Between May and June 2021, two KRAS G12C inhibitors received major FDA recognition for the treatment of KRAS G12C-mutated advanced non-small cell lung cancer.

Kirsten rat sarcoma viral oncogene homologue (KRAS) is the most frequently mutated oncogene in human cancers and encodes a guanosine triphosphatase (GTPase) protein of the Ras family. KRas acts as a cellular switch that is turned on by extracellular stimuli, such as growth factors, resulting in the activation of downstream signalling pathways, which regulate cell proliferation, migration, survival, and differentiation. In its regulatory activity of signal transduction, KRas cycles between active guanosine triphosphate (GTP)–bound (KRas-GTP) and inactive guanosine diphosphate (GDP)–bound (KRas-GDP) states.

Missense gain-of-function mutations are the main cause for the transformation of KRAS from proto-oncogene into oncogene. The resulting mutant KRas protein remains primarily in the KRas-GTP state, which constitutively activates downstream signalling pathways, leading to tumorigenesis.
These mutations are mainly represented by nucleotidic substitutions at codons 12, 13, or 61. Point mutations in KRAS codon 12 are present in up to 80% of KRAS-mutant malignancies. KRAS G12C is the most prevalent KRAS mutation in NSCLC and is present in about 13% of lung adenocarcinomas and 1–3% of other solid tumours, including colorectal, pancreatic, endometrial, bladder, ovarian, and small cell lung cancers.

Unlike other mutant KRas proteins, mutant KRasG12C retains normal intrinsic GTPase activity and cycles between the active KRas-GTP state and the inactive KRas-GDP state, characterised by a small pocket (P2) adjacent to the mutant cysteine 12 residue.
In the last few years, several small-molecule inhibitors, that selectively and irreversibly bind to cysteine 12 in the P2 pocket of mutant KRasG12C and locks it in the inactive KRas-GDP state, have been discovered. The first inhibitors of KRasG12C with known clinical efficacy were sotorasib (AMG-510) and adagrasib (MRTX-849).

Last May 28th, the U.S. Food and Drug Administration (FDA) has approved sotorasib for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), who have received at least one prior systemic therapy.
The FDA approval is based on results from a subset of patients in CodeBreaK 100, the largest clinical trial conducted to date exclusively for patients with the KRAS G12C mutation. The trial demonstrated favorable efficacy and tolerability in 124 patients with KRAS G12C mutation-positive NSCLC who had disease progression after receiving an immunotherapy and/or chemotherapy. In the trial, sotorasib demonstrated an ORR (a proportion of patients with > 30% decrease in tumour) of 36% with 81% of patients achieving disease control (percentage of patients who have achieved complete response, partial response and stable disease for more than three months). The median duration of response was 10 months. The majority of patients had low-grade adverse reactions, and only 9% of patients had permanent discontinuation of sotorasib, because of toxic effects .

Always in CodeBreak 100, although to a lesser extent, responses to sotorasib were also observed in patients with tumours different from NSCLC: colorectal (CRC), pancreatic, endometrial, and appendiceal cancers and melanoma. In particular, in the subset of patients with CRC, 7.1% achieved a confirmed response to sotorasib, with 73.8% of patients experiencing disease control. The median progression free survival in this patient subgroup was 4.0 months.

A marketing authorization application was submitted at the end of 2020 to both FDA and the European Medicines Agency (EMA). Therefore, the EU approval for the use of sotorasib in patients with KRAS G12C–mutated NSCLC is expected shortly.

Last June 24th, adagrasib received Breakthrough Therapy Designation from U.S. Food and Drug Administration for the potential treatment of patients with KRAS G12C-mutated NSCLC following prior systemic therapy.

The designation, which will expedite the development and regulatory review of the drug, is supported by preliminary results from the registrational Phase 1/2 KRYSTAL-01 trial in patients with advanced NSCLC, whose cancer harbours the KRAS G12C mutation and had progressed following prior treatment with immunotherapy and/or chemotherapy. 45% of response-evaluable patients had a partial response and 51% had stable disease.
Adagrasib demonstrated a tolerable safety profile as well.
Responses to the drug have been observed also in patients with colorectal cancer, pancreatic cancer, and other solid tumours harbouring the KRAS G12C mutation.

Other KRasG12C inhibitors are in development; among them JNJ-74699157, LY3499446 and BI1701963, which have reached the clinical trial phase.

The mutational analysis of KRAS can be performed with different methods: Real Time PCR, Pyrosequencing, MassARRAY and NGS, which are all offered by Diatech Pharmacogenetics through its CE-IVD solutions.

More information at www.diatechpharmacogenetics.com

References

  1. Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, Falchook GS, Price TJ, Sacher A, Denlinger CS, Bang YJ, Dy GK, Krauss JC, Kuboki Y, Kuo JC, Coveler AL, Park K, Kim TW, Barlesi F, Munster PN, Ramalingam SS, Burns TF, Meric-Bernstam F, Henary H, Ngang J, Ngarmchamnanrith G, Kim J, Houk BE, Canon J, Lipford JR, Friberg G, Lito P, Govindan R, Li BT. KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors. N Engl J Med. 2020 Sep 24;383(13):1207-1217.
  2. Veluswamy R, Mack PC, Houldsworth J, Elkhouly E, Hirsch FR. KRAS G12C-Mutant Non-Small Cell Lung Cancer: Biology, Developmental Therapeutics, and Molecular Testing. J Mol Diagn. 2021 May;23(5):507-520.
  3. Thein KZ, Biter AB, Hong DS. Therapeutics Targeting Mutant KRAS. Annu Rev Med. 2021 Jan 27;72:349-364.
  4. FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC
  5. Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, Falchook GS, Price TJ, Sacher A, Denlinger CS, Bang YJ, Dy GK, Krauss JC, Kuboki Y, Kuo JC, Coveler AL, Park K, Kim TW, Barlesi F, Munster PN, Ramalingam SS, Burns TF, Meric-Bernstam F, Henary H, Ngang J, Ngarmchamnanrith G, Kim J, Houk BE, Canon J, Lipford JR, Friberg G, Lito P, Govindan R, Li BT. KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors. N Engl J Med. 2020 Sep 24;383(13):1207-1217.
  6. Adagrasib Earns FDA Breakthrough Therapy Designation for KRAS G12C+ NSCLC
  7. Targeting KRASG12C in Solid Tumors: A New Anticancer Approach