Optimizing Chemotherapy Choice in the Treatment of Advanced Pancreatic Cancer—It Is Complicated

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal cancer and is expected to become the second most common cause of cancer-related death in the US by 2040.¹ Most patients present with advanced disease at the time of diagnosis with systemic chemotherapy as their primary treatment option. In 2011, fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) was compared with what was considered the standard of care, gemcitabine, in a phase 3 trial involving 342 patients with untreated metastatic pancreatic cancer.² The combination regimen showed an improvement in median overall survival from 6.8 to 11.1 months (hazard ration [HR] 0.57; 95% CI 0.45-0.73; P < .001). Two years later, Von Hoff and colleagues published the results of the randomized phase 3 trial comparing gemcitabine-nab-paclitaxel (GEMNAB) with gemcitabine in patients with metastatic pancreatic cancer.³ The addition of nab-paclitaxel to gemcitabine improved median overall survival from 6.7 to 8.5 months (HR 0.72; 95% CI 0.62-0.83; P < .001). The demographics included in each study were very different, and to date, there are no large clinical trials comparing FOLFIRINOX directly to GEMNAB with both regimens recommended as first-line treatment for advanced pancreatic cancer.

Raphael et al⁴ described the results of a retrospective study assessing survival outcomes among patients with advanced PDAC treated with FOLFIRINOX and GEMNAB using the unique data available in the publicly funded universal cancer care system in the province of Ontario, Canada, from 2008 to 2018. Gemcitabine was the only drug approved before November 2011, followed by FOLFIRINOX approval in 2011 and GEMNAB approval in 2015. Given the distinctive timeline of drug approval in Canada, this study was divided into 3 periods: period 1, 2008 to 2011; period 2, 2011 to 2015; period 3 2015 to 2018. The study included patients with advanced and unresectable or metastatic pancreatic cancer receiving first-line therapy. Between November 2008 and December 2018, 5465 patients with advanced pancreatic cancer received at least 1 dose of first-line chemotherapy. A multivariable Cox proportional hazard model was used to assess the association between chemotherapy regimen selection and overall survival, weighted by the inverse probability of treatment (IPT) approach. There were several noteworthy findings in this manuscript: (1) median overall survival increased from 5.6 months (95% CI, 5.1-6.0) in period 1 to 6.9 months (95% CI, 6.5-7.4) in period 2 and 7.7 months (95% CI, 7.3-8.2) in period 3 among all patients; (2) FOLFIRINOX was associated with better overall survival compared with GEMNAB after IPT weighting (weighted adjusted HR, 0.78; 95% CI, 0.73-0.83) and without IPT weighting (adjusted HR, 0.78; 95% CI, 0.71-0.87); and (3) in comparison of first-line gemcitabine from period 2 with GEMNAB in period 3, there were differences in overall survival in various models that were unadjusted, adjusted, matched, and IPT weighted. From their results, the authors conclude that FOLFIRINOX and GEMNAB were both associated with improvements in survival in distinct patient populations.⁴

The sample size and statistical methods were reasonable for this type of study with key potential confounders accounted. There are several observations from this study, many noted by the authors, that limit its impact on clinical practice including the overall retrospective study design and the potential for a significant selection bias. A powerful prognostic factor in PDAC, Eastern Cooperative Oncology Group (ECOG) performance status, for patients treated with FOLFIRINOX was limited to 0 or 1 but not well delineated with GEMNAB (0 or ≥1) and missing with single-agent gemcitabine. Patients receiving GEMNAB (or gemcitabine) had overall worse performance status, more advanced disease, and tended to be older vs those receiving FOLFIRINOX. Additionally, baseline characteristics for patients receiving FOLFIRINOX remained stable whereas for patients receiving GEMNAB, their baseline characteristics closely resembled the gemcitabine cohort in period 2. Notably as well, the observed overall survival was numerically shorter in this study by Raphael et al⁴ than expected from previously published data.² This may in part reflect the heterogenous real-world patient population included and the lack of funded second-line therapies at the time of this analysis (eg, liposomal irinotecan was approved for use in Canada by the end of 2017 after approval of gemcitabine).

While there are no large clinical trials directly comparing FOLFIRINOX and GEMNAB in advanced PDAC, several trials have compared the 2 combinations in different settings showing similar survival benefit. A Japanese phase 2 clinical trial comparing the 2 regimens in locally advanced PDAC showed FOLFIRINOX did not outperform GEMNAB at 1-year overall survival rates (77.4% [95% CI, 64.9%-86.0%] vs 82.5% [95% CI, 70.7%-89.9%]).⁵ The Southwest Oncology Group (SWOG) S1505 phase 2 clinical trial comparing modified FOLFIRINOX with GEMNAB, albeit in the perioperative setting, showed similar overall survival of 22.4 months and 23.6 months.⁶ Furthermore, the overall survival from recent trials including GEMNAB in advanced PDAC was much longer than reported by Raphael and colleagues.⁴ For example, the recent large but negative phase 3 HALO trial showed overall survival of over 11 months for GEMNAB with and without pegvorhyaluronidase alfa (PEGPH20).⁷ This clearly reflects a different patient population but also the real potential of better supportive care in the present age.

Finally, although understandable for this type of research, this study did not take into account the availability of biomarker-directed therapies. For example, molecular targets have demonstrated potential survival benefits. A recent study of patients with homologous recombination deficiency (HRD) genes, which can occur in as many as 19% of patients with PDAC, showed superior median overall survival when treated with first-line platinum-based therapy compared with having no HRD (25.1 months [95% CI, 21.6 months to not reached] vs 15.3 months [95% CI, 14.2 to 20.3 months]).⁸ Another study evaluated GATA6 expression, which may serve as a surrogate marker for classical subtype PDAC and predictor of better responders to modified FOLFIRINOX.⁹ Overall survival for patients with classical PDAC was longer than basallike PDAC (9.3 vs 5.9 months; HR, 0.47; 95% CI, 0.32-0.69) when treated with modified FOLFIRINOX. Other molecular targets of interest are being investigated, and taken together, treatment options for pancreatic cancer are becoming increasingly individualized.

The large real-world data reported by Raphael and colleagues⁴ establishes interesting observations regarding drug funding decisions as they affect uptake of new treatment options over time. This study does not provide enough evidence for decisions regarding treatment choices given its design and the fact that no comparative prospective data exist to support any claims of superiority for FOLFIRINOX vs GEMNAB . The observations from this study reinforce the fact that prior perceived biases regarding choices persist beyond drug funding decisions. Absent a randomized comparative trial, both FOLFIRINOX and GEMNAB remain optimal first-line therapy options for patients with unselected advanced PDAC. Perhaps, in the presence of BRCA1/2 or PALB2 mutations, a platinum-based regimen should be considered first. Moving forward, clinical trials incorporating treatment based on identification of molecular markers in PDAC must be prioritized.

Published: November 15, 2021. doi:10.1001/jamanetworkopen.2021.34458

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Tran NH et al. JAMA Network Open.

Corresponding Author: Tanios Bekaii-Saab, MD, Division of Medical Oncology, Mayo Clinic, 5881 E Mayo Blvd, Phoenix, AZ 85054 (Bekaii-Saab.Tanios@mayo.edu).

Conflict of Interest Disclosures: Dr Bekaii-Saab reported receiving grants from Bristol Myers Squibb to the Mayo Clinic outside the submitted work; receiving research funding (to institution) from Agios, Arys, Arcus, Atreca, Boston Biomedical, Bayer, Amgen, Merck, Celgene, Eli Lilly and Co, Ipsen, Clovis, Seattle Genetics, Genentech, Novartis, Mirati, Merus, Abgenomics, Incyte, Pfizer, and Bristol Myers Squibb; receiving consulting fees (to institution) from Ipsen, Arcus, Array Biopharma, Pfizer, Seattle Genetics, Bayer, Genentech, Incyte, and Merck; receiving consulting fees from Stemline, AbbVie, Boehringer Ingelheim, Janssen, Eisai, Daichii Sankyo, Natera, TreosBio, Celularity, Exact Science, Sobi, Beigene, Kanaph, Xilis, Astra Zeneca, and Foundation Medicine; and serving on the IDMC/DSMB for Suzhou Kintor, Astra Zeneca, Exelixis, Lilly, PanCan, and 1Globe. Dr Bekaii-Saab reported serving on the scientific advisory board for Imugene, Immuneering, and Sun Biopharma. No other disclosures were reported.