Pembrolizumab Plus Total Neoadjuvant Therapy Improves Long-Term OS in Locally Advanced Rectal Cancer

Thomas J. George, MD, FACP

Although adding veliparib (ABT-888) or pembrolizumab (Keytruda) to total neoadjuvant therapy did not improve short-term outcomes for patients with stage II/III locally advanced rectal cancer, pembrolizumab plus total neoadjuvant therapy was associated with improved 3-year overall survival, according to long-term data from the phase 2 NRG-GI002 trial (NCT02921256).

Findings presented at the 2023 Gastrointestinal Cancers Symposium showed that patients treated with pembrolizumab plus FOLFOX, followed by chemoradiation and then surgery, (n = 90) experienced a 3-year OS rate of 95% compared with 87% for patients treated with total neoadjuvant therapy alone (n = 95; HR, 0.35; 95% CI, 0.12-1.00; P = .04). Veliparib plus total neoadjuvant therapy (n = 90) induced a 3-year OS rate of 85% compared with 92% for patients in the control arm (n = 88; HR, 2.13; 95% CI, 0.86-5.29; P = .10).

“This is interesting and inspires us to dig deep into the data and understand more why a subset of patients seems to derive benefit through correlative biomarker analyses, which is the next step for this study,” lead study author, Thomas J. George, MD, FACP, explained.

In an interview with OncLive^®, George highlighted the long-term data from the NRG-GI002 trial, the next steps for exploring subsets of patients who may benefit from the addition of pembrolizumab or veliparib to total neoadjuvant therapy, and what the use of total neoadjuvant therapy has meant for patients with stage II/III locally advanced rectal. George is a professor in the Department of Medicine, Division of Hematology & Oncology, and the director of the Gastrointestinal Oncology Program at the University of Florida in Gainesville.

OncLive^®: What was the goal of evaluating the addition of veliparib (ABT-888) or pembrolizumab to total neoadjuvant therapy in patients with locally advanced rectal cancer?

George: This research all originated from [the need] to improve outcomes for patients with locally advanced rectal cancer. This is a disease that plagues many of our patients. They are symptomatic, have a large burden of disease, and need better outcomes.

We organized this study specifically to look at the incorporation of total neoadjuvant therapy, [which is] the inclusion of chemotherapy, chemotherapy with radiation, and surgical resection. These patients [had] bulky, large, sphincter-compromising, locally advanced rectal cancer.

Our goal was to use that total neoadjuvant therapy as a platform to add new agents into that approach and try to improve outcomes for patients. The outcomes specifically [included] reduction in the burden of disease, so [patients] could successfully undergo a complete surgical resection.

What previous efforts led to this phase 2 study?

There were a lot of early efforts to try to bring new therapies into the neoadjuvant space and to establish total neoadjuvant therapy for patients with rectal cancer. However, this was the first cooperative group study in the United States—a large, multi-institutional study incorporating more than 100 different sites—to try to generalize and bring total neoadjuvant therapy to the masses in both community and academic centers.

A lot of these studies were done as single-institution [trials] leading up to [the NRG-GI002 trial]. Colleagues in Europe presented some of the initial studies that got us thinking that total neoadjuvant therapy was going to be safe to do and could give us an opportunity to try to improve outcomes by bringing in new therapies, such as veliparib and pembrolizumab, which were the experimental arms for the study.

Can you expand on the patient population that was evaluated in this trial?

The patient population for this trial was restricted to patients with locally advanced rectal cancer. The definition of locally advanced rectal cancer [meant] that patients needed to have a diagnosis of rectal cancer of stage II or III. However, it needed to have 1 of 4 different criteria [to] qualify patients for enrollment. [These criteria included] bulky disease, such as a T4 lesion or tumor that was compromising mesorectal margins on a surgical resection; node-positive disease with multiple lymph nodes, such as N2 disease; disease that was compromising the sphincter, where a surgical resection at that point in time would compromise the ability to have anastomosis of the bowel; or patients that had a distal location of their tumor within 5 centimeters from the anal sphincter margin.

What did the long-term data from this trial show?

This was a platform study, and this is the first time that we're able to provide the updated short-term results, but also the first look at the long-term follow-up for these patients.

The first experimental arm included the incorporation of veliparib, a PARP inhibitor, to see if we could improve and take advantage of the radiation-damaging effects on DNA and prevent recovery of the tumor through inhibiting the PARP enzymes. That experimental arm demonstrated no statistically significant improvements in both short-term and long-term outcomes. Unfortunately, it did not seem to be of benefit or improve patients in an unselected population.

The second experimental arm, because this was a platform study, allowed us to test a novel immunotherapy, which was pembrolizumab, that was incorporated with radiation and in the space after radiation up until the time of surgery to take advantage of the radiation’s effects on increasing nonantigenic burden, improving the immunogenicity of the tumor, and taking advantage of that with checkpoint inhibitor therapy.

[Pembrolizumab], when incorporated into total neoadjuvant therapy, also did not demonstrate any statistically significant improvements in short-term end points or short-term outcomes for patients, including pathologic complete response [pCR], downstaging with neoadjuvant rectal score, sphincter preservation improvements, or clinical CRs. However, it did appear to have a statistically significant improvement in the 3-year OS.

There was a statistically significant 3-year OS advantage for patients treated with pembrolizumab compared with those not treated with pembrolizumab, although there were no differences in short-term outcomes.

How could these results affect current practice?

These results give us a lot of confidence that total neoadjuvant therapy for patients is here to stay. We now have established some reliable and reproducible benchmarks for how we can optimize therapy for patients today with current standards of care, and total neoadjuvant therapy is a current standard of care for patients with locally advanced rectal cancer.

However, there remains a lot of unanswered questions, both in this clinical trial dataset as to why some patients benefited and others didn't, as well as teasing out if there were subpopulations where there might be opportunities to exploit deficiencies in the way the tumors metabolize these drugs or the way the immune system engages it to improve outcomes in the future.

This [trial] also represents a platform study conducted on a national scale, supported by the National Cancer Institute, that was highly successful in enrolling well ahead of schedule. It beat all expectations in its performance. That gives us confidence that, in the future, similar designs of studies are plausible and feasible, and [these types of trials] may be a great way to accelerate progress in this disease where we need progress made.

Are there any other research efforts underway for patients with locally advanced rectal cancer that you would like to spotlight?

We are excited about the opportunity that total neoadjuvant therapy brings because if we are successful in giving every patient with high-risk disease systemic therapy and local ablative therapy with radiation, we may induce enough downstaging of the tumors that we may be able to forego surgical resection and turn this into a non-operative disease.

The next study that recently launched is the [phase 2] JANUS trial [NCT05610163]. This is an exciting study because it takes advantage of total neoadjuvant therapy, and with an opportunity to further intensify for patients to see if we can induce a higher clinical CR [rate], allowing non-operative support for patients and maybe being able to safely forego surgical resection and allow them to get on with their lives without the effects of surgery.

What is the importance of clinical trial participation for patients with locally advanced rectal cancer?

Clinical trial participation for these patients was something that took a village. We are incredibly grateful to patients’ partners, families, and caregivers that allowed patients to participate in the trials, especially their willingness to support the trial’s exploratory and correlative endpoints through additional biopsies and additional biospecimen collections. [We also thank] all the investigators and their sites, their research staff, and all the supporting structures that go into conducting research. We were fortunate to have a great village to pull this study together as fast as we did and deliver these results as quickly as we have.

Reference

George TJ, Yothers G, Rahma OE, et al. Long-term results from NRG-GI002: A phase II clinical trial platform using total neoadjuvant therapy (TNT) in locally advanced rectal cancer (LARC). J Clin Oncol. 2023;41(suppl 4):7. doi:10.1200/JCO.2023.41.3_suppl.7