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Abstract
KRAS G12C (GTPase KRas, UniProt P01116) KRAS is a constitutively activating point mutation found in ~13% of NSCLC, ~3–4% of CRC, and ~1–2% of PDAC. Once considered undruggable due to the absence of a classical binding pocket, the discovery of the switch-II pocket (S-IIP) enabled covalent inhibitors to lock the protein in its inactive GDP-bound state. This report covers the full competitive landscape: approved drugs, late-stage pipeline, emerging modalities, deal activity, and strategic white spaces as of May 2026.
Traditionally, compiling this level of analysis would require weeks of manual research across platforms like Google Patents and PubMed. With Eureka LS, the same process can be automated—from extracting molecules to mapping competitive pipelines—into a structured output like the report below.
Section I: Target Overview
Biological Profile
KRAS (Kirsten Rat Sarcoma Viral Proto-Oncogene) encodes a small GTPase that cycles between active GTP-bound and inactive GDP-bound states, regulating proliferation via MAPK/ERK and PI3K/AKT pathways. KRAS The G12C missense mutation (glycine → cysteine at codon 12) impairs intrinsic GTPase activity and reduces sensitivity to GAP-mediated hydrolysis, locking KRAS in a constitutively active state. The unique cysteine residue provides a covalent handle exploited by all first-generation inhibitors.
Key Oncology Indications
| Indication | Mutation Frequency | Primary Drugs in Development |
|---|---|---|
| NSCLC (non-squamous) | ~13% | Sotorasib, Adagrasib, Garsorasib, Fulzerasib, Glecirasib, Sosimerasib, Divarasib, Olomorasib |
| Colorectal Cancer | ~3–4% | Sotorasib + panitumumab, Adagrasib + cetuximab, Garsorasib + cetuximab |
| Pancreatic Ductal Adenocarcinoma | ~1–2% | Daraxonrasib, Adagrasib |
Section II: Drug Development History
First-in-Class Milestone
The field was unlocked by the discovery of the S-IIP by Shokat et al. (UCSF), enabling covalent GDP-state trapping. Amgen’s Sotorasib (AMG 510) became the world’s first approved KRAS G12C inhibitor (FDA, May 28, 2021) for 2L+ KRAS G12C-mutant NSCLC. Sotorasib Mirati’s Adagrasib followed (FDA, December 12, 2022), demonstrating broader CNS penetration and activity across multiple tumor types. Adagrasib
Approval Timeline
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Section III: Current Pipeline — Full Competitive Map
Approved Drugs (6 total)
| Drug | Developer | Approval | Indication | MoA |
|---|---|---|---|---|
| Sotorasib | Amgen | FDA May 2021 | NSCLC 2L+ (also CRC combo) | Covalent KRAS G12C inhibitor |
| Adagrasib | Mirati/BMS | FDA Dec 2022 | NSCLC 2L+, CRC combo | Covalent KRAS G12C inhibitor |
| Fulzerasib | Genfleet/Innovent | NMPA Aug 2024 | NSCLC | Covalent KRAS G12C inhibitor |
| Garsorasib | InventisBio/CTTQ | NMPA Nov 2024 | NSCLC | Covalent KRAS G12C inhibitor |
| Glecirasib | Jacobio/Allist | NMPA May 2025 | NSCLC (also PDAC, CRC) | Covalent KRAS G12C inhibitor |
| Sosimerasib | Jiyu/Huyabio | NMPA Feb 2026 | NSCLC | Covalent KRAS G12C inhibitor |
SotorasibAdagrasibFulzerasibGarsorasibGlecirasibSosimerasib
Late-Stage Pipeline (Phase 2/3)
| Drug | Developer | Phase | Key Feature | Indication Focus |
|---|---|---|---|---|
| Divarasib | Genentech/Roche | Phase 3 | High potency, CNS penetration | NSCLC (adjuvant, 1L, 2L) |
| Olomorasib | Eli Lilly | Phase 3 | CNS-penetrant, combination-focused | NSCLC (SUNRAY-02 with IO) |
| Calderasib (MK-1084) | Merck (MSD) | Phase 3 | Pembrolizumab combo | NSCLC adjuvant + 1L |
| Daraxonrasib (RMC-6236) | Revolution Medicines | Phase 3 | RAS(ON) non-covalent, pan-RAS | NSCLC, PDAC (RASolute 301/302/303/304) |
| Opnurasib (JDQ443) | Novartis | Phase 2 | SHP2 combo strategy | NSCLC 1L (low PD-L1/STK11) |
| Setidegrasib (ASP3082) | Astellas | Phase 3 | KRAS G12D focus (also G12C) | NSCLC, PDAC |
| GFH-375 | GenFleet/Hengrui | Phase 2/3 | KRAS G12D-focused | NSCLC, PDAC |
| INCB-161734 | Incyte | Phase 3 | KRAS G12D-focused | PDAC |
| HRS-4642 | Hengrui | Phase 2/3 | Pan-KRAS | PDAC |
DivarasibOlomorasibDaraxonrasib
Emerging Modalities (Phase 1 / Preclinical)
| Drug | Developer | Modality | Key Differentiator |
|---|---|---|---|
| Daraxonrasib | Revolution Medicines | Non-covalent RAS(ON) | Targets active GTP-bound state; pan-RAS coverage |
| Elironrasib | — | Molecular glue | Traps KRAS-SOS1 interface |
| Zoldonrasib | — | Molecular glue | Novel binding mode |
| ARV-806 | Arvinas | PROTAC | Targeted degradation of KRAS G12C |
| Setidegrasib | Astellas | PROTAC | Degrader approach, G12D primary |
| ELI-002 / ELI-002 7P | Elicio Therapeutics | Peptide vaccine | Neoantigen vaccination, adjuvant setting |
| ANOC-002/003, AFNT-211 | Anocca/Affini-T | TCR-T cell therapy | T-cell recognition of KRAS neoantigen |
ElironrasibZoldonrasibARV-806SetidegrasibELI-002
Section IV: Competitive Arena Map
Section V: Clinical Evidence & Key Trial Results
Pivotal Efficacy Data (Selected)
Sotorasib (CodeBreaK 200, Phase 3): Demonstrated PFS benefit vs. docetaxel in 2L NSCLC (ORR ~28%), establishing the first Phase 3 proof-of-concept. Combo with panitumumab in CRC (CodeBreaK 300) showed OS benefit.
Adagrasib (KRYSTAL-12, Phase 3): Confirmed superiority over docetaxel in 2L KRAS G12C NSCLC with positive evaluation. Adagrasib’s CNS penetration data and broader tumor-type activity (including PDAC) differentiate it from sotorasib.
Daraxonrasib (RASolute 301, Phase 3): Positive Phase 3 readout vs. docetaxel in RAS-mutant NSCLC — the first non-covalent RAS(ON) inhibitor to demonstrate Phase 3 success. RASolute 302 in PDAC also showed “unprecedented overall survival benefit.”
Divarasib (NAUTIKA1, Phase 2 neoadjuvant): Promising early-stage NSCLC activity, with Phase 3 KRASCENDO 3 (adjuvant) and other pivotal trials ongoing.
Olomorasib (SUNRAY-02, Phase 3): Lilly’s CNS-penetrant inhibitor entering Phase 3 in combination with IO for NSCLC.
Garsorasib (Phase 2, CRC): Positive data in colorectal cancer with and without cetuximab.
Sosimerasib (Phase 2 monotherapy): Positive Phase 2 monotherapy results in previously treated KRAS G12C NSCLC, supporting its NMPA approval.
Section VI: Route Differentiation Matrix
| Player | Covalent GDP-state | Non-covalent GTP-state (RAS-ON) | PROTAC Degrader | Molecular Glue | Vaccine/Cell Therapy | Combo Focus |
|---|---|---|---|---|---|---|
| Amgen | Strong (Sotorasib) | — | — | — | — | CRC + panitumumab |
| Mirati/BMS | Strong (Adagrasib) | — | — | — | — | CRC + cetuximab, CNS |
| Genentech/Roche | Strong (Divarasib) | — | — | — | — | Adjuvant NSCLC |
| Eli Lilly | Strong (Olomorasib) | — | — | — | — | IO combo (SUNRAY) |
| Merck MSD | Strong (Calderasib) | — | — | — | — | Pembrolizumab combo |
| Revolution Medicines | — | Strong (Daraxonrasib) | — | — | — | Pan-RAS, PDAC |
| Novartis | Moderate (Opnurasib) | — | — | — | — | SHP2 combo |
| Jacobio/AstraZeneca | Strong (Glecirasib) | Emerging (JAB-23E73 pan-KRAS) | — | — | — | PDAC, CRC |
| Arvinas | — | — | Strong (ARV-806) | — | — | Resistance setting |
| Astellas | — | — | Strong (Setidegrasib) | — | — | G12D/G12C NSCLC, PDAC |
| Elicio | — | — | — | — | Strong (ELI-002 vaccine) | Adjuvant, MRD+ |
| Anocca/Affini-T | — | — | — | — | Strong (TCR-T) | Solid tumors |
Section VII: Deal Intelligence
The KRAS space has attracted significant BD activity, reflecting the commercial validation and expanding indication scope:
| Deal | Parties | Value | Date | Signal |
|---|---|---|---|---|
| AbbVie option to acquire Kestrel Therapeutics | AbbVie ← Kestrel | Up to $1.45B | Apr 2026 | AbbVie entering KRAS space |
| Jacobio → AstraZeneca (JAB-23E73 pan-KRAS) | AstraZeneca ← Jacobio | $100M upfront + $1.915B milestones | Dec 2025 | AZ’s major bet on pan-KRAS |
| Revolution Medicines + Royalty Pharma | RevMed + Royalty Pharma | $2B funding | Jun 2025 | RAS(ON) portfolio financing |
| Bayer + Kumquat Biosciences | Bayer ← Kumquat | Up to $1.3B | Aug 2025 | Bayer entering precision oncology/KRAS |
| Jazz Pharma + Redx Pharma | Jazz ← Redx | $10M up + $870M milestones | Feb 2024 | KRAS program acquisition |
| Jacobio → Allist (Glecirasib CN rights) | Allist ← Jacobio | ¥850M (~$120M) | Aug 2024 | China regional deal |
Terminated/Failed Deals: MSD ended takeover talks with Revolution Medicines; Genentech ended SHP2 partnership with Relay Therapeutics; HOOKIPA regained KRAS vaccine rights from Roche. These signal selectivity in combination partner choices.
Section VIII: Domestic vs. Overseas Comparison
| Dimension | US/Europe | China |
|---|---|---|
| Approvals | 2 (FDA: Sotorasib, Adagrasib) | 4 (NMPA: Fulzerasib, Garsorasib, Glecirasib, Sosimerasib) |
| Innovation depth | First-in-class, non-covalent, PROTAC, vaccine, TCR-T | Primarily covalent G12C inhibitors; Jacobio JAB-23E73 (pan-KRAS) is exception |
| Phase 3 pipeline | Rich: Divarasib, Olomorasib, Calderasib, Daraxonrasib | Garsorasib/Glecirasib expanding into CRC/PDAC |
| Combination strategy | IO, SHP2, EGFR, chemotherapy combos | IO + KRAS G12C (Fulzerasib + sintilimab, Garsorasib + ivonescimab) |
| BD activity | Acquirers (AZ, AbbVie, Bayer, Merck) | Licensors (Jacobio → AZ for $2B+; Allist ← Jacobio) |
| Key advantage | Mechanistic innovation, next-gen modalities, global rights | Speed-to-market in China, cost-competitive manufacturing, local trial infrastructure |
| Key gap | High cost; some assets may face crowded market | Limited global rights; innovation primarily incremental vs. first-gen |
Section IX: Competitive Landscape Summary & White Spaces
Who Is Most Competitive?
Currently most competitive overall: Adagrasib (BMS/Mirati) — broadest approved indication scope (NSCLC + CRC combo), CNS penetration, and the most active combination development program. Adagrasib
Deepest pipeline: Revolution Medicines — Daraxonrasib’s Phase 3 positive readouts in both NSCLC (RASolute 301) and PDAC (RASolute 302) represent a paradigm shift to RAS(ON) inhibition, with multiple Phase 3 trials running simultaneously (RASolute 303, 304). Daraxonrasib
Most strategically differentiated: Eli Lilly (Olomorasib) — CNS penetration + Phase 3 IO combination trial (SUNRAY-02) positions it for a potential 1L niche. Olomorasib
White Spaces & Emerging Opportunities
| White Space | Evidence | Entry Path |
|---|---|---|
| Adjuvant / early-stage NSCLC | Divarasib (KRASCENDO 3), Calderasib (KANDLELIT-013/015), Olomorasib (SUNRAY-02) all in Phase 3 — still no approval | Combination with IO post-resection; Phase 3 data expected 2026–2027 |
| PDAC (KRAS G12C/G12D) | Daraxonrasib positive Ph3 OS in PDAC; HRS-4642, INCB-161734 in Ph2/3 for G12D | Pan-KRAS or G12D-selective agents; combination with chemotherapy |
| Resistance overcoming (post-G12C inhibitor) | PROTAC degraders (ARV-806, Setidegrasib) in Phase 1; molecular glues early stage | Degraders or non-covalent agents that bypass S-IIP resistance mutations |
| Immunotherapy combinations | Multiple Ph2/3 trials ongoing but no approved combo in 1L | IO + KRAS G12C inhibitor in PD-L1 high or selected biomarker populations |
| Non-G12C KRAS mutations (G12D, G12V) | G12D now attracting major investment (AZ/Jacobio $2B+, INCB-161734 Ph3, GFH-375 Ph3) | Next-generation covalent or non-covalent agents exploiting G12D pocket differences |
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Section VI: Conclusions
- The first-generation covalent G12C inhibitor market is crowded and commoditizing, particularly in China where four NMPA-approved drugs compete in the same 2L NSCLC indication. Differentiation will require combination data, earlier-line approvals, or expanded indication coverage.
- Revolution Medicines’ Daraxonrasib represents the most disruptive competitive threat — a non-covalent RAS(ON) inhibitor with Phase 3 positive data in both NSCLC and PDAC, potentially redefining the standard of care and extending coverage to non-G12C RAS mutations.
- The next battleground is combination strategy and earlier lines of therapy. Merck (Calderasib + pembro), Lilly (Olomorasib + IO), and Roche (Divarasib adjuvant) are all racing to capture the 1L and adjuvant NSCLC market.
- PDAC is the highest unmet need frontier — KRAS G12D dominates PDAC (~90% frequency) and is now attracting the next wave of investment (AstraZeneca/Jacobio $2B+ deal, INCB-161734 Ph3, Daraxonrasib Ph3 OS benefit).
- Next-generation modalities (PROTACs, molecular glues, vaccines, TCR-T) are still early-stage but represent the long-term competitive horizon for resistance management and broader RAS coverage. None have yet demonstrated clinical proof-of-concept sufficient for strong conclusions.
- China-based companies have achieved speed-to-market domestically but are increasingly licensing assets globally (Jacobio → AZ) rather than building independent global pipelines — a structural BD opportunity for Western acquirers.
Data sourced from structured biomedical databases as of May 2026. Clinical trial status reflects registered data; actual recruitment and data readout timelines may vary. The ~18-month patent publication lag applies to any patent trend analysis in this space.
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