By Jennifer Lubell
A Phase 2 trial demonstrated the safety of adding pembrolizumab to neoadjuvant chemoradiation to treat locally advanced rectal cancer (LARC). However, it failed to meet a primary endpoint of improving the neoadjuvant rectal (NAR) score, which combines pathologic nodal status with tumor downstaging.
Osama E. Rahma, MD, a medical oncologist at the Dana-Farber Cancer Institute in Boston, presented the results at ASCO’s 2021 Gastrointestinal Cancers Symposium (Abstract 8).
Despite low, locoregional relapse rates of 6%, just 25% to 30% of LARC patients achieve 5-year survival rates, Dr. Rahma told OBR. Given the inconsistent delivery of current therapeutic modalities, total neoadjuvant therapy (TNT) is an emerging approach to ensure that all patients receive systemic therapy.
In the NRG-GI002 trial, Dr. Rahma and his colleagues added pembrolizumab to chemoradiation as part of TNT in LARC patients, to see if survival rates would improve. TNT represented “a perfect window of opportunity to test novel drugs and their effect on the tumor microenvironment given the availability of paired tissues at diagnosis and surgery,” Dr. Rahma said.
The study included Stage II and III LARC patients at high risk for metastatic disease who had distal location bulky tumors and did not qualify for sphincter-sparing surgery. Investigators enrolled patients in 2018-2019, with a data cutoff of August 2020. Among 185 patients, 90 were randomized to the pembrolizumab experimental arm and 95 to the control arm.
Patients in the control arm received 8 cycles of modified FOLFOX6 followed by radiotherapy and 825 mg/m2 capecitabine on days that radiotherapy was administered. Patients in the experimental arm received the same regimen but followed with a combination of chemoradiation and pembrolizumab (200mg IV beginning on day 1 of radiotherapy every 3 weeks for 6 total doses). Surgery was performed 8 to 12 weeks following the last dose of radiotherapy.
NAR was the primary endpoint. Secondary endpoints included overall survival (OS), disease-free survival (DFS), toxicity, pathological complete response (pCR), clinical complete response (cCR), therapy completion, negative surgical margins, local recurrence, sphincter preservation, compliance, and exploratory molecular and radiographic predictors of response and distant failure.
A majority of the participants completed the mFOLFOX and chemoradiation regimens; 74% completed surgery and NAR analysis.
The study failed to show an improvement in the mean NAR score, which was 11.53 for the pembrolizumab group (95% CI: 8.5-14.6), compared with 14.08 for the control group (95% CI: 10.7-17.4; P=0.26).
Among the 90 patients on pembrolizumab, 70 underwent surgery and 69 had a valid NAR score. In the control group, 71 patients underwent surgery and 68 had a valid NAR score. Surgical complications in the experimental arm were numerically, but not statistically, higher.
Among the secondary endpoints, the pembrolizumab arm had numerically higher pCR rates (31.9% vs 29.4%, P=0.75) and lower sphincter sparing rates (59.4% vs 71%, P=0.15). Neither metric achieved statistical significance. Both DFS and OS are not mature and will be reported in future meetings, Dr. Rahma said.
Adding pembrolizumab to chemoradiation, however, is safe and yields no unexpected toxicities, he added.
The pembrolizumab arm had a slightly higher incidence of adverse events than the control (48.2% versus 37.3%) during and after chemoradiation.
Two deaths occurred during treatment with mFOLFOX: one on the control arm due to sepsis; the other on the experimental arm due to pneumonia. Investigators reported no statistically significant differences in radiotherapy (fractions, dose, boost fractions, or boost dose), FOLFOX, or capecitabine doses.
Demographics did not vary much among the cohorts. Notably, a third of patients on each arm were younger than 50 years of age, “consistent with a national trend we are seeing of younger patients diagnosed with rectal cancer,” Dr. Rahma said.
Combining chemoradiation and pembrolizumab could build on future studies designed to overcome resistance to immunotherapy in rectal cancer, he suggested. “Ongoing genomic and immune correlatives would inform these future combinational studies.”