Targeting KRAS G12C mutations in colon, lung, and other cancers

The KRAS G12C inhibitor drug Krazati (adagrasib, MRTX849) joins Lumakras (sotorasib) as an approved treatment for patients with non-small cell lung cancers (NSCLC) harboring KRAS G12C mutations,^1,3,4,8  These drugs are also being evaluated in colorectal cancer, and other solid tumors.

RAS is an oncogene —a gene that encodes proteins that function as switches to turn on various genes for cell growth and division. Mutations in the RAS genes result in permanently “turned on” switches that in turn result in uninhibited cell division, which can lead to cancer. There are three types of RAS oncogenes, designated NRAS, GRAS, and KRAS. Although mutations in all three can cause cancer.

KRAS mutations are the most common oncogenic alteration in all of human cancers and there are currently no effective treatments available for patients with KRAS-mutant cancers. KRAS cancer driving mutation are present in 14% of NSCLC adenocarcinomas, 4% of colorectal cancers, 2% of pancreatic cancers as well as smaller percentages of several other difficult-to-treat cancers.

About Krazati (adagrasib-MRTX849)

Krazati is an orally available small molecule that is designed to potently and selectively inhibit a form of KRAS which harbors a substitution mutation (G12C). Adagrasib works by irreversibly and selectively binding to KRAS G12C in its inactive state, blocking its signaling to other cells and preventing cancer cell growth and proliferation; this leads to cancer cell death. Adagrasib is being evaluated in a phase 1/2 trial treating patients with molecularly identified, KRAS G12C-positive advanced solid tumors.

The phase 1/2 KRYSTAL-1 clinical trial evaluated Krazati in patients with advanced or metastatic NSCLC with a KRASG12C mutation. After a median follow-up of 12.9 months, the objective response rate was 43% among the 112 patients with measurable disease, and 37% of patients had stable disease for a “disease control rate” of 80%. Average survival duration was 12.6 months with 71% of patients surviving beyond one year.⁷

An even greater response to Krazati was observed in the subpopulation of patients whose cancers had an STK11 mutation as well as a KRAS G12C mutation. STK11 mutations have been associated with inferior responses to immune checkpoint inhibitors in patients with NSCLC.⁵

According to a report presented at the 2021 ESMO Congress Krazati used alone or in combination with Erbitux produced a response rate of 22% and a disease control rate of 87% in 46 heavily pretreated patients. Moreover 32 similar patients treated with the combination of Krazati and cetuximab had a response rate of 43%, and a disease control rate of 100%. The median time to response was 1.4 months and the combination appeared well tolerated.

A confirmatory trial comparing Krazati to Taxotere chemotherapy reported at ASCO 2024 demonstrated that more patients responded to treatment with Krazati and experienced better control of their cancer, including those with central nervous system involvement.¹⁰

Research suggests they may be most effective when used in combination with other precision medicines due to a resistance mechanism that develops when they are uses as a single agent. 

Colon Cancer

The trial results of the precision cancer medicines Krazati and Lumakras administered alone or in combination with in patients with heavily pretreated colorectal cancer harboring a KRAS^G12C mutation have been reported.^6,9

KRYSTAL is a Phase 1/2 clinical trial in patients who have a KRAS^G12C mutation. The phase 1b portion of the study included patients evaluating krazati alone. The phase 2 part of the trial includes krazati monotherapy in CRC, and other solid tumors.

Preliminary data for 46 patients with pre-treated CRC who received krazati monotherapy, and 32 patients with pre-treated CRC who received the krazati + cetuximab combination was presented in early 2022.

All patients were heavily pretreated with a median of 3 prior lines of therapy and 31% of patients received at least 4 prior lines of therapy. 

• Krazati Monotherapy: Of the 45 clinically evaluable patients who received adagrasib monotherapy the response rate was 22% and the median duration of response was 4.2 months.
• Krazati + Cetuximab: The confirmed response rate for the combination was 39%. The median time to response was 1.3 months. At the time of analysis, 71% of patients remain on treatment.
• In both groups therapy was well tolerated with acceptable side effects.

Lumakras plus Panitumumab in KRAS G12C–Mutated Advanced Colon Cancer

The phase III CodeBreaK 300 clinical trial evaluated the combination of Lumakras plus panitumumab in 160 patients enrolled from sites in 12 countries between April 2022 and March 2023. Patients with advanced colon cancer were treated with two different dosing schedules of lumakras plus panitumumab or standard of care investigator’s choice of chemotherapy.

Patients treated with lumakras were significantly more likely to respond to treatment and their cancer progression-free survival averaged 5.6 months compared with only 2.2 months for patients receiving standard-care chemotherapy.

Both krazati and lumakras have clinical activity in heavily pretreated patients with CRC harboring a KRAS^G12C mutation. The addition of a second drug targeting EGFR show synergistic clinical activity and appears to work better than the KRAS targeting drugs used alone. 

• About Lumakras
• Understanding Precision Cancer Medicines for Colon Cancer

References:

1. by phase I clinical trial presented today at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics
2. Govindan et al., Annals of Oncology, Volume 30, Issue Supplement_5, October 2019. ESMO 2019
3. Abstract no: 3 LBA, “KRYSTAL-1: Activity and Safety of Adagrasib (MRTX849) in Advanced/Metastatic Non–Small-Cell Lung Cancer (NSCLC) Harboring KRAS G12C Mutation”, by Pasi Jänne, presented in the Late Breaking and Best Proffered Papers Plenary session 2, channel 1, 15.45 hrs CET on Sunday 25 October:
4. Abstract no: 4 LBA, “KRYSTAL-1: Activity and Safety of Adagrasib (MRTX849) in Patients with Colorectal Cancer (CRC) and Other Solid Tumors Harboring a KRAS G12C Mutation”, by Melissa Johnson, presented in the Targeting Oncogenic RAS signalling: New Approaches To An Old Problem scientific session, Channel 2, 19.30 hrs CET on Sunday 25
5. Abstract 99O_PR ‘KRYSTAL-1: Activity and Preliminary Pharmacodynamic (PD) Analysis of Adagrasib (MRTX849) in Patients (Pts) With Advanced Non–Small- Cell Lung Cancer (NSCLC) Harboring KRASG12C Mutation’ will be presented by Gregory Riely during the Proffered Paper Session on Thursday, 25 March, 14:35-15:55 CET on Channel 1. Journal of Thoracic Oncology, Volume 16, Number 4S, Supplement, April 2021.
6. https://www.prnewswire.com/news-releases/mirati-therapeutics-presents-positive-clinical-data-with-investigational-adagrasib-as-monotherapy-and-in-combination-with-cetuximab-in-patients-with-kras-g12c-mutated-colorectal-cancer-301379950.html
7. Jänne PA, Riely G, Gadgee SM, et al. Adagrasib in non–small-cell lung cancer harboring a KRASG12C mutation. N Engl J Med. 2022;386:22. doi:10.1056/NEJMoa2204619.
8. FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC. News release. FDA. December 12, 2022. Accessed December 12, 2022. https://bit.ly/3WdCKPs
9. https://www.nejm.org/doi/full/10.1056/NEJMoa2308795
10. Mok. ASCO 2024. Abstract LBA8509