Botensilimab plus balstilimab in microsatellite stable metastatic colorectal cancer: light and gloom

Colorectal cancer (CRC) is the second leading cause of cancer death in the United States and in Europe (1,2). Despite the use of novel therapies, such as fruquintinib explored in the FRESCO-2 trial and recently introduced into daily clinical practice, the prognosis remains poor (3). Immunotherapy has shown practice-changing results in patients with microsatellite instability-high (MSI-H) and/or mismatch repair deficiency (dMMR) metastatic CRC (mCRC); unfortunately, this characteristic accounts for only 4% of all metastatic diseases (4,5). In fact, the same notable effects of immunotherapy are not observed in microsatellite stable (MSS) or mismatch repair proficient (pMMR) mCRC: tumors with MSS have historically been considered resistant to immune checkpoint inhibitors (ICIs) due to the paucity of neoantigens on the surface of the cells and to a ‘cold’ tumor microenvironment, rich in regulatory T cells and macrophages but poor in CD8⁺ effector cells (6,7). Hence, it is necessary to study strategies to overcome this intrinsic resistance in order to use this therapeutic tool in the remaining cases.

Promising results were found by Morano and colleagues, who explored the possibility of inducing hypermutation through a temozolomide priming treatment that could immune-sensitize MSS O⁶-methylguanine-DNA methyltransferase (MGMT)-silenced mCRC (8). However, despite very promising efficacy results, the applicability of this therapeutic strategy is limited: of all patients who underwent pre-screening, only 18% were deemed eligible for treatment, and of these, only 26% actually received immunotherapy (8). Similarly, binimetinib in combination with nivolumab or ipilimumab plus nivolumab showed insufficient results about clinical benefit with either drug combination (9). Other studies evaluated combination of double ICIs, like durvalumab plus tramelimumab, showing interesting results in terms of overall survival (OS), especially in the population with elevated plasma tumor mutation burden (TMB) (10).

Many other combination strategies have failed, such as the association of ICIs with tyrosine kinase inhibitors (TKIs) (11).

Bullock and colleagues aimed to overcome resistance to ICIs by combining balstilimab (BAL), an anti-programmed cell death 1 (PD-1) monoclonal antibody, with botensilimab (BOT), a next-generation anti-cytotoxic T lymphocyte-associated protein 4 (CTLA4) monoclonal antibody. BOT has an Fc-enhanced immunoglobulin G (IgG)1 region that binds with greater affinity to Fc-gamma receptors (FcγR) present on APC and natural killer (NK) cells, and it may enhance T cell activation by strengthening the activating interaction between T cells and antigen-presenting cells (APCs). Moreover, BOT can eliminate regulatory T cells within the tumor through the activation of antibody-mediated cytotoxicity mechanisms (12).

The study is an open-label, phase I, multicenter study evaluating the use of BOT combined with or without BAL in pretreated solid tumors. Primary objectives were to assess safety and tolerability as well as to explore if the specific design of BOT translates into clinical practice.

The study design included an initial dose-escalation cohort (3+3 design) that enrolled 83 patients (of whom 10 were MSS mCRC) followed by a disease-specific expansion cohort involving 396 patients (of whom 173 were MSS mCRC).

In the first phase, four patients were randomized to monotherapy with BOT given every 3 weeks (Q3W) or every 6 weeks (Q6W), starting at dose level 0.1 up to 3 mg/kg and six patients to the combination with BAT 3 mg/kg every 2 weeks (Q2W), administered intravenously (IV) for up to 2 years.

In the second phase, the selected disease-specific expansion cohorts enrolled 29 MSS mCRC patients in the monotherapy group and 142 MSS mCRC patients in the combination one. A fixed-dose cohort evaluating BOT Q6W (150 mg) plus BAL Q3W (450 mg) administered IV for up to 2 years was also evaluated in this trial. The treatment could be given beyond progression and crossover from monotherapy was allowed. Imaging was performed Q6W.

The primary endpoints, hence, safety and tolerability, were evaluated distinctly in the first dose-escalation portion of the study and then, in MSS mCRC patients. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and duration of response (DOR).

In the whole cohort that received BOT plus BAL (overall 148 were MSS mCRC patients in the first and second part of the trial), treatment-related adverse events (TRAEs) of any grade occurred in 89% of patients. The most frequent TRAEs were fatigue (35%), diarrhea (32%), and fever (24%). Of note, 35% of patients experienced a treatment-related serious adverse event (TR-SAE); 32% of patients had a temporary treatment interruption, and 28% permanently discontinued treatment due to a TRAE. Grade 3 TRAEs occurred in 31% of patients (especially diarrhea, enterocolitis, colitis and fever, acute kidney injury). Notably, grade 4 TRAEs occurred in 2 out of 148 patients. No grade 5 treatment-related events were reported.

Of particular interest are the suggested management strategies for immunotherapy-related colitis/diarrhea. The authors recommended the use of infliximab even in cases of low-grade steroid-sensitive toxicity. Out of the 36 patients with colitis/diarrhea, 35 patients received infliximab and also received steroid therapy; with this strategy 31 patients had complete resolution of their symptoms, suggesting that early treatment with infliximab might be an effective strategy to rapidly resolve toxicity and allow for a quick resumption of treatment.

The primary endpoint of the dose-escalation part was reached, with no dose-limiting toxicities observed either in the monotherapy and in the combination therapy cohorts. The maximum tolerated dose was not achieved. Regarding the secondary endpoints, three of the six patients treated with the combination therapy had a partial response (PR). Overall, the DCR was 43% [95% confidence interval (CI): 33–55%] and median DOR was not reached (NR; 95% CI: 4.2 months–NR).

The efficacy was evaluated in the 101 of the 148 patients that reached at least 6 months of follow up in the BOT/BAL expansion cohort with a rate of 18% of objective responses (95% CI: 10–26%) including one CR and a rate of 45% of stable disease with a DCR of 61% (95% CI: 51–71%). Five patients showed at least 30% of reduction in target lesions.

The subgroup analysis showed poorer outcome in presence of active liver metastasis with a 0% of ORR compared with the 22% of the non-liver metastasis group. In addition, in the liver metastasis group, the median PFS was 1.4 months (95% CI: 1.3–1.4) and the median OS 7.4 months (95% CI: 6.1–10.3) compared to 4.1 months (95% CI: 3.3–5.5) and 20.9 months (95% CI: 16.4–NR) for the non-liver metastasis group.

Interestingly, as exploratory endpoints, the study included a biomarker and gene expression analysis on pre-treatment tumor tissues. However, due to the discrepancy of the analyses between centers and the small numbers of samples, solid results cannot be deduced.

Growing evidence is showing the potential use of immunotherapy in multiple cancer types, including CRC patients. Moreover, the rapidly increasing number of diagnoses in young patients, represent and urgent medical need to develop new treatment options for modifying natural course of MSS disease.

Based on preliminary data on Fc-enhanced CTLA4 inhibitors that may overcome the immune suppressive microenvironment and mechanisms of resistance in cold tumors, this phase I trial tested the safety and efficacy of BOT combined with BAL in MSS mCRC pretreated patients.

Notably, the study showed promising results in a landscape full of disappointing results coming from previous attempts, showing that a way to overcome MSS mCRC primary resistance to immunotherapy can be found (13,14). The combination treatment of BOT and BAL resulting in encouraging activity with an ORR of 17% and a DCR of 61% in the MSS mCRC population.

Moreover, the safety profile resulted manageable. The most frequent TRAE were diarrhea (32%) managed with the use of tumor necrosis factor (TNF) inhibitors, which allowed for a prompt recovery and rapid resumption of treatment. Hypophysitis, myocarditis, pneumonitis and hepatitis occurred rarely as for other immunotherapy combination.

Interesting results arise regarding the lack of responses in the liver metastasis group. Some recent data provide a possible explanation in the liver immunosuppressive environment that can lead to a resistance to immunotherapy (15-17). Flecchia et al. showed in a retrospective AGEO study including 399 patients that liver metastasis [odds ratio (OR) =2.19] is one of five clinical factors associated with primary resistance to immunotherapy (18). A study of patients with melanoma and non-small cell lung cancer (NSCLC) treated with the anti-PD-1 antibody pembrolizumab found that patients with liver metastasis, that showed a reduced response and a shortened PFS compared to non-liver metastasis group, had a depletion of marginal CD8⁺ T-cell infiltration leading to the so-called ‘immune desert’ state (15,19). A possible explanation of this finding comes from preclinical models that suggested the role of hepatic myeloid cells as critical mediators that induce an enhanced antigen-specific CD8⁺ T cell apoptosis (19). Yu identified the fibrinogen-like protein 1, secreted by cancer cells and hepatocytes, as protein with a crucial role in CRC progression, especially in tumor with high expression of tumor-associated Macrophages (15). Based on these findings, liver metastasis could be seen as a potential negative baseline determinant of immunotherapy response, but further studies are needed to fully understand the underlying mechanism of this phenomenon.

Regarding the non-liver metastasis group, the benefit observed marks a further step towards understanding the factors that determine the responsiveness of some patients with MSS mCRC to immunotherapy and ultimately, to the possibility of new treatment strategies for the MSS mCRC population.

However, many questions remain open. First, it is unclear the weight of prior therapies to the efficacy of BAL and BOT, considering that about 16% of patients received immunotherapy in prior lines and the most part of patients were treated with vascular endothelial growth factor (VEGF)-antibodies, but the regimes adopted in the previous lines are not reported.

Secondly, RAS and BRAF mutational status were unknown in 103 patients that could be essential to better define the responsiveness to the immunotherapeutic approach. Recent evidence has demonstrated as KRAS mutation could exhibit particular patterns of immune signature whit high tumor mutational burden and high PD-L1 expression, but at the same time shape an immune-suppressive microenvironment recruiting myeloid-derived suppressor cells (MDSCs), regulatory T cells, and cancer-associated fibroblasts (19). Interestingly, recent data on transcriptome analysis reported a negative influence by KRAS-mutant NSCLC with programmed death-ligand 1 (PD-L1) level and chemokines secretion, leading to decrease in CD8⁺ tumor-infiltrating lymphocytes (TILs) and reduced efficacy exerted by ICIs (20).

Third, there is no data of comparative efficacy against the current standards of care, more studies need to be done to find the correct place for this therapy in the landscape of the MSS mCRC treatment.

Lastly, there is still a lack of knowledge about biomarkers that can predict the response to the therapy, as TMB was available in less than one-third of patients and even less the PD-L1 expression assessment. Of note, an interim analysis from a phase 2 trial (NCT05608044) was recently released, demonstrating similar safety profile to the phase 1 study, and an ORR of 23% in the 77 MSS mCRC patients without active liver metastases. The estimated 6-, 12-, and 18-month OS rates were 86%, 71%, and 62%, respectively. The estimated median OS was 21.2 months. The Food and Drug Administration (FDA) advised against despite accelerated approval pathway for this combination therapy.

Certainly, if the results obtained will be confirmed by phase III studies (now ongoing), they will throw even more emphasis on the importance of refining patient selection, in order to reshape the course of MSS mCRC patients and provide lasting benefits.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-226/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-226/coif). D.B. reports support for attending meetings and/or travel from Merck and has served on the advisory board for Amgen. G.A. has served on the advisory boards for Amgen, Baxter, Eli-Lilly, Sanofi, and Servier. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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