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Page 10 of 12 Lo et al. J Cancer Metastasis Treat 2022;8:30 https://dx.doi.org/10.20517/2394-4722.2022.48

Ongoing systemic therapy trials in LA-PDAC
As with BR-PDAC, randomized prospective LA-PDAC trials using current conventional chemotherapy
regimens such as GnP and FFX are needed. NEOPAN (NCT02539537) is an ongoing randomized phase III
trial of FFX for 12 cycles vs. gemcitabine alone for patients with LA-PDAC, with a primary outcome of PFS.
This study will provide high-level evidence regarding the use of FFX in this patient population. LAPTOP
(NCT04247165) is a phase I/II study investigating the safety and efficacy of combining dual immunotherapy
(ex. Nivolumab and ipilimumab) with GnP followed by SBRT, hypothesizing that the combination of
cytotoxic chemotherapy and radiation therapy will work synergistically with immunotherapy to lead to
sustained responses. Overall, extensive studies of neoadjuvant immunotherapy in pancreatic cancer are still
lacking.

There is also literature that the tumour microenvironment (TME), which consists of immunosuppressive
cell types and the cytokines that recruit them, plays a critical role in the control of proliferation, metastasis,
[36]
and evasion of immune surveillance in pancreatic adenocarcinoma . Thus, the TME represents a potential
therapeutic target for enhancing anti-tumour response of immune checkpoint blockade. An ongoing
randomized phase III placebo-controlled trial (NCT03941093) aims to evaluate the efficacy of neoadjuvant
targeted therapy with a monoclonal antibody to connective tissue growth factor (pamrevlumab)/placebo in
combination with GnP or FFX prior to assessment for resection. Another novel agent, such as defactinib, a
focal adhesion kinase (FAK) inhibitor is being studied in borderline resectable and locally advanced
pancreatic adenocarcinoma (NCT04331041).

The role of radiation/chemoradiation therapy for patients with LA-PDAC will need to be further
investigated. The most recent American Society for Radiation Oncology (ASTRO) guidelines currently have
[37]
conditional recommendations based on low-quality evidence . LAP07 did not show benefit to adding
chemoradiation for either OS or PFS, but further research is needed to confirm or refute this finding as
radiation techniques improve, and dosing and timing can be adjusted (ex. upfront radiation prior to
induction chemotherapy in contrast to LAP07). Other outcome measures including local recurrence and
complication rates due to local disease would be useful to better define the role of radiation.

Overall, evidence is emerging for the benefit of resection after systemic therapy for patients with LA-PDAC
responsive to treatment. This represents a paradigm change, as these patients were traditionally thought to
have unresectable disease and that systemic chemotherapy would be the mainstay of treatment. LAP07 and
NEOLAP showed that patients who underwent curative-intent resection had longer survival time than those
who did not, and LAPACT and NEOLAP showed that improved resection rates can be attained with
current standard multi-agent chemotherapy.

CONCLUSION
The role of systemic therapy in patients with pancreatic adenocarcinoma has changed over time. For
patients with BR-PDAC, a number of trials including phase III RCTs have demonstrated evidence that
neoadjuvant treatment followed by resection leads to favorable outcomes compared to upfront resection
followed by adjuvant therapy, by improving R0 resection rates, prolonging OS, and avoiding non-curative
resections. For patients who present with LA-PDAC, whom by definition have unresectable disease,
emerging evidence shows that a proportion of patients respond well to neoadjuvant systemic therapy and
are able to be converted to a resectable state and may achieve an R0 resection and potential long-term
survival. Multiple trials are underway that also include radiation and more conventional chemotherapy
regimens to better characterize their benefits and risks for both BR-PDAC and LA-PDAC. There are also
ongoing studies on the combination of immunotherapy with chemo/radiotherapy for patients with LA-