Hopeful Signs in Pancreatic Cancer

Ronald Evans, MD

Despite improvements in the treatment of many formerly intractable cancer, the prognosis for pancreatic cancer remains dismal, with a 5-year survival rate of 8.2% (Figure).¹ Novel multimodal approaches that address the unique, aggressive biology of pancreatic cancer are needed, experts say.

“It is a very challenging diagnosis, but there are new therapies coming along based on science. This kind of knowledge is what we need to crack open the problem,” said Ronald Evans, MD, director of the Gene Expression Laboratory at the Salk Institute for Biological Studies in La Jolla, California.

In recent years, there have been significant developments in the management of pancreatic cancer, including neoadjuvant chemotherapy and radiation for patients with resectable disease and frontline use of multiagent cytotoxic therapy for metastatic disease. Several promising novel approaches that target the stem cell pathway and the tumor stroma are in the early stages of development and would be a big step forward for a subgroup of patients if they prove successful, according to Evans. Additionally, early-stage clinical trials are exploring the potential for immunotherapies including checkpoint blockade agents and chimeric antigen receptor therapies. However, much progress is still needed to improve toxicity with current chemotherapy regimens, standardization of molecular subtyping, utility of genomics testing, and screening recommendations for high-risk patients.

Optimizing Treatment Regimens

Neoadjuvant Chemotherapy

For the small percentage of patients with resectable disease, treatment has traditionally involved surgery followed by chemotherapy and radiation therapy. However, treatment in the neoadjuvant setting may improve outcomes for patients with resectable disease, according to Emma C. Fields, MD, radiation oncologist at the Virginia Commonwealth University Massey Cancer Center in Richmond, Virginia. A retrospective analysis² by Fields and colleagues showed that approximately 40% of patients had positive margins after resection; a positive margin was associated with shorter progression-free survival (PFS) than a negative margin.

According to Fields, maximizing tumor shrinkage with neoadjuvant therapy prior to surgery would help improve the likelihood of negative margins and thus survival outcomes. Furthermore, she stated that surgery for pancreatic cancer requires a lengthy recovery period during which the cancer could recur or metastasize. “Someone receives a pancreatic duodenectomy or Whipple [procedure], their recovery is 6 to 8 weeks, and then they have a CT scan showing development of disease elsewhere.”

Furthermore, Fields noted that patients may be able to tolerate intense regimens of chemotherapy and radiation better prior to surgery, which is associated with high morbidity and incidence of postoperative complications. A retrospective analysis³ showed completion of multimodality treatment in 83% of patients who received neoadjuvant therapy versus 58% of patients who received surgery first. Patients who completed multimodality therapy had better median overall survival (OS) at 36 months, compared with 11 months for those who received an incomplete regimen. Neoadjuvant treatment also tests the responsiveness of the tumor to chemotherapy and radiation, and patients unlikely to bene t from treatment could avoid unnecessary burdens from surgery and receive palliative care earlier.

According to Fields, providing radiation in the neoadjuvant setting also allows for a smaller volume of tissue to be treated. “Preoperatively, we can see the tumor and treat just around the tumor itself. Postoperatively, we treat a much larger volume because you’re dealing with an operative bed and it’s very hard to know where the tumor was with the reconstructed anatomy. So, we cover everywhere the surgeon potentially was and areas at risk.” Fields also noted that the tissues and tumor regions have better blood ow and oxygenation before surgery, which likely improve the efficacy of chemotherapy and radiation.

Although the role of neoadjuvant radiation and chemotherapy for early-stage pancreatic cancer is promising, Fields said that prospective studies in specific categories of patients (eg, those with resectable, borderline resectable, or locally advanced disease) are currently ongoing to deter- mine the benefits of neoadjuvant therapy and surgical eligibility at each stage of disease.

Chemotherapy for Metastatic Disease

Monotherapy with gemcitabine has fallen out of favor as the frontline treatment for metastatic pancreatic cancer, as the MPACT⁴ and PRODIGE 4/ ACCORD 11 trials⁵ demonstrated improvements in survival with gemcitabine plus nab-paclitaxel (Abraxane) and the 4-drug combination of leucovorin, uorouracil (5-FU), irinotecan, and oxaliplatin (FOLFIRINOX), respectively. In 2013, the FDA approved nab-paclitaxel in combination with gemcitabine for the first-line treatment of metastatic adenocarcinoma of the pancreas, which accounts for most pancreatic cancers, based on the MPACT data.

FOLFIRINOX and gemcitabine plus nab-paclitaxel have not been compared in a head- to-head trial, although many experts recommend FOLFIRINOX in patients with high performance status because the PRODIGE 4/ACCORD 1 trial results showed a longer OS with FOLFIRINOX (11.1 months) than the MPACT trial did with gemcitabine plus nab-paclitaxel (8.5 months).

However, Eileen M. O’Reilly, MD, stated during a recent OncLive^® Peer Exchange^® program⁶ that patient preferences may be worth considering in the absence of definitive data. “Some patients may have concerns about having a port and having infusion treatments with FOLFIRINOX,” said O’Reilly, associate professor of medicine at Weill Medical College of Cornell University in New York City. “Other patients may have concerns about alopecia with nab-paclitaxel—based therapy.”

Both regimens have substantial toxicity that often requires modification of the regimen. John L. Marshall, MD, chief of the Division of Hematology-Oncology at Georgetown University Hospital and director of the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancer in Washington, DC, said during the Peer Exchange^® that he usually modifies the FOLFIRINOX regimen up front by dropping the 5-FU bolus and reducing the dose of irinotecan.⁶

Many patients on gemcitabine plus nab-paclitaxel also require modified dosing, but may still be able to achieve acceptable survival outcomes. A retrospective analysis⁷ presented at the 2015 Gastrointestinal Cancers Symposium showed that patients who received nab-paclitaxel and gemcitabine on days 1 and 15 of a 28-day cycle had comparable survival length and a better toxicity profile when compared historically with the results of the MPACT trial that dosed on days 1, 8, and 15 of a 28-day cycle. Although O’Reilly stated that the lower-frequency regimen may not be suitable for all patients and is not FDA approved, she indicated that the analysis should reassure patients and physicians that reduced dosing frequency can still yield survival outcomes close to those of the full regimen.

Novel Approaches

Although gemcitabine is frequently considered part of the therapeutic regimen, recent data suggest that it is less efficacious in patients with low expression of human equilibrative nucleoside transporter 1 (hENT1).⁸ The randomized phase II GERCOR trial⁹ results showed that nab-paclitaxel plus 5-FU/leucovorin exceeded the study goal of a 4-month PFS of 50% and yielded a 12-month survival of 48%, whereas gemcitabine plus nab-paclitaxel yielded a 41% survival at 12 months (the study was not designed to compare the 2 regimens). According to the study authors, the results suggest that nab-paclitaxel is safe and effective as part of a gemcitabine-free regimen and should be tested further in phase III trials.Stem Cell Pathways

Although they make up less than 1% of all pancreatic cancer cells, cancer stem cells are a major contributor to chemoresistance and tumor initiation, growth, and metastasis. Thus, developing treatments that inhibit these stem cell pathways is of interest to many researchers.

Napabucasin (BBI-608), developed by Boston Biomedical, inhibits transcription of cancer stemness genes mediated by STAT3, which is a transcription factor that is constituently active in cancer stem cells and is thought to promote cell stemness, suppress antitumor immunity, and drive tumor-promoting inflammation. At the 2016 Gastrointestinal Cancers Symposium, researchers from Boston Biomedical presented data from 2 pancreatic cancer trials. The phase Ib trial¹⁰ showed that of the 7 evaluable patients with meta- static pancreatic ductal adenocarcinoma who received napabucasin, gemcitabine, and nab-paclitaxel, all had a partial response or stable disease and 6 had a sustained response (at least 24 weeks). The phase Ib/II study¹¹ showed disease control rates (sum of stable disease, partial response, and complete response rates) of 48% in patients with heavily pretreated pancreatic cancer and 68% in taxane-naïve patients.

“These studies continue to show napabucasin’s safety and early efficacy across doses and in combination with a variety of established agents,” said Chiang J. Li, MD, FACP, president, CEO, and chief medical officer of Boston Biomedical, in a press release.¹²

“We plan to apply these findings as we advance and expand our clinical development program for this first-in-category cancer stemness inhibitor.”

The phase III CanStem111P trial, launched in December 2016, is investigating the addition of napabucasin to the combination of nab-paclitaxel plus gemcitabine versus the 2 chemotherapeutic agents alone in patients with metastatic pancreatic adenocarcinoma who have not received prior systemic therapy for advanced disease (NCT02993731).

Vitamin D Receptor Therapy

Unlike many other cancers, immunotherapy has been largely unsuccessful in pancreatic cancer in part due to the dense desmoplastic stromal reaction that develops around the pancreatic tumor microenvironment, promoting angiogenesis and exclusion of immune cells and interacting with cancer cells to promote progression and invasion. Resetting genetic networks that promote this stromal reaction is among the goals of the Stand Up to Cancer (SU2C)-Cancer Research UK-Lustgarten Foundation Pancreatic Cancer’s Dream Team. According to the researchers, restoring the normal function of these pathways weakens this barrier surrounding the tumor, improving sensitivity to chemotherapy and possibly enabling the efficacy of immunotherapy.

Evans, co-leader of the Dream Team, and his colleagues showed that vitamin D receptors are expressed in human pancreatic stellate cells. Treatment with calcipotriol, a vitamin D ligand, reduced markers of inflammation and fibrosis, induced remodeling in the cells, increased gemcitabine levels in the tumor, reduced tumor volume, and improved survival in a mouse model.¹³ Paricalcitol, a modified form of vitamin D, showed similar effects in early human trials of pancreatic cancer in which it restored immune privilege, enabling entry of T cells into a tumor microenvironment that is typically void of T cells.

“Based on these findings, we might be able to take advantage of some of the advances in the immuno-oncology space for patients with pancreatic cancer,” said Evans. A randomized pilot trial (NCT02030860) is currently ongoing to determine the effects of paricalcitol plus neoadjuvant therapy on cellular and imaging markers, tumor response, and pancreatic stellate cell gene expression program in patients with resectable pancreatic cancer.

The most notable adverse event with vitamin D therapy is a decrease in parathyroid hormone, but Evans stated that monitoring levels and correcting the problem with dose reductions is relatively easy. He said that the safety and benefits of the strategy are well recognized because paricalcitol is currently used for secondary hyperparathyroidism associated with chronic kidney disease.

PEGylated Human Recombinant Hyaluronidase

Genomics and Molecular Subtyping

PEGylated human recombinant hyaluronidase (PEGPH20) has also shown promise in early trials. PEGPH20 disrupts the integrity of the pancreatic tumor stroma by reducing accumulation of hyaluronic acid, a component of the stroma that supports initiation and progression of cancer and impairs drug delivery to the tumor. Preclinical studies showed that the effects of PEGPH20 include depletion of stromal hyaluronic acid, re-expansion of tumor vessels, and enhanced effect of chemotherapeutic agents. A randomized phase II trial¹⁴ showed that the addition of PEGPH20 to nab-paclitaxel plus gemcitabine led to a 46% overall response rate and improved outcomes compared with the 2 chemotherapy drugs alone in patients with pancreatic cancer with high hyaluronan (HA) accumulation in the extracellular matrix of the tumor surface, suggesting that the novel agent may be an effective component for this population. The PEGPH20-containing regimen demonstrated a statistically significant improvement in PFS over the 2 chemotherapy drugs alone (HR, 0.51; P = .048) and exploratory OS of 11.5 months versus 8.5 months, respectively. Clinical trials are currently underway to test the efficacy of PEGPH20 with nab-paclitaxel plus gemcitabine in patients with previously untreated HA-high pancreatic ductal adenocarcinoma in the phase III HALO-301 trial (NCT02715804) and with modified FOLFIRINOX in patients with newly diagnosed metastatic disease (NCT01959139).With the introduction of novel therapeutic approaches, the analysis of genomics and molecular subtypes to identify patients who may bene t from these targeted therapies is of increasing interest. In addition to the association between hENT expression and effectiveness of gemcitabine,⁸ some data suggest that poly (ADP-ribose) polymerase (PARP) inhibitor-based and platinum-based therapies have clinical benefit in patients with genetic defects in the homologous recombination DNA repair pathway (HRD), particularly BRCA mutations. In a phase Ib trial, cisplatin, gemcitabine, and the PARP inhibitor veliparib (ABT-888) yielded a response rate of 66% in patients with a BRCA1 or BRCA2 mutations.¹⁵

However, the significance of many gene mutations detected through next-generation sequencing is not well known, which currently limits the clinical decision-making value of genomic tests. “In our institution, we routinely perform [molecular profiling] in patients with good performance status,” said Caio S. Rocha Lima, MD, medical oncologist and associate director of translational research at the Gibbs Cancer Center and Research Institute in Spartanburg, South Carolina, during the Peer Exchange^®.⁶ “Most of those reports will come up with the KRAS mutation...and we do not have a way to really target KRAS today.”

Although several researchers have begun to identify biological subgroups of pancreatic cancer, criteria for defining each subgroup is not well standardized and the ability of these characterizations to provide additional prognostic or predictive clinical information requires further investigation. However, George P. Kim, MD, a medical oncologist at 21st Century Oncology in Jacksonville, Florida, said during the Peer Exchange^®6 that regularly obtaining biopsies, and possibly repeat biopsies after a patient progresses, will help improve characterization of the dynamics of the cancer.

Screening Considerations

Lack of detection in early stages is a key contributor to the poor survival rates for patients with pancreatic cancer, but optimal procedures for screening such as the type of test, patient selection, and surveillance frequency are unclear. The US Preventive Services Task Force (USPSTF) states that population-based screening is not cost effective, but some experts suggest that screening high-risk individuals, particularly those with a strong family history of pancreatic cancer, may improve detection in the earlier stages, and thus survival outcomes. In 2012, the International Cancer of the Pancreas Screening Consortium¹⁶ recommended screening with endoscopic ultra- sonography and/or magnetic resonance imaging or magnetic resonance cholangiopancreatography for individuals with at least 2 relatives (and at least 1 first-degree relative) with pancreatic cancer; carriers of p16, PALB2, or BRCA2 mutations with a first-degree relative with pancreatic cancer; individuals with Peutz-Jeghers syndrome; and individuals with Lynch syndrome and a first-degree relative with pancreatic cancer. However, the consortium did not reach a consensus on the age to initiate or stop surveillance, the most optimal screening modality, the intervals for follow-up imaging, and which screening abnormalities warranted consideration of surgery.

Need for Collaboration Emphasized

A systematic review¹⁷ showed that screening of familial high-risk individuals improved curative resection rate, median survival, and diagnosis of stage I pancreatic cancer, although it also increased perceived risk, patient anxiety, and economic burden. The USPSTF is currently composing a draft research plan to review predicted improvements in cancer morbidity and mortality with screening, the diagnostic accuracy of screening tests, potential harms of screening, and benefits and harms of treating screen-detected or asymptomatic pancreatic cancer.Optimizing chemotherapy and radiation have led to incremental improvements in survival for pancreatic cancer, but experts agree that maintaining a durable treatment response and possibly achieving remission require development of novel therapies based on the unique biology of pancreatic cancer and tailored to the individual. Evans said that close collaborations between research scientists and clinical oncologists, such as those with the SU2C Dream Teams, will redefine the way to move forward with treatments for pancreatic cancer and other types of cancer. “By tackling the most lethal cancer, hopefully the lessons we learn will have widespread use for other cancers,” Evans said.

References

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