Targeting the TGF-β pathway in patients with non-small cell lung cancer

Transforming growth factor beta (TGF-β) is a potent pleiotropic cytokine comprising three isoforms. It is a uniquitous cytokine in the tumor microenvironment (TME), originating from cell types including cancer cells, T-regulatory cells, the innate immune system including natural killer (NK) cells, neutrophils and macrophages, mesenchymal stem cells and cancer-associated fibroblasts. TGF-β acts via suppressor of mothers against decapentaplegic (SMAD)-dependent and SMAD-independent signaling and is known to function both as a tumor suppressor and a tumor promoter in most epithelial malignancies such as cancers from the breast, lung, colorectum, pancreas or prostate (1). TGF-β concentrations in plasma and TME of solid tumor patients are usually associated with a worse clinical outcome (2). TGF-β is a potent inducer of epithelial-to-mesenchymal transition (EMT) in cancer cells (3), a feature that is characterized by loss of E-cadherin and overexpression of mesenchymal proteins such as N-cadherin or vimentin, facilitating tumor invasiveness and drug resistance. TGF-β is one of the most immune-suppressive cytokines and negatively regulates both innate and adaptive immune responses (4), manifesting in downregulation of CD4⁺ and CD8⁺ lymphocytes and NK cells, upregulation of T-regulatory cells, impaired antigen presentation by dendritic cells, angio-invasiveness, EMT, cancer cell migration, invasiveness and creation of an immune-suppressive TME among others. As a potent driver of EMT in advanced solid malignancies, aberrant TGF-β signaling is strongly linked with drug resistance in non-small cell lung cancer (NSCLC) (5). Importantly, TGF-β is a strong inhibitor of T-cell response by engaging TGF-β receptors on T-cells with subsequently decreased proliferation, differentiation and activation (6).

As a result of the broad effects of TGF-β as a driver of carcinogenesis, multiple TGF-β inhibitors are under clinical development across several solid malignancies. Here, we examine the clinical development of TGF-β pathway inhibitors that are also being evaluated in NSCLC, including the small molecule TGF-β-R1 kinase inhibitor galunisertib, the anti-TGF-β antibodies fresolimumab and NIS793, the bifunctional anti-programmed cell death ligand 1 (anti-PD-L1) antibody fused to a TGF-β ligand trap bintrafusp alfa and INCA33890, the bispecific antibody co-targeting programmed cell death protein 1 (PD-1) and TGF-β-R2.

The development of both TGF-β neutralizing monoclonal antibodies fresolimumab and NIS793 in cancer patients has been discontinued. NIS793 has shown proof-of-mechanism by evidence of target engagement and TGF-β pathway inhibition, but limited activity in patients with advanced solid malignancies including advanced NSCLC (7). NCT02947165 was not a lung cancer-specific trial, but 20 patients with advanced NSCLC resistant to prior immune checkpoint inhibitors (ICIs) were included into the expansion part and treated with the combination of NIS793 and the programmed cell death protein 1 (PD-1)-targeting monoclonal antibody spartalizumab. Disease stabilization was achieved in 12 of 20 (60%) patients with advanced NSCLC, while median progression-free survival (PFS) was 2.40 months (7). The small molecule TGF-β-R1 kinase inhibitor galunisertib in combination with nivolumab showed a response rate of 24% among 25 patients with pretreated, ICI-naïve, advanced NSCLC, while 4 (16%) patients had stable disease and one additional patient had a confirmed partial remission after initial pseudo-progression (8). Median duration of response with galunisertib and nivolumab was 7.43 months. This is in comparison with a response rate of 19% and a duration of response of 17.2 months with nivolumab monotherapy in a similar disease setting (9). Further development of galunisertib has similarly been discontinued. Rajan and colleagues studied bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with advanced or metastatic NSCLC who were either ICI-naïve (n=18) or ICI-experienced (n=23) (10). In this prospective, non-randomized clinical trial, objective radiological response per independent review committee assessment was the primary endpoint. While the overall response rate with bintrafusp alfa was 27.8%, formal responses were exclusively observed in ICI-naïve patients. A single ICI-experienced patient a durable remission after initial pseudoprogression, which did not qualify for a formal response (10). An indirect comparison with older clinical studies in ICI-naïve patients with relapsed, pretreated NSCLC receiving anti-PD-(L)1 monoclonal antibodies (9,11,12) suggests a potential improvement by adding a TGF-β-targeting feature to the anti-PD-(L)1 monoclonal antibody (10). An obvious comparison of bintrafusp alfa against pembrolizumab, one of the current standards in patients with advanced PD-L1-high [PD-L1-tumor proportion score (TPS) ≥50%] NSCLC, showed more severe treatment-related adverse events (42% vs. 13%), similar response rates (47% vs. 51%), numerically worse median PFS [7.0 vs. 11.1 months, hazard ratio (HR) =1.23] and similar median overall survival (OS) (21.1 vs. 22.1 months) (13). INTR@PID LUNG 037, the largest study involving a TGF-β inhibitor in cancer patients, was discontinued before the accrual of the protocol-defined number of OS events required for the OS primary analysis, although exploratory analysis exhibited similar OS with bintrafusp alfa and pembrolizumab (13). Although prior bintrafusp alfa activity data from the phase 1 study suggested a median PFS around 15.2 months in patients with PD-L1-high, ICI-naïve NSCLC, these data were from 7 patients only (14). The high proportion of patients discontinued from bintrafusp alfa treatment (25.8%) versus pembrolizumab (6.6%) may very well have negatively affected clinical outcome in INTR@PID LUNG 037 (13). The most recent bintrafusp alfa data by Cho et al. (13) and Rajan et al. (10) suggest that a better patient selection and improved toxicity management to avoid treatment discontinuation are essential to move TGF-β-targeting anticancer drugs further. Still, further development of bintrafusp alfa was discontinued in September 2021. INCA33890 is a bispecific monoclonal antibody co-targeting PD-1 and TGF-β-R2, antagonizing the TGF-β signaling pathway specifically in cells co-expressing both targets and potentially mitigating toxicity by specifically targeting TGF-β-R2, that is currently undergoing dose finding (NCT05836324). Another anti-TGF-β-R2 IgG1 mAb (LY3022859) was reported to be considered unsafe for drug-associated cytokine release syndrome and infusion-related reactions (15). Table 1 is giving an overview of clinical studies examining TGF-β pathway targeting drugs in patients with advanced NSCLC.

For TGF-β targeted anticancer treatment, translation from bench to bedside has been slow and bumpy, despite some preclinical evidence for activity in solid malignancies. None of the TGF-β inhibitors that have been evaluated in clinical trials got approval for cancer therapy as yet. More recently, integration of TGF-β targeted therapeutics into checkpoint inhibitor regimens (or formulation of bispecific monoclonal antibodies) has shown early signs of added benefit in selected cancer populations including PD-L1-high advanced NSCLC. Still we expect more innovation to come from next-generation monoclonal antibody constructs and improved patient selection through TGF-β pathway specific biomarkers. Pharmacological issues with TGF-β ligand traps including NIS793 and bintrafusp alfa might systemic rather than intratumoral TGF-β neutralization, and TGF-β-R2 targeting monoclonal antibodies including INCA33890 look more promising with regards to antitumor activity. This may be further improved by co-targeting cell surface TGF-β-R2 and PD-L1, resulting in tumor selectivity. Whether such an approach is more promising in immune-excluded or -desert tumors such as colorectal and pancreatic cancer among other, or also promising to improve upon classical ICI in immune-infiltrated tumors such as NSCLC remains to be seen. Clearly, failures with TGF-β ligand traps should not be seen as failures on tackling the TGF-β pathway altogether.

Acknowledgments

Funding: 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-24-80/prf

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-80/coif). M.J. reports receiving grants from Swiss Cancer League, payment to institution from Novartis, AstraZeneca, Bayer, BMS, MSD, Sanofi, and support for attending meetings and/or travel from Sanofi, Takeda, AstraZeneca. The author has no other conflicts of interest to declare.

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