The Potential Breakthrough in Pancreatic Cancer Treatment: Unveiling the Challenges and Promising Advances

The recent market discussions surrounding the sharp decline in the stock price of Alphamab Oncology have shed light on the potential connection to the unblinding of Phase III clinical trials for the PD-L1/CTLA-4 dual blockade therapy KN046 in pancreatic cancer patients. The market buzz not only revolves around the clinical success or failure of KN046 but also the immense market potential unleashed by the "king of cancers," pancreatic cancer. The limited treatment options available for pancreatic cancer and the urgent need for innovative therapies make the development pipeline in this field a crucial area of focus.

Pancreatic Cancer: Waiting for an Eruption in the "King of Cancers":
Pancreatic cancer, characterized by abnormal cell growth in the pancreas, stands as one of the deadliest and most challenging cancers to overcome globally. Despite having a lower patient population compared to gastric cancer, it is often referred to as the "king of cancers." The disease presents with subtle early symptoms, making it difficult to diagnose (with an early detection rate of only 5%-7%, the lowest among all cancers). As a result, 80% of patients are diagnosed at an advanced or metastatic stage, missing the optimal surgical window. Combined with limited treatment options for advanced-stage patients, the overall survival period is a mere 6-9 months, resulting in high mortality rates.

In recent years, pancreatic cancer incidence and mortality rates have been on the rise, with over 500,000 new cases globally in 2022. According to the World Health Organization's global cancer burden data, China alone accounted for over 120,000 new cases and deaths from pancreatic cancer in 2020.

Currently, treatment options for pancreatic cancer are severely limited, primarily relying on chemotherapy, with a lack of effective targeted or immune therapies. While PD-1/PD-L1 immune therapies have demonstrated significant efficacy in many cancers, they have shown poor results in pancreatic cancer, with most clinical trials ending in failure. Consequently, subsequent drug developers have deliberately avoided pursuing pancreatic cancer indications, with only a few companies exploring combination therapies. Even the ADC drug king, DS-8201, has proven ineffective against pancreatic cancer. Clinical data from the DESTINY-PanTumor02 Phase II study revealed a confirmation ORR of only 4% for DS-8201 in HER2-expressing advanced pancreatic cancer, making it the least effective among all indications.

The NCCN guidelines set challenging thresholds for first-line treatment in advanced pancreatic cancer, with ORR generally not exceeding 30%, mPFS below 6 months, and median overall survival (mOS) below 10 months. After second-line treatment, ORR is approximately 7.7%, mPFS is around 3 months, and mOS is approximately 6 months. The percentage of pancreatic cancer patients who have failed first-line systemic therapy in both China and the United States is approximately 50%.

Even the recommended first-line dual regimen (gemcitabine combined with albumin-bound paclitaxel) only achieves an mOS of 6-9 months. The difficulty in conquering pancreatic cancer has not deterred global pharmaceutical companies from relentless exploration, leading to significant breakthroughs in targeted and immune therapies.

Advancements in Targeted and Immune Therapies:
In pancreatic cancer, approximately 80% of cases are unresectable locally advanced or have distant metastases. In addition to conventional chemotherapeutic agents like gemcitabine, albumin-bound paclitaxel, and cisplatin, treatment options include PARP inhibitors (olaparib), EGFR inhibitors (erlotinib), and NTRK inhibitors (larotrectinib, entrectinib).

Olaparib, an oral PARP inhibitor developed by AstraZeneca, is the first targeted therapy that selectively kills tumor cells with DNA damage response (DDR) pathway defects, such as BRCA mutations. In the Phase III POLO trial, olaparib demonstrated a progression-free survival (PFS) of 7.4 months and a three-year survival rate of 33.9%, reducing the risk of disease progression by 47%.

Based on these remarkable results, olaparib received FDA approval in 2019, becoming the first PARP inhibitor for treating BRCA-mutated pancreatic cancer. However, its indication for pancreatic cancer is yet to be approved domestically.

It is worth noting that the gene mutation rate for BRCA1/2 germline mutations (gBRCAm) targeted by olaparib in pancreatic cancer patients is only 4%-7%, while NTRK fusion mutations targeted by NTRK inhibitors account for less than 1%. This implies that the number of actionable targets for advanced pancreatic cancer remains limited.

Pancreatic cancer's complex nature and limited treatment options have posed significant challenges for researchers and pharmaceutical companies worldwide. However, the pursuit of innovative therapies targeting this formidabledisease continues. While progress has been slow, there have been promising advancements in targeted and immune therapies, such as PARP inhibitors and combination immunotherapies.