Potential Disease-Modifying Activity of Navtemadlin (KRT-232), a First-in-Class MDM2 Inhibitor, Correlates with Clinical Benefits in Relapsed/Refractory Myelofibrosis (MF)
Authors: Vachani Pankit , Lange Andrzej , Delgado Regina Garcia , Al-Ali Haifa Kathrin , Hernández-Rivas Jesus Maria , Kiladjian Jean-Jacques , Vannucchi Alessandro , Perkins Andrew Charles , Valmeekam Venu , Krejsa Cecile Marie , Uyei Anne , McGreivy Jesse , Rothbaum Wayne P. , Mascarenhas John , Verstovsek Srdan 
Published: November 2021

Introduction

Patients (pts) with MF who discontinue ruxolitinib due to resistance or progression have a poor prognosis (median OS, 14 months; Kuykendall et al. Ann Hematol. 2018). Available therapies provide symptom control and reduce spleen volumes, but do not address the underlying pathophysiology of disease, underscoring a need for disease-modifying treatments.

Murine double minute 2 (MDM2), a key negative regulator of the tumor suppressor protein p53, is overexpressed in CD34+ cells in MF. Elevated MDM2 attenuates p53 activity resulting in proliferation of malignant CD34+ cells. Navtemadlin (KRT-232), a potent, selective, orally available MDM2 inhibitor, restores p53 function and mediates apoptosis of malignant cells, suggesting a potential for disease-modification.

As previously reported in relapsed/refractory (R/R) MF, once-daily navtemadlin at 240 mg (Day 1-7/28-day cycle) yielded a best spleen volume reduction (SVR) ≥35% by central review in 16% of pts, best total symptom score (TSS) response &gt;50% in 30% of pts, and an 87% reduction of peripheral CD34+ cells at Week 24 (Al-Ali et al. EHA 2020).

Aims

To evaluate the correlations between changes in biomarkers of disease burden (variant allele frequency [VAF] of driver mutation and high-molecular risk (HMR) genes, peripheral blood CD34+ cells, serum cytokine levels, and bone marrow fibrosis) and clinical benefits (spleen volume reduction and symptom response).

Methods

Pts with R/R MF were treated in a phase 2 trial with different doses/schedules of navtemadlin (NCT03662126). Peripheral blood samples were collected at baseline and after 12 and 24 weeks of navtemadlin. Analysis of driver and HMR mutations (ASXL1, EZH2, SRSF2, IDH1/2, U2AF1) and VAF measurements from peripheral blood were determined by next-generation sequencing. Serum TNFα was analyzed by ELISA. Bone marrow biopsies were collected at baseline and after 24 weeks of treatment; fibrosis was assessed by a central pathology review. Correlations were investigated by calculating Spearman's rank-correlation coefficients.

Results

As of April 15, 2021, of 113 pts treated with navtemadlin, 111 were evaluable for mutation analyses. At baseline, 108 pts had ≥1 driver mutation and 75 pts had ≥1 mutation in an HMR gene Driver mutations in JAK2, CALR, or MPL were reported in 81 (73%), 22 (19%) and 13 (12%) of pts, respectively; 28 (25%) carried mutations in ≥2 HMR genes. Of 65 pts evaluable for driver gene or HMR VAF reductions, a best driver gene reduction ≥20% after navtemadlin was observed in 22 (34%) pts and 19 (29%) showed a complete VAF reduction (below the limit of detection) in HMR or driver genes (Fig 1). Reduction in driver allele VAF at any time on study significantly correlated with SVR (Fig 2A); SVR responses were noted in more pts with ≥20% vs &lt;20% decrease in driver VAFs (32% vs 5%; P=0.0072).

Reductions in circulating CD34+ cells in peripheral blood observed with navtemadlin treatment correlated significantly with best SVR (Fig 2B). Navtemadlin induced reductions in serum TNFα with a median best decrease from baseline of 41%. Reductions in TNFα correlated with best SVR and TSS responses (Fig 2C and 2D).

Of 45 pts who had bone marrow biopsies at baseline and Week 24, 41 (91%) had baseline fibrosis scores ≥1, with 31 (69%) and 4 (9%) having Grade 2 and 3 fibrosis, respectively. After navtemadlin treatment, 12 (27%) showed improved fibrosis scores of ≥1 grade and 23 (51%) had stable fibrosis scores. Among responders, fibrosis scores were improved or stable in 67% of pts with SVR ≥35% and 100% of pts with TSS improvement ≥50%. Fibrosis scores were also associated with improvements in mutation burden; of 14 patients with VAF reductions ≥20% and bone marrow assessments, 4 (29%) showed improvements in fibrosis and 8 (57%) had stable fibrosis scores.

Conclusion

Among pts with R/R MF treated with navtemadlin, spleen responses correlated with reductions of MPN-driver mutation burden, decreased peripheral CD34+ cell counts, improvements in bone marrow fibrosis scores, and reduction in inflammatory cytokine, TNFα. Improvement in symptom burden significantly correlated with reductions in TNFα. The reduction in mutation burden and CD34+ cells, together with an improvement in bone marrow fibrosis, suggest that navtemadlin has a disease-modifying effect in MF. These correlations will be explored further in BOREAS, a global phase 3 study in MF that is R/R to JAK inhibitors (NCT03662126).

Figure 1 Figure 1.

Disclosures

Vachani: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Delgado: Novartis: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy. Al-Ali: Incyte: Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Pfizer: Consultancy; AbbVie: Consultancy, Honoraria. Hernández-Rivas: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kiladjian: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology, Inc.: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Other: Personal fees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Vannucchi: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Perkins: Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy; Abbvie: Honoraria, Speakers Bureau. Valmeekam: Telios Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company, Other: travel, accommodations, expenses. Krejsa: Seattle Genetics: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months; Kartos Therapeutics: Current Employment, Current holder of stock options in a privately-held company, Other: travel, accommodations, expenses; AstraZeneca: Current equity holder in publicly-traded company; Acerta Pharma: Current holder of individual stocks in a privately-held company. Uyei: Kartos Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company; Genentech/Roche: Ended employment in the past 24 months; Gilead Sciences: Current equity holder in publicly-traded company; Telios Pharma: Current holder of individual stocks in a privately-held company. McGreivy: Kartos Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Rothbaum: Quogue Capital: Current Employment; Iovance Biotherapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses; Acerta Pharma/Astra Zeneca: Current equity holder in publicly-traded company; Kartos Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Patents & Royalties; Telios Pharma: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Patents & Royalties; Quogue IP Holdings: Patents & Royalties. Mascarenhas: PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forbius: Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Promedior: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Consultancy, Research Funding; Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merus: Research Funding; Geron: Consultancy; Galecto: Consultancy; Prelude: Consultancy. Verstovsek: CTI BioPharma: Research Funding; Blueprint Medicines Corp: Research Funding; Roche: Research Funding; Ital Pharma: Research Funding; Promedior: Research Funding; PharmaEssentia: Research Funding; Protagonist Therapeutics: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Genentech: Research Funding; Gilead: Research Funding; Incyte Corporation: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy.

OffLabel Disclosure:

Navtemadlin (KRT-232) is an investigational agent that is being evaluated in a clinical trial setting.