Mantle cell lymphoma cell lines with intrinsic resistance to BTK inhibitors displayed anti-tumor activity on treatment with tazemetostat as monotherapy or in combination with zanubrutinib, according to data from a preclinical analysis.
Mantle cell lymphoma (MCL) cell lines with intrinsic resistance to BTK inhibitors displayed anti-tumor activity on treatment with tazemetostat (Tazverik) as monotherapy or in combination with zanubrutinib (Brukinsa), according to data from a preclinical analysis presented during the AACR Annual Meeting 2021.
The findings suggest that the agent could be a promising therapeutic option for patients with primary relapsed/refractory disease.
“We have previously reported that tazemetostat resensitized a subset of MCL cell lines intrinsically resistant to BTK inhibitors, ibrutinib [Imbruvica] and acalabrutinib [Calquence], and further enhanced these BTK inhibitors’ activity in sensitive cell lines. In the present study we show similar results when tazemetostat was combined with the recently approved BTK inhibitor zanubrutinib. [The Mino] xenograft in vivo study shows significant tumor growth delay with the combination of tazemetostat and zanubrutinib compared to [novel] single agents alone,” lead study author Jeffrey A. Keats, of Epizyme, the developer of tazemetostat, and colleagues wrote in a poster of the data.
Tazemetostat is a potent, oral small molecule inhibitor of EZH2 approved for the treatment of patients with epithelioid sarcoma and relapsed/refractory follicular lymphoma.
EZH2 plays a key role in B-cell maturation, and several B-cell malignancies rely on EZH2 for survival. MCL is a rare subtype of B-cell lymphoma that typically presents at an advanced stage, and most cases relapse despite the availability of effective treatments, such as BTK inhibitors.
Because tazemetostat, as a single agent or in combination with BTK inhibitors, had been shown to induce in vitro and in vivo antitumor activity in MCL models, EZH2 inhibitors represent a potentially effective treatment class for patients with MCL.
In the present study, in vivo studies demonstrated a significant prolongation in the time to tumor growth with the combination of tazemetostat and zanubrutinib in the MCL Mino cell line–derived murine xenograft model compared with single-agent treatments.
In vitro MCL models with resistance to ibrutinib and zanubrutinib were also created to determine the potential therapeutic benefit of EZH2 inhibition in a BTK inhibitor–resistant population. Notably, the cell lines retained the in vitro sensitivity to tazemetostat that had been reported in the parental cell line, indicating that tazemetostat could provide therapeutic benefit for patients with acquired resistance to BTK inhibitors.
“In vitro acquired resistance was generated in the MINO MCL cell line to the BTK inhibitors ibrutinib and zanubrutinib and demonstrated retained sensitivity to tazemetostat.
Preliminary analysis indicate that acquired resistance in these cell lines is not driven by BTK inhibitor binding site mutations. Data suggest that the PI3K-AKT pathway is activated as upregulation of the pathway at the mRNA level and increased pAKT and pERK proteins were observed in the BTK inhibitor–acquired resistant cell lines compared to the parental line, consistent with the literature,” wrote the study authors.
Moreover, “Tazemetostat induced antiproliferative effects ex vivo in samples derived from MCL patients that were relapsed or refractory to one or more current [standard of care treatments] including ibrutinib.”
“Synergy was observed in in vitro combination studies with tazemetostat and immunomodulatory drugs lenalidomide [Revlimid] and pomalidomide [Pomalyst], glucocorticoid receptor agonists prednisolone and dexamethasone, BCL-2 inhibitor venetoclax [Venclexta], and CDK4/6 inhibitor palbociclib [Ibrance] in the BTK inhibitor–acquired resistant models.”
The data suggest that tazemetostat treatment, alone or in combination with a BTK inhibitor, [standard-of-care treatments], or emerging therapies, could be a therapeutic option in the treatment of the MCL patient population that is primary refractory/relapsed to BTK inhibitor therapy,” concluded the study authors.
Keats JA, Lee A, Cunniff JC, et al. EZH2 inhibitor tazemetostat demonstrates activity in preclinical models of Bruton’s tyrosine kinase inhibitor-resistant relapsed/refractory mantle cell lymphoma. Presented at: AACR Annual Meeting 2021; April 10-15, 2021; virtual. Abstract 1161.