Preop Anti-PD-1 No Help in Locally Advanced Rectal Cancer

Adding a PD-1 inhibitor to neoadjuvant chemotherapy and radiotherapy failed to improve a rectal cancer-specific surrogate for survival in patients with locally advanced disease, a randomized trial showed.

The addition of pembrolizumab (Keytruda) improved the mean neoadjuvant rectal (NAR) score by 2.55 points versus conventional treatment with neoadjuvant FOLFOX chemotherapy followed by chemoradiation (CRT) with capecitabine. The difference did not meet the prespecified improvement target, and key secondary and exploratory endpoints also did not improve significantly.

The pembrolizumab arm also had more grade ≥3 adverse events (AEs), reported Osama Rahma, MD, of NRG Oncology and the Dana-Farber Cancer Institute in Boston, at the Gastrointestinal Cancers Symposium virtual meeting.

"Although there was a numerical increase in pathologic complete response, it did not reach statistical significance," said Rahma. "The safety profile was consistent with both CRT and pembrolizumab. While patients on both arms had similar chemo and radiation therapy exposure, 54% of patients did not receive the planned six pembrolizumab doses."

In a forward-looking commentary, invited discussant John Krauss, MD, of the University of Michigan Medical Center in Ann Arbor, asked, "What can we do different?" Borrowing from clinical experience in melanoma, he suggested combination checkpoint inhibition as an attractive option.

"We know with metastatic melanoma that the early combination of ipilimumab (Yervoy) and nivolumab (Opdivo) is superior to ipilimumab or nivolumab alone, and perhaps as many as 40% of the patients are having a long-term cure with this combination," said Krauss. "We know that ipilimumab-nivolumab works better in microsatellite-unstable colorectal cancer patients. Close to 80% of patients have a reduction in tumor from baseline. So perhaps we need to apply ipilimumab-nivolumab rather than just PD-1 inhibition alone."

"Finally, we know that ipilimumab-nivolumab can cause some responses in early mismatch repair-deficient early-stage colorectal cancer patients. Clearly, this work is something to be added on," he stated.

The current trimodal treatment paradigm for locally advanced rectal cancer consists of neoadjuvant CRT, followed by surgery and then adjuvant chemotherapy. However, 25%-70% of patients in various studies do not receive adjuvant chemotherapy. As a result, total neoadjuvant therapy (TNT) has emerged as an option to ensure that all patients receive systemic therapy, said Rahma.

Despite locoregional relapse in only 5%-6% of patients, long-term survival after TNT is only 65%, he continued. Given the large volume of evidence supporting immunomodulatory effects of radiation therapy, investigators hypothesized that resistance to immunotherapy in colorectal cancer could be overcome by combining CRT and an anti-PD-1 agent.

Rahma reported findings from NRG-GI002, a randomized phase II clinical trial platform to test novel agents in combination with neoadjuvant FOLFOX, followed by CRT. The first trial from the platform showed that adding the PARP inhibitor veliparib (ABT-888) to TNT did not significantly improve the NAR score versus standard TNT.

Eligible patients had locally advanced stage II-III rectal adenocarcinoma. The NAR endpoint combines pathologic nodal status with tumor downstaging to reflect tumor response on a continuous scale from 0 to 100, with a lower score representing a better outcome.

Investigators assumed that adding pembrolizumab to TNT would reduce a mean NAR score of 14.32 (derived from outcomes of prior studies) by 4.70, which would correlate roughly with an 18% reduction in the mortality hazard and a 3.3% absolute increase in 5-year overall survival (OS).

Of 185 randomized patients, 155 (83.8%) completed the planned eight cycles of FOLFOX, 146 (78.9%) completed CRT according to protocol, and 137 (74%) completed surgery and were eligible for NAR analysis. In the experimental arm, 37 of 81 (46%) evaluable patients received the planned six doses of pembrolizumab and 21 (26%) received five doses. The two treatment arms had no significant differences in CRT administration.

Patients in the control arm had a mean NAR score of 14.08, which declined to 11.53 with the addition of pembrolizumab (P=0.26). Other endpoints also did not differ significantly between the control and experimental arms:

• Pathologic CR: 29.4% vs 31.9% (P=0.75)
• Clinical CR: 13.6% vs 13.9% (P=0.95)
• R0 resection: 89.4% vs 94.0% (P=0.36)
• Sphincter-sparing surgery: 71% vs 59.4% (P=0.15)

Grade ≥3 AEs occurred more often in the pembrolizumab arm during chemotherapy (51% vs 41%, including one fatal AE in each group), during CRT (48.2% vs 37.3%), and postoperatively (35.6% vs 23.8%).

"Ongoing genomic and immune correlative studies will further explore immune resistance mechanisms and inform future TNT arms," said Rahma. "The disease-free survival and overall survival are not mature and will be presented in the future."

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