Editor’s note: The LAPIS Phase 3 trial was a large-scale, global, double-blind, placebo-controlled study designed to assess the efficacy of pamrevlumab in combination with chemotherapy for patients with locally advanced pancreatic cancer (LAPC). Despite not meeting its primary endpoint, the study provided significant insights into LAPC treatment, trial design, and surgical resection criteria. The trial was presented by Dr. Vincent Picozzi at the ASCO Gastrointestinal Cancers Symposium.
Pancreatic cancer remains one of the most difficult malignancies to treat, with LAPC posing a unique challenge due to its low surgical resection rates. Pamrevlumab, a fully human monoclonal antibody targeting connective tissue growth factor (CTGF), had demonstrated potential in improving resection eligibility in prior trials. Given its favorable safety profile, the LAPIS study aimed to determine whether pamrevlumab, when added to chemotherapy, could improve survival and resectability rates.
A total of 284 patients with pathology-confirmed, treatment-naïve, unresectable LAPC were enrolled and randomized in a 1:1 ratio. Patients received either chemotherapy (gemcitabine/nab-paclitaxel or FOLFIRINOX) plus pamrevlumab (35 mg/kg every 2 weeks) or chemotherapy plus placebo. Treatment cycles were conducted over a period of up to six 28-day cycles. Resectability assessments were based on CA19-9 biomarker levels, FDG-PET SUVmax, anatomic imaging, and final evaluation by the investigator surgeon. The trial focused on primary and secondary endpoints, with overall survival (OS) being the primary endpoint and event-free survival (EFS), progression-free survival (PFS), objective response rate (ORR), and safety outcomes as secondary endpoints.
Key Findings and Outcomes
Pamrevlumab did not demonstrate a statistically significant improvement in survival. The median overall survival (OS) for the pamrevlumab group was 17.3 months, compared to 18.0 months in the placebo group, with a hazard ratio of 1.08 (95% CI: 0.83–1.41, p=0.5487). Event-free survival (EFS) was 5.7 months in the pamrevlumab arm versus 5.8 months in the placebo arm, with a hazard ratio of 1.05 (95% CI: 0.78–1.39). Progression-free survival (PFS) was identical in both arms at 9.4 months, with a hazard ratio of 1.01 (95% CI: 0.65–1.56).
One of the significant findings of the LAPIS trial was the high level of agreement between the surgeon and central review board in assessing surgical resection eligibility. Approximately two-thirds of patients completed six treatment cycles, with 64.8% (92/143) in the pamrevlumab group and 68.1% (96/141) in the placebo group. Among patients with reconstructible disease (n=69), 67.6% (23/34) in the pamrevlumab group and 65.7% (23/35) in the placebo group completed chemotherapy and were evaluated for surgery. However, resection rates remained low, with only 8.8% (3/34) of pamrevlumab-treated patients and 8.6% (3/35) of placebo-treated patients achieving resection status.
Pamrevlumab did not introduce significant additional toxicity compared to the placebo group. Adverse event frequency, severity, and surgical complications were similar across both cohorts. Notably, there was one treatment-related death due to pneumonia in the pamrevlumab group. Objective response rates differed significantly between arms, with a 30.1% response rate in the pamrevlumab group versus 45.4% in the placebo group (odds ratio: 0.50; 95% CI: 0.31–0.82), suggesting that pamrevlumab may not enhance chemotherapy’s efficacy in this setting.
Limitations of the Study
Several limitations may have impacted the study’s results and interpretation. The inclusion of patients with non-reconstructible disease at baseline likely reduced the potential for curative resection. Additionally, staging laparoscopy was not mandatory, which may have influenced patient selection. Variability in supportive and perioperative care across international sites further complicated the analysis. Finally, the study was conducted during the global COVID-19 pandemic, which may have negatively impacted survival outcomes.
Conclusion and Future Implications
Although the LAPIS trial did not demonstrate a survival benefit with the addition of pamrevlumab to chemotherapy, it remains a pivotal study in LAPC for its size, novel design, rigorous execution, and introduction of innovative endpoints. The trial’s methodology, including external surgical review panels and FDG-PET imaging for resectability assessment, may shape future LAPC trial designs. Moving forward, LAPIS findings suggest the need for shorter, more targeted trials to refine therapeutic strategies and optimize patient selection criteria in LAPC treatment paradigms.
