Penipulimab plus anlotinib and chemotherapy showed improved efficacy compared with chemotherapy alone in treatment-naïve metastatic pancreatic cancer.
Penpulimab-kcqx plus anlotinib (catequentinib; AL3818) and chemotherapy (nab-paclitaxel plus gemcitabine [AG]; PAAG) demonstrated progression-free survival (PFS) and objective response rate (ORR) benefits in addition to an acceptable safety profile compared with chemotherapy alone in patients with treatment-naive metastatic pancreatic cancer, according to data from the phase 2 RCT-PAAG trial (NCT06051851) presented at the
Treatment with PAAG, led to a median a median PFS of 7.8 months (95% CI, 7.0-8.8) vs 4.5 months (95% CI, 3.6-5.5) with AG (P <.001). The ORR was 49.52% vs 25.92% (P = .002) and the disease control rate was 93.33% vs 72.22%, respectively (P <.001). In the PAAG arm, ORR comprised 2 complete responses (CR) and 50 partial responses (PR), with 46 patients having stable disease (SD), and 7 patients having progressive disease (PD). In contrast, there were no CRs, and only 14 PRs in the AG arm, with 25 patients having SD and 19 patients experiencing PD.
Overall survival (OS) data at the time of the analysis showed a numerical benefit for PAAG with a median OS of 13.9 months (95% CI, 11.6-16.3) vs 10.5 months (95% CI, 6.9-14.0) with AG (P = .070); however, the OS data were not yet fully mature.
The safety analysis, which included 105 patients in the PAAG arm and 54 patients in the AG arm, showed that the safety of PAAG was generally comparable to AG. The most common treatment-related adverse events (TRAEs) with PAAG vs AG were leukopenia (any grade, 69.52% vs 70.37%; grade 3/4, 34.29% vs 38.89%), neutropenia (64.76% vs 72.22%; 31.43% vs 40.74%), anemia (38.10% vs 35.19%; 8.57% vs 12.96%), and thrombocytopenia (62.86% vs 57.41%; 16.19% vs 12.96%).
Nonhematological adverse events included with PAAG vs AG were elevated ALT and AST (any grade, 37.14% vs 29.63%; grade 3/4, 2.78% vs 1.85%), elevated creatinine (3.81% vs 5.56%; no grade 3/4 cases), nausea and vomiting (31.43% vs 33.33%; no grade 3/4 cases), diarrhea (16.19% vs 20.37%; 2.86% vs 3.70%), fatigue (54.29 vs 44.44%; 3.81% vs 5.56%), and peripheral neuropathy (21.90% vs 16.67%; 1.90% vs 0%).
The only statistically significant difference in any-grade events was rash, which occurred in 29 (27.62%) PAAG patients compared to 7 (12.96%) AG patients (P = .037), though grade 3/4 rash remained low at 2 (1.90%) for PAAG and 0 (0.00%) for AG (P = .549).
There were no patient deaths due to TRAEs in either arm as of the data follow-up date of October 31, 2025.
“The integrated regimen of penpulimab, anlotinib and AG chemotherapy appears to be a more preferable choice than AG alone for the first-line treatment of metastatic pancreatic cancer on account of its improved efficacy and acceptable safety,” said presenting study author Juan Du, MD, Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
Du explained that the researchers launched the trial because, “The combination of gemcitabine and nab-paclitaxel remains the standard first-line treatment [in this setting], yet its therapeutic benefits remain suboptimal.”
Overall, the open-label, multicenter, randomized controlled trial (NCT06051851) enrolled patients with previously untreated metastatic pancreatic cancer. Between August 2023 and June 2025, 159 patients were randomized in a 2:1 ratio to receive PAAG (n = 105) or AG (n = 54).
Patients assigned to the experimental PAAG arm received nab-paclitaxel at 125 mg/m² intravenously on days 1 and 8 of each 21-day cycle and gemcitabine at 1000 mg/m² intravenously on days 1 and 8, in combination with penpulimab at a fixed dose of 200 mg intravenously on day 1 of each cycle. Anlotinib was administered orally once daily on days 1 through 14 of each cycle at a dose of 12 mg, with dose adjustments permitted based on individual tolerance.
Patients in the control arm received nab-paclitaxel and gemcitabine at the same doses and schedule without penpulimab or anlotinib. Imaging assessments were performed every 2 cycles, and patients who completed eight cycles without disease progression were eligible to transition to maintenance therapy.
For the PAAG group, the maintenance regimen consisted of penpulimab at 200 mg on the first day of the cycle and 12 mg of anlotinib daily from day 1 through 14. Maintenance in the AG group was nab-paclitaxel at 125mg/m² and gemcitabine at 1000 mg/m² on day 1 of each cycle.
Patient characteristics were well balanced at baseline. For the PAAG vs AG arms, the median age was 65 (range, 43-78) vs 66 (range, 46-85), respectively, and 62.14% vs 73.08% were male. ECOG performance status was 1 (79.05% vs 72.22%) or 0 (20.95% vs 27.78%). Hepatic metastasis was present in 60.95% and 61.11% of the PAAG and AG groups, respectively. The primary lesion location was head/neck for 47.62% vs 38.89% of the PAAG vs AG patients, with the primary site being body/tail for 52.38% vs 61.11%, respectively.
Biomarker levels before treatment further confirmed the similarity between the 2 cohorts. Pre-treatment CA125 levels were higher than 30.2 U/ml in 60.95% of the PAAG arm and 59.26% of the AG arm. Pre-treatment levels of CA19-9 greater than 500 U/ml were reported for 46.67% vs 50.00% of the 2 arms, respectively.
Investigators concluded that the addition of penpulimab and anlotinib to gemcitabine-based chemotherapy may represent a preferable first-line option for metastatic pancreatic cancer, with continued follow-up planned to determine whether the observed PFS benefit translates into an OS advantage.
