KRAS G12C + STK11 mutation

In this large, multicenter retrospective chart review of patients with KRAS G12C mutant NSCLC we observed a relatively short median rwPFS of 4.6 months among 10 patients with KRAS G12C mutant NSCLC treated with docetaxel with or without ramucirumab in the second-line setting, which aligns with the recently reported CodeBreak 200 dataset.

A multicenter, single-arm, open-label Phase 1/2 clinical study is planned to determine the recommended Phase 2 dose, safety, tolerability, and efficacy for the combination of ada and nab-s in patients with KRAS G12C tumors. $$table_{D2CC43B4-19F7-4EEF-B479-9D4337036322}$$Changes in TGI and Tumor RegressionTumor ModelCombination TreatmentTGI vs Single Agent (%)P Value vs Single Agent for Tumor Growth Curve (ANOVA)Tumor Regression Over 30%P Value vs Single Agents for Rate of Tumor Regression Over 30% (Chi-Square)vs nab-Svs KRASivs nab-Svs KRASiNCI-H2030nab-S + Sotorasib1291110.010.0013/60.03NCI-H2122nab-S + Sotorasib1121060.001<0.0018/10<0.001nab-S + Adagrasib1011000.001<0.0014/100.03UMUC3nab-S + Sotorasib107105<0.001<0.0016/6<0.001nab-S + Adagrasib107107<0.0010.046/60.001ANOVA, analysis of variance; KRASi, KRAS inhibitor; nab-s, nab-sirolimus; TGI, tumor growth inhibition.

Combining mTOR inhibition with KRAS G12C inhibition improves response against tumors in vivo. nab-Sirolimus showed greater potency compared to everolimus and is the preferred agent for further clinical development using this strategy.

This subgroup was associated with a statistically significant lower TTF1 (p = 0.0092) and PD-L1 (p < 0.0001) positivity. This type of combined morphological and molecular analysis can improve our understanding of tumor biology, and help us to identify specific patient subgroups that can achieve the best treatment response.

In 2021 two molecules were approved that target KRAS G12C mutated LUAD, Sotorasib, and Adagrasib, showing a partial response rate of 33,9% for Sotorasib and an overall response of 45% for Adagrasib. We realized a complex characterization of a specific subgroup of KRAS G12C - STK11 co-mutated LAUDs that could have an improved response to KRAS G12C inhibitors. This result is of high interest as previously STK11 mutated LUADs were associated with a poor prognosis, reduced PD-L1 positivity, and resistance to anti-PD1 / anti-PD-L1 blockade.

KRAS G12C LUADs have be- come a major subject of interest after promising clinical trials of Sotorasib... KRAS G12C mutated LUADs represent a particular subtype characterized by a high inflammatory infiltrate, a relatively low PD-L1 positivity and a complex molecular profile with intricate interaction with various genes including STK11. A more in-depth characterization of the tumour histology, surrounding microenviron- ment and molecular profile of this specific subtype of LUAD could be useful to better select the patients that could benefit from novel targeted therapies to achieve the best treatment response.

KRAS-G12C mutations are present in 12% of patients with NSCLC and represent a relevant subtype of NSCLC given KRAS G12C inhibitors now in clinical development . Treatment outcomes to chemo-immunotherapy are similar in patients with G12C and non-G12C subtypes . Outcomes are poor for patients with concurrent STK11 and/or KEAP1 mutations representing a significant unmet need.

This study provides real-world evidence that STK11 co-mutations are associated with worse outcomes among pts with KRAS G12C mutant LUAD treated with first-line ICI . These inferior outcomes indicate a high unmet medical need among LUAD pts harboring co-occurring KRAS G12C and STK11 mutations and demonstrate the need for effective targeted and/or combination therapies in this patient population.