Results from an experimental arm of the phase II NRG-GI002 trial using veliparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, as part of total neoadjuvant therapy (induction chemotherapy followed by chemoradiotherapy and surgery) in patients with locally advanced rectal adenocarcinoma were recently presented by George et al at the 2019 ASCO Annual Meeting (Abstract 3505). Results were reported on the primary endpoint of pathological regression via the neoadjuvant rectal cancer score, a short-term clinical trial surrogate endpoint.
After treatment with the combination chemotherapy regimen mFOLFOX6, researchers combined veliparib and capecitabine plus radiotherapy in patients who had locally advanced stage II or III rectal cancer. Patients on the control arm received the same therapy, with the omission of veliparib. In the first experimental arm of NRG-GI002, veliparib was added to radiotherapy and chemotherapy treatment regimens because PARP inhibitors have been shown to enhance the effectiveness of radiotherapy by interfering with a patient’s DNA repair mechanisms.
Results from the overall study demonstrate that the total neoadjuvant therapy approach of therapy is safe and associated with high rates (> 90%) of chemotherapy completion. However, the addition of veliparib did not demonstrate a significant improvement in reducing the amount of cancer present at the time of surgery. The primary endpoint of the mean neoadjuvant rectal score (lower number reflects more downstaging) was 12.6 for the control arm and 13.7 for the experimental arm (P = .69). However, there were numerically more patients who achieved a pathologic complete response with veliparib (22% vs 34%; P = .14). These first experimental arm results demonstrated that the addition of veliparib was associated with more short-term side effects and reduced completion of chemoradiation (85% vs 70%; P = .026). The most common grade 3 and 4 side effects that were experienced included diarrhea and cytopenias. Importantly, these side effects did not appear to negatively impact short-term patient outcomes.
“NRG-GI002 is intended to serve as a platform to test novel agents, such as veliparib, or other novel hypotheses using a total neoadjuvant treatment for rectal cancer as part of a phase II clinical trial platform,” stated lead author Thomas J. George, MD, FACP, of University of Florida Health Cancer Center. “The goal of this study was to build upon the encouraging results seen with veliparib in the phase I trial that produced few dose-limiting toxicities…Unfortunately, we did not see an improvement with the use of veliparib. However, and very importantly, we have now established that total neoadjuvant therapy can be safely and successfully delivered to patients with locally advanced rectal cancer. This ensures all patients get the treatments they need and gives us many opportunities to further improve care for this group of patients.”
Future direction on this trial includes continued analysis of secondary endpoints and biomarkers to determine which specific patients achieved benefit from the addition of veliparib and why. An ongoing second experimental arm is observing the impact of the monoclonal antibody pembrolizumab in combination with capecitabine and radiotherapy after induction mFOLFOX6 to determine if immunotherapy is also a safe, effective option for treating locally advanced rectal cancer. This second arm has completed enrollment.
Disclosure: This study was supported by the National Cancer Institute (NCI) and AbbVie. Additional support was provided from the Biomarker, Imaging, & QOL Studies Funding Program awarded by the NCI. For full disclosures of the study authors, visit coi.ascopubs.org.
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