Metastasis-Directed RT Improves PFS in Oligometastatic Pancreatic Cancer

"We are excited to see that the addition of targeted radiation therapy quadrupled the average [PFS] time, suggesting this approach potentially represents a paradigm shift in treating metastatic pancreatic cancer," according to Ethan Ludmir, MD.

The addition of metastasis-directed radiation therapy (MDT) to standard chemotherapy significantly improved progression-free survival (PFS) compared with chemotherapy alone in patients with oligometastatic pancreatic cancer, according to results of the phase 2 EXTEND trial (NCT03599765) published in the Journal of Clinical Oncology.¹

Findings showed that, at a median follow-up of 17.3 months, the median PFS was 10.3 months (95% CI, 4.6-14.0) with the addition of MDT to chemotherapy vs 2.5 months (95% CI, 1.7-5.1) with chemotherapy alone, leading to a 57% reduction in the risk of disease progression or death (HR, 0.43; 95% CI, 0.20-0.94; P = .030). The estimated 1-year PFS rates were 42% (95% CI, 19%-64%) and 9% (95% CI, 1%-29%), respectively.

“Patients with metastatic pancreatic cancer have limited treatment options and poor outcomes,” first author Ethan Ludmir, MD, assistant professor of gastrointestinal radiation oncology at The University of Texas MD Anderson Cancer Center in Houston, Texas, stated in a news release.² “We are excited to see that the addition of targeted radiation therapy quadrupled the average [PFS] time, suggesting this approach potentially represents a paradigm shift in treating metastatic pancreatic cancer.”

MTD is designed with high-dose ablative radiation to target metastases and is currently being investigated for patients with oligometastatic disease.

In the multicenter, phase 2 basket EXTEND study, investigators enrolled 40 patients between March 19, 2019, and February 13, 2023 who had up to 5 metastatic sites in the pancreatic cancer basket. Patients were randomly assigned 1:1 to receive MDT plus chemotherapy (n = 19) vs chemotherapy alone (n = 21).

To be eligible for enrollment, patients needed to be at least 18 years old, have an ECOG performance status of 0 to 2, have received 4 or fewer prior lines of systemic therapy for their metastatic disease, and have up to 5 sites of metastatic disease amenable to MDT. Patients were stratified by number of metastatic lesions (1-2 vs 3-5), number of prior lines of therapy (0-1 vs >1), and cancer antigen 19-9 (CA19-9) level (<90 U/mL vs ≥90 U/mL).

The primary end point was PFS in the per-protocol population and was evaluated after all patients had at least 6 months of follow-up. Secondary outcome measures included overall survival (OS) in the intent-to-treat population, time to next-line systemic therapy, time to local failure, time to new lesion formation, toxicity, and quality of life. Systemic immune response measures served as an exploratory end point.

Regarding baseline characteristics, the median age was 68 years (range, 31-84) and 67 years (range, 45-75) in the MDT and chemotherapy-alone arms, respectively; 53% and 38% of patients were female, respectively. In the respective arms, patients were Asian (5%; 5%), Black/African American (5%; 29%), and White/Caucasian (89%; 67%); additionally, most were non-Hispanic or Latino (89%; 90%). Most patients had 1 to 2 metastatic lesions (79%; 76%), and more than half had liver as their site(s) of metastatic disease (58%; 71%). Five and 10% of patients had lung-limited disease, and most did not have prior lines of systemic therapy for metastasis with disease progression (53%; 71%). More than half in each arm had CA19-9 levels less than 90 U/mL (53%; 52%), and most patients had metachronous as their oligometastatic state (63%; 67%). The median time from initial diagnosis to enrollment was 12 months (range, 5-29) and 9 months (range, 4-88), respectively.

Further findings showed that systemic immune activation events were linked with MDT and correlated with the improved PFS. A post hoc analysis showed that baseline CA19-9 levels were prognostic (≥90 U/mL vs <90 U/mL; HR, 2.96; 95% CI, 1.40-6.24; P = .004).

Additionally, the median OS was 12 months (95% CI, 8-23) for MDT compared with 10 months (95% CI, 7-not available [NA]) for chemotherapy alone (HR, 0.58; 95% CI, 0.25-1.34; P = .20). The median time to new lesion recurrence was 14 months (95% CI, 6-NA) and 5 months (95% CI, 3-NA), respectively (HR, 0.51; 95% CI, 0.18-1.49; P = .22).

The median time to subsequent systemic therapy was 19 months (95% CI, 8-NA) with the addition of MDT vs 8 months (95% CI, 3-NA) in the control arm (HR, 0.53; 95% CI, 0.19-1.51; P = .24). One-year freedom from subsequent systemic therapy rate was 76% (95% CI, 48%-91%) vs 50% (95% CI, 25%-71%), respectively. Investigators noted that of the 18 patients alive at disease progression in the chemotherapy-alone arm, 3 crossed over to receive MDT.

Thirteen patients in each arm died due to their cancer (n = 23) and dissection of thoracoabdominal aortic aneurysm, COVID-19 pneumonia, and pulmonary embolism (n = 1 each). Regarding safety, there were no reports of grade 3 or higher adverse effects that were related to MDT.

“The results suggest that metastasis-directed therapy is effective and safe for patients with oligometastatic pancreatic cancer,” principal investigator Chad Tang, MD, associate professor of radiation oncology at The University of Texas MD Anderson Cancer Center, also stated in the news release.² “Nevertheless, larger trials are necessary to confirm the survival advantage observed with metastasis-directed local treatment and to investigate systemic immune activation as a potential mechanism for therapeutic benefits.”

The phase 3 EXPAND trial, set to evaluate whether MTD improves both PFS and OS in patients with oligometastatic pancreatic cancer, is expected to open later this year.

References

1. Ludmir EB, Sherry AD, Fellman BM, et al. Addition of metastasis-directed therapy to systemic therapy for oligometastatic pancreatic ductal adenocarcinoma (EXTEND): a multicenter, randomized phase ii trial. J Clin Oncol. Published online ahead of print August 5, 2024. doi:10.1200/JCO.24.00081
2. Adding metastasis-directed radiation therapy boosts progression-free survival in metastatic pancreatic cancer. News release. MD Anderson Newsroom. August 5, 2024. Accessed August 6, 2024. https://www.mdanderson.org/newsroom/adding-metastasis-directed-radiation-therapy-boosts-progression-free-survival-in-metastatic-pancreatic-cancer.h00-159699912.html