Results From the KRYSTAL Study Support Adagrasib Use in KRAS G12C–Mutant NSCLC

An investigational KRAS G12C inhibitor for treating patients with non–small cell lung cancer demonstrates high response rates in pretreated disease and infers viability of this therapy approach.

In a presentation at the European Lung Cancer Virtual Congress 2021, clinical activity with the investigational, highly selective, oral small molecular inhibitor adagrasib was seen in patients with non–small cell lung cancer (NSCLC) and mutations in KRAS G12C, confirming feasibility of the oncogene as a therapeutic target in this tumor type.1

Results were presented from the phase 1/2 KRYSTAL study (NCT03785249), which evaluated adagrasib in 79 patients with advanced or metastatic NSCLC with mutant KRAS G12C, most of whom (92%) were previously treated with chemotherapy and a PD-1/L1 inhibitor.

“As we strive to identify the oncogenic driver in more and more of our patients with NSCLC, it becomes critical that we develop therapies that can target these identified oncogenic drivers,” Gregory Riely, MD, PhD, of the Memorial Sloan Kettering Cancer Center and lead study author, said in a press release. “KRAS mutations are the most frequent oncogenic driver that we see in patients with NSCLC, and we’ve known about KRAS-mutant NSCLC for 30 years. We are now, finally, seeing drugs that can target this subgroup of patients.”

In 51 patients evaluated for clinical activity, 23 (45%) had a partial response to therapy and 26 had stable disease. In a sub-population of patients with co-mutations in STK11 (n = 14), the objective response rate (ORR) was 64%.2

“The 45% response rate is unprecedented activity in patients with KRAS G12C–mutant NSCLC,” Myung-Ju Ahn, MD, from Samsung Medical Center at Sungkyunkwan University School of Medicine in Seoul, Korea, said in a press release. “A response of this magnitude could not be expected with other chemotherapy or immunotherapy in pre-treated KRAS-mutated patients, suggesting that KRAS G12C is a therapeutic target.”

In a pharmacodynamic and mechanistic biomarker analysis of 3 patients with pre- and post-treatment tumor biopsies, it was revealed that therapy resulted in downregulation of KRAS/MAPK pathway genes. In patients with co-mutations in STK11, low expression of immune transcripts such as CD4 and CD8 were noted at baselines and were increased after adagrasib therapy, which may suggest a potential immune response.

Positive responses in those with STK11 co-mutations are promising given that these patients typically have an inferior response to immune checkpoint inhibition. “Finding that the response rate was higher for patients with STK11 mutations suggests that this group of patients, who otherwise don’t benefit from checkpoint inhibitors, may have even better response to adagrasib.”

Adagrasib demonstrated a tolerable safety profile, with common (>20%) treatment-related adverse events including nausea (54%), diarrhea (48%), vomiting (34%), fatigue (28%), and increased alanine aminotransferase (23%).

“Given the low toxicity, adagrasib could potentially be combined with chemotherapy, immunotherapy or other molecules to increase activity in patients with KRAS G12C­–mutant NSCLC,” Ahn said.

Notably, results from this study are comparable with those of KRAS G12C inhibitor sotorasib, which were presented from the CodeBreaK 100 trial (NCT03600883) at the recent International Association for the Study of Lung Cancer’s 2020 World Conference on Lung Cancer Singapore.3 The confirmed ORR and disease control rates were 37.1% and 80.6%, respectively, at a median follow-up of 12.2 months. The median duration of response was 10 months.

“Having more KRAS G12C inhibitors gives us additional opportunities to explore combinations of these inhibitors with other classes of agents, including immune checkpoint inhibitors as well as other small molecule MAP kinase inhibitor combinations,” said Riely.

References

1. Second drug targeting KRASG12C shows benefit in mutated non-small-cell lung cancer. News release. European Society for Medical Oncology. March 29, 2021. Accessed March 29, 2021. https://bit.ly/3rrYKGI

2. Riely G, Ou SI, Rybkin I, et al. 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. J Thoracic Oncol. 2021;16(suppl 4):99O_PR. https://bit.ly/3rvczEd

3. Li BT, Skoulidis F, Falchook G, et al. CodeBreaK 100: Registrational Phase 2 Trial of Sotorasib in KRAS p.G12C Mutated Non-small Cell Lung Cancer. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual. Abstract PS01.07.