Pancreatic Ductal Carcinoma: Slow Progress for a Hard-to-Treat Cancer

Johanna C. Bendell, MD

The incidence of pancreas cancer continues to rise in many countries.¹ In 2017, an estimated 53,600 cases were diagnosed in the United States, representing an approximately 45% increase over the past decade.^2,3 Pancreatic ductal adenocarcinoma (PDAC), which is considered incurable, accounts for more than 90% of pancreatic cancer cases.⁴

Amid this backdrop, a panel of experts from North America and Europe discussed emerging issues in the treatment of PDAC during an OncLive Peer Exchange^® program. Although the incidence of the disease has risen, “outcomes for patients with advanced PDAC have recently begun to improve, owing to refinement in the use of combination chemotherapy and new sequencing strategies for therapies,” said Johanna C. Bendell, MD, who moderated the session.

Evolving Approach to Drug Development

Novel Targets Emerging

Despite the improvement, 5-year and 10-year survival rates for PDAC remain low,4 and new, more effective therapies are urgently needed. The panel members reviewed data from recent studies of novel therapies being evaluated in PDAC and shared their perspectives on the significance of the findings for clinicians and patients.PDAC is a highly heterogeneous disease, according to Winson Y. Cheung, MD, MPH, who said the focus of drug development should be on “enriching the right patient subsets and targeting therapies to these individual groups” instead of treating everyone as though they had the same cancer. Tanios Bekaii-Saab, MD, FACP, predicted that patients with PDAC eventually will stratified into subgroups based on the degree of microsatellite instability (MSI) or presence of mutations that affect DNA damage response (DDR). Precision targeting has the potential to improve outcomes in PDAC.PARP and ATR Inhibitors

Manuel Hidalgo, MD, PhD, said that approximately 15% of patients with pancreas cancer harbor genetic mutations implicated in DDR dysfunction. Studies in patients with hereditary forms of pancreatic cancer have identified several defects in DDR, including mutations of BRCA1/2 genes; the ataxia telangiectasia mutated kinase (ATM) gene; and the DNA mismatch repair genes MLH1, MSH2, MSH6, and PMS2. ⁵ However, Hidalgo said, “We’re learning more and more that even unselected cases have germline mutations in some of the genes that compose the [DDR] pathway.”

BRCA1/2 mutations appear to be the most prevalent genetic alterations in patients with PDAC, especially in those of Ashkenazi Jewish heritage.⁵ Although the exact prevalence varies between studies, 5% of unselected patients and 12% of Ashkenazi Jewish patients included in a recent single-center study harbored a BRCA1/2 mutation.⁵

Cells deficient in BRCA1 and BRCA2 proteins are sensitive to inhibitors of the poly (ADP-ribose) polymerase (PARP) enzyme, several of which have been approved by the FDA to treat patients with ovarian cancer. PARP inhibitors are now being studied for PDAC.⁶ Findings from an in vitro proof-of-concept study, presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, showed that a BRCA1-mutated, patient-derived xenograft model of pancreatic cancer responded strongly to monotherapy with the PARP inhibitor olaparib (Lynparza).⁷ In general, cell lines with DDR dysfunction were more sensitive to cisplatin, olaparib, and kinase inhibitors of ataxia telangiectasia and RAD3-related (ATR) gene activity.⁷ The in vitro study also showed that cell lines treated with the ATR inhibitor AZD6738 or the ATM inhibitor AZD0156, both of which are investigational, became sensitized to cisplatin.7 A phase II study of maintenance therapy with the PARP inhibitor rucaparib (Rubraca) in patients with advanced PDAC and a BRCA or PALB2 mutation began recruiting in June 2017.⁸

STAT3 Inhibitors

Constitutive activation of signal transducer and activator of transcription 3 (STAT3) upregulates antiapoptotic proteins, preventing apoptosis and contributing to the development and progression of pancreatic cancer.⁹ Thus, STAT3 is an emerging molecular target in PDAC. The novel agent napabucasin (BBI-608) is a STAT3 inhibitor that is also referred to as a stemness inhibitor. “[Stem cells] are supposed to be the hardiest, most stubborn cancer cells—they are essentially chemotherapy resistant and radiation resistant,” said BekaiiSaab.

Cells with low stemness make up a small proportion of cancer cells in the beginning, but under pressure from chemotherapy or radiation, he explained, they acquire more stem features until stemness-high cells “ultimately become the bulk of cancer cells.” As the population of stemness-high cells expands, the cancer becomes increasingly resistant to treatment. “BBI-608, at least preclinically, was shown to block the stemness features and sensitize cancer cells to the effects of chemotherapy—specifically taxanes and gemcitabine,” he said.

In a phase Ib/II study, patients with metastatic PDAC received napabucasin with gemcitabine and nab-paclitaxel.¹⁰ Bekaii-Saab, who was one of the investigators, said the overall response rate was 55%, which included a 4% complete response rate and a 51% partial response rate.¹⁰ The promising results provided the impetus for CanStem 111P, a phase III study comparing the triplet regimen with the combination of gemcitabine and nab-paclitaxel (NCT02993731). CanStem 111P has enrolled more than 1000 patients, making it one of the largest studies ever conducted in pancreatic cancer, Bekaii-Saab said. “BBI-608 looks promising, but the ultimate test will be the results of the phase III study,” he said.

Hyaluronan

Hyaluronan (HA) is a component of the extracellular matrix, and Ramesh K. Ramanathan, MD, said accumulation of HA in the tumor stroma is a poor prognostic factor. The novel agent PEGPH20 degrades HA in the stroma, enhancing treatment response. “In preclinical models with gemcitabine, pretreating with PEGPH20 improved survival in mice— very impressive survival,” Ramanathan said. Data from a randomized phase II study of PEGPH20 (N = 279) were presented at the 2017 ASCO meeting.11 Patients with untreated metastatic PDAC received nab-paclitaxel and gemcitabine with or without PEGPH20. The triplet was associated with significantly better progression-free survival (PFS) than the nab-paclitaxel/gemcitabine combination (6.0 vs 5.3 months; HR, 0.73; 95% CI, 0.53-1.00; P = .048). When investigators stratified patients by HA expression, PFS in HAhigh expressers was also significantly better with the triplet regimen versus the doublet (9.2 vs 5.2 months; HR, 0.51; 95% CI, 0.26-1.00; P = .048).¹¹

Bendell said the phase II study found that PEGPH20 increased the risk of thromboembolic events, which was not observed in the phase I study. “We also learned that, for this particular drug, we need to give some low-molecular-weight heparin,” she said. After patients with an increased risk of thromboembolic events were excluded, the remaining participants received enoxaparin prophylaxis, and the difference in thromboembolic events between treatment arms was not significant.¹¹

“Also, this drug causes musculoskeletal events, where you had to give prophylactic steroids,” Ramanathan added. In the phase II study, 56% of patients in the PEGPH20 arm experienced muscle spasms compared with 3% of patients in the nab-paclitaxel/gemcitabine arm.¹¹ The ongoing phase III HALO-109-301 trial is enrolling previously untreated patients with stage IV pancreatic cancer who have high HA expression.

Immunotherapy Combinations

Ramanathan said the Southwest Oncology Group (SWOG) research group recently halted a phase Ib/II trial evaluating PEGPH20 with a modified FOLFIRINOX chemotherapy regimen (leucovorin, fluorouracil, irinotecan, and oxaliplatin) after an interim analysis showed no benefit. It is important to note, he said, that the SWOG study enrolled an unselected population and used a lower dose of PEGPH20 to reduce the risk of adverse effects when combined with FOLFIRINOX.Immune checkpoint inhibitors are approved for several solid tumor types and many patients are learning about them through the media. “I can’t tell you how many patients come into my clinic and say, ‘I want the Jimmy Carter drug—pembrolizumab [Keytruda]—for my pancreas cancer,’” said Bendell, referring to the PD-1 inhibitor that the former president received as a treatment for metastatic melanoma.

She noted that checkpoint inhibitors are widely available in the United States and said she frequently cautions colleagues against administering them as single agents for pancreas cancer due to a lack of evidence of their efficacy. Hidalgo agreed and said checkpoint inhibitors should not be used except perhaps for patients with MSI-high tumors.

Thomas Seufferlein, MD, PhD, said that although immunotherapy agents have potential in pancreas cancer, “Simple checkpoint inhibition is probably not going to work...We don’t even know for sure whether they work in combinations in pancreatic cancer.”

Underscoring that perspective, Hidalgo told the story of a patient with squamous cell carcinoma of the lung and pancreas cancer whom he was treating with gemcitabine, nab-paclitaxel, and pembrolizumab. “The lung cancer is responding, but the pancreas cancer is progressing,” he said.

Cheung said he used to treat patients with melanoma and that when immunotherapy agents worked, they worked extremely well. “I think we’re all still very hopeful that maybe different combinations might do the trick,” he said. “Maybe there are bifunctional antibodies that will give us a better answer by really forcing the immune system into the tumor,” Seufferlein said.

Progress Depends on Clinical Trials

Ramanathan suggested costimulatory molecules because vaccine adjuvants might provide the big breakthrough for immunotherapy in PDAC everyone hopes for. “It has to happen. If it can happen in melanoma, why not in pancreatic cancer?” he said. “I think it’s going to be a combination of immunotherapy with a microenvironment drug, but we’ll see,” said Bendell.Panel members agreed that progress in PDAC requires improving the clinical trial process. “In the current trials, the vast majority [of participants] are young patients, Eastern Cooperative Oncology Group [ECOG] performance status 0 or 1,” Cheung said, noting that these are not the kinds of patients routinely seen in practice. “It would be nice to see more pragmatic trials, where ECOG2 individuals and older people were also enrolled,” he said. Cheung also called for outcomes-based or population-based studies to assess how the agents perform in the real-world setting.

Seufferlein said he would like smarter, evidence-based trials that avoid involving many patients who ultimately will derive no benefit. “We also have to make an effort to collect biological materials because we rely on those to really make future decisions on the treatment," he said. “This is an extra effort, but it is worthwhile.”

References

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9. Glienke W, Hausmann E, Bergmann L. Downregulation of STAT3 signaling induces apoptosis but also promotes anti-apoptotic gene expression in human pancreatic cancer cell lines. Tumour Biol. 2011;32(3):493-500. doi: 10.1007/s13277-010-0143-4.
10. Bekaii-Saab TS, Starodub A, El-Rayes BF, et al. A phase Ib/II study of cancer stemness inhibitor napabucasin (BBI-608) in combination with gemcitabine (gem) and nab-paclitaxel (nabPTX) in metastatic pancreatic adenocarcinoma (mPDAC) patients (pts). Presented at: 2017 ASCO Annual Meeting; June 2-6, 2017; Chicago, IL. Abstract 4106. ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.4106.
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