With the worst 5-year overall survival of all cancers and the second-leading cause of cancer death, pancreatic adenocarcinoma remains a dismal prognosis for the vast majority of patients. However, more accurate tumor staging and better understanding of distinct molecular subgroups have started to drive clinical advances.
Jennifer J. Knox, MSc, MD, FRCPC
At the Special Conference on Pancreatic Cancer, sponsored by the American Association for Cancer Research (AACR) and held virtually this year, Jennifer J. Knox, MSc, MD, FRCPC, provided an overview of the treatment landscape in pancreatic cancer, including how molecular profiling is uncovering specific targets and allowing for more refined approaches with standard chemotherapies.1
“Understanding how we can further interrogate the tumor microenvironment and metabolic pathways and elicit immune responses in this ‘cold’ tumor will further improve our treatment options,” noted Dr. Knox, Clinician Investigator at Princess Margaret Cancer Centre, Toronto, Canada. “Never have efforts been more focused for success in pancreatic cancer.”
Three Negative Trials in Metastatic Setting
As Dr. Knox explained, accurate tumor staging informs both treatment selection and the design of clinical trials. Unfortunately, she noted, the majority of patients present with metastatic or locally advanced incurable cancer. In this setting, the current standards are either modified FOLFIRINOX (leucovorin, fluorouracil, irinotecan, oxaliplatin) or the doublet of gemcitabine plus nab-paclitaxel, which demonstrated modest improvements in survival and quality of life over single-agent gemcitabine. Both regimens, however, have resulted in median survivals of less than 1 year.
Recent strategies have focused on adding targeted agents in the first-line setting to the better-tolerated doublet of gemcitabine plus nab-paclitaxel. However, these approaches have failed to advance the field. The following three negative trials were reported this year:
- RESOLVE evaluated the addition of the Bruton’s tyrosine kinase inhibitor ibrutinib, which yielded results favoring the control arm.
- CanSTEMIIIP evaluated the addition of the stem cell agent napabucasin and closed early for futility.
- HALO-301 evaluated the addition of the stroma-targeting agent PEGPH20 (pegylated recombinant human hyaluronidase) and showed no improvement in overall survival. Dr. Knox called the results of the HALO-301 study, which targeted the desmoplastic architecture of pancreatic cancer with PEGPH20, “very disappointing.”
Clinicians are left to choose from either FOLFIRINOX or gemcitabine plus nab-paclitaxel, but these regimens have not been compared head to head for efficacy. Aside from a known germline pathogenic variant in BRCA1 and BRCA2, patient selection for either regimen is driven by performance status and/or patient preference for toxicity, schedule, and drug delivery.
“What is really needed is a biomarker from the patient’s tumor that would predict response, but this is not easy to find,” shared Dr. Knox.
Data from the COMPASS genomic trial, however, have suggested that a basal-like subgroup was most likely to have a non–oxaliplatin-sensitive signature.2 This formed the basis of the PASS-01 trial, which will randomly assign patients with metastatic pancreatic cancer in the first line between these two standards of care and treat until first disease progression. “This is an opportunity to get a lot of tumor samples as well as liquid biopsies to try to develop better biomarker predictors,” said Dr. Knox.
“Never have efforts been more focused for success in pancreatic cancer.”— Jennifer J. Knox, MSc, MD, FRCPC
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Targeted Treatments: HRD, KRAS Wild-Type, MSI-High
Further progress is being made with pancreatic cancer deficient in homologous recombination repair (HRD), which accounts for approximately 5% to 10% of cases. Data support better survival when core homologous recombination genes (BRCA1, BRCA2, and PALB2) are treated with a platinum salt, explained Dr. Knox, who noted “striking differences in survival” from recent studies. The Know Your Tumor registry trial showed a median survival of 2.4 years vs 1.5 years, for example, when patients with metastatic HRD-mutated disease were treated with platinum as compared with another chemotherapy regimen.3 According to Dr. Knox, this finding justifies germline and somatic testing, as the result affects treatment choice.
There is also excitement in the maintenance setting, said Dr. Knox, based on pivotal POLO trial data. These findings showed that maintenance PARP (poly [ADP-ribose] polymerase) inhibition extends progression-free survival after platinum-based chemotherapy vs placebo in patients with germline BRCA1 and BRCA2 metastatic disease.4 (For more on maintenance therapies in pancreatic cancer, see page 25.) Results of the trial showed a median progression-free survival of 7.4 months with olaparib maintenance vs 3.8 months with placebo.
“Investigators should be congratulated for undertaking such a challenging trial in a rare biomarker subset, but it is sobering that there is no difference in survival,” said Dr. Knox. “Most experts are hoping to see a stronger influence with other combinations and to find other ways of targeting this pathway.”
The KRAS wild-type, seen in approximately 10% of cases, is another unique subset that offers “highly druggable fusions” such as NTRK, NRG1, ALK, RET, FGRR, and alterations in BRAF. In fact, said Dr. Knox, the limited data are so compelling that ASCO recently updated its guidelines for second-line therapy to take into account some of these rare mutations and to recommend germline testing for BRCA as well.5
Finally, for the approximately 1% of tumors that are microsatellite instability (MSI)-high or mismatch repair–deficient, data from KEYNOTE-158 demonstrated activity with pembrolizumab.6 However, the 20% response rate was far worse than other cancers, said Dr. Knox.
Resectable Pancreatic Cancer: Moving in the Right Direction
One of the most significant advances for patients with pancreatic cancer in recent times has come in the setting of nonmetastatic disease, according to Dr. Knox. In this setting, 6 months of adjuvant modified FOLFIRINOX showed a “stunning improvement in survival” over adjuvant gemcitabine in the PRODIGE24-CCTG PA6 trial.7 In selected patients post-resection (R0 or R1), median disease-free survival was 21.6 vs 12.8 months (hazard ratio [HR] = 0.58, P < .0001), and median overall survival was 54.4 vs 35 months (HR = 0.64, P = .003), strongly favoring FOLFIRINOX.
“If you look at the evolution of adjuvant therapy over time, you can see how the needle has moved in the right direction.”— Jennifer J. Knox, MSc, MD, FRCPC
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“These data represent the best outcomes to date for resected patients,” said Dr. Knox. “If you look at the evolution of adjuvant therapy over time, you can see how the needle has moved in the right direction. It is important to note, however, that up to 50% of resected cases never receive any adjuvant data,” she added. “Hopefully, this is now changing.”
Future Directions
According to Dr. Knox, there are a number of strategies to improve curative approaches, including studying therapy in the neoadjuvant setting. Although recent data from SWOG-S1505 demonstrated similar efficacy with neoadjuvant modified FOLFIRINOX and gemcitabine/nab-paclitaxel, she said, these results leave an opening for trials comparing neoadjuvant and adjuvant strategies.8
Converting high-risk patients to R0 resection with preoperative regimens may also have an impact on survival. There is not an ideal regimen, said Dr. Knox, but upfront FOLFIRINOX
chemoradiation is favored in patients with borderline resectable cancer. Although patients with locally advanced disease are at much higher risk because of the suspicion of micrometastatic disease, she added, there may be a subset that benefits from neoadjuvant chemotherapy and local approaches.
Finally, said Dr. Knox, the biologic complexity of pancreatic cancer needs higher level models, and artificial intelligence is poised to deliver advances in the field. “Volumes of information from numerous patient sources may be able to identify patterns with machine learning that lead to better treatments for our patients,” she concluded. “I think that is coming quite soon.”
DISCLOSURE: Dr. Knox has served as a consultant for AstraZeneca, Merck, Roche, Eisai, and Pfizer and has received grant/research support from AstraZeneca, Ibsen, and Merck.
REFERENCES
1. Knox JJ: Clinical advances in pancreas adenocarcinoma. AACR Virtual Special Conference: Pancreatic Cancer. Plenary Session 2. Presented September 29, 2020.
2. O’Kane GM, Grünwald BT, Jang GH, et al: GATA6 expression distinguishes classical and basal-like subtypes in advanced pancreatic cancer. Clin Cancer Res 26:4901-4910, 2020.
3. Pishvaian MJ, Blais EM, Brody JR, et al: Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: A retrospective analysis of the Know Your Tumor registry trial. Lancet Oncol 21:508-518, 2020.
4. Golan T, Hammel P, Reni M, et al: Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med 381:317-327, 2019.
5. Sohal DPS, Kennedy EB, Cinar P, et al: Metastatic pancreatic cancer: ASCO guideline update. J Clin Oncol. August 5, 2020 (early release online).
6. Marabelle A, Le DT, Ascierto PA, et al: Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: Results from the phase II KEYNOTE-158 study. J Clin Oncol 38:1-10, 2020.
7. Conroy T, Hammel P, Hebbar M, et al: FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med 379:2395-2406, 2018.
8. Ahmad SA, Duong M, Sohal DPS, et al: Surgical outcome results from SWOG S1505: A randomized clinical trial of mFOLFIRINOX versus gemcitabine/nab-paclitaxel for perioperative treatment of resectable pancreatic ductal adenocarcinoma. Ann Surg. July 24, 2020 (early release online).
