GEMPAX, do we have another second-line option after mFOLFIRINOX in pancreatic cancer?

Metastatic pancreatic adenocarcinoma (mPDAC) remains one of the most aggressive and lethal cancers in oncology practice with 5-year survival rates just above 10% for all stages combined. Unfortunately, despite the ongoing development of novel antineoplastic agents, the options available for treatment of mPDAC remains limited. First-line systemic options, independent of molecular profile, include FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin), NALIRIFOX (5-fluorouracil, leucovorin, liposomal irinotecan, and oxaliplatin), gemcitabine and nab-paclitaxel (GnP), and gemcitabine (GEM) alone (1-3). Second-line options are limited. The NAPOLI-1 trial, which evaluated the regimen of liposomal irinotecan and fluorouracil, is the only phase III clinical trial that demonstrated safety and overall survival (OS) benefit of second-line therapy in patients previously treated with GnP (4). Prior to the GEMPAX UNICANCER trial, second-line options after FOLFIRINOX/NALIRIFOX were based on results from phase 2 trials.

After first-line fluorouracil-based therapy, second-line therapy is limited to GnP or clinical trials. With the greater accessibility to next-generation sequencing over the last decade, there have been many trials performed to evaluate novel targeted therapies (5). Protocols involving patients receiving second-line therapy have considered new chemotherapy combinations, chemotherapy with novel targeted therapy, chemotherapy with novel immunotherapy agents, or single-agent targeted therapy or immunotherapy (6-11) (Table 1). Common to all these efforts is the limited clinical benefit with response rates from 3.1% to 36%, and limited impact on progression-free survival (PFS) and OS. A few examples include the combination of anti-PD-1 therapy and hypofractionated radiation, anlotinb and anti-PD-1, and GnP plus MUC5AC (7,9,12). The results of these recent efforts, highlight the need for additional options.

The study to be reviewed here by De La Fouchardière and colleagues is a phase III open-label, randomized multi-center trial comparing GEM vs. gemcitabine/paclitaxel (GEMPAX) in the second-line setting following FOLFIRNOX in the treatment of patients with mPDAC (13). The primary end point was OS from time of randomization to death, regardless of cause of death. Secondary end points were PFS, overall response rate (ORR), quality of life (QOL), and safety evaluation. This study was available at 31 French oncology centers. Patients were randomized in a 2:1 fashion, favoring the GEMPAX arm. Patients enrolled between June 2019 and March 2021 with restaging evaluation every 8 weeks until progression and/or data cutoff in June 2022.

The trial met criteria to assess the primary and secondary endpoints. Although there was no difference in median OS [hazard ratio (HR) =0.87; 95% confidence interval (CI): 0.63 to 1.20; P=0.4095], subgroup analysis did identify better outcomes in GEMPAX in patients younger than 65 years and with elevated baseline carbohydrate antigen 19-9 (CA19-9). There was a statistically significant benefit of GEMPAX by PFS (HR =0.64; 95% CI: 0.47 to 0.89; P=0.0067) and ORR (17.1% vs. 4.2%, P=0.008) when compared to GEM. Incidence of any grade treatment-related toxicity was similar between arms, 93.5% for GEMPAX and 82.9% for GEM, however the incidence of grade 3 or higher was 2-fold higher in the GEMPAX arm (58% vs. 27%). 65.9% of patients completed a baseline and on-treatment QOL questionnaire. At baseline the QOL scores were similar, but on-treatment QOL scores dropped to a greater degree in six categories for the GEM only arm (P=0.049). Overall, the trial did not demonstrate a statistically significant difference in OS between GEMPAX and GEM. Authors suggest that despite this limitation, the superior ORR and PFS suggest that GEMPAX does have superior anti-tumor activity than GEM with outcomes similar to those seen in other GnP second-line trials (2,7,14). Based on these similarities, administration of GEMPAX after FOLFIRINOX should be considered, specifically in those with oxaliplatin induced neuropathy, younger than 65 years, and with elevated serum CA19-9.

Critical review of this study identified several key issues preventing this data from providing a more meaningful contribution to the body of second-line mPDAC therapeutic options. The authors concede and we agree that the decision to have OS as the primary endpoint complicates how to interpret these results. Second-line therapy in mPDAC, independent of first-line agent, is associated with modest response rates of 10–20% and PFS of 3–5 months (15). If patients remained in optimal health after completion of this trial, third-line therapy was considered and included taxanes, platinum salts, or irinotecan which potentially led to interference with OS data. For these reasons, although OS is the favored statistical endpoint, greater consideration should be given to using PFS as the primary endpoint instead in future efforts evaluating second-line therapies (16). If the results of second-line phase II trials (14,17,18) evaluating GnP, which used PFS as the primary endpoint, are any indication, the statistically significant improvement of PFS of GEMPAX would suggest that GEMPAX could be considered as a second-line option.

Second, is the query of why paclitaxel was the taxane chosen for this prospective analysis. The authors acknowledge the superiority of nab-paclitaxel vs. paclitaxel regarding proven superior tissue distribution and tumor penetration. Multiple prospective phase II trials have demonstrated that GnP after FOLFIRINOX is safe. Although there have been no randomized studies of GnP compared to GEM in the second-line setting, a cross-trial comparison of results suggests similar ORR, PFS, and toxicity (19). Considering there was inadequate pre-clinical data provided to support evaluating GEMPAX and recent data highlighting the associated financial toxicity of GnP, it leaves the impression that paclitaxel was chosen solely to influence insurance reimbursement considerations.

Acknowledging the importance of molecular profiling in 2024, the authors made no attempt to investigate any correlations between genomic profile and clinical outcomes associated with the use of paclitaxel. Ongoing efforts to use the transcriptional profile to guide assess biomarker-driven therapies and characterize malignant potential is essential to optimal care of patients with mPDAC (20,21). Classification of cancer by the transcriptional subtypes classical and basal has helped inform sensitivity to multi-agent regimens, and presence of DNA repair deficiency has highlighted the sensitivity to platinum-based regimens and PARP inhibitors (20,22). Although the effective novel targeted therapeutic options remain limited, advances in investigational strategies continues to highlight the benefits of genomic profiling.

Overall, De La Fouchardière et al. [2024] were able to demonstrate that PFS, ORR, and QOL were better with GEMPAX as compared to GEM but were not able to demonstrate superior OS, the primary outcome being studied. We can learn from this study that mPDAC treatment options remain limited and that the trial design of this study fell short of meaningfully expanding the repository of anti-neoplastic agents. Future studies to be considered include combination targeted therapy with GnP, or even possibly GEMPAX vs. GnP in the second line. In summary, De La Fouchardière and colleagues’ findings demonstrate safety of GEMPAX in the second line and the potential option to substitute paclitaxel for nab-paclitaxel if drug access was an issue. Unfortunately, the modest improvement of GEMPAX on median OS limits any meaningful contribution to the paradigm of mPDAC therapy and highlights the desperate need for therapeutic options.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Translational Medicine. The article has undergone external peer review.

Peer Review File: Available at https://atm.amegroups.com/article/view/10.21037/atm-24-182/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-24-182/coif). K.J.P. reports one-time advisory board honoraria with Ipsen, Exelixis, and Novartis. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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