1. Mechanisms of Resistance to KRASG12C Inhibitors
Victoria Dunnett-Kane, Colin Lindsay, Pantelis Nicola, Fiona Blackhall Cancers (Basel) . 2021 Jan 5;13(1):151. doi: 10.3390/cancers13010151.
KRAS is one of the most common human oncogenes, but concerted efforts to produce direct inhibitors have largely failed, earning KRAS the title of "undruggable". Recent efforts to produce subtype specific inhibitors have been more successful, and several KRASG12Cinhibitors have reached clinical trials, including adagrasib and sotorasib, which have shown early evidence of efficacy in patients. Lessons from other inhibitors of the RAS pathway suggest that the effect of these drugs will be limited in vivo by the development of drug resistance, and pre-clinical studies of G12C inhibitors have identified evidence of this. In this review we discuss the current evidence for G12C inhibitors, the mechanisms of resistance to G12C inhibitors and potential approaches to overcome them. We discuss possible targets of combination therapy, including SHP2, receptor tyrosine kinases, downstream effectors and PD1/PDL1, and review the ongoing clinical trials investigating these inhibitors.
2. KRAS mutation: from undruggable to druggable in cancer
Lamei Huang, Fang Wang, Liwu Fu, Zhixing Guo Signal Transduct Target Ther . 2021 Nov 15;6(1):386. doi: 10.1038/s41392-021-00780-4.
Cancer is the leading cause of death worldwide, and its treatment and outcomes have been dramatically revolutionised by targeted therapies. As the most frequently mutated oncogene, Kirsten rat sarcoma viral oncogene homologue (KRAS) has attracted substantial attention. The understanding of KRAS is constantly being updated by numerous studies on KRAS in the initiation and progression of cancer diseases. However, KRAS has been deemed a challenging therapeutic target, even "undruggable", after drug-targeting efforts over the past four decades. Recently, there have been surprising advances in directly targeted drugs for KRAS, especially in KRAS (G12C) inhibitors, such as AMG510 (sotorasib) and MRTX849 (adagrasib), which have obtained encouraging results in clinical trials. Excitingly, AMG510 was the first drug-targeting KRAS (G12C) to be approved for clinical use this year. This review summarises the most recent understanding of fundamental aspects of KRAS, the relationship between the KRAS mutations and tumour immune evasion, and new progress in targeting KRAS, particularly KRAS (G12C). Moreover, the possible mechanisms of resistance to KRAS (G12C) inhibitors and possible combination therapies are summarised, with a view to providing the best regimen for individualised treatment with KRAS (G12C) inhibitors and achieving truly precise treatment.
3. First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced KRASG12C Solid Tumors (KRYSTAL-1)
Karen L Velastegui, Igor I Rybkin, Richard C Chao, Ticiana A Leal, James G Christensen, Xiaohong Yan, Kyriakos P Papadopoulos, Lyudmila Bazhenova, Melissa L Johnson, Cornelius Cilliers, Pasi A Jänne, Sai-Hong Ignatius Ou, Minal A Barve, Joshua K Sabari J Clin Oncol . 2022 Aug 10;40(23):2530-2538. doi: 10.1200/JCO.21.02752.
Purpose:Adagrasib (MRTX849) is an oral, highly selective, small-molecule, covalent inhibitor of KRASG12C. We report results from a phase I/IB study of adagrasib in non-small-cell lung cancer, colorectal cancer, and other solid tumors harboring theKRASG12Cmutation.Materials and methods:Patients with advancedKRASG12C-mutant solid tumors were treated with adagrasib 150 mg orally once daily, 300 mg once daily, 600 mg once daily, 1,200 mg once daily, or 600 mg orally twice a day using an accelerated titration design, which transitioned to a modified toxicity probability interval design when a predefined degree of toxicity was observed or target adagrasib exposure was achieved. Safety, pharmacokinetics, and clinical activity were evaluated.Results:Twenty-five patients were enrolled and received at least one dose of adagrasib. The recommended phase II dose (RP2D) was 600 mg twice a day on the basis of safety, tolerability, and observed pharmacokinetics properties. No maximum tolerated dose was formally defined. After a median follow-up of 19.6 months, eight of 15 patients (53.3%; 95% CI, 26.6 to 78.7) with RECIST-evaluableKRASG12C-mutant non-small-cell lung cancer treated at 600 mg twice a day achieved a confirmed partial response. The median duration of response was 16.4 months (95% CI, 3.1 to not estimable). The median progression-free survival was 11.1 months (95% CI, 2.6 to not estimable). One of two patients withKRASG12C-mutant colorectal cancer treated at 600 mg twice a day achieved a partial response (duration of response, 4.2 months). At the RP2D, the most common treatment-related adverse events (any grade) were nausea (80.0%), diarrhea (70.0%), vomiting (50.0%), and fatigue (45.0%). The most common grade 3-4 treatment-related adverse event was fatigue (15.0%).Conclusion:Adagrasib 600 mg twice a day was well tolerated and exhibited antitumor activity in patients with advanced solid tumors harboring theKRASG12Cmutation.
