Gemcitabine/nab-paclitaxel with pamrevlumab: a novel drug combination and trial design for the treatment of locally advanced pancreatic cancer

Abstract

PurposePancreatic ductal adenocarcinomas exhibit a high degree of desmoplasia due to extensive extracellular matrix deposition. Encasement of mesenteric vessels by stroma in locally advanced pancreatic cancer (LAPC) prevents surgical resection. This study sought to determine if the addition of a monoclonal antibody to connective tissue growth factor, pamrevlumab, to neoadjuvant chemotherapy would be safe and lead to improved resectability in this surgically adverse patient population.MethodsIn this phase I/II trial, 37 patients with LAPC were randomised 2:1 to gemcitabine/nab-paclitaxel plus (Arm A, n=24) or minus (Arm B, n=13) pamrevlumab. Those who completed six cycles of treatment were assessed for surgical eligibility by protocol-defined criteria. Resection rates, progression-free and overall survival were evaluated.ResultsEighteen (75%) patients in Arm A and seven (54%) in Arm B completed six cycles of therapy with similar toxicity patterns. In Arms A and B, carbohydrate antigen 19–9 response, as defined by ≥50% decline from baseline, occurred in 13 (65%) and 5 (42%), respectively. Sixteen (16%) per cent of patients were radiographically downstaged by National Comprehensive Cancer Network criteria (5 in Arm A (21%) and 1 (8%) in Arm B). Positron emission tomography normalised in 9 (38%) vs 3 (23%) of patients in Arm A vs Arm B, respectively, and correlated with surgical exploration. Eligibility for surgical exploration was 17 (71%) vs 2 (15%) (p=0.0019) and resection was achieved in 8 (33%) vs 1 (8%) of patients in Arm A vs Arm B (p=0.1193), respectively. Postoperative complication rates were not different between arms.ConclusionsNeoadjuvant chemotherapy with pamrevlumab holds promise for enhancing resection rates in patients with LAPC without added toxicity. This combination merits evaluation in a larger patient cohort.

The State-of-the-Art of Phase II/III Clinical Trials for Targeted Pancreatic Cancer Therapies

“…Therefore, one anti-CTGF antibody, pamrevlumab, has been investigated in phase I/II clinical trials for the treatment of locally advanced, unresectable pancreatic cancer in combination with gemcitabine and nabpaclitaxel [67]. Results showed 71% of the pamrevlumab-treated group to be eligible for surgical exploration following treatment (n = 24), compared to 15% of patients not receiving pamrevlumab (n = 13) [68]. A phase III clinical trial is currently evaluating pamrevlumab plus gemcitabine and nab-paclitaxel for the treatment of locally advanced pancreatic cancer (NCT03941093).…”

Dynamic Stromal Alterations Influence Tumor-Stroma Crosstalk to Promote Pancreatic Cancer and Treatment Resistance

“…In the clinic, resection of locally advanced disease is often prevented by the encasement of major mesenteric vessels by the dense ECM. Neoadjuvant chemotherapy in combination with a monoclonal antibody against connective tissue growth factor (pamrevlumab) holds promise for improving resection rates in patients with locally advanced PDAC, as a pre-clinical study showed this combination reduced the dense and fibrotic encapsulation of critical blood vessels [ 134 ]. Furthermore, in pre-clinical mouse models of PDAC, the heparan-based mimetic necuparanib exhibits multi-targeting anti-tumor activity, reducing proliferation and invasion in vitro and extending survival as well as reducing metastases in vivo [ 135 ].…”

Multidisciplinary management of locally advanced pancreatic adenocarcinoma: Biology is King

“…The surrounding tissue stroma is an example of how the host's immune reaction to the tumor can become yet another obstacle. A small Phase I/II trial examined whether adding a CTGF inhibitor to the standard gemcitabine/ nab ‐paclitaxel combination therapy would lead to improved resectability in patients with locally advanced disease 75 . While their sample size was relatively small ( n = 37), the authors reported a higher rate of surgical exploration (17 [71%] vs. 2 [15%], p = .0019) and a higher rate of resection with half of those patients obtaining an R0 resection.…”