CAN-2409 Plus Valacyclovir Generates Positive Phase 2 Survival Results in PDAC

Paul Peter Tak, MD, PhD, FMedSci

Candel Therapeutics, Inc, has announced that neoadjuvant treatment with the investigational, off-the-shelf, replication-defective adenovirus aglatimagene besadenovec (CAN-2409) plus valacyclovir (Prodrug) and standard-of-care (SOC) chemoradiation, followed by resection, elicited a sustained survival benefit vs the SOC alone in a phase 2 study (NCT02446093) of patients with borderline resectable pancreatic ductal adenocarcinoma (PDAC).¹

Updated interim survival data from the ongoing trial showed that treatment with CAN-2409 (n = 13) plus valacyclovir led to an estimated median overall survival (OS) of 28.8 months vs 12.5 months in the control group. At 24 months, the OS rate was 71.4% and 16.7% in patients treated with CAN-2409 vs those treated with the SOC, respectively. At 36 months, the estimated OS rate was 47.6% in the CAN-2409 group vs 16.7% in the control group.

At the data cutoff of March 29, 2024, 4 out of 7 patients who were treated with CAN-2409 were still alive, with 2 patients surviving more than 50.0 months from enrollment. Notably, 1 out of 6 patients who were randomly assigned to SOC chemotherapy remained alive at 50.6 months.¹

Notably, CAN-2409 plus valacyclovir was granted fast track designation by the FDA in December 2023 for the treatment of PDAC. The regulatory decision was supported by data from this phase 2 clinical trial.²

“The failure of conventional immunotherapy to improve outcomes in pancreatic cancer is attributed to the highly immunosuppressive tumor microenvironment, which is largely devoid of immune cells,” Paul Peter Tak, MD, PhD, FMedSci, president and chief executive officer of Candel Therapeutics, stated in the press release.¹ “The immunological changes induced by CAN-2409, evident in the pancreatic tissue and the peripheral blood after administration, suggest that CAN-2409 is able to change the balance between the tumor and the patient’s antitumor immune response, which can convert progressive cancer into a chronic disease associated with improved survival.”

Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States and is projected to represent 3.3% of new cancer cases in 2023, with approximately 64,050 new cases and 50,550 deaths. Surgical resection offers the only potential for cure and though neoadjuvant chemotherapy aims to reduce tumor size for improved surgical outcomes, long-term cures are rare due to disease recurrence. Notably, PD-1 therapy has produced limited responses in PDAC due to the dense stromal environment. The need for more effective treatment options in PDAC led to the investigation of CAN-2409.

CAN-2409 is engineered to transport the herpes simplex virus (HSV)–derived thymidine kinase gene directly to a patient's tumor, prompting a tailored, systemic immune reaction against the cancer. Valacyclovir is then converted into a lethal compound, selectively targeting nearby cancer cells. This approach attempts to initiate a personalized CD8-positive T-cell response against both the injected tumor and distant metastases.¹

This investigational, randomized, open-label phase 2 clinical trial is assessing the safety, preliminary efficacy, and biological impact of administering CAN-2409 alongside valacyclovir in patients with borderline resectable PDAC undergoing neoadjuvant chemoradiation prior to surgery. Patients in the experimental arm received 3 courses of intravenous CAN-2409 plus valacyclovir via a 2-3 injection after induction chemotherapy, during chemoradiation therapy or after stereotactic body radiation therapy, and at the time of surgery. Notably, patients who experienced disease progression or metastases could receive up to 2 additional courses of the experimental combination.³

After a protocol amendment in 2022, the enrollment of patients with locally advanced PDAC was discontinued to focus exclusively on those with borderline resectable disease.¹

“Given the frequent recurrence and short survival [observed] with SOC chemotherapy for non-metastatic PDAC, effective new treatment options are urgently needed,” Garrett Nichols, MD, MS, chief medical officer of Candel Therapeutics, added in the press release. “We are very encouraged by the improved survival associated with CAN-2409, which has been shown to be durable after prolonged follow-up based on the updated data shown in this randomized clinical trial. CAN-2409 was generally well tolerated without significant additional local or systemic toxicity when added to SoC chemoradiation.”

Previously reported preclinical and clinical data have shown consistent and robust activation of immune responses after treatment with CAN-2409. In pancreatic tissue samples from patients treated with CAN-2409 in combination with valacyclovir and the SOC, notable clusters of CD8-positive granzyme B-positive cytotoxic tumor infiltrating lymphocytes, dendritic cells, and B cells were detected within the tumor microenvironment, which is not seen with the SOC alone. Additionally, elevated levels of soluble granzymes B and H, along with pro-inflammatory cytokines like IFN-γ, were noted in peripheral blood following CAN-2409 treatment.

CAN-2409 has maintained a positive safety and tolerability profile to date, with the combination regimen continuing to elicit tolerable safety responses and no dose-limiting toxicities and no cases of pancreatitis.

Over 1,000 patients have received CAN-2409 and presented with manageable adverse effects (AEs), suggesting potential for combination therapies without significant concerns of overlapping AEs.

Candel Therapeutics will continue to evaluate CAN-2409 in non–small cell lung cancer, borderline resectable PDAC, and localized, non-metastatic prostate cancer.

References

1. Candel Therapeutics announces positive interim data from randomized phase 2 clinical trial of CAN-2409 in non-metastatic pancreatic cancer. News release. Candel Therapeutics, Inc. April 4, 2024. Accessed April 4, 2024. https://ir.candeltx.com/news-releases/news-release-details/candel-therapeutics-announces-positive-interim-data-randomized
2. Candel Therapeutics receives FDA fast track designation for CAN-2409 in pancreatic cancer. News release. Candel Therapeutics, Inc. December 12, 2023. Accessed April 4, 2024. https://ir.candeltx.com/news-releases/news-release-details/candel-therapeutics-receives-fda-fast-track-designation-can-0
3. Neoadjuvant CAN-2409 in combination with chemoradiation or SBRT for borderline resectable pancreatic adenocarcinoma (PaTK02). ClinicalTrials.gov. Updated January 8, 2024. Accessed April 4, 2024. https://clinicaltrials.gov/study/NCT02446093