Lumakras (sotorasib)

Sotorasib was associated with significantly improved OS, TTNTD, and TTDD compared with docetaxel in 2 L+ for locally advanced or metastatic NSCLC under real-world conditions in England.

The labeled 960 mg dose did not demonstrate meaningful improvement in efficacy, while toxicity remained substantial. These findings support efforts under Project Optimus to identify the lowest effective dose. Lower doses, including 240 mg, may provide comparable outcomes while reducing toxicity, pill burden, and treatment costs.

P1, N=49, Active, not recruiting, Amgen | Recruiting --> Active, not recruiting | N=500 --> 49 | Trial completion date: Oct 2031 --> Nov 2026 | Trial primary completion date: Oct 2028 --> Oct 2026

Mouse experiments confirmed the biosafety and efficacy of AMG510 combined with 3-MA in vivo. The results of this study revealed that AMG510 exhibited favorable antitumor activity against KRAS G12C-mutant pancreatic cancer in vitro and in vivo, and the combination of AMG510 and 3-MA may represent a candidate therapeutic regimen for the clinical treatment of KRAS G12C-mutant pancreatic cancer.

P1/2, N=13, Not yet recruiting, Orion Corporation

In this MAIC analysis, soto960+pani demonstrated statistically significant improvement in response rates and OS in patients with chemorefractory KRAS G12C-mutated mCRC.

KRASG12C inhibitors such as adagrasib and sotorasib have shown promise in treating KRASG12C- mutant non-small cell lung cancer (NSCLC), but treatment resistance remains a major challenge. Given the observed HER2 expression in a subset of patient tumors, this combination is promising and it is currently under investigation (NCT07012031). Our findings also highlight the limitations of applying current HER2 IHC interpretation guidelines to NSCLC, underscoring the need for optimized assays to guide patient treatment selection.

In contrast, in NCI-H358 cells, forskolin increased CREB phosphorylation but failed to rescue sotorasib-induced growth inhibition, highlighting a pronounced cell type-dependent response to sotorasib. Collectively, our findings identify suppression of the cAMP/PKA/CREB signaling axis as a key mechanism underlying sotorasib-induced intestinal epithelial injury and provide mechanistic insight into the tissue-selective gastrointestinal toxicity of KRAS G12C-targeted therapy.

Finally, FHD-286 and sotorasib combination treatment results in potent anti-tumor efficacy in both G12Ci-resistant and - sensitive organoid models and in vivo patient-derived xenograft (PDX) systems. These data nominate mSWI/SNF inhibition as a combination strategy to improve KRAS inhibitor efficacy, response duration, and to mitigate emergence of resistance.

These candidates displayed favorable predicted binding energetics, stable ligand-protein interactions over extended simulation timescales, and low structural similarity to clinically approved KRAS G12C inhibitors sotorasib and adagrasib. In cellular NanoBRET target-engagement assays, selected scaffolds, including K788-7251 and AN-989/14669131, exhibited sub-micromolar engagement of KRAS G12C with minimal endothelial cytotoxicity. Collectively, these findings identify structurally distinct, KRAS G12C inhibitor chemotypes and provide tractable starting points for the development of next-generation targeted therapies.

P1, N=104, Recruiting, Bayer | Trial completion date: Mar 2028 --> May 2027 | Trial primary completion date: Jul 2027 --> Jan 2027