This is a first-in-human Phase Ia/Ib, open-label, multicenter dose-escalation and dose-expansion study designed to evaluate the safety, pharmacokinetics, and preliminary activity of GDC-6036 as a single agent and in combination with other anti-cancer therapies in patients with advanced or metastatic solid tumors that harbor the KRAS G12C mutation. The combination therapies in this study are atezolizumab (Arm B), cetuximab (Arm C), bevacizumab (Arm D), erlotinib (Arm E), and GDC-1971 (Arm F) in NSCLC, CRC, and solid tumors. The study is designed with the intention to include new, additional treatment arms during study conduct (via protocol amendments) to explore combinations of GDC-6036 with other anti-cancer therapies based on emerging nonclinical and clinical data with GDC-6036, other KRAS G12C inhibitors, or evolving standard-of-care treatment. Anticipated future combinations with GDC-6036 may include RTK/RAS/MAPK pathway-targeting therapies, agents that target compensatory pathways that may mediate intrinsic or acquired resistance to treatment, immunotherapies, agents that modulate the tumor microenvironment, and standard-of-care agents to further explore safety, pharmacokinetics, and preliminary activity.

The Kirsten rat sarcoma viral oncogene homolog (KRAS) is a central component of the RAS/MAPK signal transduction pathway, an intracellular network of proteins that transmit extracellular growth factor signals to regulate cell proliferation, differentiation, and survival. Mutations in KRAS can result in alterations at several amino acids, including glycine 12 (G12), glycine 13, and glutamine 61, commonly found in solid tumors and associated with tumorigenesis and aggressive tumor growth (Der et al. 1982; Parada et al. 1982; Santos et al. 1982; Taparowsky et al. 1982; Capon et al. 1983). Oncogenic KRAS mutations that result in the change from G12 to cysteine (G12C) are prevalent in non-small cell lung cancer (NSCLC) (~12%), colorectal cancer (CRC) (~4%), and other tumor types (£ 4%) (Bailey et al. 2016; Campbell et al. 2016; Giannakis et al. 2016; Hartmaier et al. 2017; Jordan et al. 2017).

Advanced stage tumors harboring the KRAS G12C mutation (hereafter referred to as KRAS G12C-positive tumors), including NSCLC, CRC, and other solid tumors, are incurable and carry a poor prognosis (Roman et al. 2018; Wan et al. 2019). In addition, patients with advanced stage KRAS G12C-positive cancers may derive limited benefit from select chemotherapies and targeted therapies, thus, restricting effective available treatment options (Roman et al. 2018).

Initial systemic treatment options for advanced stage or metastatic NSCLC (without known oncogenic drivers that have available targeted therapies) include PD-1/PD-L1 inhibitors with or without chemotherapy (Gong et al. 2018).  Subsequent treatment options may include platinum-containing chemotherapy combinations followed by single-agent chemotherapy with limited duration of disease control (NCCN 2020a).

Although a minority of patients achieve long-term disease control, in general, advanced stage or metastatic NSCLC remains an incurable disease.  Recent data suggest that KRAS mutation status may be associated with response to single-agent PD-1 inhibitor therapy and that chemotherapy plus a PD-1 inhibitor may be effective regardless of KRAS mutation status (Gadgeel et al. 2019; Herbst et al. 2019).

For advanced or metastatic CRC, systemic treatment can consist of combinations of active agents or select individual agents and includes 5-fluorouracil/leucovorin, capecitabine, irinotecan, oxaliplatin, bevacizumab, cetuximab, panitumumab,ziv-aflibercept, ramucirumab, regorafenib, trifluridine-tipiracil, pembrolizumab, nivolumab, ipilimumab, and encorafenib. Treatment is selected based on the goals of care, type and timing of prior therapy, mutational profile of the tumor, anticipated toxicity profile, and patient’s performance status (NCCN 2020b). Specifically, KRAS mutations were associated with resistance to anti-EGFR therapies (Lièvre et al. 2006; Karapetis et al.2008; Van Cutsem et al. 2009; Misale et al. 2012). Thus, patients whose cancers harbor KRAS mutations are not eligible for treatment with cetuximab or panitumumab (NCCN 2020b) and treatment options remain limited.

Other tumor types with the KRAS G12C mutation include cancers of the pancreas, breast, ovary, endometrium, and appendix, as well as gastric cancer and myeloma (Hartmaier et al. 2017). Treatment is based on tumor type as well as patient’s performance status, goals of care, and prior therapy.  However, because the prevalence of KRAS G12C-positive tumors is low, there is no specific guidance on treatment or management.

Although previously considered an "undruggable" cancer target, the landmark discovery of the switch II pocket within KRAS has enabled the development of covalent inhibitors specific for KRAS G12C (Ostrem et al. 2013). The clinical development of covalent inhibitors of KRAS G12C offers a potential therapeutic intervention to prevent or delay the progression of cancers that harbor a KRAS G12C mutation (McCormick 2019).

Early clinical data from covalent inhibitors specific for KRAS G12C demonstrate single-agent anti-tumor activity and potential to improve treatment options and outcomes for patients with advanced stage cancer that harbors the KRAS G12C mutation (Jänne et al. 2019; Hong et al. 2020).