Need of the hour—advancements in treatment of pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies with dismal long-term outcomes. A majority of patients unfortunately have metastatic disease at diagnosis. Currently, FOLFIRINOX (5-fluorouracil, irinotecan, oxaliplatin) and gemcitabine with nab-paclitaxel are the two commonly used frontline treatment options. The median overall survival (OS) with these regimens when compared to gemcitabine in phase III randomized trials was 11.1 and 8.5 months respectively (1,2). More recently, NALIRIFOX (nano liposomal irinotecan, 5-fluorouracil, oxaliplatin) was compared to gemcitabine nab-paclitaxel in the phase III randomized NAPOLI-3 trial and showed a median OS of 11.1 months with the triplet regimen, similar to seen with FOLFIRINOX in previous studies (3). FOLFIRINOX, NALIRIFOX and gemcitabine with nab-paclitaxel are now the recommended frontline treatment options for metastatic PDAC based on National Comprehensive Cancer Network (NCCN) guidelines. However, OS remains less than 1 year after diagnosis of upfront metastatic disease despite adequate systemic treatment based on these current guidelines. Clearly, therapeutic advances in this field are crucial.

This single arm, multicenter phase Ib clinical trial by Zhang et al. attempted to establish the MTD of gemcitabine and nab-paclitaxel with afatinib, a 2^nd generation tyrosine kinase inhibitor (TKI) (4). Based on a ‘3+3’ statistical design, the MTD of gemcitabine and nab-paclitaxel (1,000 mg/m²/125 mg/m²) and afatinib (30 mg) was established with an acceptable safety profile in 11 patients. Unfortunately, 2 deaths were reported due to infectious complications, but deemed unrelated to study drugs. Overall, 4/11 (36.4%) experience grade 3 or higher adverse effects. The authors must be commended on their attempt to add to our knowledge to improve outcomes for our patients with pancreatic cancer. It must be noted that this is a phase Ib trial with a very small analyzable sample population (n=11) and no other conclusions besides MTD and safety profile, such as clinical endpoints of survival and response rates, can be extrapolated. A larger trial with an adequate sample size will be required to answer these questions. EGFR/HER1/ErbB1 is a transmembrane glycoprotein expressed in normal tissues but is abnormally activated in many epithelial tumors including non-small cell lung cancer (NSCLC). Many TKIs, including erlotinib, afatinib, osimertinib, etc., are approved in EGFR-mutant NSCLC. EGFR expression is thought to responsible for tumor initiation in the presence of oncogenic KRAS mutation and plays in essential role in acinar to ductal metaplasia based on genetic studies in mice (5,6). Blockade of EGFR signaling with the EGFR TKI (PKI166) alone or in combination with gemcitabine has been shown to inhibit growth and metastasis of human pancreatic carcinoma cells implanted into the pancreas of nude mice (7). However, clinical outcomes with this strategy of EGFR inhibition have shown minimal benefits, if any, in pancreatic cancer. Published in 2007, NCIC CTG PA.3 was a phase III, randomized clinical trial which evaluated addition of erlotinib, a 1^st generation TKI inhibiting EGFR, to gemcitabine, the then standard of care for 1^st line treatment of metastatic pancreatic cancer. While there was a statistically significant improvement in OS with addition of erlotinib (hazard ratio =0.82; 95% confidence interval: 0.69 to 0.99; P=0.038), clinically this benefit was not significant with an improvement of only 11 days (median 6.24 vs. 5.91 months) (8). The regimen of gemcitabine + erlotinib is still listed as a potential option in the NCCN guidelines, but is not routinely used in clinical practice. Zhang et al. () have attempted to add to this strategy by using afatinib, a 2^nd generation pan-ErbB TKI and gemcitabine/nab-paclitaxel, one of the current standards of care. While it is possible that this strategy can be explored further in a larger trial adequately powered for clinical efficacy as a primary end point, the field has moved further significantly since conception of this trial in 2016 and our understanding of pancreatic cancer biology has also improved as detailed below. Resources must be used wisely in our endeavors to improve clinical outcomes as well quality of life of our pancreatic cancer patients. Advancements in precision genomics in recent years have shed significant light on the genomic landscape of pancreatic cancer. KRAS mutations are the most predominant, occurring in around 90% of patients, followed by TP53, CDKN2A, and SMAD4 (9). KRAS, while traditionally termed ‘undruggable’, has recently seen exciting innovation with drugs sotorasib and adagrasib showing encouraging clinical activity in patients with KRAS G12C mutations (10-13). Clinical trials are ongoing with KRAS G12D, G12V as well as pan-RAS inhibitors with encouraging preclinical evidence (e.g., NCT05737706, NCT06040541, NCT06056024) (14,15). Our understanding of the functional complexity of the microenvironment have shed light on difficulties treating this cancer. A prominent desmoplastic reaction is responsible for poor vascularization thereby limiting chemotherapy exposure as well poor immune cell infiltration. The milieu is also predominantly immunosuppressive with a dominance of cancer-associated fibroblasts (CAFs), myeloid derived stem cells (MDSCs), tumor-associated macrophages (TAMs) and regulatory T cells while lacking effector T cells and antigen presenting cells (16,17). Immunotherapy by itself has been discouraging in pancreatic cancer given the complex milieu but studies are ongoing to determine novel immunotherapy combination strategies (e.g., NCT03193190), including with KRAS mutation specific vaccines (e.g., NCT05726864) Phenotypic states based on gene expression profiles differentiated PDAC into ‘classical’ and ‘basal’ or ‘quasi-mesenchymal’ subtypes with differential responses to chemotherapy. The ‘basal’ subtype is associated with a worse prognosis than the ‘classical’ subtype and shows inherent resistance to FOLFIRINOX. This suggests that treatment approaches tailored to phenotypic gene expression could help improve survival outcomes and are being evaluated in clinical trials (e.g., NCT04469556) (18-20). Ultimately, a multi-pronged approach with traditional chemotherapy, targeting oncogenic driver mutations as well as the stromal and immune microenvironment will be required to make a meaningful impact on clinical outcomes.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-73/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-73/coif). C.W. reports grants from Genentech, Dicephera, Elicio, Actuate Therapeutics, BMS, consulting fees from Novartis, Genentech, and holds stock or stock options in VRise Therapeutics, CyMon Bio, Inc. 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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