SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2024, about 234,580 new cases of lung cancer will be diagnosed and 125,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers.
The KRAS (kirsten rat sarcoma viral oncogene homologue) proto-oncogene encodes a protein that is a member of the small GTPase super family. The KRAS gene provides instructions for making the KRAS protein, which is a part of a signaling pathway known as the RAS/MAPK pathway. By relaying signals from outside the cell to the cell nucleus, the protein instructs the cell to grow, divide and differentiate. The KRAS protein is a GTPase, and converts GTP into GDP. To transmit signals, the KRAS protein must be turned on by binding to a molecule of GTP. When GTP is converted to GDP, the KRAS protein is turned off or inactivated, and when the KRAS protein is bound to GDP, it does not relay signals to the cell nucleus. The KRAS gene is in the Ras family of oncogenes, which also includes two other genes, HRAS and NRAS. When mutated, oncogenes have the potential to change normal cells cancerous.
KRAS is the most frequently mutated oncogene in human cancers and are often associated with resistance to targeted therapies and poor outcomes. The KRAS G12C mutation occurs in approximately 25% of Non Small Cell Lung Cancers (NSCLC) and in 3-5% of colorectal cancers and other solid cancers. KRAS G12C is one of the most prevalent driver mutations in NSCLC and accounts for a greater number of patients than those with ALK, ROS1, RET, and TRK 1/2/3 mutations combined. KRAS G12C cancers are genomically more heterogeneous and occur more frequently in current or former smokers, and are likely to be more complex genomically than EGFR mutant or ALK rearranged cancers. G12C is a single point mutation with a Glycine-to-Cysteine substitution at codon 12. This substitution favors the activated state of KRAS, resulting in a predominantly GTP-bound KRAS oncoprotein, amplifying signaling pathways that lead to oncogenesis.
Adagrasib (KRAZATI®) is a potent, orally available, small molecule covalent inhibitor of KRAS G12C. This drug irreversibly and selectively binds KRAS G12C in its inactive, GDP-bound state. Unlike Sotorasib (LUMAKRAS®), which is also a selective covalent inhibitor of KRAS G12C, Adagrasib has a longer drug half-life of 23 hours, as compared to 5 hours for Sotorasib, has dose-dependent extended exposure, and can penetrate the CNS. Approximately, 27-42% of patients with NSCLC harboring KRAS G12C mutations have CNS metastases, with poor outcomes. The U.S. FDA granted accelerated approval for Adagrasib as a targeted treatment for patients with KRASG12C-mutated locally advanced or metastatic NSCLC who have received at least one prior systemic therapy in December 2022.
KRYSTAL-12 trial is a pivotal, open-label, multicenter, randomized, Phase III study designed to compare Adagrasib against standard-of-care chemotherapy (Docetaxel) in patients with KRASG12C-mutated NSCLC who had received prior platinum-based chemotherapy concurrently or sequentially with anti-PD-(L)1 therapy. In this study, 453 patients were randomized 2:1 to receive either Adagrasib 600 mg orally twice a day (N=301) or Docetaxel 75 mg/m2 IV every 3 weeks (N=152). Importantly, patients in the Docetaxel arm had the option to crossover to Adagrasib upon confirmed disease progression. Patients were stratified by region (non-Asia Pacific versus Asia Pacific) and by whether they received concurrent or sequential chemoimmunotherapy. Patients with stable brain metastases were allowed. Both treatment groups were well balanced. The median age was 64.5 years, 95% of patients had adenocarcinoma histology with metastatic disease and approximately 75% of patients were former smokers and previously received concurrent chemoimmunotherapy. The Primary endpoint of the study was Progression Free Survival (PFS) as assessed by Blinded Independent Central Review (BICR). Secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), Duration of Response (DOR), Safety assessments and Patient-Reported Outcomes. At the time of this analysis, 29% of patients had crossed over from Docetaxel treatment to receive Adagrasib.
With a median follow-up of 9.4 months, the trial met its Primary endpoint, with Adagrasib demonstrating a significant improvement in PFS over Docetaxel (median PFS 5.5 versus 3.8 months; HR=0.58, P<0.0001). The benefit of Adagrasib over Docetaxel was maintained across key subgroups. The ORR was also significantly higher with Adagrasib compared with Docetaxel (32% versus 9%; Odds Ratio 4.68; P<0.0001). The median Duration of Response was 8.3 months versus 5.4 months respectively, and responses were sustained at least 6 months in 64% and 39% of patients, respectively. Among those patients with CNS metastases at baseline, intracranial responses were observed in 24% of patients receiving Adagrasib and 11% of patients receiving Docetaxel, with intracranial Disease Control Rate of 82% and 56%, respectively. There was also a significant benefit in the Patient-Reported Outcomes of median time to deterioration. There were no new safety signals noted with Adagrasib and the safety data was consistent with the known safety profile. Grade 3 or more treatment-related adverse events occurred in 47% of patients treated with Adagrasib and 45.7% of patients treated with Docetaxel and treatment discontinuation rates were 7.7% versus 14.3%, respectively.
In summary, the KRYSTAL-12 trial confirmed Adagrasib as a superior treatment option compared to Docetaxel in patients with previously treated KRASG12C-mutated locally advanced or metastatic NSCLC. Adagrasib significantly improved Progression Free Survival, Overall Response Rate, and Duration of Response, with a notable impact on intracranial disease control rates. Its safety profile was manageable, aligning with expectations from earlier studies. These findings underscore the potential of Adagrasib in this patient population and highlight ongoing research efforts to further optimize treatment strategies in this challenging patient population.
KRYSTAL-12: Phase 3 study of adagrasib versus docetaxel in patients with previously treated advanced/metastatic non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation. Mok TSK, Yao W, Duruisseaux M, et al. J Clin Oncol. 2024;42(suppl 17):LBA8509.
