KRAS Inhibitors (2026): The Complete Guide to Targeted Therapy, Resistance, and the Future of Precision Oncology
Abstract
Background: KRAS, once considered an "undruggable" oncoprotein, is now targetable across multiple mutation subtypes and represents one of the most rapidly evolving areas of precision oncology, spanning non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC).
Objective: To synthesize the current (September 2026) regulatory status, pivotal trial evidence, resistance mechanisms, and combination strategies for KRAS G12C-selective inhibitors and the newer pan-RAS(ON) and G12D-selective inhibitor class.
Methods: Narrative review of FDA drug labels, FDA approval and withdrawal records, peer-reviewed trial publications, conference proceedings (ASCO 2026, ESMO GI 2026), and manufacturer disclosures, cross-checked against primary regulatory sources current as of September 8, 2026.
Results: Two KRAS G12C inhibitors (sotorasib, adagrasib) hold FDA approval in NSCLC; a third combination (sotorasib plus panitumumab) is approved in colorectal cancer. The FDA withdrew the accelerated approval of adagrasib plus cetuximab in colorectal cancer effective September 1, 2026, after the confirmatory KRYSTAL-10 trial failed both primary endpoints. Separately, the FDA approved daraxonrasib, a multi-selective RAS(ON) inhibitor, on August 26, 2026 — the first RAS-targeted therapy ever approved for pancreatic cancer — based on a near-doubling of median overall survival in the Phase 3 RASolute 302 trial. Divarasib, an investigational next-generation G12C inhibitor, has reported topline Phase 3 superiority over both approved G12C agents. Three additional G12C inhibitors (fulzerasib, glecirasib, garsorasib) are approved only in China.
Conclusions: KRAS-directed therapy is shifting from single-mutation, response-rate-driven accelerated approvals toward survival-powered, pathway-level RAS(ON) inhibition. Regulatory volatility in the G12C class — one withdrawal, one unresolved confirmatory trial dispute — underscores the importance of distinguishing accelerated approval from confirmed clinical benefit when counseling patients.
Two KRAS inhibitors are FDA-approved for lung cancer (sotorasib, adagrasib), and one combination (sotorasib plus panitumumab) is approved for colorectal cancer. As of September 1, 2026, adagrasib plus cetuximab is no longer FDA-approved for colorectal cancer after its confirmatory trial failed. The newest and most significant 2026 development is daraxonrasib, approved August 26, 2026 as the first-ever RAS-targeted drug for metastatic pancreatic cancer, nearly doubling median survival (13.2 vs. 6.7 months) versus chemotherapy. Several next-generation and pancreatic-focused KRAS drugs (divarasib, zoldonrasib) remain investigational. This is an educational overview, not personal medical advice — treatment decisions for KRAS-mutant cancer should always be made with a treating oncologist.
- Withdrawn: The FDA withdrew the accelerated approval of adagrasib (Krazati) plus cetuximab (Erbitux) for KRAS G12C-mutated metastatic colorectal cancer, effective September 1, 2026, after the confirmatory Phase 3 KRYSTAL-10 trial failed to demonstrate a statistically significant progression-free or overall survival benefit over chemotherapy.
- Approved: The FDA approved daraxonrasib (Revolution Medicines) on August 26, 2026, for adults with metastatic pancreatic adenocarcinoma who have received at least one prior line of systemic therapy — the first RAS-targeted therapy ever approved in pancreatic cancer.
- Unresolved: Sotorasib's original 2021 accelerated approval in NSCLC remains unconverted to full approval; in 2023 an FDA advisory committee found its confirmatory trial (CodeBreaK 200) uninterpretable, and a new confirmatory study is due no later than February 2028.
- Background: From "Undruggable" to Precision Target
- Methods
- KRAS Biology and Mutation Landscape
- Approved KRAS G12C Inhibitors: Sotorasib and Adagrasib
- Regulatory Volatility: One Withdrawal, One Unresolved Dispute
- Emerging and Regionally Approved G12C Inhibitors
- Why KRAS Therapy Fails: Resistance Mechanisms
- The Pan-RAS(ON) Paradigm Shift
- KRAS in Pancreatic Cancer: The Hardest Frontier
- Combination Therapy Strategies
- Evidence Summary Table
- Discussion and Future Directions
- Limitations of This Review
- Frequently Asked Questions
- Key Takeaways
- References
1. Background: From "Undruggable" to Precision Target
For decades, KRAS mutations were considered one of the most intractable problems in oncology. The KRAS protein's smooth surface and picomolar affinity for GTP left few pockets for a drug to bind, and it was widely described in the literature as "undruggable."
That changed in the early 2020s with the discovery of a shallow, mutation-specific pocket accessible only in the G12C-mutant, GDP-bound (inactive) state of the protein. This enabled the first generation of covalent KRAS G12C inhibitors, sotorasib and adagrasib, both now FDA-approved.
.png "Pancreatic Cancer Breakthrough 2026")
By 2026, the field has moved well beyond that first breakthrough. A second, mechanistically distinct class of "RAS(ON)" inhibitors — which bind the active, GTP-loaded state of RAS regardless of which downstream mutation is present — has produced the first RAS-targeted drug approval in pancreatic cancer, historically the most KRAS-dependent and treatment-resistant of the major solid tumors. At the same time, the G12C class has experienced its first major regulatory setback, illustrating that accelerated approval based on response rate does not guarantee eventual survival benefit.
2. Methods
This is a narrative (non-systematic) review. Sources include FDA drug labels and the FDA's public accelerated-approval and withdrawal registries, manufacturer and academic-center press releases, peer-reviewed and conference-presented trial data (ASCO 2026, ESMO GI 2026), and secondary oncology-news reporting cross-checked against primary sources. All efficacy and safety figures cited below are drawn from labeled indications or publicly reported trial results as of September 8, 2026, and are referenced individually in Section 16.
3. KRAS Biology and Mutation Landscape
KRAS (Kirsten rat sarcoma viral oncogene homolog) encodes a small GTPase that cycles between an inactive GDP-bound ("off") state and an active GTP-bound ("on") state, transmitting growth and survival signals through the MAPK (RAS–RAF–MEK–ERK) and PI3K–AKT–mTOR pathways. Oncogenic mutations — overwhelmingly clustered at codon 12 — impair the protein's intrinsic and GAP-stimulated GTPase activity, locking it in the active "on" state and driving continuous proliferative signaling.
KRAS mutation frequency and subtype distribution vary substantially by tumor type and are not interchangeable:
| Cancer Type | Approx. % with Any KRAS Mutation | Dominant Subtype(s) |
|---|---|---|
| Pancreatic ductal adenocarcinoma | >90% | G12D (~40%), G12V (~30%); G12C is rare (~1–2%) |
| Colorectal cancer | ~40–45% | G12D and G12V predominant; G12C only ~3–4% of all CRC |
| Non-small cell lung cancer (adenocarcinoma) | ~25–30% | G12C most common (~40% of KRAS-mutant cases), then G12V, G12D |
Figures are approximate ranges synthesized across published cohort and pan-cancer genomic studies; exact percentages vary by dataset and population.
This subtype heterogeneity is the central reason a single KRAS drug has never fit all patients: a G12C-selective inhibitor is structurally incapable of binding G12D- or G12V-mutant protein, which is why pancreatic cancer — dominated by G12D and G12V — was left out of the first wave of KRAS drug approvals entirely.
4. Approved KRAS G12C Inhibitors: Sotorasib and Adagrasib
Both approved first-generation KRAS G12C inhibitors are covalent, irreversible binders of the mutant cysteine-12 residue that lock KRAS G12C in its inactive, GDP-bound state, blocking downstream MAPK signaling.
4.1 Sotorasib (Lumakras, Amgen)
Sotorasib was the first KRAS-targeted drug ever approved, receiving FDA accelerated approval in May 2021 for previously treated KRAS G12C-mutated NSCLC, based on the single-arm Phase 2 CodeBreaK 100 trial (confirmed ORR 36%, disease control rate 81%). In January 2025, the FDA approved sotorasib plus the anti-EGFR antibody panitumumab for previously treated KRAS G12C-mutated metastatic colorectal cancer, based on the randomized Phase 3 CodeBreaK 300 trial, in which the 960 mg combination arm achieved a median progression-free survival of 5.6 months versus 2.0 months for standard of care (ORR 26% vs. 0%).
4.2 Adagrasib (Krazati, Bristol Myers Squibb)
Adagrasib received its first FDA approval in December 2022 for previously treated KRAS G12C-mutated NSCLC (Phase 2 KRYSTAL-1, ORR ~43%). In June 2024, the FDA granted accelerated approval to adagrasib plus cetuximab for previously treated KRAS G12C-mutated metastatic colorectal cancer. As detailed in Section 5, that colorectal indication was withdrawn in September 2026 after its confirmatory trial failed; adagrasib's original NSCLC approval is unaffected.
Safety Profile (FDA Label Data)
Adagrasib's FDA-labeled pooled safety population (n=366, single-agent use across indications) reported gastrointestinal adverse events (nausea, diarrhea, or vomiting) in 89% of patients (9% Grade 3), and fatal adverse reactions in 11% of patients — most commonly pneumonia (3.4%), respiratory failure (1.7%), and sudden death (1.7%). In combination with cetuximab specifically, overall hepatotoxicity occurred in 38% of patients (10% Grade 3/4), and serious adverse reactions occurred in 30% of the combination-treated population, versus 57% for single-agent adagrasib across the broader pooled population. These figures come directly from the FDA-approved prescribing information rather than from any single trial arm, and patients should discuss individualized risk with their oncologist rather than extrapolating pooled population data to their own case. Adagrasib launched in 2022 with a wholesale acquisition cost of approximately $19,750 per month ($237,000 per year); current retail cash prices are somewhat higher.
5. Regulatory Volatility: One Withdrawal, One Unresolved Dispute
The KRAS G12C class illustrates a broader tension in modern oncology drug regulation: accelerated approval based on tumor response rate does not always predict a survival benefit when tested in a randomized confirmatory trial.
5.1 KRYSTAL-10: Adagrasib Plus Cetuximab in Colorectal Cancer
KRYSTAL-10 was the designated confirmatory trial for adagrasib plus cetuximab's 2024 accelerated approval in colorectal cancer. This global, open-label Phase 3 trial randomized 461 patients with previously treated KRAS G12C-mutated metastatic CRC to adagrasib plus cetuximab or investigator's choice chemotherapy (FOLFIRI or mFOLFOX6, with or without a VEGF/VEGFR inhibitor). Presented at the 2026 ESMO Gastrointestinal Cancers Congress, the trial missed both dual primary endpoints:
- Progression-free survival: 7.5 months (adagrasib + cetuximab) vs. 8.1 months (chemotherapy); hazard ratio 0.89 (95% CI, 0.71–1.13; p=0.32)
- Overall survival: 21.6 months vs. 21.7 months; hazard ratio 0.83 (95% CI, 0.67–1.03; p=0.09)
- Objective response rate was numerically much higher with the targeted combination (47% vs. 16%), but this did not translate into a survival advantage.
Because KRYSTAL-10 was the required confirmatory trial, the FDA withdrew the colorectal cancer accelerated approval for adagrasib plus cetuximab effective September 1, 2026. The withdrawal does not affect adagrasib's separate, already-established NSCLC approval. Bristol Myers Squibb has noted the result still supports the biological activity of KRAS G12C plus EGFR blockade in this population, even though the specific regimen tested did not clear the bar for continued approval.
5.2 Sotorasib's Unresolved Confirmatory Trial
Sotorasib's original 2021 NSCLC approval has faced a parallel, still-unresolved dispute. Its confirmatory Phase 3 trial, CodeBreaK 200, was reviewed by an FDA Oncologic Drugs Advisory Committee in October 2023, which voted that the trial's progression-free survival endpoint could not be reliably interpreted, citing an imbalance in early dropout and control-arm limitations. Rather than granting full approval, the FDA issued a Complete Response Letter in December 2023 and required a new confirmatory study, due no later than February 2028. As of this update, sotorasib's NSCLC indication remains under accelerated approval, unconverted.
Taken together, two of the field's most established KRAS G12C regimens have now been subject to formal FDA confirmatory-trial scrutiny — one resulting in outright withdrawal, the other still pending years later. This is a materially different risk profile than the pathway offers for a drug like daraxonrasib (Section 8), which was approved directly on the strength of a positive, survival-powered randomized trial rather than an accelerated pathway.
6. Emerging and Regionally Approved G12C Inhibitors
Beyond sotorasib and adagrasib, several next-generation G12C inhibitors are in the pipeline. Their regulatory status differs sharply by region, and this distinction is frequently lost in casual reporting.
6.1 Approved Only in China (Not FDA-Approved)
- Fulzerasib (Dupert, Innovent Biologics): Approved by China's National Medical Products Administration (NMPA) for advanced KRAS G12C-mutated NSCLC after at least one prior line of therapy. Supporting Phase 2 data (n=116) reported a confirmed objective response rate of 47–49% and a disease control rate around 91%.
- Glecirasib (JAB-21822): NMPA-approved in China; also under investigation with and without cetuximab in previously treated KRAS G12C-mutated colorectal cancer.
- Garsorasib (D-1553): NMPA-approved in China for KRAS G12C-mutated NSCLC.
None of these three agents currently holds FDA or EMA approval.
6.2 Divarasib (Genentech/Roche) — Investigational, Head-to-Head Phase 3 Win
Divarasib is a next-generation, investigational oral G12C inhibitor with FDA Breakthrough Therapy Designation (2022) and Orphan Drug Designation (2026) for KRAS G12C-mutated NSCLC. In July 2026, Roche/Genentech announced topline results from Krascendo 1, the first global head-to-head Phase 3 trial pitting a KRAS G12C inhibitor directly against the two approved agents: 338 patients with previously treated KRAS G12C-mutated advanced NSCLC were randomized to divarasib monotherapy versus investigator's choice of sotorasib or adagrasib. Divarasib met its primary endpoint of blinded independent central review-assessed progression-free survival with a statistically significant, clinically meaningful improvement, and also achieved statistically significant overall survival superiority at a prespecified interim analysis — a notable result in a historically poor-prognosis, previously treated population. No new safety signals were reported. Full efficacy data have not yet been presented at a medical meeting as of this writing; Genentech has stated it plans to submit the data to regulators. Divarasib remains investigational and is not yet approved anywhere.
7. Why KRAS Therapy Fails: Resistance Mechanisms
The central limitation of KRAS-targeted therapy is not drug design but tumor evolution. Cancer cells under G12C-inhibitor pressure adapt through several overlapping mechanisms:
- Pathway reactivation — tumors bypass KRAS inhibition by reactivating EGFR signaling or the MAPK cascade downstream of KRAS.
- Secondary mutations — new mutations arise within KRAS itself or in downstream effectors (e.g., NRAS, BRAF, MEK1).
- Bypass signaling — alternative survival routes emerge via MET amplification, PI3K activation, or HER2 upregulation.
- Tumor microenvironment adaptation — tumors become more immunosuppressive and fibrotic, creating drug-tolerant niches.
Because resistance is typically polyclonal and emerges through multiple independent routes simultaneously, single-agent KRAS inhibition is now understood as a temporizing measure rather than a curative strategy for most patients, reinforcing the shift toward combination regimens discussed in Section 10.
8. The Pan-RAS(ON) Paradigm Shift
The most consequential development in KRAS biology since G12C inhibitors themselves is the emergence of RAS(ON) inhibitors — molecular-glue compounds that bind active, GTP-loaded RAS in complex with cyclophilin A, blocking downstream signaling regardless of the specific underlying mutation (G12C, G12D, G12V, and others). This reframes the clinical question from "which mutation does this tumor have?" to "is RAS signaling active in this tumor?"
8.1 Daraxonrasib (Revolution Medicines) — Now FDA-Approved
Daraxonrasib is a multi-selective, once-daily oral RAS(ON) inhibitor. On August 26, 2026, the FDA approved daraxonrasib for adults with metastatic pancreatic adenocarcinoma who have received at least one prior line of systemic therapy or are not candidates for multiagent chemotherapy — the first RAS-targeted therapy ever approved for pancreatic cancer.
The approval was based on the Phase 3 RASolute 302 trial (published in the New England Journal of Medicine and presented in the ASCO 2026 plenary session), which enrolled 500 patients with previously treated metastatic PDAC randomized to daraxonrasib or a second line of chemotherapy:
- Overall survival: median 13.2 months (daraxonrasib) vs. 6.7 months (chemotherapy) — a 60% reduction in risk of death (hazard ratio 0.40)
- Progression-free survival: median 7.2 months vs. 3.6 months
- Objective response rate: 31.6% vs. 11.2% in the overall population (33.2% vs. 11.8% among patients with a confirmed RAS G12 mutation)
- Safety: most common adverse effects were rash, oral mucositis (stomatitis), nausea, and diarrhea; no new safety signals versus earlier Phase 1/2 data
This is a rare instance in recent oncology drug development of an approval built directly on a randomized, survival-powered Phase 3 trial rather than the accelerated, response-rate pathway that produced (and later cost) the adagrasib-cetuximab colorectal indication.
8.2 Zoldonrasib (RMC-9805) — G12D-Selective, Investigational
Zoldonrasib is a covalent, G12D-selective RAS(ON) inhibitor and holds FDA Breakthrough Therapy Designation for KRAS G12D-mutated disease. It remains investigational. In an ongoing Phase 1 trial (RMC-9805-001) in previously treated KRAS G12D-mutant metastatic PDAC, zoldonrasib was well tolerated, with treatment-related adverse events (nausea, diarrhea, vomiting, rash) predominantly Grade 1 and no Grade 4–5 events reported. Early combination data presented at ESMO GI 2026 showed:
- First-line zoldonrasib plus chemotherapy (mFOLFIRINOX or gemcitabine/nab-paclitaxel): objective response rates of 82% and 61% respectively (n=81 total), supporting the ongoing Phase 3 RASolute 305 trial.
- Chemotherapy-free zoldonrasib plus daraxonrasib in previously treated (2L/3L+) G12D-mutant PDAC (n=60): objective response rates of 50% (second-line) and 47% (third-line or later), supporting the planned Phase 3 RASolute 309 trial.
No targeted therapy is currently FDA-approved specifically for RAS G12D-mutant cancers; zoldonrasib and related G12D-directed programs (including earlier-stage compounds such as MRTX1133) remain under active clinical investigation.
9. KRAS in Pancreatic Cancer: The Hardest Frontier
Pancreatic cancer remains the most KRAS-dependent common solid tumor, with mutations present in more than 90% of cases — predominantly G12D and G12V, not G12C, which is why the first wave of G12C-selective drugs never reached this population. Compounding the biology, PDAC's dense desmoplastic stroma limits drug penetration, and most patients present with metastatic or locally advanced disease due to a lack of early symptoms.
Until August 2026, no RAS-directed therapy had ever been approved for pancreatic cancer. Daraxonrasib's approval — nearly doubling median overall survival in the second-line setting — represents the first proof that direct RAS pathway inhibition can meaningfully extend survival in this historically undertreated cancer. Biomarker testing for RAS mutation status is now clinically actionable for pancreatic cancer patients considering second-line therapy, and it is reasonable for patients to ask their oncology team whether comprehensive genomic profiling has been performed. Zoldonrasib's ongoing Phase 3 programs (Section 8.2) suggest a G12D-specific option, and potentially G12D/pan-RAS combination regimens, may follow in the next several years, pending confirmatory trial results.
10. Combination Therapy Strategies
Across tumor types, KRAS inhibition is increasingly deployed as one component of a multi-drug strategy rather than as monotherapy:
- KRAS + EGFR blockade — used in colorectal cancer (sotorasib + panitumumab, approved; adagrasib + cetuximab, withdrawn) to prevent EGFR-mediated feedback reactivation, with mixed results underscoring that this strategy is not uniformly effective across regimens.
- KRAS + SHP2 or SOS1 inhibition — under investigation to block upstream nucleotide-exchange activation and delay adaptive resistance; several SHP2 inhibitors remain in early-phase combination trials.
- KRAS + immunotherapy — KRAS-mutant tumors, particularly in pancreatic cancer, are often immunologically "cold." Combination strategies aim to increase immune infiltration and improve checkpoint-inhibitor response, though clinical validation is still preliminary.
- RAS(ON) + RAS(ON) doublets — the zoldonrasib-plus-daraxonrasib chemotherapy-free combination (Section 8.2) is an early example of stacking two mechanistically related but mutation-selective RAS(ON) agents.
11. Evidence Summary Table
Evidence tiers (adapted CEBM scale): 1b = individual randomized controlled trial; 2b = individual cohort study or single-arm registration trial; 4 = case series / early-phase dose-escalation data.
↔ Swipe the table sideways to see all columns on mobile.
| Agent | Target | Indication | Regulatory Status | Pivotal Trial | Tier |
|---|---|---|---|---|---|
| Sotorasib | G12C | NSCLC, 2L+ | FDA accelerated (2021; unconverted, PMR due 2028) | CodeBreaK 100 (Ph2) | 2b |
| Sotorasib + panitumumab | G12C + EGFR | mCRC, 2L+ | FDA approved (Jan 2025) | CodeBreaK 300 (Ph3) | 1b |
| Adagrasib | G12C | NSCLC, 2L+ | FDA approved (Dec 2022) | KRYSTAL-1 (Ph2) | 2b |
| Adagrasib + cetuximab | G12C + EGFR | mCRC, 2L+ | Withdrawn Sept 1, 2026 | KRYSTAL-10 (Ph3, negative) | 1b |
| Fulzerasib / Glecirasib / Garsorasib | G12C | NSCLC (± CRC) | China NMPA only; not FDA-approved | Regional Ph2 | 2b |
| Divarasib | G12C (next-gen) | NSCLC, 2L+ | Investigational; BTD + ODD; FDA submission planned | Krascendo 1 (Ph3, topline positive) | 1b |
| Daraxonrasib | Multi-selective RAS(ON) | Metastatic PDAC, 2L+ | FDA approved Aug 26, 2026 | RASolute 302 (Ph3) | 1b |
| Zoldonrasib | G12D-selective RAS(ON) | PDAC, NSCLC, CRC (G12D) | Investigational; FDA BTD | RMC-9805-001 (Ph1) | 4 |
12. Discussion and Future Directions
Three trends define the current state of KRAS-directed oncology heading into 2027:
- Mutation-agnostic RAS targeting is displacing mutation-specific targeting as the field's center of gravity, driven by daraxonrasib's survival benefit in a mutation-heterogeneous pancreatic cancer population.
- Confirmatory-trial risk in the G12C class is now clearly established rather than theoretical, with one withdrawal and one multi-year unresolved dispute among the two originally approved drugs. Clinicians and patients evaluating a KRAS G12C combination regimen should understand whether its approval rests on confirmed survival benefit or on a still-pending confirmatory trial.
- Head-to-head, survival-powered trial design (as used in Krascendo 1 and RASolute 302) is becoming the field's new evidentiary standard, replacing single-arm response-rate trials as the basis for approval and for comparing competing agents within the same class.
Longer-term directions under active investigation include synthetic lethality approaches that exploit vulnerabilities created by KRAS mutation, AI-driven personalized combination selection based on tumor genomics and resistance patterns, and early interception strategies targeting KRAS-mutated precancerous lesions before invasive cancer develops. None of these are yet in late-stage clinical testing.
13. Limitations of This Review
This is a narrative, not a systematic, review, and reflects publicly available data as of September 8, 2026. Trial results described as "topline" (notably Krascendo 1) have not yet undergone full peer-reviewed publication, and exact hazard ratios and confidence intervals were not available at the time of writing. Regulatory status, particularly for accelerated approvals and pending confirmatory trials, is subject to change and should be verified against current FDA records before clinical decision-making. This article does not constitute medical advice and does not replace consultation with a qualified oncologist familiar with an individual patient's tumor genomics and treatment history.
14. Frequently Asked Questions
No. The FDA withdrew the accelerated approval of adagrasib plus cetuximab for KRAS G12C-mutated metastatic colorectal cancer effective September 1, 2026, after the confirmatory KRYSTAL-10 trial failed to show a statistically significant survival benefit over chemotherapy. Adagrasib remains approved for KRAS G12C-mutated non-small cell lung cancer, and sotorasib plus panitumumab remains an approved option in colorectal cancer.
Daraxonrasib, approved by the FDA on August 26, 2026, is the first RAS-targeted therapy ever approved for metastatic pancreatic cancer. In its pivotal trial, it nearly doubled median overall survival (13.2 vs. 6.7 months) compared with chemotherapy in previously treated patients.
G12C inhibitors (sotorasib, adagrasib, divarasib) are mutation-specific and only work against tumors carrying the exact G12C mutation. RAS(ON) inhibitors (daraxonrasib, zoldonrasib) bind the active form of the RAS protein and can, depending on their selectivity, act across multiple KRAS mutation subtypes, including G12D and G12V, which are more common in pancreatic and colorectal cancer than G12C.
Not yet as a G12D-selective agent. Daraxonrasib's pancreatic cancer approval covers RAS G12-mutant disease broadly (including G12D and G12V) rather than being G12D-specific. Zoldonrasib, a G12D-selective RAS(ON) inhibitor, remains investigational, with Phase 3 trials ongoing.
Resistance develops through multiple, often simultaneous mechanisms: reactivation of bypass signaling pathways (EGFR, MET, PI3K), secondary mutations in KRAS or downstream genes, and changes in the tumor microenvironment. This is why combination regimens, rather than single-agent KRAS inhibition, are increasingly the standard approach.
15. Key Takeaways
- Two KRAS G12C inhibitors (sotorasib, adagrasib) remain FDA-approved for NSCLC; sotorasib plus panitumumab remains approved for colorectal cancer.
- Adagrasib plus cetuximab's colorectal cancer approval was withdrawn September 1, 2026 after its confirmatory Phase 3 trial (KRYSTAL-10) failed both primary endpoints.
- Sotorasib's NSCLC approval remains on accelerated status, unresolved since a 2023 FDA advisory committee dispute over its own confirmatory trial.
- Daraxonrasib, approved August 26, 2026, is the first RAS-targeted drug ever approved for pancreatic cancer, nearly doubling median overall survival versus chemotherapy.
- Divarasib has reported a positive head-to-head Phase 3 trial against both approved G12C drugs but remains investigational pending full data and regulatory submission.
- Fulzerasib, glecirasib, and garsorasib are approved only in China and are not available in the United States.
- No KRAS G12D-selective drug is yet approved anywhere; zoldonrasib is the most clinically advanced candidate, in Phase 3 development.
- Resistance to KRAS inhibition is multifactorial, which is why combination therapy — not monotherapy — is now the dominant treatment paradigm.
16. Conclusion
KRAS has moved from "undruggable" to partially druggable, and — with daraxonrasib's 2026 approval — into a new era of pathway-level RAS control that extends benefit beyond any single mutation subtype. At the same time, the field's first wave of accelerated approvals is undergoing genuine regulatory stress-testing, with one high-profile withdrawal and one long-unresolved dispute. The practical implication for patients and clinicians is the same one that governs all of precision oncology: an approval is not a guarantee of durable benefit, and biomarker-matched trial enrollment, wherever available, remains the most direct way to access next-generation RAS-targeted strategies as they mature.
Conflict of Interest Disclosure: The Cancer Advisor Editorial Team has no financial relationship with Amgen, Bristol Myers Squibb, Genentech/Roche, Revolution Medicines, Innovent Biologics, or any other manufacturer of the therapies discussed in this article.
Medical Disclaimer: This article is for educational purposes only and is not a substitute for professional medical advice, diagnosis, or treatment. Drug approval status, trial data, and pricing change frequently; always verify current information with your oncology team and the FDA before making treatment decisions. Nothing in this article should be used to initiate, modify, or discontinue any cancer treatment without physician guidance.
References
- U.S. Food and Drug Administration. Withdrawn Cancer Accelerated Approvals (Krazati/adagrasib, withdrawal date 9/1/2026). fda.gov.
- Tabernero J, et al. KRYSTAL-10: Phase 3 adagrasib plus cetuximab vs. chemotherapy in KRAS G12C-mutated mCRC. Presented at ESMO Gastrointestinal Cancers Congress 2026.
- Bristol Myers Squibb. KRAZATI (adagrasib) full prescribing information. accessdata.fda.gov / DailyMed.
- Wolpin BM, et al. RASolute 302: Phase 3 daraxonrasib vs. chemotherapy in metastatic pancreatic ductal adenocarcinoma. New England Journal of Medicine, 2026; presented ASCO Annual Meeting 2026.
- Dana-Farber Cancer Institute. FDA Approves Daraxonrasib for Metastatic Pancreatic Cancer Following Landmark Clinical Trial. Newsroom release, August 26, 2026.
- Genentech/Roche. Divarasib shows superiority in head-to-head Phase III trial (Krascendo 1) against approved KRAS G12C inhibitors in NSCLC. Press release, July 2, 2026.
- FDA approves sotorasib with panitumumab for KRAS G12C-mutated colorectal cancer. FDA news release, January 16, 2025; CodeBreaK 300 trial data.
- Amgen. Regulatory update on status of Lumakras (sotorasib); FDA Oncologic Drugs Advisory Committee review of CodeBreaK 200, October 2023.
- Innovent Biologics. Fulzerasib (Dupert) receives NMPA approval in China for advanced KRAS G12C-mutated NSCLC.
- Revolution Medicines. Zoldonrasib (RMC-9805) Phase 1 (RMC-9805-001) and ESMO GI 2026 combination data presentations.
- Pan-cancer genomic analyses of KRAS mutation subtype distribution across pancreatic, colorectal, and lung cancer cohorts (multiple sources, 2024–2026).
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