Another Breach in the Wall: Drugs Directly Targeting KRAS G12D Arrive for the First Time!
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Since discovery of the RAS oncogene in the 1980s, KRAShas been considered one of the hardest drivers to treat. Over the past five years, covalent inhibitors developed for the G12C variant have opened a clinical door; selective agents targeting the G12D mutation are now emerging. Phase 1/1b/2 data presented at ESMO 2025 highlighted early but strong signals from HRS-7058 (G12C), INCB161734 and HRS-4642 (G12D), alongside GFH375 (G12D) monotherapy and the HRS-4642 + gemcitabine/nab-paclitaxel combination, particularly in pancreatic cancer.
Why Does It Matter?
KRASis a central hub initiating and sustaining tumor growth in lung, pancreatic, and colorectal cancers. For decades, it was called ‘undruggable’ because its small, smooth protein surface offered few opportunities for drug binding, and KRAS operates as an intracellular ‘on–off’ switch. In the late 2010s, identification of the ‘switch-II pocket’ led to selective inhibitors binding covalently to the G12C variant, bringing the field into clinical practice. However, G12D —one of the most common KRAS subtypes, particularly in pancreatic cancer—remained more challenging because it is unsuitable for covalent binding. This brought noncovalent inhibitors and even protein degrader strategies into consideration.
The real clinical need in pancreatic cancer, where options remain largely limited to chemotherapy, is targeted approaches delivering durable responses and longer survival . Yet KRAS inhibition alone quickly encounters resistancein most tumors: losses of tumor suppressor genes (e.g., TP53, CDKN2A, SMAD4) and bypass signaling (RTK/PI3K/EGFR) intervene. Current research therefore follows two crucial tracks:
- G12D-specific agents with greater potency and selectivity (GFH375, HRS-4642, INCB161734), and
- Early ctDNA monitoring to identify responses promptly and transition to rational combination strategies (immunotherapy/chemotherapy/EGFR axis).
ESMO 2025 data mark a crucial turning point: for G12C, HRS-7058 shows activity similar to previous class effects; for G12D, GFH375produces meaningful responses in heavily pretreated pancreatic cancer as monotherapy . Meanwhile, the HRS-4642 + chemotherapy combination demonstrates both observable tumor shrinkage and ctDNA clearance in first-line treatment, suggesting ‘a major breach in the wall.’ The next challenge is to match the right patient to the right dose and combinationwith early biomarker guidance informing that choice.
KRAS G12C vs G12D: A Brief Biological Framework
- G12C: Covalent binding is possible; highly targetable in non-small cell lung cancer (NSCLC).
- G12D: Unsuitable for covalent binding; selective noncovalent inhibitors (HRS-4642, INCB161734, GFH375) and degrader approaches (ASP3082) are being explored.
- Resistance: Tumor suppressor loss (TP53, CDKN2A, SMAD4) and bypass pathways (RTK/PI3K/EGFR) may limit response.
- Biomarker: Serial ctDNA measurements offer a practical window into early pharmacodynamic response.
HRS-7058 (G12C) – NSCLC (naive)
ORR: 43.5% • DCR: 94.2%
INCB161734 (G12D) – Pancreatic adenocarcinoma
ORR: 20% → 34% (600→1200 mg) • ctDNA ≥90% reduction: 41% → 72%
GFH375 (G12D) – Pancreatic adenocarcinoma (previously treated)
ORR: 40.7% • DCR: 96.7% • mPFS: 5.52 months
HRS-4642 + GA – Pancreatic adenocarcinoma (1st line)
ORR: 63.3% • DCR: 93.3% • Complete ctDNA clearance: 88.9% (week 9)
ESMO 2025 Findings: By the Numbers
HRS-7058 (KRAS G12C) – Abstract 914O
- NSCLC (naive, n=69): ORR 43.5%, DCR 94.2%
- NSCLC (prior G12Ci, n=34): ORR 20.6%, DCR 91.2%
- Colorectal (n=41): ORR 34.1%, DCR 78.0%
- Pancreatic adenocarcinoma (n=4): ORR 75.0%, DCR 100%
- ≥G3 TRAEs: 14.1%
Interpretation: Efficacy resembles that of other G12C inhibitors; responses in patients previously receiving G12Ci suggest different resistance pathwaysmay be involved.
INCB161734 (KRAS G12D) – Abstract 916O
- Pancreatic adenocarcinoma (600 mg qd, n=25): ORR 20%, DCR 64%
- Pancreatic adenocarcinoma (1200 mg qd): ORR 34%, DCR 86%
- Early ctDNA response: KRAS G12D VAF reduction of ≥90% seen in 41% → 72% (600→1200 mg)
- Safety: ≥G3 TRAEs 15%; common AEs: nausea 58%, diarrhea 51%, vomiting 46%, fatigue 18%; no DLTs, no discontinuations
Interpretation: Serial ctDNA measurements clearly reveal a dose–effect relationship; the safety profile is manageable.
GFH375 (KRAS G12D) – Monotherapy, Pancreatic Adenocarcinoma (LBA84)
- N=66 advanced pancreatic adenocarcinoma; ECOG 1 <%100>, stage IV 95.5%; ≥2 prior treatment lines 68.2%.
- Dose: 600 mg QD (RP2D). mPFS: 5.52 months (90% CI 4.27–7.20); Month 4 PFS rate: 78.2%.
- ORR: 40.7% (24/59) • DCR: 96.7% (57/59). Target lesion shrinkage in 91.5%of responders.
- ctDNA (baseline): Samples in 62/66; 71% KRAS G12D-positive. Co-mutations: TP53 79.5%, CDKN2A 22.7%, SMAD4 15.9% (others: ARID1A/POLE 11.4%, BRCA1/RB1 9.1%, BRCA2/FGFR3 6.8%).
- Co-mutation and response: SMAD4 mutation carriers had an ORR of 83.3% (5/6) vs 35.1% (13/37) wild-type. No significant difference for TP53/CDKN2A.
- Safety: AEs in every patient; ≥G3 TRAEs 31.8%. Common AEs (≥20%): diarrhea 56.1%, decreased neutrophils 48.5%, vomiting 47.0%, nausea 47.0%, anemia 42.4%, WBC↓ 36.4%, decreased appetite/hypoalbuminemia 33.3%, PLT↓ 28.8%, asthenia 25.8%, AST↑ 24.2%, ALT↑ 22.7%. No fatal TRAEs; discontinuation 7.6%, dose reduction 6.1%, interruption 37.9%. Mean dose intensity 93%.
Interpretation: Monotherapy in heavily pretreated pancreatic adenocarcinoma shows high DCR and meaningful ORR; particularly notable responses with SMAD4 mutations.
HRS-4642 + Gemcitabine/Nab-Paclitaxel – Pancreatic Adenocarcinoma (Phase 1b/2)
- N=31; mostly metastatic (87.1%), ECOG 0–1. Dose escalation: HRS-4642 IV Q3W 500 mg (day 1) + 1200 mg (day 8), with standard GA.
- 1st line (previously untreated, n=30): ORR 63.3% (95% CI 43.9–80.1), DCR 93.3%; PR 19/30, SD 9/30, PD 1/30. Most responses are ongoing; median duration of response not reached.
- ctDNA: In the KRAS G12D-positive subgroup, at week 3, complete clearance 52.6% (10/19), at week 9, 88.9% (16/18).
- Safety: TRAEs in every patient; ≥G3 87.1%. Dose reduction 48.4%, interruption 61.3%, treatment discontinuations 0, deaths 0. Most common ≥15%: WBC↓ 90.3%, neutrophils↓ 87.1%, PLT↓ 74.2%, ALT↑ 51.6%, hypoalbuminemia 45.2%, AST↑ 29.0%, etc. Safety was reported as ‘manageable’ (predominantly hematological).
Interpretation: In 1st-line treatment, adding selective G12D blockade to chemotherapy provides a strong pharmacodynamic signal in both ORR and ctDNA clearance as outcomes.
Comparative Summary Table
| Agent / Setting | ORR | DCR | mPFS / Other | Safety – ≥G3 |
|---|---|---|---|---|
| HRS-7058 (G12C) – NSCLC (naive) | 43.5% | 94.2% | — | 14.1% |
| INCB161734 (G12D) – Pancreatic | 20% → 34% | 64% → 86% | ctDNA ≥90% reduction: 41% → 72% | 15% (no DLTs/discontinuations) |
| GFH375 (G12D) – Pancreatic (previously treated) | 40.7% | 96.7% | mPFS 5.52 months; month 4 PFS 78.2% | 31.8%; no fatalities |
| HRS-4642 + GA – Pancreatic (1L) | 63.3% (95% CI 43.9–80.1) | 93.3% | Complete ctDNA clearance: 52.6% (week 3) → 88.9% (week 9) | 87.1% ≥G3; discontinuations/deaths 0 |
Toxicity: Where Should We Be Careful?
- HRS-4642 (monotherapy, 915O): ≥G3 TRAEs 23.8% (hypertriglyceridemia, neutropenia, hypercholesterolemia); 1 treatment-related death.
- HRS-4642 + GA: Hematological ≥G3 events high (87.1%); dose reductions/interruptions common, but discontinuations 0, deaths 0.
- GFH375: ≥G3 TRAEs 31.8%; predominantly GI and hematological; no fatalities.
- INCB161734: ≥G3 TRAEs 15%; no DLTs. Nausea/diarrhea/vomiting common.
- ASP3082 (degrader): In preliminary data, ≥G3 TRAEs 5% – better tolerability due to its mechanism is possible.
DROZDOGAN Academy Commentary
- A crucial threshold for G12D: GFH375 monotherapy and HRS-4642 + GA provided the first clinically meaningful signals in pancreatic adenocarcinoma. Monotherapy stood out in heavily pretreated patients with 40.7% ORR and 5.5 months mPFS ; the combination stood out in the 1st line with 63.3% ORR and ctDNA clearance as its key findings.
- ctDNA as a compass: In INCB161734 and HRS-4642 + GA studies, early ctDNA clearance, as an indicator of dose–effect relationships and response durability , is promising.
- Respecting biology: With GFH375, SMAD4 co-mutation carriers’ ORR reaching 83.3%suggests subgroup sensitivity; future biomarker-based patient selection is inevitable.
- The combination era: For durable G12C/G12D responses, rational combinations involving a PD-1 inhibitor + chemotherapy and/or degrader approaches should be tested rapidly.
- Cautious optimism: The data are early-phase; confirmatory phase 2/3 studies are needed for OS and durability.
Clinical Impact: Who and When?
- NSCLC (G12C): With HRS-7058, high DCR and meaningful ORR; activity also in prior G12Ci recipients.
- Pancreatic adenocarcinoma (G12D): In heavily pretreated patients, GFH375 monotherapy offers a promising signal ; in the 1st line, HRS-4642 + GA shows encouraging response depth and ctDNA clearance as findings.
- CRC (G12C): HRS-7058 ORR 34.1%; combinations targeting EGFR pathways should be considered.
Looking Ahead
Final word: For G12D, the wall has been breached at last. INCB161734 and HRS-4642 planned combination arms, along with confirmatory phases of GFH375 monotherapy, may be key to durable responses and OS gainsin the future. ctDNA monitoring is a candidate for standardization in early decision support.
Sources
- Huang D, et al. HRS-7058 (KRAS G12C) phase 1 multicenter study. ESMO 2025 – Abstract 914O.
- Zhou C, et al. HRS-4642 (KRAS G12D) phase 1 study. ESMO 2025 – Abstract 915O.
- Desai J, et al. INCB161734 (KRAS G12D) first-in-human study. ESMO 2025 – Abstract 916O.
- Aiping Zhou, et al. GFH375 Monotherapy, KRAS G12D-mutated PDAC (LBA84), ESMO 2025 – poster presentation.
- Liwei Wang, et al. HRS-4642 + Gemcitabine/Nab-Paclitaxel, KRAS G12D-mutated PDAC, Phase 1b/2 – ESMO 2025.
- Genes Dev. 2025;39:132–162 – resistance mechanisms in KRAS G12C.
- Ann Oncol. 2024;35(Suppl 2):S486–487 – early-phase data for ASP3082 (KRAS G12D degrader).
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