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Neoadjuvant botensilimab plus balstilimab response pattern in locally advanced mismatch repair proficient colorectal cancer.

ABSTRACT: In patients with locally advanced cancer without distant metastases, the neoadjuvant setting presents a platform to evaluate new drugs. For mismatch repair proficient/microsatellite stable (pMMR/MSS) colon and rectal cancer, immunotherapy has shown limited efficacy. Herein, we report exceptional responses observed with neoadjuvant botensilimab (BOT), an Fc-enhanced next-generation anti-CTLA-4 antibody, alongside balstilimab (BAL; an anti-PD-1 antibody) in two patients with pMMR/MSS colon and rectal cancer. The histological pattern of rapid immune response observed ("inside-out" (serosa-to-mucosa) tumor regression) has not been described previously in this setting. Spatial biology analyses (RareCyte Inc.) reveal mechanisms of actions of BOT, a novel innate-adaptive immune activator. These observations have downstream implications for clinical trial designs using neoadjuvant immunotherapy and potentially sparing patients chemotherapy.

SUBMITTER: Kasi PM

PROVIDER: S-EPMC10611560 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Neoadjuvant botensilimab plus balstilimab response pattern in locally advanced mismatch repair proficient colorectal cancer.

Kasi Pashtoon Murtaza PM Hidalgo Manuel M Jafari Mehraneh D MD Yeo Heather H Lowenfeld Lea L Khan Uqba U Nguyen Alana T H ATH Siolas Despina D Swed Brandon B Hyun Jini J Khan Sahrish S Wood Madeleine M Samstein Benjamin B Rocca Juan P JP Ocean Allyson J AJ Popa Elizabeta C EC Hunt Daniel H DH Uppal Nikhil P NP Garrett Kelly A KA Pigazzi Alessio A Zhou Xi Kathy XK Shah Manish A MA Hissong Erika E

Oncogene 20230921 44

In patients with locally advanced cancer without distant metastases, the neoadjuvant setting presents a platform to evaluate new drugs. For mismatch repair proficient/microsatellite stable (pMMR/MSS) colon and rectal cancer, immunotherapy has shown limited efficacy. Herein, we report exceptional responses observed with neoadjuvant botensilimab (BOT), an Fc-enhanced next-generation anti-CTLA-4 antibody, alongside balstilimab (BAL; an anti-PD-1 antibody) in two patients with pMMR/MSS colon and rec ...[more]

PMID: 37731056

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Project description:ImportanceTotal neoadjuvant therapy (TNT) is the standard treatment for locally advanced rectal cancer, especially for patients with high-risk factors. However, the efficacy of TNT combined with immunotherapy for patients with proficient mismatch repair (pMMR) rectal cancer is unknown.ObjectivesTo evaluate the safety and efficacy of TNT with induction chemoimmunotherapy followed by long-course chemoradiation in patients with high-risk, pMMR rectal cancer and to identify potential molecular biomarkers associated with treatment efficacy.Design, setting, and participantsThis cohort study was a single-arm phase 2 trial conducted at Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, from June 2020 to October 2021. Biopsies and plasma were collected before treatment for whole-exome sequencing and cell-free DNA sequencing, respectively. Data were analyzed from May 2022 to September 2022.InterventionsParticipants received 3 cycles of induction oxaliplatin and capecitabine combined with camrelizumab and radiotherapy (50.6 Gy in 22 fractions) with concurrent capecitabine. Patients without disease progression received 2 cycles of consolidation oxaliplatin/capecitabine.Main outcomes and measuresThe primary end point was pathologic complete response rate.ResultsOf 25 patients enrolled (19 men [76%]; 6 women [24%]; median [IQR] age, 58 [48-64] years), 22 patients (88%) completed the TNT schedule. The pathologic complete response rate was 33.3% (7/21). Twelve patients (48%) achieved clinical complete response, and 4 patients (16%) chose to watch and wait. R0 resection was achieved in 21 of 21 patients, and the major pathologic response rate was 38.1% (8/21). The most common adverse event was nausea (80%, 20/25); grade 3 toxic effects occurred in 9 of 25 patients (36%). Patients with tumor shrinkage of 50% or greater after induction oxaliplatin/capecitabine and camrelizumab or clinical complete response had higher percentages of LRP1B mutation. Mutation of LRP1B was associated with high tumor mutation burden and tumor neoantigen burden. Patients with high tumor mutation burden all benefited from therapy.Conclusions and relevanceThis study found that TNT with induction chemoimmunotherapy followed by long-course chemoradiation was safe and effective for patients with high-risk rectal cancer with pMMR status. Longer follow-up and larger clinical studies are needed to validate this innovative regimen. There is also an urgent need to further validate the predictive value of LRP1B and discover other novel biomarkers with potential predictive value for rectal cancer.

Project description:BackgroundMismatch repair-proficient (pMMR) colorectal cancers (CRCs) are thought to be primarily resistant to immune checkpoint inhibitor (ICI) monotherapy. However, recent clinical trials have reported that early-to-mid stage (non-metastatic) CRC responds well to ICI monotherapy. We hypothesized that the efficacy of immunotherapy is linked to a series of gene expression profiles that can characterize the pMMR CRC disease stage.MethodsUsing The Cancer Genome Atlas (TCGA) CRC data sets, we first investigated transcriptomic features that continuously changed (were continuously upregulated or downregulated) with pMMR CRC disease-stage progression. We defined these gene sets as stage-associated genes. The deconvolution algorithm then enriched these genes with the dynamic changes in the cell type populations of the CRC tumor microenvironment (TME). Finally, the stage-associated genes were cross-referenced to the current transcriptome profile data on ICI treatment of pMMR CRC, which revealed the gene set specifying an effective pMMR tumor response.ResultsIn total, 774 genes were found to increase in expression and 845 genes to decrease in expression as the stage increased. Using deconvolution methods, we discovered 2 major disease stage-associated alterations in the cellular composition of pMMR CRCs, including changes in cell types involved in host immune responses and tumor cell metastasis. The central memory CD8+ T cell population decreased as the pMMR CRC disease stage increased, but the endothelial cell populations associated with proliferation and metastasis increased. Using a different cell type annotation set (LM22), we discovered that as the disease progressed, M1 macrophages and CD8+ T cells decreased in the TME. In mismatch repair-deficient patients with CRC, however, such a decrease was not observed. Finally, we identified 27 signature genes that can be used to assess ICI efficacy in treatment-naïve patients with pMMR CRC.ConclusionsThe current study sought to identify the underlying molecular mechanisms, pathways, and cell landscapes that explain why early-to-mid stage pMMR CRC responds well to ICI treatment. This analysis might be valuable for the selection of patients who might benefit from immunotherapeutic strategies.

Project description:BackgroundWe examined the predictive value of mismatch repair (MMR) status in relation to responses to neoadjuvant therapy and the prognosis of locally advanced rectal cancer patients.MethodsA total of 854 consecutive patients with locally advanced rectal cancer with MMR status who underwent neoadjuvant therapy followed by curative surgery between January 2013 and December 2018 were included this retrospective study. MMR status was determined by an analysis of MMR protein expression by immunohistochemistry (IHC). Propensity score matching was performed to reduce imbalances in baseline characteristics. The categorical variables were compared using the Chi-square test or Fisher's exact test. Local recurrence-free survival (LRFS) and disease-free survival (DFS) curves were estimated using the Kaplan-Meier method.ResultsDeficient MMR (dMMR) was detected in 63 of the 854 (7.4%) patients. Patients with dMMR had a lower proportion of tumor regression grade (TRG) of 0-1 compared with proficient MMR (pMMR) (28.6% vs. 43.7%; P=0.027). After propensity score matching at 1:4 for patients who received chemotherapy alone, proportion of TRG of 0-1 was observed to be significantly lower in dMMR than pMMR patients (9.1 vs. 30.3%%; P=0.013). For patients who received chemoradiation, after matching, no significant difference in the proportion of TRG 0-1 and the pathological complete response (pCR) rate was observed. The multivariable analysis revealed that patients whose tumors had dMMR had significantly longer DFS than those whose tumors had pMMR [hazards ratio (HR) =0.38, 95% confidence interval (CI): 0.18-0.81, P=0.013]. In the subgroup analysis, dMMR was only a statistically significant prognostic factor for DFS in patients with ypStage II/III (HR =0.38, 95% CI: 0.17-0.86; P=0.020).ConclusionsWe found that patients with dMMR responded worse to chemotherapy alone than patients with pMMR, in terms of TRG. Also, dMMR is a good prognostic marker for DFS in patients with ypStage II/III after neoadjuvant therapy.

Dataset Information

Neoadjuvant botensilimab plus balstilimab response pattern in locally advanced mismatch repair proficient colorectal cancer.

Publications

Neoadjuvant botensilimab plus balstilimab response pattern in locally advanced mismatch repair proficient colorectal cancer.

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