Abstract IA-08: Clinical advances in pancreas adenocarcinoma

Abstract Pancreatic adenocarcinoma (PDAC) remains one of the most lethal cancers today and is expected to be the second cause of cancer death in the coming decade. Multiple factors including rising incidence, late stage at presentation, disease aggression and ineffective treatment strategies contribute to poor 5-year survival rates estimated at 8-11% in North America and European countries (1,2). Today, we are beginning to see advances as we more accurately define tumor stage to provide better assessments for treatment and understand distinct molecular subgroups used to optimize therapeutic strategies. Molecular profiling of PDAC can uncover specific targets but can also allow for more refined approaches with our standard chemotherapeutics. Understanding how we can further interrogate the tumor microenvironment, metabolic pathways and illicit immune responses in this ‘cold’ tumor will further improve our treatment options. Many exciting opportunities will be discussed at this meeting. Despite multiple large phase III trials, the most prominent advances in recent years have come from combination chemotherapy regimens showing modest improvements in survival and quality of life parameters over single agent gemcitabine in the first-line metastatic setting. The current standards are either modified (m) FOLFIRINOX or the doublet of nab-paclitaxel plus gemcitabine (GnP), however both still result in median survivals of less than 1 year. As no studies have compared these 2 regimens head to head for efficacy, and aside from a known germline pathogenic variant in BRCA1/2, patient selection for either regimen is driven by performance status and/or patient preference for toxicity, schedule and drug-delivery. Exploring biomarkers or molecular profiling that may predict differential responses to chemotherapy upfront are key to advancing the field (3, 4) as only 50-60 % of patients with PDAC are well enough to move to second-line metastatic strategies (5). For example, the trial ‘Pancreatic Adenocarcinoma Signature Stratification for treatment (PASS-01)’, launching this year will evaluate the 2 standard regimens in fit first-line metastatic patients but will also explore high content molecular profiling, chemotherapy signatures, patient derived organoid models and other putative biomarkers to predict responses to chemotherapy and hypothesize alternatives(4). Building on first line systemics, the recent focus adds new agents to the better tolerated GnP standard. Targeting stroma in PDAC is a significant area of research including strategies aimed at targeting the desmoplastic architecture to decrease tumor pressure and vascular compression, thus improving drug delivery to cancer cells. We recently saw the negative data from the phase III HALO 301 trial. (6) This randomized double-blinded phase III trial compared PEGPH20 plus GnP to GnP for patients with hyaluronan (HA)-high metastatic adenocarcinoma following a promising randomized phase II trial in this enriched population. The primary endpoint of OS was not met with a median OS of 11.2 and 11.5 months (HR 1.00, p=0.096). There was a higher response rate in the experimental arm but with no improvement in duration of response, PFS or OS. The authors discuss potential reasons for this failure including underestimating the complexity of the the fibro-inflammatory infiltrate in the TME. While pre-clinical data demonstrated that desmoplastic stroma may limit the movement of systemic agents to the TME, there is also evidence from other studies that stromal elements may restrain PDAC progression (7). Finally, the IHC assay for HA has some reliability concerns and indeed less data when used to evaluate metastatic biopsies rather than the primary. Insights will no doubt arise from this disappointing result. Other important negative trials reported in the past year include the RESOLVE trial which added ibrutinib (BTK inhibitor) to GnP with a median survival favoring the control (8). The CanStemIIIP trial evaluating the stem cell agent napabucasin added to GnP was closed for futility on an interim analysis (press release Jul 2019) More promising, strategies combining immunotherapy to chemotherapy are pending and may show subsets that benefit (9) as is the anticipated anti-mitichondrial drug, devimistat added to mFOLFIRINOX in the first-line setting (10). Further progress is being made with PDAC deficient in homologous recombination repair (HRD). The sum of data supports a better survival seen when BRCA-1/2 cases are treated with a platinum salt. A retrospective study demonstrated a median survival of 2.4 years vs 1.5 years when metastatic HRD mutated patients were treated with a platinum vs another chemo regimen (11). Potentially this population represents approximately 10% of patients and therefore justifies germline and somatic testing as the result affects chemotherapy choice. Maintenance therapy after platinum-based chemotherapy control was studied in the landmark POLO phase III trial. Patients with germline BRCA1/2 were randomized 2:1 to PARP inhibitor olaparib or placebo after a minimum of 16 weeks of platinum-based chemotherapy with response or stable disease. The primary endpoint was met with a PFS of 7.4 vs 3.8 months (HR 0.53, p=0.0038) (12). Unfortunately, no improvement in OS was seen at 18.9 vs 18.1 months (HR 0.91, p=0.68). This trial does stand as a proof of principal biomarker-selected strategy, rather rare in oncology and appears to be changing practice for some pancreas cancer patients. Recent ASCO guidelines were updated to acknowledge that in this specific population in the maintenance setting after platinum- based chemotherapy, options include continuing the active chemotherapy or switching to olaparib (13). The KRAS WT group is a distinct entity that can harbor rare but highly druggable fusions such as NTRK, NRG1, ALK as well as alterations in BRAF (14,15). ASCO guidelines recently updated recommendations for therapy after failure of first-line chemotherapy highlighting treatment with larotrectinib or entrectinib in the presence of an NTRK fusion (13). Similarly, rare subsets testing positive for mismatch repair-deficiency could be considered for pembrolizumab (13). Clearly one the most significant advances for pancreatic cancer patients in recent times was the striking benefit seen with 6 months of adjuvant mFOLFIRINOX over adjuvant gemcitabine in the PRODIGE24-CCTG PA6 trial (16). In selected patients post resection (R0 or R1) median disease-free survival was 21.6 vs 12.8 months (HR 0.58, p<0.0001) and median OS was 54.4 vs 35 months (HR 0.64, p=0.003) all strongly favoring mFOLFIRINOX and representing the best outcomes to date for resected patients. Alternatively, the APACT trial (17) evaluating adjuvant GnP vs. gemcitabine did not meet its primary endpoint of DFS but survival data is maturing. The scope for improving patient outcomes by sequencing chemotherapy with surgery is striking. Yet older population data suggest that only 50% of patients receive any adjuvant chemotherapy, likely due to a combination of post-op frailty plus nihilism towards the benefits of chemotherapy. Hopefully, this is now changing. Also, there is strong traction to study therapy in the neoadjuvant setting to improve deliverability of the chemo, higher R0 resections, a testing of chemosensitivity and better selection for surgery. Recent presentation of SWOG S1505 demonstrated similar efficacy of either neoadjuvant mFOLFIRINOX or GnP (18) but leaves the door open for trials comparing neoadjuvant to adjuvant strategies. In addition, optimizing the best pre-operative regimens in high risk populations such as borderline and locally advanced patients with the potential to convert to a R0 resection is a high priority including the addition of chemoradiation, and newer local techniques such as SBRT. As integrated somatic and germline profiling becomes standard, we will increasingly see targeted approaches for subsets of patients. However, we will require more innovative approaches leveraging our understanding of the interplay between TME, metabolic profiles and microbioata. Never have efforts been more focused for success in pancreas cancer. References 1) Huang L et al. Stratified survival of resected and overall pancreatic cancer patients in Europe and the USA in the early twenty-first century: a large, international population-based study. BMC Med 2018 2) Bray F et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries . CA Cancer J Clin2018 3) O'Kane GM et al. GATA6 Expression Distinguishes Classical and Basal-like Subtypes in Advanced Pancreatic Cancer. Clin Cancer Res 2020. 4) NCT04469556 Pancreatic Adenocarcinoma Signature Stratification for treatment (PASS-01) 5) Walker EJ and Ko AH. Beyond first-line chemotherapy for advanced pancreatic cancer: an expanding array of therapeutic options? World J of Gastro. 2014 6) Van Cutsem E et al. Randomized Phase III Trial of Pegvorhyaluronidase alfa with nab-Paclitaxel Plus Gemcitabine for Patients with Hyaluronan-High Metastatic Adenocarcinoma. J Clin. Onc. 2020 7) Sinn M et al. a-smooth muscle actin expression and desmoplastic stromal reaction in pancreatic cancer: results from the CONKO-001study. Br J Cancer 2014 8) Tempero M et al. ESMO 21st World Congress in GI, Jul 2019.

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