Slicing the pie: Personalized medicine changing pancreatic cancer outcomes
Our understanding of pancreatic cancer biology is advancing rapidly.
Genomics, proteomics, metabolomics and in-depth analyses of the tumor immune microenvironment have uncovered new therapeutic targets for which promising novel agents are being tested.
As pancreatic cancer is set to become the second leading cause of cancer-related death in 2030, these innovative treatment strategies could not come at a better time.
Decades of limited progress
Since the approval of gemcitabine for advanced pancreatic cancer in the mid-1990s, tremendous efforts have been devoted to investigating gemcitabine-based combination therapies.
In 2005, the addition of the oral EGFR inhibitor erlotinib to gemcitabine demonstrated an improvement in OS, becoming the first combination regimen to do so. However, the magnitude of OS benefit was small, just under 2 weeks. Despite this, the combination received FDA approval, highlighting true desperation.
In 2011 and 2013, two combination chemotherapy regimens were approved in the metastatic setting — gemcitabine plus nanoparticle albumin-bound (nab)-paclitaxel (Abraxane, Celgene) and FOLFIRINOX, a regimen consisting of 5-FU, leucovorin, irinotecan and oxaliplatin. Both treatment regimens outperformed gemcitabine monotherapy by several months, and they remain the standard of care as first-line therapy for patients with metastatic disease.
In 2015, FDA approved the combination of 5-FU, leucovorin and liposomal irinotecan in the second-line setting.
However, even with these gains, the median life expectancy for metastatic pancreatic cancer remains less than 1 year.
Benefits of targeted treatment
With next-generation sequencing, one can now rapidly and affordably identify genomic alterations in tumors and potentially match them to an ever-growing number of targeted therapies.
Results of a retrospective analysis of the Know Your Tumor registry trial revealed an OS improvement among patients harboring actionable mutations treated with targeted agents compared with those treated with standard therapies. Of the 1,082 patients with biopsy-confirmed pancreatic cancer who underwent molecular profiling, 26% had an actionable alteration.
Median OS was 2.6 years among the 46 patients who received matched therapy compared with 1.5 years among the 143 patients in whom an alteration was detected but who received standard, unmatched treatment.
This study was retrospective and limited by potential selection biases, and further validation with a large prospective trial is needed. However, it suggests that genomic profiling of tumors can be used to identify a sizable subset of patients for whom precision medicine can improve survival.
The largest subset of patients with pancreatic cancer known to benefit from precision medicine-guided selection of therapies includes those harboring mutations in the DNA damage response pathway. BRCA1/BRCA2, PALB2, ATM, RAD50 and NBS1 are examples of proteins involved in the repair of double-strand breaks through homologous recombination.
Although there is considerable variability in reported rates of germline and somatic mutations in these genes, it is estimated that the incidence of mutations may be as high as 25%. Individuals with these mutations typically have higher response rates to treatment with platinum-based chemotherapy, topoisomerase inhibitors and poly(ADP-ribose) polymerase (PARP) inhibitors.
PARP inhibitors have emerged as an effective treatment option for BRCA-mutated pancreatic cancer. By inhibiting PARP, these agents prevent cellular repair of single-strand DNA breaks, which subsequently degenerate to double-strand breaks.
Based on findings of the POLO trial, the PARP inhibitor olaparib (Lynparza, AstraZeneca) received FDA approval for maintenance treatment of adults with deleterious or suspected deleterious germline BRCA-mutated metastatic pancreatic adenocarcinoma.
The study showed that patients with germline BRCA1/BRCA2 mutations who received olaparib following at least 16 weeks of first-line platinum-based chemotherapy without progression had longer median PFS than those treated with placebo (7.4 months vs. 3.8 months; P = .004).
Considering these findings, it is becoming clear that efforts need to be made to study and confirm if patients with pancreatic cancer with similar mutations in the DNA damage response pathway respond to PARP inhibitors.
Several other disease-agnostic treatments have been shown to induce responses, occasionally durably, in patients with pancreatic cancer.
For example, although quite rare in patients with pancreatic cancer (< 1%), mismatch repair deficiency typically predicts favorable and pronged response to immune checkpoint blockade.
More recently, tropomyosin receptor kinase inhibitors, such as larotrectinib (Vitrakvi, Bayer) and entrectinib (Rozlytrek, Genentech), which target TRKA, TRKB, TRKC, ROS1 and ALK encoded by NTRK1, NTRK2, NTRK3, ROS1 and ALK, respectively, have also shown promise in this disease. Data are limited, but these agents are associated with response rates exceeding 75%, regardless of tumor histology.
Additional targets of interest
BRAF, mutated in approximately 3% of patients with pancreatic cancer, is another target of interest. Case reports with BRAF/MEK inhibitor combinations have shown encouraging results, and these combinations are being studied in several ongoing trials.
Perhaps one of the most elusive cancer targets is KRAS. Approximately 95% of patients with pancreatic adenocarcinoma carry a mutation in or have amplification of KRAS. To date, however, no KRAS-directed therapy has demonstrated meaningful clinical benefit.
Alternatively, targeting downstream molecules in the Ras-Raf-MEK-ERK pathway may hold promise. This has proved to be challenging as there is significant redundancy in this pathway, allowing for continued signal transduction and cell survival. Therefore, a combinatorial approach will likely be necessary. Recently, KRAS-mutated pancreatic cancer has been shown responsive to a combination of MEK and autophagy inhibition in preclinical models.
Unique to pancreatic tumors is a dense stromal component that, by acting as a barrier to drug penetrance, is thought to play a substantial role in resistance to chemotherapy.
Similarly, other key players in the tumor immune microenvironment — such as tumor-associated macrophages, carcinoma associated fibroblasts, myeloid-derived suppressor cells, T regulator cells, etc — likely contribute to treatment resistance. An improved understanding of these molecular targets has led to numerous novel agents that are currently under investigation in clinical trials.
Human recombinant PEGylated hyaluronidase (PEGPH20, Halozyme) is one such agent that initially showed great promise in preclinical and early-phase trials. PEGPH20 degrades hyaluronan (HA), a major component of the extracellular matrix, and had demonstrated benefit among patients with HA-high tumors when given in combination with gemcitabine plus nab-paclitaxel in phase 2 trials. However, this drug ultimately failed to demonstrate improvement in OS in a large, randomized phase 3 trial.
Agonistic CD40 antibodies recently entered phase 2 trials. CD40 is expressed on and can trigger activation in a variety of immune cell types, including macrophages and dendritic cells. It is also expressed in some tumor types, including some pancreatic tumors, in which antibody-dependent cytotoxicity can be induced. Phase 1 trials have demonstrated striking efficacy of these agents in combination with chemotherapy, supporting further study in several ongoing phase 2 trials.
The burgeoning field of metabolomics also has produced several promising agents. Devimistat (CPI-613, Rafael Pharmaceuticals) is a novel lipoate analog that inhibits pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase. Combining this agent with modified FOLFIRINOX in patients with metastatic pancreatic cancer resulted in a 61% objective response rate, including a 17% complete response rate, in a phase 1 study. Devimistat is undergoing investigation in combination with modified FOLFIRINOX in a phase 3 trial.
With a growing number of precision-guided novel targeted agents, the outlook for patients with pancreatic cancer is shifting from one of despair to one of hope, although work remains to be done.
This hope stems from discoveries of actionable targets, in part identified through increased molecular testing, and trials demonstrating improved outcomes with newer therapies. Success in BRCA1/BRCA2-mutated pancreatic cancer is just the beginning and should encourage clinicians to sequence tumors in treatment-eligible patients with metastatic disease. As multiple new and exciting approaches are on the horizon, precision-guided therapy will be the key to improving outcomes in pancreatic cancer.
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To contribute to this column or suggest topics, email Wafik S. El-Deiry, MD, PhD, FACP, at firstname.lastname@example.org.