Big Gain in PFS With Metastasis-Directed RT for Oligometastatic Pancreatic Cancer

Patients with oligometastatic pancreatic cancer lived more than four times longer without disease progression when they received metastasis-directed radiotherapy (RT) in addition to chemotherapy, a small randomized trial showed.

Patients who received metastasis-directed therapy (MDT) had a median progression-free survival (PFS) of 10.3 months as compared with 2.5 months with chemotherapy alone. MDT was associated with systemic immune activation and correlated with longer PFS. No patient had grade ≥3 adverse events associated with MDT, reported Chad Tang, MD, of the University of Texas MD Anderson Cancer Center in Houston, and co-authors in the Journal of Clinical Oncology.

Investigators are “delighted, elated” by the results, co-author Ethan B. Ludmir, MD, also of MD Anderson, told MedPage Today.

“As skepticism goes, there was a pretty heavy amount of skepticism that the pancreatic cancer cohort of this trial would not get a [positive] signal, so we were very pleasantly surprised,” he said. “This was coupled with the fact that [the effect] doesn’t seem to be random. Rather, we ended up seeing both improved progression-free survival and an impressive and sustained activation of the systemic immune system, based on peripheral blood draws.”

“Pancreatic cancer is notoriously resistant to immunotherapy,” Ludmir continued. “It’s very effective at concealing itself from the immune system. Conceivably what’s happening is that ablative radiation is allowing for exposure of cancer neoantigens to the immune system. So, you’re killing two birds with one stone. You’re ablating with high-dose radiation the metastatic disease that you can see and you’re augmenting the immune system’s ability to detect and clear the microscopic disease that is not yet seen on the CT scan.”

Despite the enthusiasm, the results should not be considered practice changing at this point, he said. The findings need to be confirmed in larger, phase III studies, one of which, called EXPAND, will begin patient accrual next month if all goes well.

Long-term outcomes for metastatic pancreatic ductal adenocarcinoma (PDAC) remain poor, associated with a median PFS of 5-7 months. Some evidence suggests that patients with limited metastatic disease (oligometastatic) may have better outcomes with strategies that combine chemotherapy with comprehensive MDT to all radiologically detectable metastatic sites, the authors noted in their introduction.

Retrospective evidence suggested potential benefits of MDT for patients with oligometastatic PDAC, including time off chemotherapy, although the issue has not been evaluated in randomized trials, the authors continued.

Given the background information, investigators tested the hypothesis that adding MDT to systemic therapy would improve PFS for patients with oligometastatic PDAC. The multicenter phase II EXTEND trial is a randomized basket study involving patients with various solid tumors. Histology-specific tumors were prespecified and independently powered.

A previous report from the study showed that adding MDT to systemic therapy led to significant improvement in PFS for patients with oligometastatic prostate cancer. The strategy also will be evaluated in breast and kidney cancers, said Ludmir. Initial positive clinical trial results with MDT involved oligometastatic non-small cell lung cancer.

Eligible patients had received no more than four prior lines of systemic therapy, and they had no more than five metastatic sites amenable to MDT. Patients were randomly assigned to receive chemotherapy alone or plus MDT for all active radiologic disease. The primary endpoint was PFS, measured from randomization to radiologic disease progression.

Data analysis included 40 randomized patients, most of whom (78%) had one or two metastatic sites. Patients allocated to MDT received local RT for 31 (94%) metastatic sites. The most common RT prescriptions were 50 Gy in four fractions and 70 Gy in 10 fractions. Stereotactic ablative RT was recommended whenever feasible.

After a median follow-up of 17.3 months, the 7.8-month difference in median PFS favoring MDT translated into a statistically significant 57% reduction in the hazard ratio for progression or death (95% CI 0.20-0.94, P=0.030). The estimated 1-year PFS was 42% with MDT and 9% with systemic therapy alone.

New lesions developed in eight patients randomized to MDT and nine in the control group. Median time to new lesion recurrence was 14 months in the MDT arm and 5 months in the control arm. Median time to next-line systemic therapy was 19 months in the MDT group versus 8 months in the control group. Thirteen patients died in each treatment arm, and median overall survival was 12 months with MDT and 10 months with systemic therapy alone.

Systemic CD8+ T-cell activation occurred after MDT but not in patients treated with chemotherapy alone. The population of proliferative CD8+ T cells was significantly greater in the MDT arm (P=0.02). Activated or highly activated CD8+ cells increased over time in the MDT arm but not the control arm.

“I think this is an exciting paradigm,” said Ludmir. “I think this is very timely because we’re seeing targeted therapies against KRAS emerge as a new frontier in pancreatic cancer, and we’re finally seeing traction where systemic therapies really have not moved much in the last decade. This is very timely in terms of considering alternative paradigms that integrate local therapies effectively.”

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