Targeting KRAS G12C Cancer Mutations

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 non-small cell lung cancers (NSCLC) adenocarcinomas, 4% of colorectal cancers, and 2% of pancreatic cancers as well as smaller percentages of several other difficult-to-treat cancers.

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.

Two drugs targeting KRAS G12C are currently available; Krazati (adagrasib, MRTX849) joined Lumakras (sotorasib) as approved treatments for patients with NSCLC harboring KRAS G12C mutations,^1,3,4,8 These drugs are also being evaluated in colorectal cancer, other solid tumors, and in combination with other therapies. Maximizing the potential of precision cancer medicines targeting KRAS G12C will probably require combination strategies and earlier use of these drugs.

About Krazati (adagrasib-MRTX849)

Krazati is an orally available small molecule that is designed to irreversibly and selectively bind 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.  The FDA granted accelerated approval to adagrasib in combination with cetuximab in June, 2024. In the Krystal clinical trial 94 patients with recurrent locally advanced or metastatic KRAS G12C-mutated CRC were treated with adagrasib plus cetuximab. Overall, 34% responded to treatment (all responses were partial responses) and the median response duration was 5.8 months. Thirty-one percent of responding patients had a DOR of at least 6 months.

NSCLC

The phase 1/2 KRYSTAL-1 clinical trial evaluated Krazati in patients with advanced or metastatic NSCLC with a KRAS G12C mutation and the trial results were updated at the 2023 World Lung Congress in September. After a median follow-up of 26 months, the objective response rate remained at 43%.  The median overall survival duration was 14 months with a 1-year survival rate of 53% and 2-year rate of 31%. The median duration of survival without cancer progression was 7 months and patients experienced a one and two-year rate of 35% and 14% respectively. Patients with CNS metastases achieved a median survival duration of 15 months and remained without cancer progression months on average.^7,18

An even greater response 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 2022 ESMO Congress Adagrasib 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 adagrasib 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. 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

Updated results of the Phase 1/2 KRYSTAL–1 study evaluating Krazati alone or in combination with cetuximab in patients with heavily pretreated colorectal cancer harboring a KRAS^G12C mutation were presented during the Presidential Symposium at the European Society for Medical Oncology Congress (ESMO) 2022.⁶

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. All patients had received a prior fluoropyrimidine-containing regimen. Most patients received an anti-VEGF therapy and approximately 20% of patients in both cohorts had received prior regorafenib and/or TAS102.

• Krazati Monotherapy: Of the 45 clinically evaluable patients who received 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.
• In both groups therapy was well tolerated with acceptable side effects.

Krazati has promising clinical activity in heavily pretreated patients with CRC harboring a KRAS^G12C mutation. The addition of cetuximab to Krazati appears to show further synergistic clinical activity.

• More About Krazati

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About Lumakras (sotorasib)

Lumakras irreversibly inhibits KRAS G12C by permanently blocking it in an inactive GDP-bound state and represents a first-in-class novel small molecular inhibitor that specifically binds to a mutant protein in KRAS which “turns off” the signals it sends to trigger cell division and cancer cell growth.

Results from the CodeBreaK 100 clinical study, evaluating Lumakras (sotorasib) in patients with KRAS G12C-mutant advanced NSCLC confirmed a response rate of 40% and reported an overall survival rate of 51% at one and 32% at 2 years in patients with KRAS G12C–mutant NSCLC the majority of whom were previously treated with both platinum-based chemotherapy and anti–PD-1/PD-L1 treatment. The median duration of response was 12 months and 51% of responders were in response for at least 12 months.^13-16

• More about Lumakras

Novel KRAS G12C Inhibitors 

Divarasib

Divarasib (GDC-6036) is a selective, oral KRAS G12C inhibitor reported to be 5 to 20 times more potent and 10 to 50 times more selective in vitro than the currently approved KRAS G12C inhibitors Lumakras and Krazati in colon cancer.

In an early phase trial published in Sept 2023 a response rate of 53% was reported for NSCLC and 29% for advanced colon cancer. The median time to cancer progression was 13.1 and 5.6 months respectively for single agent divarasib in NSCLC and colon cancer. Divarasib was well tolerated, and nausea, diarrhea, and vomiting were the main reported side effects.

In patients with colorectal cancer treated with the Divarasib-Erbitux combination was reported to produce an overall response rate of 62% which is twice the 36% response rate reported for Divarasib as a single agent.^10,11

An upcoming phase 1/1b INTRINSIC study (NCT04929223) is recruiting patients with colon cancer for treatment with divarasib plus Erbitux with or without FOLFOX (leucovorin calcium, fluorouracil, and oxaliplatin) and the phase 2/3 BFAST study (NCT03178552) is recruiting patients with NSCLC.

LY3537982

Initial trail results of LY3537982, an investigative KRAS G12C inhibitor we released at AACR 2023. An overall response rate of 38% was reported for patients with NSCLC who did not receive prior treatment with a KRAS G12C inhibitor. Across patients with CRC (n = 20), pancreatic (n = 12), or other tumor types (n = 21), the response rates were 10%, 42%, and 52%, respectively^.9

LY3537982-Combinations

LY3537982 plus pembrolizumab (Keytruda). Nine patients who were KRAS G12C inhibitor naïve were evaluable and had an ORR of 78% with all 7 responders achieving a partial response. Four patients who had prior treatment with a KRAS G12C inhibitor had an ORR of 25% with 1 patient achieving a PR and 2 patients reporting stable disease for a DCR of 75%.

LY3537982 in combination with cetuximab (Erbitux) produced a response rate of 45% in 5 patients with advanced colon cancer. Enrollment is ongoing for both the NSCLC and CRC combination cohorts, as well as the other dose-expansion cohorts.

IBI351 KRAS G12C+ Advanced NSCLC

Updated results in 67 patients with NSCLC receiving the inhibitor were presented at the 2023 American Association for Cancer Research Annual Meeting. Researchers reported a 67% partial response rate in advanced NSCLC patients with a KRAS G12C mutation.¹²INLINE.

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. Murciano-Goroff YR, Heist RS, Kuboki Y, et al. A first-in-human phase 1 study of LY3537982, a highly selective and potent KRAS G12C inhibitor in patients with KRAS G12C-mutant advanced solid tumors. Cancer Res. 2023;83(suppl 8):CT028. doi:10.1158/1538-7445.AM2023-CT028
10. Desai J, Han SW, Lee JS, et al. Phase Ib study of GDC-6036 in combination with cetuximab in patients with colorectal cancer (CRC) with KRAS G12C mutation. Cancer Res.2023;83(suppl 8):CT029. doi:10.1158/1538-7445.AM2023-CT029
11. Desai J, Han SW, Forster MD, et al. Phase Ia study to evaluate GDC-6036 monotherapy in patients with colorectal cancer (CRC) with KRAS G12C mutation. Ann Oncol. 2022;33 (suppl 7):S701-702. doi:10.1016/j.annonc.2022.07.500
12. Zhou Q, Xu C, Yang N, et al. Phase 1 study of IBI351 (GFH925) monotherapy in patients with advanced solid tumors: updated results. Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, FL. Abstract CT030.
13. DA approves first targeted therapy for lung cancer mutation previously considered resistant to drug therapy. News release. FDA. May 28, 2021. . https://bit.ly/3c172Ah
14. AACR-NCI-EORTC 2021, Abstract LBA6581, and LBA6580.
15. Dy GK, Govindan R, Velcheti V, et al. Long-term outcomes with sotorasib in pretreated KRASp.G12C-mutated NSCLC: 2-year analysis of CodeBreaK100. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022, New Orleans, LA. Abstract CT008.
16. KRAS G12C inhibitor sotorasib may offer long-term clinical benefit in patients with non-small cell lung cancer. News release. American Association for Cancer Research; April 10, 2022. Accessed April 10, 2022. https://bit.ly/3rhUk8a
17. Sacher A, LoRusso P, Patel MR, et al. Single-agent divarasib (GDC-6036) in solid tumors with a KRAS G12C mutation. N Engl J Med. 2023;389(8):710-721. doi:10.1056/NEJMoa2303810
18. Gadgeel SM, Jänne PA, Spira AI, et al. KRYSTAL-1: two-year follow-up of adagrasib (MRTX849) monotherapy in patients with advanced/metastatic KRASG12C-mutated NSCLC.Presented at: International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer; September 9-12, 2023; Singapore.