Total Neoadjuvant Therapy in the Treatment of Locally Advanced Rectal Cancer

March 10 2020

The initial results of the phase II NRG Oncology GI002 trial examining total neoadjuvant therapy (TNT) with the PARP inhibitor veliparib for locally advanced rectal cancer (LARC) were recently presented at the American Society of Clinical Oncology (ASCO) 2019 Annual Meeting. Results from this rapidly completed trial indicated that TNT can be used effectively in the treatment of LARC; however, veliparib did not yield statistically significant improvements for patients.

The main focus of NRG-GI002 is to serve as a platform trial to test novel agents in the pre-operative setting for patients with locally advanced rectal cancer. This study takes advantage of a continuously available control arm with additional arms added through protocol amendments to speed up the ability to bring new potential treatments to patients more quickly than traditional clinical trials.TNT therapy includes both chemotherapy and chemo-radiotherapy in a ‘one-two’ punch against the cancer followed by surgery to remove any remaining disease.

After veliparib (a PARP inhibitor) exhibited favorable results in the phase I trial with few added toxicities, researchers incorporated this new therapy into the phase II clinical trial platform as the first experimental arm. The primary endpoint was to track pathological regression and downstaging through the neoadjuvant rectal cancer score as a short-term surrogate endpoint for survival. “Although the first arm (veliparib) in NRG-GI002 did not show improvement when added to TNT, this trial allowed us to confirm that TNT can be safely and successfully delivered to this patient population. Ultimately, these results allow us to consider and investigate other ways to improve treatment outcomes for our patients with rectal cancer,” remarked Thomas J. George, MD, of the University of Florida Health Cancer Center and Principal Investigator for the NRG-GI002 trial.

Patients who participated on NRG-GI002 received induction chemotherapy and were then randomly assigned to receive radiotherapy and chemotherapy with or without the addition of veliparib. Lastly, all patients received surgery following all chemotherapy and radiotherapy treatment.

Results showed that, not only was the TNT approach considered safe, it was also associated with high rates (>90%) of chemotherapy completion for patients. This is much better than the traditional post-operative approach where nearly half of patients may not get their recommended chemotherapy because of challenges recovering from surgery. However, adding veliparib to the treatment did not significantly further reduce the amount of cancer present at the time of surgery. The mean neoadjuvant rectal score was 12.6 for the control arm and 13.7 for the experimental arm of this study (P= .69). Interestingly, more patients who received veliparib did achieve pathological complete response (22% without veliparib vs. 34% with veliparib; P=.14) despite having more toxicity and difficulty completing their chemo-radiotherapy. This suggested that a relatively small group of patients treated with veliparib obtained significant benefit and their cancers might be sensitive to this approach.

Researchers are continuing to analyze the secondary endpoints and biomarkers from NRG-GI002 to determine if specific patients could receive added benefit from veliparib and why they would benefit. Ongoing arms in the study include the incorporation of immunotherapy (pembrolizumab) in combination with chemo-radiotherapy as part of TNT in an attempt to leverage the patient’s immune system as a partner in the treatment of LARC.

ASCO’s Interview with Principal Investigator, Dr. George

NRG-GI002 on ClinicalTrials.gov

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