Introduction to Adagrasib
Adagrasib, developed by Mirati Therapeutics Inc. and Zai Lab Limited, is a groundbreaking oral, selective KRAS G12C inhibitor. This drug has been making significant waves in the oncology field, particularly for patients with non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) harboring the KRAS G12C mutation.
Clinical Trials Update
KRYSTAL-1 Trial
The KRYSTAL-1 trial, a multicohort Phase 1/2 study, has been pivotal in demonstrating the efficacy of adagrasib. This trial evaluated adagrasib as a monotherapy or in combination for patients with KRAS G12C-mutated solid tumors. Key findings include:
- Objective Response Rate (ORR): 43.0% with a median duration of response (DOR) of 12.4 months[1][5].
- Median Progression-Free Survival (PFS): 6.9 months[1][5].
- Median Overall Survival (OS): 14.1 months, with 52.8% of patients alive at one year and approximately one in three patients (31.3%) alive at two years[1][5].
KRYSTAL-7 Trial
The KRYSTAL-7 Phase 2 study explored the combination of adagrasib with pembrolizumab in first-line NSCLC patients with a KRAS G12C mutation. The results showed:
- ORR and Disease Control Rate (DCR): 63% ORR and 84% DCR in patients with PD-L1 TPS ≥50%[3].
- Safety Profile: Manageable, with a low rate of treatment-related adverse events (TRAEs) leading to discontinuation[3].
KRYSTAL-12 Trial
The pivotal Phase 3 KRYSTAL-12 study evaluated adagrasib as a monotherapy in patients with pretreated locally advanced or metastatic NSCLC harboring a KRAS G12C mutation. The trial met its primary endpoint of progression-free survival (PFS) and the key secondary endpoint of ORR, showing a statistically significant and clinically meaningful benefit compared to standard-of-care chemotherapy[4].
Market Analysis
Competitive Landscape
Adagrasib enters a market where KRAS inhibitors are gaining traction, particularly for NSCLC. Here are some key points:
- NSCLC Market: Adagrasib competes directly with Amgen’s LUMAKRAS, another KRAS G12C inhibitor. However, early data suggest that adagrasib may offer greater efficacy and safety compared to LUMAKRAS[2].
- CRC Market: Adagrasib has the potential to be the first-in-class KRAS inhibitor approved for use in combination with ERBITUX in previously treated KRAS G12C-mutation-positive metastatic CRC, with no direct competition in this niche[2].
Market Potential
Despite being second to market for NSCLC, adagrasib's clinical success is highly likely due to the significant unmet need for effective therapies in this biomarker-defined population. Here are some projections:
- Sales Potential: While the smaller patient population for KRAS G12C mutations might limit overall sales, the drug's potential in both NSCLC and CRC markets is substantial. Early estimates suggest a potential market value of $1.23 billion[2].
- Combination Therapies: The potential for combination with immunotherapies, such as pembrolizumab, further enhances adagrasib's market prospects. This combination has shown promising early signs of durability and a manageable safety profile[3].
Gaps in Treatment Adagrasib Fills
Unmet Clinical Needs
Adagrasib addresses several critical gaps in the treatment of KRAS-mutant cancers:
- Limited Treatment Options: Current therapies for KRAS-mutant cancers are not wholly effective, and patients often have few options after progressing from previous treatments. Adagrasib provides a targeted and more effective treatment option[2].
- Baseline Treated CNS Metastases: Adagrasib has shown clinical benefit for patients with baseline treated, stable CNS metastases and co-mutations such as KEAP1, STK11, or TP53[1].
CNS Penetration
Adagrasib's ability to penetrate the central nervous system (CNS) is a significant advantage, offering hope for patients with CNS metastases, a common complication in advanced cancers[3].
Hurdles to Blockbuster Status
Competition and Market Dynamics
To achieve blockbuster status, adagrasib must overcome several hurdles:
- Early Market Entry by Competitors: Amgen’s LUMAKRAS has the advantage of being earlier to market, although adagrasib's potential for superior efficacy and safety could influence its uptake[2].
- Dosage Frequency: Adagrasib's twice-daily administration compared to LUMAKRAS's once-daily administration may impact patient preference and compliance[2].
Regulatory Approvals and Recommendations
FDA and EMA Approvals
- FDA Approval: Adagrasib received accelerated approval from the U.S. FDA in December 2022 for patients with previously treated KRAS G12C-mutated advanced/metastatic NSCLC[1].
- EMA and MHRA Review: The European Medicines Agency (EMA) and the Medicines and Healthcare products Regulatory Agency (MHRA) are currently reviewing adagrasib for approval[1].
CHMP Recommendation
The Committee for Medicinal Products for Human Use (CHMP) has recommended adagrasib for pretreated KRAS G12C+ advanced NSCLC, marking an important step towards European approval[5].
Safety and Tolerability
Adverse Events
The safety profile of adagrasib has been favorable:
- Manageable Adverse Events: Most treatment-related adverse events were low grade, with fewer gastrointestinal TRAEs and no grade ≥3 hepatotoxicity in patients who had received prior immunotherapy[1].
- Combination Therapy Safety: The combination of adagrasib with pembrolizumab showed a consistent safety profile with either agent as monotherapy, with a low rate of TRAEs leading to discontinuation[3].
Expert Insights
Clinical Benefits
"Data presented to date indicate that adagrasib prescribed following or in combination with immunotherapy offers a tolerable safety regimen for first-line NSCLC patients with a KRAS G12C mutation," said Marina C. Garassino, M.D., professor of medicine, UChicago Medicine[3].
Market Impact
"The study data demonstrates compelling results, providing hope for patients with this specific mutation," said Shirish Gadgeel, MD from Henry Ford Cancer Institute. "Exploratory analyses indicated that adagrasib provided promising clinical benefit for a broad group of patients"[1].
Key Takeaways
- Efficacy: Adagrasib has demonstrated durable clinical activity in KRAS G12C-mutated NSCLC, with significant ORR, DOR, PFS, and OS rates.
- Safety: The drug has a manageable safety profile, both as monotherapy and in combination with immunotherapies.
- Market Potential: Adagrasib has substantial market potential, particularly in filling unmet clinical needs for KRAS-mutant cancers.
- Regulatory Approvals: Adagrasib has received FDA approval and is under review by EMA and MHRA, with a CHMP recommendation for European approval.
FAQs
What is adagrasib and how does it work?
Adagrasib is an oral, selective KRAS G12C inhibitor that targets the KRAS G12C mutation, a common mutation in certain cancers like NSCLC and CRC. It works by inhibiting the KRAS G12C protein, thereby preventing cancer cell growth and proliferation.
Which cancers is adagrasib approved for?
Adagrasib has received accelerated FDA approval for previously treated KRAS G12C-mutated advanced/metastatic NSCLC. It is also being evaluated for use in CRC and other solid tumors.
How does adagrasib compare to other KRAS inhibitors like LUMAKRAS?
Adagrasib may offer greater efficacy and safety compared to LUMAKRAS, although it requires twice-daily administration. Early data suggest that adagrasib could be a preferred option due to its clinical benefits.
What are the common side effects of adagrasib?
Adagrasib has a manageable safety profile with mostly low-grade adverse events. Common side effects include gastrointestinal issues, but there are no significant hepatotoxicity concerns.
Is adagrasib used in combination with other therapies?
Yes, adagrasib is being evaluated in combination with immunotherapies like pembrolizumab. These combinations have shown promising early signs of durability and a manageable safety profile.
Sources
- International Association for the Study of Lung Cancer. "KRYSTAL-1 Trial Finds that Adagrasib Demonstrates Durable Clinical Activity." September 10, 2023.
- Clarivate. "Adagrasib."
- Mirati Therapeutics, Inc. "Mirati Presents Late-Breaking Results Evaluating the Combination of Adagrasib and Pembrolizumab in First-Line Non-Small Cell Lung Cancer (NSCLC)." October 17, 2023.
- Bristol Myers Squibb. "Bristol Myers Squibb Announces Pivotal KRYSTAL-12 Confirmatory Trial Evaluating KRAZATI (adagrasib) Meets Primary Endpoint of Progression-Free Survival for Patients with Pretreated KRAS G12C-Mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer." March 28, 2024.
- Onclive. "CHMP Recommends Adagrasib for Pretreated KRAS G12C+ Advanced NSCLC." November 14, 2023.
