KRAS: Old Target, New Hope

KRAS: Old Target, New Hope

Systemic, Targeted, & Immune Therapies
Jun 18, 2021
Leah Lawrence
As more data emerge and more investigational drugs are studied, the “undruggable” target is coming into focus.
Tetsuya Mitsudomi

The KRAS gene is thought to be mutated in about 30% of patients with lung adenocarcinoma in the United States, according to Tetsuya Mitsudomi, MD, professor in the Division of Thoracic Surgery, Department of Surgery, at Kindai University Faculty of Medicine in Osaka-Sayama, Japan, and President of the IASLC. 

Lungs with tumors

Discovered decades ago, KRAS had long been thought to be an undruggable target. However, the recent development of novel drugs acting against the KRAS G12C mutation have begun to show promise in clinical trials. 

Sotorasib

The first drug, sotorasib (LUMAKRAS, Amgen), was granted priority review by the U.S. Food and Drug Administration (FDA) for an application to treat patients with KRAS G12C–mutated, locally advanced metastatic NSCLC. On May 28, 2021, the drug received formal, conditional approval by the FDA.1

This application is based on the full results of the phase II CodeBreaK 100 clinical trial, which included 126 patients with KRAS G12C mutations whose disease had progressed after no more than three prior therapies. Patients were treated with sotorasib (960 mg once daily) until further disease progression.

Data presented at the IASLC 2020 World Conference on Lung Cancer earlier this year showed durable clinical benefit in a phase I cohort of 59 patients with heavily pretreated disease.2 The objective response rate was 32.2% with a mediation duration of response of almost 11 months. Median PFS was 6.3 months. 

In the full cohort of 124 patients, overall response was 37.1% with a disease control rate of 80.6%. Median time to objective response was 1.4 months with a median duration of response of 10 months. Median PFS was 6.8 months, little changed from the initial cohort.

“This [PFS] is longer compared with other chemotherapeutic trials in patients with KRAS mutations,” Dr. Mitsudomi said. 

He noted that exploratory data were also presented on PD-L1 status and STK11 mutations, and there appeared to be some interesting signals. For example, the response rate appeared to be lower for patients with higher PD-L1 expression, Dr. Mitsudomi said, but only a small number of patients were tested. 

“Stay tuned,” he said. 

Amgen is currently conducting a global phase III trial comparing sotorasib with docetaxel. In late April, Amgen also announced that it would—at the request of the FDA—conduct a post-marketing trial testing the 960-mg once-daily dose against a lower daily dose. 

Adagrasib

“Another similar active drug against G12C is adagrasib,” said Dr. Mitsudomi. “If you see the structure of these two drugs, they are different and may have somewhat complementary roles.”

At the European Lung Cancer Virtual Congress 2021 (ELCC 2021), Gregory J. Riely, MD, PhD, of Memorial Sloan Kettering Cancer Center, and colleagues presented updated data on adagrasib (Mirati Therapeutics), an investigational agent that is a potent, covalent inhibitor of KRAS G12C that irreversibly and selectively binds to KRAS G12C.3

The phase I/II KRYSTAL-1 study evaluated adagrasib at a dose of 600 mg twice daily in 79 patients with pretreated advanced or metastatic NSCLC that harbored the KRAS G12C mutation. The drug demonstrated clinical activity in these patients. 

Of 51 evaluable patients, 23 (45%) had a partial response and 26 (51%) had stable disease. In a subpopulation of patients with STK11 co-mutations, the overall response rate was 64%. Among patients in the phase I population, the duration of response was 8.2 months. 

The most common treatment-related adverse events were nausea (54%), diarrhea (48%), vomiting (34%), fatigue (28%), and increased alanine aminotransferase (23%). Most side effects were grade 1 or 2.

Looking at pre- and post-treatment biopsies, the researchers found down-regulation of KRAS/MAPK pathway genes, including DUSP6 and SPRY4. 

Although the response rate appears to be slightly higher for adagrasib compared to sotorasib, the higher toxicity with adagrasib may be an important difference. Generally, however, both drugs are well-tolerated. Based on these data, the U.S. Food and Drug Administration granted adagrasib Breakthrough Therapy Designation on June 24, 2021 for the potential treatment KRAS G12C NSCLC following prior systemic therapy.

Caveats

Discussing the adagrasib data at ELCC 2021, Alastair Greystroke, PhD, of Newcastle University, United Kingdom, noted that with the inclusion of patients with KRAS G12C mutations, almost half of all patients with lung adenocarcinoma may soon have a targetable abnormality. However, he said that although the data on STK11 is very provocative, it needs to be confirmed in larger cohorts. 

According to Dr. Greystroke, data presented at ELCC 2021 showed that when using this agent at the recommended phase II dose, high concentrations are seen in the blood stream—well above what is needed for potential efficacy. 

“At those levels you can see potential downstream modulation,” Dr. Greystroke said. “This gives us confidence that if we do need to drop the dose to allow potential combination with small molecule inhibitors due to overlapping toxicity of pharmacokinetics, it is safe to do and shouldn’t impact efficacy.”

In fact, trials combining adagrasib with small molecule inhibitors will likely be of great importance, he said. 

“We are already learning a lot about the resistance mechanisms to KRAS G12C inhibitors, which can be both upstream through activation of EGFR, HER2, and FGFR, or downstream mutations in the MAPK/MEK pathway,” he said. 

Indeed, tempered enthusiasm may be warranted. In April, Mark Awad, MD, PhD, of Dana-Farber Cancer Institute, presented late-breaking data on mechanisms of acquired resistance to KRAS G12C inhibition in cancer at the 2021 American Association for Cancer Research Annual Meeting.4

The study looked at patients with mutated NSCLC or colorectal cancer who were enrolled in adagrasib clinical trials and developed subsequent disease progression. At the time of acquired resistance, Dr. Awad and colleagues observed multiple on-target acquired KRAS alterations, including C12W, C12F, C12V, a KRAS G13D mutation, and others. Additional off-target bypass mechanisms of resistance were also detected, such as EGFR or MET amplification; activating NRAS, BRAF, MAP2K1, and RET mutations; and oncogenic fusions involving RET, BRAF, RAF1, and FGFR. 

As research into the KRAS G12C mutation continues, future trials will need to address how to overcome mechanisms of resistance, likely through the development of combination treatment strategies or further advancement of pan-KRAS inhibitors that are designed to interact with active KRAS regardless of mutational status. 

Additionally, KRAS mutations are heterogeneous, with many other mutations outside of G12C. Mirati is also testing a drug that targets KRAS G12D but has delayed initiation of that trial until 2022.

References
  • 1. U.S. Food and Drug Administration. FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC. May 28, 2021. Accessed June 3, 2021. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accel…
  • 2. IASLC. Sotorasib Provides Durable Clinical Benefit for Patients with NSCLC and KRAS Mutations. January 28, 2021. Accessed May 6, 2021. https://www.iaslc.org/iaslc-news/press-release/sotorasib-provides-durab…
  • 3. Riely G, Ou S-HI, Spira A, et al. 990_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. Presented at: European Lung Cancer Virtual Congress 2021; March 25-21, 2021.
  • 4. Awad M, Liu S, Arbour K, et al. LB002—Mechanisms of acquired resistance to KRAS G12C inhibition in cancer. Presented at: American Association for Cancer Research Annual Meeting 2021; April 10-15, 2021; Virtual.

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About the Authors

Leah Lawrence

Contributing Writer