HRS-4642 / Jiangsu Hengrui Pharma - LARVOL DELTA

The KRAS targeting revolution in metastatic pancreatic cancer: insights from the landmark RASolute-302 trial and emerging allele-specific strategies at ASCO 2026. (PubMed, J Hematol Oncol) - "This correspondence highlights how the first-in-class pan-RAS (ON) inhibitor daraxonrasib (RMC-6236) virtually doubled median overall survival (13.2 vs. 6.6 months) and progression-free survival compared to chemotherapy in second-line mPDAC, establishing a new standard of care...These include the selective KRAS G12D inhibitor DN022150 and promising horizontal combinations pairing the G12D inhibitor HRS-4642 with either the anti-PD-L1 antibody adebrelimab or a Nectin-4-targeted antibody-drug conjugate (ADC). Furthermore, we address the KRAS G12C cohort where farnesyl transferase co-inhibition (darlifarnib plus adagrasib) successfully bypasses adaptive resistance. Ultimately, the therapeutic landscape of mPDAC is transitioning toward tailored genomic frameworks. Future success will rely on optimizing the clinical sequencing or combination of pan-RAS and allele-specific agents, guided by real-time liquid biopsies, to permanently dismantle resistance and transform mPDAC into..."

IO biomarker • Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

Chemotherapy-free phase 1/2 trial of HRS-4642 plus adebrelimab in previously treated metastatic KRAS G12D-mutant pancreatic cancer. (PubMed, Cancer Cell) - P1/2 | "In the RP2D cohort (n = 37), the confirmed objective response rate was 43.2% (95% confidence interval [CI], 27.1-60.5), disease control rate was 81.1% (95% CI, 64.8-92.0), median duration of response was 6.9 months (95% CI, 4.8-8.6), median progression-free survival was 5.7 months (95% CI, 4.0-7.5), and median overall survival was 11.5 months (95% CI, 9.2-16.9). This chemotherapy-free regimen is tolerable and shows encouraging antitumor activity in refractory KRAS G12D-mutant PDAC, warranting further investigation."

IO biomarker • Journal • P1/2 data • Dyslipidemia • Hematological Disorders • Metabolic Disorders • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

HRS-4642 Plus Chemotherapy ± Adebrelimab as Perioperative Therapy in KRAS G12D-Mutant Pancreatic Cancer: Preliminary Results of a Phase 2 Study (ESMO 2026) - No abstract available

Late-breaking abstract • P2 data • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

HRS-4642 combined with gemcitabine and nab-paclitaxel in KRAS-G12D mutant advanced pancreatic cancer: A phase Ib/II study (ESMO 2025) - P1/2 | "Conclusions HRS-4642 combined with GA showed encouraging antitumor activity and manageable safety profile in advanced KRAS -G12D mutant PDAC. Follow-up is ongoing for long-term efficacy and safety data."

IO biomarker • Metastases • P1/2 data • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

SHR-A2102, a Nectin-4 targeted antibody-drug conjugate, combined with HRS-4642 in previously treated pancreatic ductal adenocarcinoma harboring KRAS G12D mutation. (ASCO 2026) - P2 | "SHR-A2102 combined with HRS-4642 showed a tolerable safety profile and promising preliminary anti-tumor activity in advanced PDAC harboring KRAS G12D mutation, irrespective of Nectin-4 expression."

ADC • Hematological Disorders • Oncology • Pancreatic Ductal Adenocarcinoma • KRAS • NECTIN4

An Open-Label, Multicenter, Phase IB/II Clinical Study of HRS-7172 in Combination With Antitumor Therapy in Participants With Solid Tumors (clinicaltrials.gov) - P1/2 | N=140 | Not yet recruiting | Sponsor: Jiangsu HengRui Medicine Co., Ltd.

New P1/2 trial • Oncology • Pancreatic Cancer • Solid Tumor

Perioperative HRS-4642, Chemotherapy, and Adebrelimab in KRAS G12D-Mutant Pancreatic Cancer: Preliminary Phase 2 Results (ESMO 2026) - No abstract available

P2 data • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

HRS-4642 Combined with Adebrelimab and Chemotherapy as Firstline Treatment for KRAS G12D Mutant Advanced Non-small Cell Lung Cancer: A Phase 1b/2 Study (ESMO 2026) - No abstract available

Clinical • Metastases • P1/2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

KRAS-G12D inhibitor HRS-4642 plus chemotherapy in advanced KRASG12D-mutant pancreatic cancer: a phase 1b/2 trial. (PubMed, Nat Med) - P1/2 | "This phase 1b/2 study evaluated HRS-4642 in combination with nab-paclitaxel and gemcitabine (AG) in patients with advanced KRASG12D-mutant PDAC. In conclusion, HRS-4642 combined with AG demonstrates promising antitumor activity and a manageable safety profile in advanced KRASG12D-mutant PDAC, supporting further investigation. Clinicaltrials.gov registration: NCT06520488 ."

Journal • P1/2 data • Hematological Disorders • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

HRS-4642 with dual immunotherapy and chemotherapy for advanced pancreatic cancer: Preliminary results from Arm 1 of a phase II study (ESMO 2026) - No abstract available

Metastases • P2 data • Oncology • Pancreatic Cancer • Solid Tumor

A Phase Ib/II Study of HRS-4642 plus Nimotuzumab in Patients with KRAS G12D-Mutant Advanced Pancreatic Ductal Adenocarcinoma (ESMO 2026) - No abstract available

Clinical • Metastases • P1/2 data • Oncology • Pancreatic Ductal Adenocarcinoma • KRAS

KRAS G12D inhibitor HRS-4642 in patients with KRAS G12D-mutant advanced solid tumors: A phase I trial (ESMO 2025) - "These data support further investigation of HRS-4642, including in combination regimens. Legal entity responsible for the study Jiangsu Hengrui Pharmaceuticals, Co., Ltd."

Clinical • IO biomarker • Metastases • P1 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

A first-in-human phase I study of a novel KRAS G12D inhibitor HRS-4642 in patients with advanced solid tumors harboring KRAS G12D mutation (ESMO 2023) - P1 | "Conclusions HRS-4642 showed a tolerable safety profile and preliminary anti-tumor activity in advanced solid tumors harboring KRAS G12D mutation. Dose escalation is ongoing and expected to proceed to dose expansion soon."

Clinical • Late-breaking abstract • Metastases • P1 data • Appendix Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • KRAS

Progress and challenges in the design and development of selective KRAS G12D-targeted drug discovery: inhibitors, degraders and emerging therapeutic strategies. (PubMed, Future Med Chem) - "Building on this breakthrough, advances have been made in KRAS G12D-targeted drug development, including potent non-covalent inhibitors such as MRTX1133, HRS-4642, LY3962673, and INCB161734, as well as RAS(ON) tri-complex inhibitors such as RMC-9805...Among the developed pan-RAS inhibitors, RMC-6236 is the most advanced candidate in clinical development. In parallel, targeted protein degradation strategies, particularly PROTAC-based degraders such as ASP3082 and RP03707, have emerged as promising alternatives to overcome resistance and improve therapeutic durability. Combination strategies involving EGFR inhibitors, chemotherapy, and immunotherapy are also expanding clinical potential. This review summarizes recent progress in KRAS G12D-targeted inhibitors and degraders, highlighting current challenges and future opportunities for improving KRAS-directed cancer treatment."

IO biomarker • Journal • Review • Colorectal Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Targeted Protein Degradation • KRAS

The ongoing first-line treatment race for metastatic pancreatic ductal adenocarcinomas: will a tough disease lose its horror? (PubMed, Future Oncol) - "PDACs are K-RAS addicted (incidence >90%), however, RAS oncogenes have been regarded to be "undruggable." Several highly specific inhibitors have been developed with atebimetinib (MEK inhibitor), daraxonrasib (tri-complex pan-K-RAS inhibitor), zoldonrasib (tri-complex K-RAS G12D inhibitor), INCB161734 (non-covalent ON/OFF inhibitor specific for K-RAS G12D), HRS-4642 (liposomal G12D inhibitor), and setidegrasib (G12D degrader) currently undergoing phase III evaluation in first-line PDACs. Since the benefits provided by chemotherapy regimens are limited, it is conceivable that the novel targeted approaches may have the potential to overcome these limitations. Of note, outcomes for some of these compounds numerically exceeded the historical benchmarks with standard chemotherapy suggesting that a chemotherapy backbone might no longer be needed in the future."

Journal • Oncology • Palliative care • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS

An Exploratory Clinical Study of HRS-4642 in Combination With Immunotherapy and Chemotherapy for Pancreatic Cancer (clinicaltrials.gov) - P2 | N=60 | Recruiting | Sponsor: Shanghai Zhongshan Hospital | Not yet recruiting ➔ Recruiting

Enrollment open • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Glutamine-restricted diets restore sensitivity to KRASG12D inhibitor through the reversal of ANXA1 mediated metabolic reprogramming. (PubMed, Cell Rep Med) - "HRS-4642, a non-covalent inhibitor targeting KRASG12D, demonstrates potent antitumor efficacy but may ultimately lead to resistance...Additionally, we find that ANXA1 upregulation facilitates mitochondrial localization of GLS1, thereby altering glutamine metabolism. These findings highlight ANXA1-mediated glutamine metabolism as a key driver of KRASG12D inhibitor resistance and support glutamine-restricted diets as a potential therapeutic strategy for KRASG12D mutant PDAC."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • ANXA1 • KRAS

HRS-4642-302: HRS 4642 Injection Combined With AG Versus Placebo Combined With AG Therapy in First-Line Advanced or Metastatic Pancreatic Cancer (clinicaltrials.gov) - P3 | N=588 | Recruiting | Sponsor: Jiangsu HengRui Medicine Co., Ltd. | Not yet recruiting ➔ Recruiting

Enrollment open • Trial initiation date • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

KRAS-mediated CCDC6 degradation drives xCT upregulation and ferroptosis evasion. (PubMed, Apoptosis) - "Crucially, pharmacological inhibition of CCDC6 turnover using proteasome, GSK3β, or specific KRAS mutant inhibitors (Sotorasib, Adagrasib, HRS4642) restored CCDC6 protein levels and robustly sensitized KRAS-mutated cells to ferroptosis-inducing agents like Sulfasalazine. This work uncovers a novel KRAS/CCDC6/xCT signaling axis that mediates ferroptosis resistance in KRAS-mutated cancers. Moreover, it identifies CCDC6 turnover as a critical vulnerability and a promising therapeutic target to enhance the efficacy of ferroptosis-inducing agents."

Journal • Colorectal Cancer • Oncology • Solid Tumor • ATF4 • CCDC6 • ETS1 • KRAS

Neoadjuvant HRS-4642 Plus Chemotherapy With or Without Immunotherapy for Pancreatic Cancer (clinicaltrials.gov) - P2 | N=60 | Not yet recruiting | Sponsor: Changhai Hospital

New P2 trial • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Reversal of KRAS G12D inhibitor resistance by nimotuzumab via MEK/ERK-mediated unfolded protein response in pancreatic cancer. (PubMed, Cancer Lett) - P1 | "Our findings not only reveal a clinically relevant resistance mechanism to KRAS G12D inhibition but also provide a rational, effective combined strategy. Ultimately, the combination of HRS-4642 with nimotuzumab offers a promising therapeutic strategy for PDAC patients harboring KRAS G12D mutations, laying a foundation for advancing clinical research in overcoming resistance to KRAS G12D-targeted therapies."

Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

HRS-4642 combined with adebrelimab in previously treated patients with metastatic pancreatic ductal adenocarcinoma. (ASCO 2026) - P1/2 | "HRS-4642 combined with adebrelimab showed a manageable safety profile and promising anti-tumor activity in metastatic PDAC harboring KRAS G12D mutation."

Clinical • IO biomarker • Metastases • Oncology • Pancreatic Ductal Adenocarcinoma • KRAS

HRS-4642 With Nimotuzumab and Chemotherapy for First-line Treatment of Advanced Pancreatic Cancer Patients (clinicaltrials.gov) - P2 | N=133 | Recruiting | Sponsor: Zhejiang University | N=32 ➔ 133

Enrollment change • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

HRS-4642 Combined With Nimotuzumab in the Treatment of Recurrent or Metastatic Pancreatic Ductal Adenocarcinoma (clinicaltrials.gov) - P1/2 | N=20 | Active, not recruiting | Sponsor: West China Hospital | Trial primary completion date: Jan 2027 ➔ Aug 2026 | Recruiting ➔ Active, not recruiting

Enrollment closed • Trial primary completion date • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma

Exploratory Clinical Study of HRS-4642 Combined With Adebrelimab in the Treatment of Advanced Pancreatic Ductal Adenocarcinoma (clinicaltrials.gov) - P1/2 | N=130 | Recruiting | Sponsor: Fudan University | N=35 ➔ 130 | Trial completion date: Sep 2026 ➔ Mar 2028 | Trial primary completion date: Jun 2026 ➔ Jun 2027

Enrollment change • Trial completion date • Trial primary completion date • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor