A review of novel therapies for pancreatic cancer and potential future treatments for the disease found that new therapies are urgently needed for patients, with a number of potential options on the horizon. Presented at the 2021 annual meeting of the American Society of Clinical Oncology, the research indicates that mutations of the KRAS gene could serve as a potential target for treatment, but that the targetable KRAS G12C mutation is very rare in pancreatic cancer, and the mutations more commonly seen are currently not targetable. Additionally, treatments combining chemotherapy and immunotherapy may be the future of immunotherapy for pancreatic cancer.
The development of precision medicine for pancreatic cancer has faced a number of challenges, including a lack of specific molecular-targeted drugs.
“We know we can sequence the tumor samples properly,” said Angela Lamarca, MD, PhD. “We know we can identify the genetic alterations in that tumor tissue. Unfortunately, we are lacking in specific molecular-targeted drugs at the moment, and we are therefore identifying alterations that are not targetable as-yet.”
There are several potential targets for precision medicine, but each with their own issues. Germline BRCA 1 and BRCA 2 mutations occur in only 5% to 7% of patients with pancreatic cancer, and although treatment of these mutations using platinum-based chemotherapy in combination with maintenance olaparib in the POLO trial showed an improvement in progression-free survival (PFS), there was no significant impact on overall survival (OS). However, these findings still suggests that a better understanding of molecular biology can lead to improvements for patients.
“There is data showing that, even if olaparib is not available, using platinum-based chemotherapy for these patients is of benefit, which is in a way a form of precision medicine,” Lamarca said.
KRAS mutations are another potential target for precision medicine. These are some of the most common seen in pancreatic cancer, with more than 90% of patients presenting with a KRAS mutation. However, G12C mutations, which are targetable, occur in less than 1% of patients with pancreatic cancer, meaning that the overwhelming majority of patients with KRAS mutations do not have a mutation that is currently targetable with available treatments.
“I think it’s really important that we understand that precision medicine is not the only thing that is happening in pancreatic cancer,” Lamarca said. “There is a huge effort in new combinations, mainly in chemotherapy strategies. We know that Folfirinox is the combination to beat, and in trying to do this, we have new triplet strategies being explored.”
Immunotherapy is also being revisited as a potential treatment option across a broader group of patients with pancreatic cancer. Originally, immunotherapy was utilized as a treatment for patients with MMR deficient malignancies, which accounted for less than 5% of patients. However, the recent COMBAT trial has shown that immunotherapy in combination with pembrolizumab and chemotherapy shows significant improvements in partial response rates.
New drugs are also being developed to specifically target the stroma of the tumor. This includes pamrevlumab, which showed promising results in phase 1 and phase 2 trials for the treatment of locally advanced pancreatic cancer, mainly in the increase of patients who became resectable. According to Lamarca, the question remains if treatments targeting the stroma will play a role in metastatic cancer treatments.
Pierce LJ, Peters S, Klein A, Bruns CJ, Hong TS, Lamarca A. ASCO/European Society for Medical Oncology (ESMO) Joint Session: Pancreatic Cancer—Challenges and Future Directions. Presented at: 2021 ASCO Annual Meeting; June 4, 2021; virtual.