20 Years of Trials, Hope and Progress for Patients with Pancreatic Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the most challenging malignancies to treat today, as pancreatic cancer will claim 49,830 lives in the US this year and is on track to become the second deadliest malignancy by 2030.¹

The incidence rates have been slowly increasing over the past 2 decades clearly not following the downward trend seen with some other cancers. This is attributed to lack of effective prevention, systematic screening, and early detection.

Tomislav Dragovich, MD, PhD

Most cases are detected at an advanced and incurable stage, which translates into poor survival rates. Therapeutic advances in the past 2 decades were incremental and are based on additive improvements in surgery, imaging, radiation, and systemic therapy, but the hope is that these advances will favorably impact pancreatic cancer statistics in the coming years.

Looking Back at The Treatment Landscape of PDAC

The stage was set back in 1997 with the pivotal approval of gemcitabine, a monotherapy for metastatic pancreatic cancer based on data from a small, randomized trial.² The clinical benefit response (CBR) used in this study established a new surrogate endpoint for clinical trials, especially in a cancer associated with severe constitutional symptoms. As a “first” chemotherapy drug approved based on randomized data, gemcitabine became a backbone for testing new cytotoxic or targeted drugs for patients with pancreatic cancer.

The list of cytotoxic drugs tested agents is long and inclusive of almost all classes of chemotherapeutics. Unfortunately, no positive randomized trials were reported until early 2010s. The disease was rightly nicknamed the “graveyard of chemotherapy”.³ The same was holding true for targeted therapies or biologics with a modest exception of erlotinib,⁴ but the drug development field for pancreatic cancer was littered by negative trials in the early 2000s.^5,6

Fortunately, the fundamental advances in molecular biology and genomics informed us of underlying molecular mechanisms that drive pancreatic cancer proliferation and resistance to anti-cancer therapy. The empirical experience and resistance to targeted agents was explainable by the fact that there are no prevalent driver mutations in pancreatic cancer. In addition, there is also a predominance of non-druggable molecular alterations such as those affecting cancer suppressor genes targets.⁷

Chemotherapy and Mutations in PDAC

While various chemotherapy drugs used alone or in combination with targeted agents and/or biologicals failed to move the efficacy bar set by gemcitabine, combinations of chemotherapy drugs had more success. A combination of fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) demonstrated superior survival and response rates when compared to gemcitabine (NCT00112658).⁸

A few years later a combination of gemcitabine and nab-paclitaxel again demonstrated superiority to gemcitabine in another study (NCT00844649).⁹ These 2 regimens were never compared head-to-head and therefore represent standard choices for first-line chemotherapy for metastatic pancreatic cancer. More recently, a new “triple” combination of gemcitabine, nab-paclitaxel and cisplatin (GAP) demonstrated encouraging response rate in a phase 2 trial (NCT01893801).¹⁰ For the first time the chemotherapy combination regimens are pushing median survival of patients with metastatic disease beyond 12 months.

In the second line setting for metastatic disease, a liposomal formulation of irinotecan plus fluorouracil/leucovorin demonstrated superiority when compared to fluorouracil/leucovorin in a phase 3 trial called NAPOLI-1 (NCT01494506).¹¹ This was a longtime unmet need for this patient population.

As it happens, breakthroughs often arise from studying small and genetically well-defined subsets of cancers. In pancreatic cancer it came from exploiting a concept of synthetic lethality.^12,13 In this case, the focus was on pancreatic cancer patients carrying mutations of BRCA 1 and 2 genes, and while relatively rare, these mutations are associated with increased responsiveness to DNA intercalating agents such as platinum drugs and mitomycin C.¹⁴

As predicted by the synthetic lethality model, the tumors carrying BRCA 1 or 2 mutations are very sensitive to another category of drugs known as PARP (poly adenosine-diphosphate ribose polymerase) inhibitors. Indeed, when tested in a subset of patients with metastatic pancreatic cancer carrying BRCA mutations, a study (NCT02184195) showed that olaparib (Lynparza) significantly prolonged survival and time to progression in platinum responsive patients.¹⁵

KRAS oncogene mutations are also prevalent in the tumor of patients with pancreatic cancer but unfortunately not easily amenable to drug targeting. Recently, selective KRAS G12 C inhibitors have demonstrated promising clinical activity, this including pancreatic cancers carrying specific mutation. While these are important inroads, large majority of patients with pancreatic cancer lack actionable genomic targets such as KRAS G12C, BRCA 1 or 2, MSI-H (microsatellite instability-high), HER2 or NTRK and are not candidates for targeted therapy at present time.

Checkpoint Inhibitors and The Role of Precision Medicine

Some of transformational advances in therapy of solid tumors came with discovery of checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4 antibodies. These drugs profoundly changed outcomes in patients with melanoma, lung cancer and some other solid tumors. Unfortunately, the initial trials in patients with pancreatic cancer were disappointing. The resistance of pancreatic cancer to checkpoint inhibition is thought to be due to predominance of immunosuppressive cells in the stroma. Pancreatic cancer stroma is compared to “immune desert”.¹⁶

Some of the novel approaches are based on the attempt to change and overcome this hostile immune environment by inhibiting suppressive cells such as carcinoma associated fibroblasts (CAFs), tumor associated macrophages (TAMs) and myeloid derived suppressor cells (MDSC). The other approaches exploit immunotherapy in genetically defined subsets of pancreatic cancer such as MSI-H tumors or those with BRCA-ness in one study (NCT03404960),¹⁷ or a promising combination of checkpoint inhibitors and vaccine therapy.¹⁸

Targeting of pancreatic cancer stroma has been another logical and scientifically appealing approach, with one of the targets being the connective tissue matrix in pancreatic tumors.¹⁹ Even though it has produced encouraging results in a preclinical model and early clinical trials, the PEG Hyaluronidase (PEGHP20) trial (NCT01959139) failed to improve patient outcomes when combined with chemotherapy in randomized trials.²⁰

Targeting metabolic pathways in patients with pancreatic cancer has been another approach of great interest as the disease creates an anaerobic microenvironment and hypoxia favoring resistance to chemotherapy and radiation. Metformin was one of metabolic agents that has been tested in several trials, but we are still without conclusive and validated evidence of activity.²¹

Glufosfamide was another example of an agent designed to exploit “metabolic escape” of pancreatic cancer cells and utilize glucose transporters to deliver cytotoxic payload. Despite very promising results in a phase 2 trial (NCT01144455), the randomized trial did not reach the efficacy endpoint.²² The complex interplay between stroma, immune system and pancreatic cancer cells is difficult to replicate in vitro or on in vivo, which limits predictability of some sophisticated existing preclinical models.

Advances Help to Reconsider Surgery in the PDAC Landscape

Advances in systemic therapy for metastatic disease brought renewed enthusiasm and were tested in the adjuvant setting.²³ As reported in a long term follow up from the AIO/PRODIGE adjuvant trial, many more patients are cured because of use of adjuvant chemotherapy with FOLFIRINOX regimen.

Eschewing resistance mechanisms, postoperative morbidities, and probing cancer biology earlier during treatment are advantages associated with neoadjuvant chemotherapy, with several promising investigations reported recently. Patients with a borderline resectable pancreatic cancer were enrolled in a phase 2 trial with FOLFIRINOX and the 2-year survival rate was high at 55% and 31 of 48 of enrolled patients underwent an R0 resection.²⁴ In another preoperative trial (NCT02562716), a modified FOLFIRINOX and radiotherapy achieved high R0 resection rate (14/15 patients) and was well tolerated.²⁵ In the phase 2 randomized trial SWOG 1505 (NCT02562716), mFOLFIRINOX was compared to gemcitabine plus nab-paclitaxel in patients with resectable disease.²⁶

There was no significant difference in terms of efficacy between the 2 regimens in this patient population and the delay of surgery did not seem to compromise the outcome. The key question in this setting is how to best select patients that will benefit from neoadjuvant therapy and spare the other ones from potentially highly morbid and unnecessary surgery.²⁷

Surgery was always considered to be the only potentially curative approach for pancreatic cancer. Unfortunately, surgery alone provides cure only to minority of patients with resectable disease. We are now in position to better understand the systemic nature of pancreatic cancer and underlying pathophysiology as reasons for failure of local therapy.

The recent advances in systemic therapy are changing our approach to surgery. It is now considered an important component of curative therapy but not the only curative modality. In addition to increasing use of perioperative therapy recent advances in surgical technique such as minimally invasive and robotic pancreatectomy and total mesopancreas resection are under active investigation.^28,29

Beyond commonly used intensity–modulated radiotherapy IMRT, novel radiation therapy approaches are emerging. Stereotactic body radiation therapy (SBRT) is investigated as an effective and well tolerated palliative option for patients that are not surgical candidates or consolidation after systemic therapy. In addition, this approach has been increasingly utilized in neoadjuvant setting.³⁰

Pancreatic cancer clinically manifests with a variety of symptoms, often very difficult to control. The pain is certainly the most feared one and its pathophysiology is unique.³¹ Pancreatic cancer cells have an affinity to neurotrophic growth factors expressed on the surface of nerve sheets. The cancer spreads and invades along the celiac nerve plexus and bundles often resulting in mid or low back pain).

Celiac plexus blocks done either by endoscopic ultrasound or CT- guided approach is often effective in mitigating pain and decreasing the need for opioid drugs. Other supportive care interventions such as early bile duct stenting, nutritional support and management of anxiety and stress, through behavioral counseling, are of critical importance to achieve best palliation and disease control.

Detecting Pancreatic Cancer and Impacting Outcomes Earlier

It is important to keep in mind association of pancreatic cancer with hereditary cancer syndromes and therefore all newly diagnosed patients should be offered genetic counseling. In addition to identifying other family members at risk, this informs providers how to best tailor therapy for those that carry germline mutations such as BRCAs and/ or MMR deficiency.

Screening and early detection is an important concept for a disease where there is such a small window of curability. While MRI and EUS surveillance have a role in high-risk population we clearly need more sensitive and less invasive tests that could be applied to broader populations.³²

As clinicians we are all looking for a next exciting breakthrough that will bring us closer to eradicating or curing pancreatic cancer. If we are to predict future based on history, the success will likely come with incremental improvements in all modalities (surgery, radiation, and systemic therapy) over time. At the same time, we remain hopeful that a breakthrough will perhaps come sooner in the form of highly effective targeted therapy combination, or an effective new way of manipulating immune response against pancreatic cancer.

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