TEST:

Resolution ctDx Lung Assay™

Chemoimmunotherapy remains a major treatment option for metastatic HER2-mutant NSCLC. ctDNA can rapidly detect HER2 and co-mutations, and it has the potential to guide and monitor optimal first-line therapy. As a negative prognostic biomarker, detectable ctDNA at baseline would need to be taken into account for patient selection in future studies.

55% (17/31) received chemoimmunotherapy with pembrolizumab as the first-line treatment...Additionally, 19% of patients (6/31) received a HER2-targeted antibody-drug conjugates (ADC) as first-line treatment with a median TTD of 6 months (95% CI 2-10), including 5 with T-DM1 and one who received first-line T-DXd treatment with a TTD of 9 months... Baseline plasma ctDNA has the potential to guide first-line targeted therapy for patients with HER2-mutant NSCLC. As an independent negative prognostic biomarker, detectable ctDNA at baseline would need to be taken into account for patient selection in future studies to avoid underestimating the effects of therapy.

At baseline, lower G12C AF and lower number of altered genes were associated with improved outcomes, suggesting there may be benefit to early initiation of sotorasib when co-mutational burden is low. Changes in ctDNA early in treatment are dynamic. Absence of detectable ctDNA at C2D1 may be associated with longer PFS.

Genomic alterations observed in KRAS p.G12C-mutated NSCLC patients treated with sotorasib suggest acquired resistance can arise via a range of mechanisms; however, new RTK alterations were frequently apparent at disease progression. This highlights a potential benefit of combining sotorasib with upstream inhibitors of RTK, such as SHP2 or EGFR inhibitors. Overall, pat-terns of acquired resistance suggested by DNA analysis of plasma samples at baseline and disease progression support the develop-ment of KRASG12C inhibitor combination therapies.

P1/2 | "Based on the largest descriptive dataset to-date, diverse mechanisms of acquired resistance occur in KRAS p.G12C-mutated NSCLC and CRC pts treated with sotorasib. New RTK pathway alterations frequently emerged at progression, highlighting the potential role for combining sotorasib with upstream inhibitors of RTK, such as SHP2 or EGFR inhibitors. Serial plasma DNA analysis revealed acquired resistance patterns that support the development of KRASG12C inhibitor combination therapies."

Our results show that ctDNA may match patients to life-prolonging targeted therapy and have prognostic importance . ctDNA may provide data about a patient’s cancer missed by spatially restricted tissue sequencing.