VenEx precisely predicts ven-aza response

In this issue of Blood, Kytölä et al demonstrate the utility of ex vivo drug-sensitivity testing for venetoclax to accurately predict response and overall survival to the venetoclax and azacitidine (Ven-Aza) regimen in older patients with acute myeloid leukemia (AML) in the prospective VenEx trial,¹ which included de novo and relapsed/refractory disease. Although the Ven-Aza regimen achieves complete remission (CR) or CR with incomplete hematologic recovery (CRi) in two-thirds of untreated patients, the response rate in secondary or relapsed AML is lower, 21% to 40% CR/CRi. Thus, the ability to select patients who are likely to respond would be helpful. The ex vivo drug-sensitivity test exhibited both positive and negative predictive values after stratification using a drug-sensitivity score (DSS) derived from the assay.

AML is an aggressive hematologic malignancy with poor prognosis, particularly in older patients. The use of the Bcl-2 inhibitor venetoclax in combination with a hypomethylating agent (HMA; eg, azacitidine or decitabine) has dramatically improved remission rate and survival for older patients and younger patients with comorbidities and received initial regulatory approval after a phase 2 open-label clinical trial.² The molecular age in AML diagnostics emerged in the past 15 years,³ and with it the dream of personalizing therapy for this markedly heterogeneous disorder, as well as all other cancers. The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial was a vast undertaking, with ∼6000 patients with cancer enrolled in 24 (expanded to 38) treatment arms based on individual mutations.⁴ With a few exceptions, the majority of treatment arms, typically the single-agent arms, demonstrated very low response rates, attributed to co-occurring mutations and the tumor microenvironment. Beat AML was a multicenter trial in AML with a similar vision, with 10 substudies based on the dominant clone found by molecular and/or cytogenetic evaluation. The study enrolled 487 patients, with 224 treated in a substudy, 103 receiving standard of care, and the remaining patients receiving alternative therapy or palliative care. The feasibility of this approach was established, and survival was longer for those enrolled in the substudies than for those who received standard of care.⁵ However, it was clear that more than targeting the dominant clone was needed to substantially alter prognosis, and investigators in the field believed that direct testing of drugs would be the best option for individual patients.

Cancer drug testing began in the mid-20th century, but the tests did not accurately predict response for individual patients. Subsequently, new efforts arose with high-throughput drug screening of 2-dimensional cultures, testing of spheroids, organoids, and patient-derived xenografts, and eventually, cases were reported demonstrating exceptional response after treatment based on the assay.

In the field of AML, the 2013 work by Pemovska et al is considered pivotal by reporting an “individualized systems medicine” analysis of 28 AML cases with drug screening against a panel of 187 drugs,⁶ and examples of how the results could be applied. More recently, Malani et al presented multiparameter flow cytometry–based high-throughput drug screening results of 186 patients. Thirty-seven of those patients with relapsed/refractory AML received treatment based on a functional precision medicine tumor board (integrated clinical, molecular, and functional data) and 59% achieved an objective response, with CR observed in 13%.⁷ Kornauth et al performed image-based single-cell functional precision medicine with a panel of 139 drugs in 143 patients with leukemia and lymphoma, with 54% of the 56 treated patients achieving an improvement in progression-free survival as compared with the preceding regimen.⁸ Despite these successes, challenges persisted, with lack of widespread knowledge of the advances in the oncology community.

Fortunately, the VenEx trial reported here is a brilliant example of the power of functional precision medicine. The simplicity of assessing the single agent venetoclax in a rapid 48-hour multiparameter flow cytometry–based in vitro assay in a prospective, multicenter trial demonstrating accurate predictions of both positive and negative responses to the combination of venetoclax and azacitidine (see figure) represents a major advance. There have also been observations on the success of venetoclax/HMA combinations in those with specific molecular features, such as better response rates with an IDH2 mutation, and worse outcomes with TP53 mutations. A molecular prognostic risk signature (mPRS) model was developed that focused on response to venetoclax/HMA therapy that delineated a lower benefit risk group with a TP53 mutation, an intermediate benefit risk group with FLT3-ITD or K/N RAS mutations, and the remainder were considered to have a higher benefit risk.^9,10 Although the response rates in the intermediate and lower benefit risk groups were similar, a distinct survival advantage was seen in the intermediate group.^9,10 The results of the venetoclax sensitivity test as reported in the VenEx trial provide better stratification of patients, with highly significant positive and negative predictive values.

The phase 2 trial conducted by the Finnish AML Group (VenEx) enrolled 104 patients, 48 previously untreated, 39 relapsed/refractory (R/R), and 17 previously treated secondary AML (sAML). Testing results were obtained for 102 patients. The results for newly diagnosed patients included a CR/CRi rate of 85% with median overall survival (OS) of 28.7 months for those considered sensitive to venetoclax vs 38% with 5.5-month median OS for those found resistant on ex vivo testing (P = .0017). For patients with relapsed/refractory and secondary AML, the CR/CRi rate was 62% vs 0% and median OS 9.7 months vs 3.3 months (P = .0002) for a sensitive vs resistant result on ex vivo testing. For all patients with a sensitive test result, the overall response rate (ORR = CR/CRi/morphologic leukemia-free state) was 88%, which is also the positive predictive value, and results were similar for those who had previously received HMA. In summary, sensitivity in the functional test robustly predicted CR/CRi, ORR, and OS in all settings, and assignment of mPRS scores for study participants demonstrated improved survival predictions with the VenEx drug-sensitivity test in the higher and intermediate benefit risk mPRS groups.

In conclusion, Kytölä et al have validated in a prospective clinical trial a robust functional precision medicine test for venetoclax capable of predicting response to the Ven-Aza regimen so that individual patients can receive the right therapy at the right time.

Conflict-of-interest disclosure: P.S.B. is the principal investigator on a research grant to the institution from GPCR Therapeutics.