There is a type of cancer known as the silent "killer."

Its early symptoms are not obvious,

so that when it is discovered, it is already in the advanced stage.

It is pancreatic cancer.

Pancreatic cancer is highly malignant,

with a 5‑year survival rate of less than 10%,

far lower than that of breast cancer and lung cancer.

That is why many people call it the "king of cancers."

Pancreatic cancer is an extremely aggressive malignancy with persistently high mortality rates, and its global incidence has been on a continuous rise in recent years. Its biggest challenge in diagnosis and treatment lies in its insidious onset and the lack of specific early symptoms, resulting in most patients being diagnosed at advanced stages, which renders treatment extremely difficult and prognosis poor. According to research data published in CA: A Cancer Journal for Clinicians in 2024, the five-year survival rate for pancreatic cancer patients is only 13%, and it has now risen to become the sixth leading cause of cancer death worldwide. In 2022, there were over 510,000 new cases and 460,000 deaths globally. Projections indicate that the disease will further climb to become the second leading cause of cancer death by 2040, posing a severe challenge to global public health.

For a long time, chemotherapy has been the mainstay of treatment for advanced pancreatic cancer, but its efficacy has reached a clear bottleneck. Since 2025, with breakthroughs in targeted therapy, immunotherapy, bispecific antibodies, and other technologies, the field of pancreatic cancer drug development has witnessed multiple key advances, bringing new therapeutic hope to patients.

Source: Internet

I. Targeting KRAS Mutations to Break the "Undruggable" Bottleneck

KRAS mutations represent the most critical molecular driver of pancreatic cancer, with over 90% of pancreatic ductal adenocarcinoma (PDAC) patients harboring KRAS mutations, among which the KRAS G12D subtype accounts for up to 40%. For nearly 40 years, KRAS was considered an "undruggable" target due to its protein structural characteristics. However, the clinical breakthrough of oral KRAS G12D inhibitors in 2025 marked a major milestone in the field.

In October 2025, Jiangsu Hengrui Medicine announced the phase 1b/2 clinical data of HRS-4642 in combination with gemcitabine and nab-paclitaxel for the treatment of KRAS G12D-mutated advanced pancreatic cancer at the 2025 ESMO Congress. HRS-4642 is a self-developed, high-affinity, selective, and long-acting non-covalent KRAS G12D inhibitor, and it is also the first reported clinically effective KRAS G12D-specific inhibitor. Prior to this, the basic research results of HRS-4642 were published in the international top medical journal Cancer Cell, confirming that it can specifically bind to KRAS G12D, dual-block downstream signaling pathways, and tend to accumulate intratumorally, with excellent pharmacokinetic and pharmacodynamic characteristics. It not only provides a new option for patients with KRAS G12D mutations but also promotes the development of innovative druggability technologies such as non-covalent binding.

Clinical data demonstrated that after a median follow-up of 7.5 months, the confirmed objective response rate (ORR) reached 63.3%, with more than half of patients showing significant tumor shrinkage, representing a substantial improvement over standard chemotherapy. The disease control rate (DCR) was as high as 93.3%, indicating effective control of tumor growth in the vast majority of patients, whereas DCR with prior chemotherapy typically does not exceed 70%. The median progression-free survival (PFS) was not yet mature, but the 6-month PFS rate reached 89.3%, reflecting a significant reduction in the risk of disease progression.

Source: Cancer Cell

II. Bispecific Antibodies: Overcoming the Toxicity Dilemma

Bispecific antibodies simultaneously target two distinct antigens on the surface of tumor cells, enabling precise tumor killing and modulation of the tumor microenvironment while reducing the toxicity risks associated with single-target agents. At the 2026 ASCO GI Symposium, Phanes Therapeutics presented key clinical data for its proprietary bispecific antibody, spevatamig. With a disease control rate (DCR) of 93% and significantly prolonged survival, spevatamig offers breakthrough hope for the treatment of pancreatic cancer—often referred to as the “king of cancers”—and overcomes the hematological toxicity limitations of traditional CD47-targeting therapies.

Spevatamig is engineered using Phanes Therapeutics’ proprietary PACbody® and SPECpair® bispecific antibody platforms. Its two arms target CLDN18.2 and CD47, respectively. By optimizing the anti‑CD47 arm and implementing a single‑arm targeting design, spevatamig effectively reduces CD47‑associated hematological toxicity and CLDN18.2‑related gastrointestinal toxicity.

Clinical data demonstrated that among 15 patients with mPDAC receiving first‑line treatment with spevatamig at 2 mg/kg once weekly in combination with GnP, 6 patients achieved partial response (5 confirmed, 1 pending), and 8 patients achieved stable disease. The disease control rate (DCR) was 93% (compared with 48% in a key clinical study), and the objective response rate (ORR) was 40%.

Currently, spevatamig is in Phase II clinical development in both the U.S. and China, making it the most advanced pipeline among global therapeutics targeting the same pathway. Previously, the agent received Orphan Drug Designation for pancreatic cancer and Fast Track Designation for metastatic Claudin18.2‑positive pancreatic cancer from the U.S. FDA. The interim data from the TWINPEAK study presented here marks a critical step toward the clinical application of spevatamig.

Source：Internet

III. Immunotherapy: Triplet Regimens Break Through the Bottleneck in First-Line Treatment

Due to the unique “immune desert” tumor microenvironment of pancreatic cancer, traditional PD‑1/PD‑L1 inhibitors have shown dismal efficacy as monotherapies in metastatic pancreatic ductal adenocarcinoma (mPDAC), failing to meet the core criteria for clinical translation. Neither pembrolizumab nor nivolumab, among other representative agents, has demonstrated significant improvements in patient outcomes. To date, no monotherapy has been approved globally for first‑line, second‑line, or subsequent treatment of mPDAC. To overcome the limitations of single‑agent therapy, numerous clinical studies have explored combinations of conventional PD‑1/PD‑L1 inhibitors with chemotherapy (e.g., gemcitabine plus nab‑paclitaxel), but most of these regimens have only yielded modest improvements without achieving substantive breakthroughs. In 2025, the approval of a phase III clinical trial for a PD‑1/TGF‑β dual‑functional fusion protein combination regimen marked a critical breakthrough in addressing this long‑standing challenge.

TQB2868, independently developed by Chia Tai Tianqing, simultaneously blocks the PD‑1/PD‑L1 pathway and neutralizes TGF‑β in the tumor microenvironment, thereby exerting both immune checkpoint inhibition and tumor microenvironment remodeling effects. Its triplet combination regimen—comprising TQB2868, anlotinib, and AG chemotherapy—was approved by the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) in China in June 2025 to initiate a phase III registrational clinical trial.

The results of the Phase II clinical study for this combination regimen were first presented at the 2025 ASCO Annual Meeting, demonstrating remarkable clinical benefits. Among mPDAC patients receiving TQB2868 in combination with anlotinib and chemotherapy, the objective response rate (ORR) reached 63.9% and the disease control rate (DCR) was 100%. The median progression-free survival (PFS) was not reached, with a 6-month PFS rate of 86%. Although the median overall survival (OS) was also not reached, the data suggests the potential to break the 1-year barrier for the first time in this patient population. (This expectation is based on current Phase II trends and requires verification in large-sample Phase III studies.)

Source： ASCO

Summary

Since 2025, pancreatic cancer drug development has achieved critical breakthroughs across multiple directions: KRAS G12D inhibitors have broken through the “undruggable” barrier, bispecific antibodies have addressed the toxicity challenges of traditional targets, and “immunotherapy + targeted therapy + chemotherapy” combinations are poised to fill the gap in first-line immunotherapy. All these advances are centered on precision medicine, and through target innovation, technological optimization, and regimen synergy, they have significantly improved both efficacy and safety.

In the future, as multiple phase III clinical trials progress, it is expected that more novel drugs or regimens will be approved for marketing, potentially reshaping the treatment landscape of pancreatic cancer. Meanwhile, personalized therapies (such as mRNA vaccines), the development of multi-target agents, and the optimization of combination treatment strategies will continue to be major research hotspots, offering greater possibilities for further improving survival rates and quality of life in patients with pancreatic cancer.

Zvast Biotchenology Pancreatic Cancer Models