Krazati (adagrasib)

P1, N=52, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Aug 2030 --> Dec 2026

A 58-year-old man with KRAS-G12C-mutated stage IVB lung adenocarcinoma initiated first-line treatment with carboplatin + pemetrexed + pembrolizumab...Intravenous methylprednisolone led to rapid defervescence and biochemical improvement...Thereafter, he initiated adagrasib, achieving a durable partial response. This case illustrates discordance between metabolic quiescence and later structural damage in immune checkpoint inhibitor-associated aortitis. This supports long-term structural surveillance, as 18F-FDG PET/CT normalization does not guarantee structural safety.

When combined with EGFR inhibitors (osimertinib and gefitinib) in PC9 cells, the mimics showed a higher rate of growth inhibition compared with the controls and reduced IC50 values. Similarly, conmiR-15/107 enhanced growth inhibition by the KRAS inhibitors sotorasib and adagrasib in H358 cells...Long-term assays showed that the mimics reduced the survival and delayed the proliferation of DTPs in osimertinib-treated PC9 cells as well as sotorasib-treated H358 cells. These findings support conmiR-15/107 as a potential adjunct to targeted therapy, capable of enhancing treatment efficacy and delaying resistance in lung adenocarcinoma.

P2, N=200, Active, not recruiting, Mirati Therapeutics Inc. | Recruiting --> Active, not recruiting

Although covalent inhibitors like sotorasib against KRASG12C have been developed, their efficacy is often limited by acquired resistance...Here, we report DJX-A-KM, a small-molecule degrader of KRASG12C, designed by incorporating an acrylamide warhead into the MRTX849 scaffold...This strategy also enables the development of pan-KRAS degraders against a broader spectrum of KRAS mutations. Our work presents a small-molecule degrader recruiting FBXO28 and provides a blueprint for exploring E3 ligases in protein degradation.

Two covalent inhibitors, sotorasib and adagrasib, which target a specific codon 12 mutation (G12C), had received accelerated approvals for clinical use. This appears to be due to a lack of effect on downstream KRAS effectors such as the ribosomal protein S6, highlighting the need for strategies that take into account potential context-dependent processes. Together with other recent reports on high-affinity binding of MRTX1133 to other non-G12D KRAS mutants, our findings further reveal the usefulness of MRTX1133 as a chemical probe that continues to provide novel insights on KRAS biology and inhibition mechanisms.

While KRAS was long considered undruggable, the development of mutant-specific inhibitors, including covalent inhibitors targeting KRASG12C (such as Sotorasib and Adagrasib) and non-covalent inhibitors targeting KRASG12D (such as Mirati's MRTX1133), has shown promise. In cellular models of KRAS-mutated NSCLC and PDAC, this nanoplatform achieved comparable or superior therapeutic outcomes with respect to the individual drugs. This study provides a compelling proof-of-concept for the in vitro delivery of KRASG12C mutant-specific inhibitors and degraders to human tumors through a tumor microenvironment-activated nanomedicine approach and lays the groundwork for future studies in physiologically relevant models to assess TME-specific activation and tumor selectivity.

P1/2, N=31, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Mar 2028 --> Mar 2029 | Trial primary completion date: Mar 2026 --> Mar 2029

Adagrasib monotherapy yielded a median PFS of 4.4-5.6 months, an OS of 10-19.8 months, and an ORR of 19-23%, while its combination with cetuximab reported a PFS of 6.9 months, an OS of 13.4-15.9 months and an ORR of 34-46%...When combined with panitumumab, 960 mg sotorasib demonstrated better results with a PFS of 5.6-5.7 months, OS of 15.2 months and an ORR of 12.5-30%. Similarly, divarasib monotherapy led to a PFS of 5.6-6.9 months and an ORR of 20%, while its combination with cetuximab resulted in a PFS of 8.1 months and an ORR of 62.5%. Combination therapy of olomorasib and MK-1084, which are new-generation KRAS p.G12C (c.34G > T) inhibitors, with cetuximab also demonstrated highly promising efficacy with ORR of 38-44% and 50%, respectively...Initial results of KRAS-G12C inhibitors appear highly promising when they are combined with anti-EGFR therapy compared to historical therapeutic agents indicated for patients with chemotherapy-refractory CRC. Encouraging benefits warrant frontline trials with these novel therapeutics.

P1, N=40, Not yet recruiting, TOLREMO therapeutics AG | N=90 --> 40

Our results suggest that targeting polyamine metabolism with SAM486A enhances the efficacy of KRASG12C inhibitors and may mitigate resistance. This combination represents a promising therapeutic approach for KRASG12C-mutant NSCLC and warrants further clinical investigation.

P1, N=64, Terminated, Mirati Therapeutics Inc. | Phase classification: P1/2 --> P1 | N=228 --> 64 | Trial completion date: Jul 2026 --> Feb 2026 | Active, not recruiting --> Terminated | Trial primary completion date: Jun 2026 --> Feb 2026; business objectives have changed