Abstract LB107: Association of circulating free DNA (cfDNA) maximum variant allele frequency (mVAF) levels with clinical outcomes in patients (pts) with metastatic nonsquamous non-small cell lung cancer (NSCLC) treated with pembrolizumab (pembro) + chemotherapy (chemo) in the phase 2 KEYNOTE-782 trial
Authors: Bar Jair , Esteban Emilio , Rodríguez-Abreu Delvys , Ponce-Aix Santiago , Szalai Zsuzsanna , Felip Enriqueta , Gottfried Maya , Pulla Mariano Provencio , Robinson Andrew , Fülöp Andrea , Rao Suman Bannur , Camidge D. Ross , Speranza Giovanna , Hunkapiller Nathan , McDaniel Robert , Jung Byoungsok , Burkhardt David , Mauntz Ruth , Chen Cai , Pena Carol , Cristescu Razvan , Dettman Elisha J. , Townson Steven M. , Kobie Julie , Csőszi Tibor 
Published: April 2024

Abstract
Background: The phase 2 KEYNOTE-782 trial (NCT03664024) was designed to prospectively evaluate plasma-derived biomarkers of response to first-line pembro + chemo in pts with metastatic nonsquamous NSCLC. This exploratory analysis of KEYNOTE-782 evaluated the association of cfDNA mVAF levels with clinical outcomes.
Methods: Adults with untreated stage IV nonsquamous NSCLC received pembro 200 mg Q3W + chemo (pemetrexed + carboplatin or cisplatin). cfDNA was isolated from plasma samples collected at baseline (BL) and cycle 2 (C2) and sequenced using a targeted NGS-based assay previously used to assess blood tumor mutational burden from cfDNA for the primary analysis. cfDNA mVAF was quantified for each patient. The associations of BL cfDNA mVAF (all pts) and change in cfDNA mVAF from BL at C2 (pts with ≥1 detectable variant at BL; cfDNA+) as continuous variables with ORR, PFS, and OS were evaluated; 1-sided α was prespecified at 0.05 after multiplicity adjustment. ORR, PFS, and OS were also descriptively evaluated by cfDNA bins (BL mVAF, &gt;0 vs 0; mVAF change from BL, ≥median vs &lt;median). Results: Of 101 pts with evaluable cfDNA samples at BL, 83 (82.2%) were cfDNA+; 74 of these 83 pts had evaluable cfDNA samples at C2. Low BL mVAF was associated with improved ORR, PFS, and OS (P &lt;0.01, each). The area under the receiver operating characteristic curve (AUROC) for discriminating response was 0.61 (95% CI, 0.50-0.72). Among pts with BL mVAF &gt;0 (n = 83) vs 0 (n = 18), ORR (95% CI) was 38.6% (28.1-49.9) vs 55.6% (30.8-78.5), median PFS (95% CI) was 6.6 mo (4.9-9.0) vs 19.7 mo (9.8-not reached [NR]), and median OS (95% CI) was 13.6 mo (9.4-22.5) vs 31.6 mo (20.1-NR). Larger reductions in mVAF from BL at C2 were associated with improved ORR, PFS, and OS (P &lt;0.05, each). The AUROC for discriminating response was 0.69 (95% CI, 0.57-0.82). After adjustment for best overall response, change in mVAF from BL at C2 was not associated with PFS or OS (P &gt;0.05). In a descriptive evaluation for pts with a mVAF change from BL at C2 ≥median of 0.15 (n = 37) vs &lt;median (n="37)," orr="" (95%="" ci)="" was="" 18.9%="" (8.0-35.2)="" vs="" 64.9%="" (47.5-79.8),="" median="" pfs="" 5.1="" mo="" (4.2-11.1)="" 7.2="" (6.2-21.7),="" and="" os="" 12.8="" (7.9-18.1)="" 25.9="" (15.3-nr).="" conclusions:="" in="" pts="" with metastatic nonsquamous NSCLC treated with pembro + chemo, low cfDNA mVAF levels at BL and larger reductions in cfDNA mVAF levels were associated with improved clinical outcomes. However, after correction for clinical response, the prognostic value of cfDNA mVAF reduction was not significant. Further studies are warranted to elucidate the utility of cfDNA for disease monitoring in this setting.
Citation Format: Jair Bar, Emilio Esteban, Delvys Rodríguez-Abreu, Santiago Ponce-Aix, Zsuzsanna Szalai, Enriqueta Felip, Maya Gottfried, Mariano Provencio Pulla, Andrew Robinson, Andrea Fülöp, Suman Bannur Rao, D. Ross Camidge, Giovanna Speranza, Nathan Hunkapiller, Robert McDaniel, Byoungsok Jung, David Burkhardt, Ruth Mauntz, Cai Chen, Carol Pena, Razvan Cristescu, Elisha J. Dettman, Steven M. Townson, Julie Kobie, Tibor Csőszi. Association of circulating free DNA (cfDNA) maximum variant allele frequency (mVAF) levels with clinical outcomes in patients (pts) with metastatic nonsquamous non-small cell lung cancer (NSCLC) treated with pembrolizumab (pembro) + chemotherapy (chemo) in the phase 2 KEYNOTE-782 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB107.