plus Osimertinib in EGFR-Mutated NSCLC

Julia Rotow, MD, clinical director, Lowe Center for Thoracic Oncology, physician, Dana-Farber Cancer Institute, discusses results from a first-in-human phase 1 study (NCT04721015) of the EGFR-targeting, BCL-XL–inhibiting antibody-drug conjugate (ADC) ABBV-637 in combination with osimertinib (Tagrisso) in patients with relapsed/refractory, EGFR-mutated non–small cell lung cancer (NSCLC).

At the 2023 ESMO Congress, investigators shared data from the investigation, reporting that ABBV-637 combined with osimertinib was clinically active when used as a second- or third-line treatment option. The regimen also had a manageable safety profile in this patient population, though ongoing research is needed to confirm optimal biomarkers for patient selection, according to Rotow.

Investigators compiled preliminary efficacy data after a median follow-up of 4.5 months, and follow-up is still ongoing, she begins. In the overall study population, the confirmed overallresponse rate (ORR) in the second- or third-line treatment was 11.9%, and the disease control rate (DCR) was 69%. It appeared that disease control was sustained throughout the follow-up period, but it's worth noting that this follow-up is currently of a short duration, Rotow states. When investigators specifically examined the patients treated in the second-line cohort after receiving prior osimertinib, the ORR was 10%, with a DCR of 65%, she emphasizes. These findings indicate that re-exposure to a TKI is not the driving factor behind responses to ABBV-637 plus osimertinib, as these patients had progressed on their prior TKI, Rotow says.

The lung cancer field has a strong interest in identifying biomarkers to guide the selection of second-line acquired resistance therapy for patients with EGFR-mutated NSCLC, she continues. Often, therapies guided by specific biomarkers achieve higher response rates in this patient group, potentially because of the varying nature of acquired resistance among individual patients. However, this isn't always the case, Rotow emphasizes. In the data presented from this phase 1 trial, investigators were unable to identify a biomarker for patient enrollment.

However, exploratory analyses focused on well-known baseline mechanisms of resistance to EGFR inhibitors and TKIs, such as bypass resistance mechanisms, she highlights. In these analyses, investigators observed an initial indication of reduced response rates in patients with known bypass mechanism resistance, although this finding needs confirmation from larger cohorts with longer follow-up periods, Rotow says. More comprehensive information is also needed regarding biomarkers and patients’ apoptotic statuses, she concludes.