KRASG12C is one of the most common driver oncogenes in lung cancer, occurring in nearly 14% of lung adenocarcinomas. Adagrasib (KRAZATI) is a potent covalent KRASG12C inhibitor, which has demonstrated deep and durable responses with promising PFS and OS in patients with previously treated, advanced KRASG12C-mutated NSCLC, including in those with brain metastases, in the Phase II KRYSTAL-1 trial. The primary analysis from the confirmatory, randomized, open-label Phase III KRYSTAL-12 trial comparing adagrasib vs docetaxel in patients with advanced KRASG12C-mutated NSCLC who had previously received chemotherapy and immunotherapy was recently reported at ASCO. In the Phase III KRYSTAL-12 trial, adagrasib demonstrated a statistically significant and clinically meaningful improvement in PFS over docetaxel in patients with previously treated KRASG12C-mutated NSCLC. PFS benefit was observed across key subgroups. 

After a median follow-up of 9.4 months, patients treated with adagrasib demonstrated a median PFS of 5.5 months, compared with 3.8 months with standard-of-care chemotherapy, reducing the risk for disease progression by 42%. ORR was also significantly higher with adagrasib vs docetaxel (32% vs 9%). in Addition, the disease control rate (DCR) was 78% with adagrasib, compared with 59% with docetaxel.Adagrasib showed intracranial efficacy among patients with brain metastases at baseline, with a response rate that was more than double that observed with docetaxel. Overall, the responses were deep and appeared to be durable. 

The safety profiles of adagrasib and docetaxel were consistent with previous reports, with no new safety signals. These results reinforce adagrasib as an efficacious treatment option for patients with KRASG12C-mutated NSCLC after disease progression on prior chemotherapy and immunotherapy. Nevertheless, despite the substantial reduction in risk and successful achievement of the study's primary endpoint, adagrasib merely extended PFS by 1.65 months in addition to docetaxel, reaching a median of 5.49 months (PFS to 5.5 months versus 3.8 months). The modest increase in median PFS may present challenges for Bristol Myers Squibb in persuading the US FDA regarding adagrasib's efficacy.

A Phase III trial comparing first-line adagrasib plus pembrolizumab vs pembrolizumab alone is currently enrolling patients with advanced KRASG12C-mutated NSCLC and PD-L1 TPS ≥ 50% (KRYSTAL-7; NCT04613596).

KOL insights

“The upper bound of the docetaxel range is the lower bound of the adagrasib range. It’s important that we have to think about from a patient’s perspective: Would you rather have your disease controlled for two and a half months? Or would you like to take a chance to six and a half” – Expert Opinion.

“So far, KRYSTAL-12 hasn’t accrued enough deaths to be able to do an overall survival analysis, and BMS remained blinded on that endpoint.” – Expert Opinion.

Conclusion

The identification of G12C inhibitors has sparked increased interest in developing novel  inhibitors specifically targeting other prevalent KRAS mutations. KRAS mutations are seen most frequently in pancreatic cancer, followed by CRC and NSCLC. The most frequent KRAS variant observed in NSCLC is G12C. In addition, the most common  KRAS variation in CRC and pancreatic cancer is G12D. Clinical development efforts are underway to explore alternative strategies for targeting KRAS beyond G12C inhibitors, such as cancer vaccines, adoptive cell therapy, PROTACs, and CRISPR/Cas9. Emerging KRAS key players are strategically prioritizing safer combination therapies with reduced toxicity, aiming to improve treatment outcomes and enhance patient care for KRAS-mutant cancers. As per DelveInsight’s estimates, the market size of KRAS inhibitors in the 7MM is expected to reach USD 9.5 million by 2032. Since the majority of treatments for NSCLC  now target the G12C variant, this variant type is likely to become very crowded and competitive. Future opportunities in G12C may be found in R/R patient’s pool of approved  KRAS drugs and in the first-line setting.

Adagrasib received accelerated approval in the US, and conditional approval in Europe for previously treated locally advanced or metastatic NSCLC harboring a KRASG12C mutation. Adagrasib is recommended by the NCCN Clinical Practice Guidelines in Oncology as category 2A in patients with advanced KRASG12C-mutated NSCLC and brain metastases. 

The confirmatory Phase III KRYSTAL trials have demonstrated the significant efficacy of adagrasib in treating KRASG12C-mutated NSCLC, marking a substantial advancement for lung cancer patients. Despite its modest difference in median PFS compared to docetaxel, adagrasib's deep and durable responses, along with its favorable safety profile, reinforce its position as a valuable treatment option for patients who have progressed on prior chemotherapy and immunotherapy. The ongoing Phase III KRYSTAL-7 trial investigating adagrasib in combination with pembrolizumab holds promise for further enhancing outcomes in this patient population. 

The FDA recently declined Amgen's request for full approval of LUMAKRAS in NSCLC, citing concerns about the reliable interpretation of the primary endpoint in the Phase III trial, CodeBreak 200. Despite the setback, LUMAKRAS remains available in the market as the agency has asked for another confirmatory trial instead of withdrawing it.