KRYSTAL-2: A phase I/II trial of adagrasib (MRTX849) in combination with TNO155 in patients with advanced solid tumors with KRAS G12C mutation.
Authors: Sabari Joshua K. , Park Haeseong , Tolcher Anthony W. , Ou Sai-Hong Ignatius , Garon Edward B. , George Ben , Janne Pasi A. , Moody Susan Elizabeth , Tan Eugene Y. , Sen Suman Kumar , Peters Dana , Yan Xiaohong , Christensen James G , Chi Andrew S. , Heist Rebecca Suk 
Published: January 2021

TPS146 Background: KRAS is the most frequently mutated oncogene in cancer and a key mediator of the RAS/MAPK signaling cascade that promotes cellular growth and proliferation. KRAS G12C tumor mutations occur in approximately 14% of patients with lung adenocarcinoma and 3-4% of colorectal adenocarinoma. SHP2 is a phosphatase that acts as a key mediator of signaling from receptor tyrosine kinases (RTKs) to downstream RAS/MAPK pathways. Adagrasib (MRTX849) is a specific small-molecule investigational inhibitor of KRAS G12C that covalently binds to and locks mutant KRAS in its GDP-bound inactive form. Adagrasib has been optimized for a long half-life and extensive tissue distribution to enable inhibition throughout the entire dosing interval. Preliminary results from a Phase 1/2 study of adagrasib demonstrated promising antitumor activity and tolerability across multiple KRAS G12C tumor types. TNO155 is a selective inhibitor of SHP2 with demonstrated inhibition of RTK signaling and significant antitumor activity in preclinical models. Preclinical studies have shown that resistance to KRAS G12C inhibition may be mediated by SHP2-dependent feedback loops. Because KRAS G12C retains some level of cycling between GTP- and GDP-bound states, KRAS G12C that is not bound by inhibitor can activate downstream signaling. Active SHP2 functions to increase the active state of RAS proteins (including mutant KRAS) and also increases ERK pathway activation. Therefore, the addition of TNO155 to adagrasib may augment antitumor activity and overcome resistance by inhibiting cycling to GTP-bound KRAS and/or through inhibition of feedback activation and more comprehensively inhibiting downstream ERK signaling. In KRAS G12C human tumor models, adagrasib combined with a SHP2 inhibitor demonstrated greater activity compared to each agent alone. These data provide support for clinical evaluation of this combination in KRAS G12C tumors. Methods: KRYSTAL-2 is a multicenter Phase 1/2 study evaluating adagrasib and TNO155 in patients with advanced solid tumors harboring a KRAS G12C mutation. Overall objectives of the trial include evaluating safety, tolerability, and PK. The Phase 1 portion will evaluate adagrasib and TNO155 utilizing a modified Toxicity Probability Interval dose escalation design to identify maximum tolerated dose and recommended Phase 2 dose. The Phase 2 portion utilizes a Simon's optimal two-stage design to evaluate the clinical activity of adagrasib with TNO155 in 2 cohorts of up to 108 patients—CRC (54 patients) and NSCLC (54 patients). Efficacy endpoints include Objective Response Rate (RECIST 1.1), Duration of Response (DOR), Progression-free Survival (PFS), and Overall Survival (OS). The study is currently enrolling and patients will receive study treatment until disease progression, unacceptable adverse events, patient withdrawal, or death. Clinical trial information: NCT04330664.