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by Dr. C.H. Weaver M.D. 6/2022

The investigational KRAS G12C inhibitor drug Adagrasib (MRTX849) yielded clinical responses in patients with non-small cell lung cancer (NSCLC) and colorectal cancer, and other solid tumors harboring KRAS G12C mutations, according the results of a from the phase I - II Krystal clinical trials.1,3,4

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.

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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.

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About Adagrasib (MRTX849)

Adagrasib is an investigational, 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 adagrasib 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 adagrasib was observed in the subpopulation of patients whose cancers had an STK11 mutation as well as a KRASG12C 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 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. 

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Updated results of the Phase 1/2 KRYSTAL–1 study evaluating adagrasib alone or in combination with cetuximab in patients with heavily pretreated colorectal cancer harboring a KRASG12C mutation were presented during the Presidential Symposium at the European Society for Medical Oncology Congress (ESMO) 2022.6

About The KRYSTAL-1 Clinical Trial

KRYSTAL is a Phase 1/2 trial in patients who have a KRASG12C mutation. The phase 1b portion of the study included patients evaluating adagrasib alone. The phase 2 part of the trial include adagrasib monotherapy in CRC, and other solid tumors.

Preliminary data for 46 patients with pre-treated CRC who received adagrasib monotherapy and 32 patients with pre-treated CRC who received the adagrasib + 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. 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. 

  • Adagrasib 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.
  • Adagrasib + 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.

Adagrasib has promising clinical activity in heavily pretreated patients with CRC harboring a KRASG12C mutation. The addition of cetuximab to adagrasib appears to show further synergistic clinical activity. 

Over the last several years the clinical successes of genotype-directed therapy for patients with EGFR-mutated and ALK-rearranged lung cancers has been impressive. KRAS-mutant lung cancer however is much more common, and it finally appears as though researchers are zeroing in on its treatment with precision medicines. In addition to Adagrasib another medication Lumakras (sotorasib-AMG510) was approved by the FDA in May 2021. Doctors may finally have a treatment for this difficult to treat genetically driven 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