In patients with advanced, refractory colorectal cancer (CRC), combining immune checkpoint inhibition with durvalumab plus tremelimumab may prolong overall survival (OS) compared with best supportive care (BSC), according to the results of a recent phase II study published in JAMA Oncology. Researchers also found that elevated plasma tumor mutation burden (TMB) — gathered via cell-free DNA (cfDNA) analysis — may help identify patients who will most likely benefit from this treatment,
“Despite recent approval of agents such as trifluridine/tipiracil (TAS-102) and regorafenib, outcomes for patients with advanced colorectal cancer remain poor and new treatments are needed,” wrote Eric X. Chen, MD, PhD, of the Princess Margaret Cancer Center, Toronto, Canada, and colleagues.
In patients with advanced colorectal cancer, systemic therapy is the primary treatment modality, effecting median overall survival (OS) durations that approach 30 months. But, outcomes for these patients remain poor.
Historically, single-agent immune checkpoint inhibition has not been effective in patients with advanced refractory CRC except in those who are microsatellite-instability-high. Previous studies have shown that pembrolizumab and nivolumab — both anti-PD-1 mABs — show promise in patients with advanced CRC with tumors that are DNA mismatch repair deficient/microsatellite instability-high. Results were not as promising with single-agent immune checkpoint inhibitors in those with DNA mismatch repair proficient/microsatellite stable CRC.
Building on these studies, Chen and fellow researchers hypothesized that combined PD-L1 and CTLA-4 blockade may achieve greater anticancer activity in patients with advanced, metastatic, refractory CRC. In this multicenter phase 2 trial, they randomized 179 patients 2:1 (median age: 65 years) to treatment with either tremelimumab (75 mg every 28 days for the first four cycles) plus durvalumab (1,500 mg every 28 days) plus best supportive care (BSC) or BSC alone. Treatment was continued until clinical or radiological evidence of progression, intolerable toxic effects, withdrawal of consent, or death.
Durvalumab is a selective, high-affinity human IgG1 monoclonal antibody (mAB) against programmed death ligand 1 (PD-L1). Tremelimumab is a selective human IgG2 monoclonal antibody against cytotoxic T-cell lymphocyte antigen-4 (CTLA-4).
All patients had histologically confirmed adenocarcinoma of the colon or rectum, treatment with all available standard systemic therapies, age of 18 years of greater, adequate organ function, ECOG performance score of 0 or 1, and measurable disease. Serum samples were collected before initial study treatment was administered, and again at 8 weeks and upon disease progression, and analyzed for circulating cell-free DNA.
After a median follow-up of 15.2 months, median overall survival (OS) was greater in patients treated with durvalumab/tremelimumab compared with BSC (6.6 versus 4.1 months, respectively; HR: 0.72; 90% CI: 0.54-0.97; P = 0.07). Progression-free survival (PFS), however, did not differ significantly between the two groups (1.8 versus 1.9 months; HR: 1.01; 90% CI: 0.76-1.34).
No patient demonstrated complete response, and stable disease as the best response occurred in 21.8% of patients in the treatment group compared with 6.6% of those in the BSC group. Disease control was achieved in 22.7% and 6.6% of patients, respectively (OR: 4.16; 90% CI: 1.40-12.3; P=0.06).
The incidence of grade 3 and 4 adverse events was higher in the durvalumab/tremelimumab group compared with the BSC group, with 64% versus 20%, respectively, having at least one grade 3 or higher adverse event.
In the 169 patients with available samples, circulating cfDNA analysis was successful in 168. Among those who were microsatellite stable (MSS), researchers observed a significantly improved OS in those treated with durvalumab/tremelimumab (HR: 0.66; 90% CI: 0.49-0.89; P = 0.02). Further, they saw the greatest OS benefit in MSS patients with a plasma TMB of 28 variants or more per megabase (21% of MSS patients; HR: 0.34; 90% CI: 0.18-0.63; P = 0.004).
“Tumor variation burden has emerged as a potential biomarker for response to immune checkpoint blockade. High TMB is consistently associated with benefit from immune checkpoint blockade across different types of malignant diseases, such as melanoma, lung, and bladder cancers. A TMB of 28 or more was found to be the optimal threshold as a potential biomarker,” noted Chen and colleagues. “
Study limitations include missing baseline blood samples from 11 patients in the BSC group, although the effects on findings are minimal. In addition, differences between the two groups may have favored the treatment group, in that there were more women and Asians in the treatment group, and more patients with BRAF variations and fewer post-progression therapies in the BSC group.
In an accompanying editorial, Ryan B. Corcoran, MD, PhD, of Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA and Axel Grothey, MD, of the West Cancer Center and Research Institute, OneOncology, Germantown, TN, differ in their interpretation of these results, particularly regarding OS survival differences according to TMB.
“Although the TMB data are important, in particular in view of the larger OS difference observed in the TMB-high cases, the improved HR is mainly driven by the fact that patients with higher TMB did worse in the BSC arm. There is no indication that higher TMB was associated with better efficacy of the immunotherapy combination regimen (OS: TMB high, 5.5 months; TMB low, 6.9 months). This is a very important point because the way the results were presented leave the suggestion that high TMB is a positive predictive marker for improved immunotherapy combination efficacy compared with low TMB, but this is quite obviously not the case,” they wrote.
They also cited the absence of differences in median PFS between the two groups, along with the significant incidence of toxicity experienced by 62% of patients in the treatment group with grade 3 or higher adverse events, compared with only 20% in the BSC group.
“The results seen with durvalumab and tremelimumab in treatment-refractory MSS colorectal cancer can only be considered hypothesis generating, and the likelihood of true efficacy of this immunotherapy combination in MSS cancers is low,” concluded Corcoran and Grothey.
In patients with advanced refractory colorectal cancer, combined immune checkpoint inhibition may prolong overall survival. The study also suggests that tumor variation burden may be a potential biomarker for response to immune checkpoint blockade.
Be aware that this is a phase II study and the editorialist suggested that the results are, at best, “hypothesis generating.”
E.C. Meszaros, Contributing Writer, BreakingMED™
Chen has participated in clinical trials sponsored by Astra Zeneca, Merck, BMS, and Boston Biomedical, received research support (drugs only) from Astra Zeneca, and honoraria from Eisai and Taiho.
During the writing of the accompanying editorial, Corcoran reported receiving grants from AstraZeneca, and Grothey reported grants and nonfinancial support from Bayer, Merck, and Genentech.
This study was partially funded by AstraZeneca, which also provided durvalumab and tremelimumab. The Canadian Cancer Trials Group is funded by the Canadian Cancer Society.
Cat ID: 23
Topic ID: 78,23,730,23,935,192