KRAS is a well-known oncogene that is highly prone to mutations in various cancers, including PDAC, NSCLC, and CRC. These mutations are associated with poor prognosis and high fatality rates. The discovery of driver genes and the development of specific inhibitors have significantly transformed cancer treatment approaches and improved clinical outcomes.
Targeted therapies have been shown to prolong progression-free survival and exhibit lower toxicity compared to standard chemotherapy. However, despite several decades of research, there have been limited effective strategies for targeting KRAS mutations, except for recent advancements like LUMAKRAS (sotorasib) and KRAZATI (adagrasib), which have been approved to target a specific mutated form of KRAS known as KRASG12C.
Targeting KRAS directly has been a formidable challenge due to its intrinsic characteristics. As a result, researchers have explored alternative approaches, such as targeting downstream signaling molecules, employing epigenetic methods like telomerase inhibitors and RNA interference, and utilizing synthetic lethality strategies involving cyclin-dependent kinase inhibitors.
Signaling within cells is a key function of KRAS, and KRAS mutations are intimately linked to the onset and development of tumors. If effective, attacking mutant KRAS might open up a new path for targeted oncology treatment. However, it has been difficult to directly target KRAS, thus scientists are now concentrating on RAF, ERK, and MEK as other important molecules in the KRAS signaling cascade.
Regrettably, despite years of research, there have been limited breakthroughs in effectively treating KRAS-driven tumors using current strategies. One of the major challenges lies in the heterogeneity observed in KRAS-mutant tumors, which contributes to the lack of success in targeting KRAS nonspecifically. Consequently, there is an urgent need for highly selective inhibitors that can precisely target different mutant KRAS variants. This demand aligns perfectly with the principles of precision oncology, where tailored therapies hold the key to unlocking better treatment outcomes.
Harmful mutations in the KRAS gene have been identified as the primary cause of cancer for numerous individuals over many years. However, until May 2021, no effective treatments were available to counteract the cancer-promoting actions of mutant KRAS proteins. The FDA granted accelerated approval to a drug called LUMAKRAS (sotorasib) to address this issue. LUMAKRAS is designed to treat patients with non-small cell lung cancer (NSCLC) that has either spread locally (locally advanced) or to distant parts of the body (metastatic).
These patients must have previously undergone at least one other systemic cancer treatment, such as chemotherapy, and possess a specific KRAS mutation known as G12C in their tumors. LUMAKRAS has also been approved in 50 countries worldwide.
Unleashing the Light: Advancing LUMYKRAS for Precision Targeting in Diverse KRAS Cancers
Sotorasib, the active compound in LUMAKRAS, acts as a selective and irreversible inhibitor of KRASG12C. By binding covalently to a specific pocket in the inactive form of the KRAS protein, known as the GDP-bound conformation, sotorasib effectively immobilizes KRASG12C, preventing its oncogenic signaling.
The FDA’s approval of LUMAKRAS was based on early findings from a study involving 124 patients with KRAS G12C-mutant NSCLC who had undergone previous treatments. In the clinical trial, named CodeBreak 100, sotorasib demonstrated the ability to reduce tumor size in 36% of participants, with these responses lasting for an average of 10 months. This is particularly noteworthy when compared to standard therapies, which typically achieve tumor shrinkage in less than 20% of patients with recurrent NSCLC following prior treatment, and such effects tend to be short-lived.
LUMAKRAS has received regulatory approval from the Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK for the treatment of NSCLC in September 2021. In March 2022, National Institute for Health and Care Excellence (NICE) published its final appraisal document recommending Lumykras. It has also been approved in Europe and Japan in January 2022.
The company responsible for LUMAKRAS is actively exploring its potential through a comprehensive global clinical development program that encompasses various cancer types, including NSCLC, CRC, and other solid tumors. They have recently completed the submission of Phase III confirmatory data from the LUMAKRAS CodeBreak 200 trial, along with data from a Phase II dose comparison substudy, to both the FDA and the European Medicines Agency (EMA). Additionally, they have fully enrolled participants in a Phase III study evaluating LUMAKRAS in combination with VECTIBIX as a third-line treatment for CRC, and the results are expected to be available in the second half of 2023.
Moreover, the company plans to present data from a combination study involving LUMAKRAS and standard chemotherapy in NSCLC, as well as data from a study combining LUMAKRAS with VECTIBIX and standard chemotherapy in CRC, at the American Society of Clinical Oncology (ASCO) annual meeting in 2023. These presentations will shed light on the progress made and the potential benefits of using LUMAKRAS in combination therapies for these specific cancer types.
During the Phase 1b trials (CodeBreak 100/101), which evaluated different doses of LUMAKRAS in combination with either KEYTRUDA or TECENTRIQ, liver toxicity, a known autoimmune-related side effect of checkpoint inhibitors, was observed. Severe liver toxicity at grades 3 or 4 was observed in 50% of the participants. This concern regarding liver safety was amplified by the fact that the combinations only resulted in a response rate of 29% among the 58 patients enrolled in various cohorts. In contrast, LUMAKRAS administered as a standalone treatment showed a response rate of 36%, which increased to 41% with extended follow-up.
Despite the liver toxicity issue, the company has decided to proceed with the combination of LUMAKRAS and KEYTRUDA in the dose-expansion phase of the study, specifically focusing on treatment-naïve NSCLC patients. However, they have modified the approach by using a lower dose of LUMAKRAS (240mg) as a standalone treatment initially, before introducing KEYTRUDA.
Breaking Boundaries in Cancer Treatment: KRAZATI Redefines KRAS Inhibition, Inspiring Hope for a Range of Patients
Amgen initially claimed the crown as the pioneering company with the first approved KRAS inhibitor in the market. However, their moment in the spotlight was fleeting, as KRAZATI (adagrasib) swiftly emerged the following year, closely followed by the approval of sotorasib. This rapid succession in the KRAS inhibitor landscape marked an intriguing and dynamic shift, highlighting the fierce competition and groundbreaking advancements in the field.
KRAZATI, an inhibitor of the RAS GTPase family, has received approval for the treatment of locally advanced or metastatic NSCLC in adult patients with the KRAS G12C mutation. This approval was based on the results of the KRYSTAL-1 clinical trial, which involved 112 patients. These patients had previously undergone platinum-based chemotherapy and treatment with an immune checkpoint inhibitor, but their disease had progressed. The trial showed that KRAZATI achieved an overall response rate (ORR) of 43%, indicating a significant reduction in tumor size for many patients. The median duration of response (DOR) was measured at 8.5 months. The FDA has granted adagrasib fast-track, breakthrough therapy, and orphan drug designations for the treatment of NSCLC, highlighting its importance in addressing the unmet medical needs of this patient population.
The launch of KRAZATI coincided with a decrease in sales for LUMAKRAS. Amgen attributed this decline to a price adjustment made as part of a reimbursement agreement in Germany. Adagrasib, a KRAS inhibitor, has been included as the recommended treatment in the National Comprehensive Cancer Network (NCCN) guidelines for CNS cancers. It is specifically recommended for patients with KRAS-mutated NSCLC that has spread to the CNS, as well as for patients with KRAS-mutation-positive pancreatic adenocarcinoma. This recognition in the NCCN guidelines emphasizes the significance of adagrasib as a targeted therapy for these specific patient groups.
The company is currently enrolling participants in the KRYSTAL-10 clinical study, a Phase III trial for patients with second-line CRC. This study aims to evaluate the combination of adagrasib and cetuximab compared to chemotherapy. The enrollment process is expected to be completed by the end of 2023. Additionally, the FDA has granted Breakthrough Therapy Designation (BTD) to adagrasib in combination with cetuximab for the treatment of advanced CRC with the KRASG12C mutation. This designation applies to patients whose cancer has progressed after prior treatment with chemotherapy and anti-VEGF therapy. The company is preparing a supplemental New Drug Application (SNDA) for the use of adagrasib in third-line and beyond CRC treatment and plans to submit it to the FDA by the end of 2023.
The company intends to share updated data on the combination of adagrasib with pembrolizumab in first-line NSCLC and the first-line development plans in the second half of 2023. Additionally, data from the Phase III study (KRYSTAL-12) comparing adagrasib to docetaxel in second-line NSCLC will be presented in 2024.
Amgen and Mirati Therapeutics are leading the charge in a thrilling race to develop groundbreaking KRAS inhibitors for cancer treatment. Their cutting-edge candidates have shown remarkable success in targeting G12C-mutant tumors, but there’s a critical gap that remains—an urgent need for treatments that address other variants of the KRAS gene. This unmet need presents a compelling challenge that has captured the attention of numerous key players in the field. These visionary researchers are now forging ahead, exploring alternative KRAS variants and expanding their research horizons to encompass a diverse array of cancer types beyond NSCLC. This bold shift in focus holds tremendous potential for the development of truly transformative therapies that can unlock the secrets of a wider spectrum of KRAS mutations and effectively target multiple types of cancer. Brace yourself for an era of breakthroughs as the quest for comprehensive KRAS inhibition takes center stage in the fight against cancer.
