Phase 1 Study of KT-413, a Targeted Protein Degrader of IRAK4 and IMiD Substrates, in Adult Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Background: Oncogenic mutations in myeloid differentiation primary response 88 (MYD88) occur in approximately 25% of diffuse large B-cell lymphoma (DLBCL) cases, including approximately 30% of activated B-cell DLBCL and up to 70% of primary extranodal DLBCL, and are associated with poor survival following 1^st line therapy. Furthermore, based on new genetic classifications, co-mutations in MYD88 and CD79 (C5 and MCD subgroups) are associated with an inferior survival after standard R-CHOP. MYD88 mutations result in activation of the NF-κB pathway which drive a range of pro-tumor activities, including upregulation of proinflammatory cytokines and genes involved in tumor cell proliferation and survival. Activation of this pathway results in upregulation of IRF4 through the transcription factors Ikaros and Aiolos, which in turn further augments NF-kB activation while simultaneously downregulating Type I IFN signaling, thereby preventing oncogene-induced cell death. Constitutive NF-kB pathway activation resulting from MYD88 mutations is dependent on the interleukin-1 receptor associated kinase 4 (IRAK4), a key component of the myddosome complex which normally stimulates NF-kB signaling following TLR or IL-1R engagement and MYD88 activation. KT-413 is a potent and selective heterobifunctional small molecule protein degrader mediating the degradation of both IRAK4 and the IMiD substrates Ikaros and Aiolos via the ubiquitin-proteasome system. The therapeutic hypothesis is that degradation of IRAK4 and IMiD substrates will maximize NF-κB inhibition while simultaneously upregulating the Type I Interferon response, thus restoring the apoptotic response and enabling oncogene-mediated cell death, resulting in robust antitumor response in MYD88-mutant DLBCL. KT-413 induced strong antitumor activity, including complete or partial regressions, in the in-vivo preclinical models of MYD88^MT DLBCL and showed strong tumor growth inhibition in MYD88^MT patient-derivedxenograft models (Mayo 2021).

Methods: KT-413 is being evaluated in an open label, dose escalation (Phase 1a) study in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) according to the 2016 World Health Organization (WHO) classification, followed by dose expansion (Phase 1b) in patients with R/R DLBCL with documented tumor MYD88 mutation status. All patients must have at least one bi-dimensionally measurable disease site per Lugano Classification and be relapsed and/or refractory to at least 2 accepted standard systemic regimens and ineligible or refused autologous stem cell transplant (ASCT) or CAR-T therapy; however, prior ASCT or CAR-T therapy are not exclusionary. Patients with known CNS lymphoma or meningeal involvement are excluded as well as those that received prior treatment with an IRAK4 inhibitor, experienced disease progression on IMiD-containing regimen < 6 months, are R/R after ≥ 2 prior IMiD-containing regimens or discontinued a prior IMiD therapy due to IMiD-related toxicity. Patients who underwent a prior allogeneic hematopoietic stem cell transplant are also excluded. The Phase 1a (n=40) utilizes an accelerated titration followed by a 3+3 design in ascending doses of IV administered KT-413 in once every 21-day cycles to identify the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) (primary endpoint). Secondary and exploratory endpoints include pharmacokinetics (PK) and preliminary pharmacodynamic effects (PD) using blood and tumor tissue, respectively. Once a tolerable and pharmacologically optimal dose is determined in 3-6 patients, it will be confirmed by enrolling additional patients with B-cell NHL, for a total of nine patients. In Phase 1b, up to 40 R/R DLBCL patients will be enrolled into one of two cohorts (n=20): MYD88^MT or MYD88^WT and treated at the RP2D to further characterize safety, tolerability, preliminary efficacy, PK, and PD. Enrollment in the Phase 1a portion of the KT413-DL-101 study is ongoing. NCT05233033.

Lue:Epizyme: Consultancy; TG Therapeutics: Consultancy. Williams:Pharmacyclics: Research Funding; TG Therapeutics: Consultancy; Research to Practice: Honoraria; Astra Zeneca: Consultancy; Gilead: Consultancy; International Oncology Network: Honoraria; Janssen: Consultancy, Research Funding; Kite Pharma: Consultancy; Kymera: Consultancy, Research Funding. Westin:Bristol Myers Squibb: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Merck: Consultancy; MorphoSys/Incyte Corporation: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; MonteRosa: Consultancy; Calithera: Consultancy, Research Funding; Iksuda: Consultancy; AstraZeneca: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Abbvie/GenMab: Consultancy; SeaGen: Consultancy. Ewesuedo:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. McDonald:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Agarwal:Kymera Therapeutics: Current Employment. Henrick:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company; Forma Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Perea:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company; Agios: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Gollob:KymeraTx: Current Employment.