Abstract LB054: Confirmation of target inhibition and anti-tumor activity of the SHP2 inhibitor RMC-4630 via longitudinal analysis of ctDNA in a phase 1 clinical study
Authors: Hayes Josie L. , Koczywas Marianna , Ou Sai-Hong Ignatius , Janne Pasi A. , Pacheco Jose M. , Ulahannan Susanna , Wang Judy S. , Burris Howard A. , Riess Jonathan W. , McCoach Caroline , Gordon Michael S. , Capasso Anna , Chen Ariel , Dua Richa , Bitman Bojena , Guerra Martha , Wang Hongfang , Wang Xiaolin , Haura Eric 
Published: July 2021

Abstract
RMC-4630 is a potent, selective, orally bioavailable allosteric inhibitor of SHP2, a central node in the RAS signaling pathway. Preclinical data have demonstrated that RMC-4630 can shrink tumors carrying certain mutations in the RAS pathway such as KRASG12C, NF1LOF, and BRAFClass3. Longitudinal circulating tumor DNA (ctDNA) was isolated from blood using GuardantOMNI in 80 patients with relapsed/refractory solid tumors in the phase 1 dose-escalation trial of RMC-4630 (NCT03634982) to characterize and confirm RAS pathway mutations and to evaluate molecular responses in patients receiving RMC-4630 monotherapy. Safety, PK and efficacy findings from this study are reported in a separate abstract. 78 of 80 patients had baseline somatic mutations detected in plasma, of which 60 were either KRASG12X, NF1LOF, or BRAFClass3; 48 of these 60 patients also had on-treatment ctDNA assessments and these patients constitute the population reported here. 9 of 48 patients (19%) had KRASG12C detected at baseline, available scan results and a ctDNA sample after 4 weeks of receiving RMC-4630. A decrease in KRASG12C variant allele frequency (VAF) was detected in 5/9 patients (56%) with clearance in 1 patient with a partial response. Decrease in KRASG12C VAF was associated with change in tumor volume (PCC=0.85, p=0.008), preceding scan results by approximately 1 month, suggesting that change in KRASG12C VAF may be an early measure of drug activity or possibly response. 5 of 48 patients (10%) had NF1LOF detected at baseline. A decrease, or stability in NF1LOF VAF on treatment compared to baseline was detected in 4 (80% of all NF1LOF patients). The decrease in NF1LOF VAF was not associated with change in tumor volume and may represent effects of RMC-4630 on a subclone harboring NF1LOF. One patient had a detectable BRAFClass3 mutation at baseline, which decreased in VAF on treatment compared to baseline. Of the remaining patients there were 12 KRASG12D, 9 KRASG12V and other KRASG12X. The majority progressed with an increase in VAF of all mutations including KRASG12X, suggesting that the KRASG12X-containing clone is responsible for escape from single agent RMC-4630. In most instances the increase in KRASG12X VAF in blood preceded determination of clinical progression. Longitudinal assessment of ctDNA indicates that some patients with RAS-addicted tumors undergo a molecular response on treatment with the SHP2 inhibitor RMC-4630.
Citation Format: Josie L. Hayes, Marianna Koczywas, Sai-Hong Ignatius Ou, Pasi A. Janne, Jose M. Pacheco, Susanna Ulahannan, Judy S. Wang, Howard A. Burris, Jonathan W. Riess, Caroline McCoach, Michael S. Gordon, Anna Capasso, Ariel Chen, Richa Dua, Bojena Bitman, Martha Guerra, Hongfang Wang, Xiaolin Wang, Eric Haura. Confirmation of target inhibition and anti-tumor activity of the SHP2 inhibitor RMC-4630 via longitudinal analysis of ctDNA in a phase 1 clinical study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB054.