Updates in Clinical Management of Pancreatic Cancer

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Andrew H. Ko
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The mainstay of treatment for patients with metastatic pancreatic cancer is chemotherapy, but the development of targeted therapies and immunotherapies heralds a new era in their care. Although actionable alterations are detected infrequently, routine molecular testing should be performed in all patients. The NCCN Guidelines provide the current evidence-based recommendations for maintenance therapy in the metastatic setting. For patients with resectable, borderline resectable, and locally advanced or unresectable tumors, critical questions remain regarding the role of radiation therapy.

“We know chemotherapy remains the mainstay of treatment [for metastatic pancreatic cancers, comprising the majority of patients], but, even with our contemporary regimens…survival still remains poor,” commented Andrew H. Ko, MD, Professor of Clinical Medicine and Associate Chief, Division of Hematology/Oncology, University of California San Francisco (UCSF), and a member of the UCSF Helen Diller Family Comprehensive Cancer Center. At the NCCN 2024 Annual Conference, Dr. Ko discussed emerging therapies that are changing the paradigm in this setting, the potential treatment-decisive role of genomic and molecular profiling, as well as considerations for the management of those with earlier-stage disease.

Chemotherapeutic Landscape for Metastatic Pancreatic Cancer

Both FOLFIRINOX (fluorouracil [5-FU], leucovorin, irinotecan, and oxaliplatin) and gemcitabine + nab-paclitaxel have previously demonstrated efficacy in the frontline treatment of patients with metastatic pancreatic cancer, according to Dr. Ko. Thus, he explained, “People have wondered, why not a direct head-to-head comparison?”

The phase III JCOG1611-GENERATE trial of modified FOLFIRINOX (n=175) versus gemcitabine + nab-paclitaxel (n=176) brought this to fruition in an exclusively Japanese patient population, demonstrating a median overall survival (OS) of 14.0 versus 17.0 months, respectively, and progression-free survival (PFS) of 5.8 versus 6.7 months, respectively.1 The objective response rate (ORR) was 32.4% with modified FOLFIRINOX and 35.4% with gemcitabine + nab-paclitaxel. Neutropenia (51.5% vs 60.3%), febrile neutropenia (8.8% vs 3.4%), anorexia (22.8% vs 5.2%), and diarrhea (8.8% vs 1.1%) were among the most frequently reported grade 3 and 4 toxicities. With just an estimated 0.73% chance of modified FOLFIRINOX achieving superiority at the final analysis, the study was terminated for futility. According to Dr. Ko, “The authors argue that gemcitabine + nab-paclitaxel should represent the go-to frontline standard,” but both may be equally viable selections.

Following the results of the phase III NAPOLI-1 trial, the FOLFIRINOX regimen was modified to replace irinotecan with nanoliposomal irinotecan, an agent that was originally approved by the FDA for use in the second-line setting, to form NALIRIFOX. The phase III NAPOLI-3 trial provided a foundation for the recent approval of this new frontline standard. Compared with gemcitabine + nab-paclitaxel, treatment with NALIRIFOX resulted in superior OS (median OS, 11.1 vs 9.2 months; P=.036) and PFS (7.4 vs 5.6 months; P<.0001), as well as an improved ORR (41.8% vs 36.2%).2

“In the original study of FOLFIRINOX, the median OS was [also] 11.1 months,” Dr. Ko remarked. “It really raises the question [of whether] we should typically be using [NALIRIFOX] in substitution for FOLFIRINOX.”

Treatment-emergent adverse events of grade ≥3 were documented in 87% of patients treated with NALIRIFOX and 86% of those who received gemcitabine + nab-paclitaxel.2 The most frequently reported treatment-emergent grade 3 and 4 adverse events were neutropenia (14%), diarrhea (20%), and hypokalemia (15%) with NALIRIFOX, and neutropenia (25%), anemia (17%), and peripheral neuropathy (6%) with gemcitabine + nab-paclitaxel. Of note, the study investigators reported lower rates of grade 3 and 4 peripheral sensory neuropathy and neutropenia with the novel regimen compared with historical data for FOLFIRINOX.

Is There a Role for Molecular Testing?

“Right now, our selection of treatment is based primarily on clinical criteria,” Dr. Ko commented. “Emerging evidence for molecular and genetic subtyping of pancreatic cancer may help guide the selection of some therapies, but it is important to note this only applies to a minority of patients.”

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pancreatic Adenocarcinoma now recommend germline testing for all patients diagnosed with pancreatic cancer, regardless of their family history.3 In addition, Dr. Ko noted, somatic testing should be considered, as it may identify potential actionable mutations. He highlighted homologous recombination deficiency (HRD)–associated pathway mutations as the most common actionable finding, occurring in approximately 10% to 15% of all pancreatic cancers.

“If you identify a patient with BRCA, PALB2, or other HRD pathway mutations, either through germline or somatic testing, they should receive platinum-based chemotherapy along their treatment course, ideally in the frontline setting,” Dr. Ko remarked. This recommendation, he stated, advocates for both oxaliplatin-based regimens, such as FOLFIRINOX, as well as cisplatin-based therapies, with patients who have BRCA/PALB2-mutated disease having been found to exhibit robust sensitivity to either.

Targeted Therapies for Metastatic Disease

Approximately 70% to 95% of pancreatic cancers harbor an aberration of the KRAS gene,4 which, according to Dr. Ko, makes it the “holy grail” of therapeutically actionable mutations. “[It is noteworthy that] KRAS G12C mutations comprise only approximately 2% of all patients with pancreatic cancer. There is now a class of drugs that are direct inhibitors,” he explained, highlighting the promising ORRs associated with sotorasib and adagrasib for patients with KRAS G12C–associated advanced pancreatic cancer who have previously undergone treatment with chemotherapy.

“On the horizon, and of equal or greater excitement, are other RAS inhibitors,” Dr. Ko commented. A study of the RASMULTI(ON) inhibitor RMC-6236, which included pretreated patients with KRAS mutations of the more commonly observed G12 codon genotypes (G12D, G12V, and G12R), revealed an ORR of 20%.5 “[This represents] very promising, albeit preliminary, data,” he remarked. “Preliminary studies of other inhibitors specific for the G12D genotype also have some encouraging signals of activity, so stay tuned.”

Microsatellite instability–high/defective mismatch repair–driven agents were discussed as a second example of molecularly selected therapy, with approximately 1% of pancreatic cancers falling into this category.6 Dr. Ko noted that, although some pretreated patients with pancreatic cancer who received pembrolizumab experienced an objective response in the KEYNOTE-158 trial, the response rate was still the lowest among all of the evaluated solid tumors with microsatellite instability–high or defective mismatch repair. Alternatives recommended by the NCCN Guidelines include dostarlimab-gxly and, for patients with high tumor mutational burden, nivolumab + ipilimumab.3

As a third example, Dr. Ko presented the following FDA approved pan-cancer drugs, along with their corresponding rare gene fusion and mutational targets: entrectinib and larotrectinib for NTRK gene fusions; dabrafenib + trametinib for BRAF V600E mutations; and selpercatinib for RET gene fusions. “Even though these gene fusions and mutations are present in <1% [of patients with pancreatic cancer], their identification is critical given their therapeutic actionability,” he noted.

Maintenance Therapies for Metastatic Disease

In the management of metastatic pancreatic cancer, maintenance therapy is especially efficacious in patients with BRCA1/2- and PALB2-mutated disease who received platinum-based chemotherapy, given the availability of tailored agents, according to Dr. Ko. The FDA-approved PARP inhibitors olaparib and rucaparib, in particular, are recommended by the NCCN Guidelines in this clinical context (Figure 1).3

Figure 1.
Figure 1.

NCCN recommendations for maintenance therapy. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pancreatic Adenocarcinoma. Version 1.2024 [PANC-F, 7 of 12].

©2024 National Comprehensive Cancer Network® (NCCN®). All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. To view the recent and complete version of these NCCN Guidelines, go to NCCN.org.

Citation: Journal of the National Comprehensive Cancer Network 22, Supplement; 10.6004/jnccn.2024.5019

“This leverages this concept of synthetic lethality,” he remarked. “When you add a PARP inhibitor, you’re further encouraging cell death by preventing these cancer cells from repairing themselves.”

The POLO-1 trial laid the groundwork for the recommendation of olaparib, in which patients with germline BRCA mutations who underwent frontline platinum-based chemotherapy for at least 16 weeks and demonstrated stable or responding disease were randomly assigned to receive olaparib or placebo. The median duration of PFS was nearly doubled with olaparib (7.4 vs 3.8 months; P=.004).7 However, this did not appear to translate to an OS benefit, as patients in both arms survived for a median of approximately 19.0 months (P=.35).8

The current NCCN Guidelines, which also delineate options for most patients who lack these mutations, were further discussed (Figure 1). For those who underwent frontline therapy with FOLFIRINOX, the following regimens are recommended: capecitabine, 5-FU + leucovorin, FOLFIRI (leucovorin/5-FU/irinotecan), and FOLFOX (leucovorin/5-FU/oxaliplatin).3 Patients who initially received gemcitabine + nab-paclitaxel may either be transitioned to a modified dose schedule or single-agent gemcitabine.

Dr. Ko wrapped up his discussion on the current treatment landscape in advanced disease with the presentation of a therapeutic sequencing schema (Figure 2).

Figure 2.
Figure 2.

Sequencing therapy in advanced pancreatic cancer (2024).

Abbreviations: 5-FU, 5-fluorouracil; CapeOx, capecitabine/oxaliplatin; dMMR, defective mismatch repair; FOLFIRINOX, 5-FU/leucovorin/irinotecan/oxaliplatin; FOLFOX, leucovorin/5-FU/oxaliplatin; ICI, immune checkpoint inhibitor; LV, leucovorin; MSI-H, microsatellite instability–high; Nal-IRI, nanoliposomal irinotecan; NALIRIFOX, liposomal irinotecan/5-FU/leucovorin/oxaliplatin; TMB, tumor mutational burden.

Citation: Journal of the National Comprehensive Cancer Network 22, Supplement; 10.6004/jnccn.2024.5019

Investigational Approaches

“[The pancreatic tumor microenvironment] is immunosuppressive, so rather than having cytotoxic CD8-positive T cells, it contains a lot more regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages,” Dr. Ko explained. “On top of that, the extracellular component of pancreatic cancers…may represent a physical barrier to the effective delivery of chemotherapy and other agents.” Due to this, he noted, recent studies have been conducted to attempt to move beyond conventional chemotherapy. Of particular interest are stromal-targeting, immune-oncology, and molecularly targeted agents.

“My feeling is [that immune-oncology agents] are not going to supplant chemotherapy,” Dr. Ko commented. “They may be used in combination with, complementary to, or sequenced following [such intervention].”

Managing Locally Advanced and Borderline Resectable Pancreatic Cancers

Pivoting to discuss the management of locally advanced and borderline resectable disease, Dr. Ko highlighted the role of up-front systemic therapy. However, he subsequently stated: “A big issue is determining where chemoradiation fits, if at all, in the neoadjuvant setting.”

Two phase III studies of patients with locally advanced disease emphasize the challenge of defining its role. Findings from the first, LAP07, showed that, although adding radiation therapy (RT) to chemotherapy did not improve OS, it led to lower rates of locoregional disease progression.9 In patients who underwent surgery, the CONKO-007 trial revealed higher rates of R0 resection and negative circumferential resection margins for those who received neoadjuvant chemoradiotherapy; however, its impact appeared to be negligible for the entire study cohort.10

Furthermore, whether RT may be of clinical utility for patients with borderline resectable disease has also been investigated, particularly in the Alliance A021501 trial.11 However, Dr. Ko explained that this trial did not definitively answer the question of whether RT can or should be used in this neoadjuvant context.

Managing Localized Pancreatic Cancer

According to Dr. Ko, for patients with localized, resectable tumors, 6 months of treatment with modified FOLFIRINOX is the accepted “gold standard” in the adjuvant setting. The results of the PRODIGE 24 trial demonstrated the superiority of this regimen over gemcitabine (median OS, 54.4 vs 35.0 months).12

“In the same way that RT is controversial in the locally advanced and borderline resectable settings, it is also an unresolved issue in the postoperative adjuvant setting,” Dr. Ko stated. The results of the ongoing NRG/RTOG 0848 trial may offer insight, he added (ClinicalTrials.gov identifier: NCT01013649).

Additionally, even for up-front resectable tumors, neoadjuvant therapy has gained traction because of its conceptual advantages over adjuvant therapy (Figure 3). The results of both the PREOPANC and Prep-02/JSAP-05 studies, according to Dr. Ko, underscore promising outcomes for patients who are able to undergo successful surgery after neoadjuvant therapy.13,14

Figure 3.
Figure 3.

Neoadjuvant versus adjuvant therapy for resectable disease.

Citation: Journal of the National Comprehensive Cancer Network 22, Supplement; 10.6004/jnccn.2024.5019

Studies are currently underway to define a potential role for neoadjuvant therapy.

References

  • 1.

    Ohba A, Ozaka M, Ogawa G, et al. Nab-paclitaxel plus gemcitabine versus modified FOLFIRINOX or S-IROX in metastatic or recurrent pancreatic cancer (JCOG1611, GENERATE): a multicentred, randomized, open-label, three-arm, phase II/III trial. Ann Oncol 2023;34(Suppl 2):Abstract 1616O.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Wainberg ZA, Melisi D, Macarulla T, et al. NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial. Lancet 2023;402:12721281.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Tempero MA, Malafa MP, Benson AB, et al. NCCN Clinical Practice Guidelines in Oncology: Pancreatic Adenocarcinoma. Version 1.2024. Accessed April 6, 2024. Available at: https://www.nccn.org

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Bryant KL, Mancias JD, Kimmelman AC, Der CJ. KRAS: feeding pancreatic cancer proliferation. Trends Biochem Sci 2014;39:91100.

  • 5.

    Arbour KC, Punekar S, Garrido-Laguna I, et al. Preliminary clinical activity of RMC-6236, a first-in-class, RAS-selective, tri-complex RAS-MULTI(ON) inhibitor in patients with KRAS mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). Ann Oncol 2023;34(Suppl 2):Abstract 652O.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Hu ZI, Shia J, Stadler ZK, et al. Evaluating mismatch repair deficiency in pancreatic adenocarcinoma: challenges and recommendations. Clin Cancer Res 2018;24:13261336.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med 2019;381:317327.

  • 8.

    Golan T, Hammel P, Reni M, et al. Overall survival from the phase 3 POLO trial: maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. J Clin Oncol 2021;39(Suppl 3):Abstract 378.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Hammel P, Huguet F, van Laethem JL, et al. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: the LAP07 randomized clinical trial. JAMA 2016;315:18441853.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Fietkau R, Ghadimi M, Grützmann R, et al. Randomized phase III trial of induction chemotherapy followed by chemoradiotherapy or chemotherapy alone for nonresectable locally advanced pancreatic cancer: first results of the CONKO-007 trial. J Clin Oncol 2022;40(Suppl):Abstract 4008.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Katz MHG, Shi Q, Meyers J, et al. Efficacy of preoperative mFOLFIRINOX vs mFOLFIRINOX plus hypofractionated radiotherapy for borderline resectable adenocarcinoma of the pancreas: the A021501 phase 2 randomized clinical trial. JAMA Oncol 2022;8:12631270.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med 2018;379:23952406.

  • 13.

    Versteijne E, Suker M, Groothuis K, et al. Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer: results of the dutch randomized phase III PREOPANC trial. J Clin Oncol 2020;38:17631773.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Unno M, Motoi F, Matsuyama Y, et al. Randomized phase II/III trial of neoadjuvant chemotherapy with gemcitabine and S-1 versus upfront surgery for resectable pancreatic cancer (Prep-02/JSAP-05). J Clin Oncol 2019;37(Suppl):Abstract 189.

    • PubMed
    • Search Google Scholar
    • Export Citation

Disclosures: Dr. Ko has disclosed receiving grant/research support from AbGenomics Corporation, Apexigen, Inc., Astellas Pharma US, Inc., Biomed Valley Discoveries, Inc., Bristol Myers Squibb, Celgene Corporation, Genentech, Inc., Merck & Co., Inc., and Verastem Oncology; and serving as a scientific advisor for Aadi Bioscience Inc., Arcus Biosciences, Eisai Inc., FibroGen, Inc., Genentech, Inc., GRAIL, Ipsen, and Merus.

Correspondence: Andrew H. Ko, MD, FASCO, UCSF Helen Diller Family Comprehensive Cancer Center, 550 16th Street, Box 3211, San Francisco, CA 94143. Email: andrew.ko@ucsf.edu
  • Collapse
  • Expand
  • Figure 1.

    NCCN recommendations for maintenance therapy. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pancreatic Adenocarcinoma. Version 1.2024 [PANC-F, 7 of 12].

    ©2024 National Comprehensive Cancer Network® (NCCN®). All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. To view the recent and complete version of these NCCN Guidelines, go to NCCN.org.

  • Figure 2.

    Sequencing therapy in advanced pancreatic cancer (2024).

    Abbreviations: 5-FU, 5-fluorouracil; CapeOx, capecitabine/oxaliplatin; dMMR, defective mismatch repair; FOLFIRINOX, 5-FU/leucovorin/irinotecan/oxaliplatin; FOLFOX, leucovorin/5-FU/oxaliplatin; ICI, immune checkpoint inhibitor; LV, leucovorin; MSI-H, microsatellite instability–high; Nal-IRI, nanoliposomal irinotecan; NALIRIFOX, liposomal irinotecan/5-FU/leucovorin/oxaliplatin; TMB, tumor mutational burden.

  • Figure 3.

    Neoadjuvant versus adjuvant therapy for resectable disease.

  • 1.

    Ohba A, Ozaka M, Ogawa G, et al. Nab-paclitaxel plus gemcitabine versus modified FOLFIRINOX or S-IROX in metastatic or recurrent pancreatic cancer (JCOG1611, GENERATE): a multicentred, randomized, open-label, three-arm, phase II/III trial. Ann Oncol 2023;34(Suppl 2):Abstract 1616O.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Wainberg ZA, Melisi D, Macarulla T, et al. NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial. Lancet 2023;402:12721281.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Tempero MA, Malafa MP, Benson AB, et al. NCCN Clinical Practice Guidelines in Oncology: Pancreatic Adenocarcinoma. Version 1.2024. Accessed April 6, 2024. Available at: https://www.nccn.org

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Bryant KL, Mancias JD, Kimmelman AC, Der CJ. KRAS: feeding pancreatic cancer proliferation. Trends Biochem Sci 2014;39:91100.

  • 5.

    Arbour KC, Punekar S, Garrido-Laguna I, et al. Preliminary clinical activity of RMC-6236, a first-in-class, RAS-selective, tri-complex RAS-MULTI(ON) inhibitor in patients with KRAS mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). Ann Oncol 2023;34(Suppl 2):Abstract 652O.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Hu ZI, Shia J, Stadler ZK, et al. Evaluating mismatch repair deficiency in pancreatic adenocarcinoma: challenges and recommendations. Clin Cancer Res 2018;24:13261336.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med 2019;381:317327.

  • 8.

    Golan T, Hammel P, Reni M, et al. Overall survival from the phase 3 POLO trial: maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. J Clin Oncol 2021;39(Suppl 3):Abstract 378.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Hammel P, Huguet F, van Laethem JL, et al. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: the LAP07 randomized clinical trial. JAMA 2016;315:18441853.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Fietkau R, Ghadimi M, Grützmann R, et al. Randomized phase III trial of induction chemotherapy followed by chemoradiotherapy or chemotherapy alone for nonresectable locally advanced pancreatic cancer: first results of the CONKO-007 trial. J Clin Oncol 2022;40(Suppl):Abstract 4008.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Katz MHG, Shi Q, Meyers J, et al. Efficacy of preoperative mFOLFIRINOX vs mFOLFIRINOX plus hypofractionated radiotherapy for borderline resectable adenocarcinoma of the pancreas: the A021501 phase 2 randomized clinical trial. JAMA Oncol 2022;8:12631270.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med 2018;379:23952406.

  • 13.

    Versteijne E, Suker M, Groothuis K, et al. Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer: results of the dutch randomized phase III PREOPANC trial. J Clin Oncol 2020;38:17631773.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Unno M, Motoi F, Matsuyama Y, et al. Randomized phase II/III trial of neoadjuvant chemotherapy with gemcitabine and S-1 versus upfront surgery for resectable pancreatic cancer (Prep-02/JSAP-05). J Clin Oncol 2019;37(Suppl):Abstract 189.

    • PubMed
    • Search Google Scholar
    • Export Citation
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