Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial

Abstract

Microsatellite stable metastatic colorectal cancer (MSS mCRC; mismatch repair proficient) has previously responded poorly to immune checkpoint blockade. Botensilimab (BOT) is an Fc-enhanced multifunctional anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody designed to expand therapy to cold/poorly immunogenic solid tumors, such as MSS mCRC. BOT with or without balstilimab (BAL; anti-PD-1 antibody) is being evaluated in an ongoing expanded phase 1 study. The primary endpoint is safety and tolerability, which was evaluated separately in the dose-escalation portion of the study and in patients with MSS mCRC (using combined dose-escalation/dose-expansion data). Secondary endpoints include investigator-assessed RECIST version 1.1-confirmed objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and progression-free survival (PFS). Here we present outcomes in 148 heavily pre-treated patients with MSS mCRC (six from the dose-escalation cohort; 142 from the dose-expansion cohort) treated with BOT and BAL, 101 of whom were considered response evaluable with at least 6 months of follow-up. Treatment-related adverse events (TRAEs) occurred in 89% of patients with MSS mCRC (131/148), most commonly fatigue (35%, 52/148), diarrhea (32%, 47/148) and pyrexia (24%, 36/148), with no grade 5 TRAEs reported and a 12% discontinuation rate due to a TRAE (18/148; data fully mature). In the response-evaluable population (n = 101), ORR was 17% (17/101; 95% confidence interval (CI), 10-26%), and DCR was 61% (62/101; 95% CI, 51-71%). Median DOR was not reached (NR; 95% CI, 5.7 months-NR), and median PFS was 3.5 months (95% CI, 2.7-4.1 months), at a median follow-up of 10.3 months (range, 0.5-42.6 months; data continuing to mature). The combination of BOT plus BAL demonstrated a manageable safety profile with no new immune-mediated safety signals and encouraging clinical activity with durable responses. ClinicalTrials.gov identifier: NCT03860272 .

Fig. 1. Participant flow diagram of the C-800-01 study and all treated patients with MSS mCRC (n = 148; analysis population).

^a One patient was enrolled but was never treated.

Fig. 2. Clinical efficacy by liver involvement in response-evaluable patients with MSS mCRC (n = 101).

Liver involvement was characterized as patients with active LM, treated LM that were resected or ablated without recurrence or no history of LM. a, Best overall response. b, Response over time. ^a Indicates a RECIST 1.1–confirmed CR or PR. The first blue bar on the right represents the CR.

Fig. 3. Clinical outcomes by liver involvement in response-evaluable patients with MSS mCRC (n = 101).

Liver involvement was characterized as patients with active LM, treated LM that were resected or ablated without recurrence or no history of LM. No active LM included patients with treated LM together with patients with no history of LM. a, PFS. b, OS.

Fig. 4. Responder characteristics (n = 19).

NLM was defined as patients with no history of LM (n = 17) or patients whose LM were resected or ablated without recurrence (treated; n = 2). Arrows indicate patients who, at the time of the data cutoff, were ongoing on treatment. ^a One patient later progressed. ^b One patient with a RECIST 1.1 response at 6 weeks had surgical resection of a target lesion that was considered clinical progression based on increase from nadir at 12 weeks after receiving steroids for an immune-mediated TRAE and was not confirmed; remaining target lesions then progressed. ^c Patient with treated LM (all other bars represent patients with no history of LM). NE, not evaluable.

Extended Data Fig. 1. Study schema for enrolled patients in the dose-escalation or dose expansion (N=479).

NSCLC; non-small cell lung cancer; PD-1, programmed cell death protein 1; Q3W, every 3 weeks; R/R relapsed/refractory.

Extended Data Fig. 2. Biomarker analysis of pretreatment tumor tissue in patients with microsatellite stable metastatic colorectal cancer (n=38).

(a) Clinical benefit by tumor mutational burden (TMB) at baseline (pretreatment). TMB was assessed by whole-exome sequencing (WES) using Personalis ImmunoID NeXT™ platform v1.0. TMB was defined as tumor-specific nonsynonymous somatic variants (and insertion-deletions)/megabase (Mb). Complete response (CR) or partial response (PR) and stable disease (SD) for at least 12 weeks was defined as per Response Evaluation Criteria in Solid Tumors version 1.1. Statistical analysis was performed using Kruskal-Wallis (ANOVA) nonparametric one-way test (p=0.7290, Kruskal-Wallis H=0.6321), followed by post-hoc Dunn test for adjusted multiple comparisons (CR/PR vs SD: mean rank difference= 1.111, z=0.2449, adjusted p=1; CR/PR vs PD: mean rank difference= 3.747, z=0.7503, adjusted p-value=1; SD vs PD: mean rank difference= 2.636, z=0.6199, adjusted p-value=1). Multiplicity adjusted p-values of 1 are indicated as p>0.9999 on the graph. Mut/Mb, mutations per megabase; PD, progressive disease.

Extended Data Fig. 3. Gene expression analysis of pretreatment tumor tissue in patients with microsatellite stable metastatic colorectal cancer (n=38).

The following plots compare patient outcomes (nine patients with partial responses [PRs], 18 with stable disease [SD] of at least 12 weeks, and 11 with progressive disease [PD]) across published gene signatures. Bulk RNA-Seq expression data was derived from pretreatment samples and the log2 gene transcripts per million (TPM) counts data were transformed to z-score values. The gene signatures were then calculated by averaging the gene expression values sample-wise and the results were compared across outcomes. Statistical comparisons used a two-sided nonparametric Dunn test and adjusted p-values were calculated with the Bonferroni method. (a) The interferon gamma (IFNy) signature (Ayers et al.) has been used to evaluate immune checkpoint blockade therapies for treating various cancer types. The upregulation of genes in the IFNy signature are indicative of a robust immune response to cancer. (b) The neutrophil signature (Bagaev et al.) includes a set of genes that are expressed by neutrophil cells in response to inflammation and infection. Upregulation of this signature can be used as an indicator of a poor response to checkpoint inhibitors. (c) The other signatures from Bagaev et al. provide additional biomarkers for probing the immune status of patients with cancer, predicting therapeutic responses, and guiding individual immunotherapy approaches. CAF, cancer-associated fibroblast; DC, dendritic cell; EMT, epithelial-to-mesenchymal transition; MHC, major histocompatibility complex; NK, natural killer; TAM, tumor-associated macrophage; T_reg, regulatory T cells.