Lower-intensity CPX-351 plus venetoclax induction for adults with newly diagnosed AML unfit for intensive chemotherapy

CPX-351, a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is an approved therapy for newly diagnosed therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes in patients who are candidates for intensive chemotherapy.¹ In the primary analysis of the pivotal phase 3 trial conducted in adults aged 60 to 75 years with newly diagnosed, high-risk/secondary AML considered fit for intensive chemotherapy, CPX-351 significantly improved the rates of both overall survival (OS; 9.56 vs 5.95 months; 1-sided P = .003) and overall remission (complete remission [CR] plus CR with incomplete hematologic recovery [CRi]; 47.7% vs 33.3%; 2-sided P = .016), compared with standard cytarabine plus daunorubicin (7+3) chemotherapy.² 

For older adults with AML who are not considered eligible for intensive chemotherapy, the combination of hypomethylating agents (HMAs) and the B-cell lymphoma-2 inhibitor venetoclax is now the preferred treatment regimen.^3,4 This treatment approach is based, in part, on results from the phase 3 VIALE-A study, which demonstrated improved OS (14.7 vs 9.6 months; P < .001) and remission rates (CR or CRi; 66.4% vs 28.3%; P < .001) for the combination of azacitidine plus venetoclax vs azacitidine plus placebo.⁵ Venetoclax exhibits potent clinical activity in multiple hematologic malignancies when combined with various classes of agents, including cytotoxic chemotherapy, immunotherapy, and molecularly targeted agents.^5-11 Although the combination of HMAs and venetoclax represents a major advancement in the management of AML, long-term follow-up from the VIALE-A study suggests that the regimen is noncurative, and typically, treatment is continued until progression or unacceptable toxicity.^12-14 Dose delays and reductions for myelosuppression and cytopenia are common during treatment and have an uncertain effect on patient outcomes.^5,15 In addition, biologic subsets of AML, particularly patients with TP53 mutations, do not appear to have a survival benefit from the addition of venetoclax to HMAs and continue to have poor outcomes regardless of the choice of therapy.^16,17 

Given its superiority to 7+3 in older adults with high-risk/secondary AML, CPX-351 has garnered interest either alone or as a component of combination therapy in other AML indications.^18-20 Preclinical data suggest a rationale for combining CPX-351 and venetoclax. Daunorubicin and cytarabine have been shown to bypass an intrinsic resistance mechanism associated with venetoclax by decreasing Mcl-1 protein levels, resulting in synergistic induction of cell death when used in combination with venetoclax.²¹ Additionally, in an in vitro study, CPX-351 plus venetoclax demonstrated synergistic or additive antitumor effects in multiple AML and acute lymphoblastic leukemia cell lines.²² Therefore, we sought to test the combination of lower-intensity CPX-351 plus venetoclax in patients with newly diagnosed AML who were considered unfit for intensive chemotherapy. The objective of this study was to determine the recommended phase 2 dose (RP2D) and assess the safety, efficacy, and pharmacokinetics (PK) of lower-intensity CPX-351 plus venetoclax.

This phase 1b, multicenter, open-label study (ClinicalTrials.gov identifier NCT04038437) comprised 2 phases: a dose-exploration phase to determine the safety and RP2D for the combination of CPX-351 plus venetoclax; and an expansion phase to further investigate the safety and efficacy at the RP2D. A generalized semimechanistic population PK-pharmacodynamic nonlinear mixed-effects model, which simulated absolute neutrophil and platelet profiles after the combination of lower-intensity CPX-351 plus venetoclax, facilitated the initial dose selection, suggesting that this combination might be tolerated without significant hematologic adverse events (AEs).²³ However, because the myelosuppressive effect of lower-intensity CPX-351 was anticipated to be greater than that of low-dose cytarabine, this informed the decision to use a venetoclax therapy duration of 2 to 21 days in this study to ameliorate myelosuppression, rather than the recommended 1 to 28 days when venetoclax is administered with low-dose cytarabine or HMA.²⁴ 

In the dose-exploration phase, 3 dose levels of CPX-351 were assessed using a 3+3 design, based on the incidence of dose-limiting toxicities (DLTs). The dose-exploration phase first determined the maximum tolerated dose as the highest dose level at which either 0 of 3 or 1 of 6 evaluable patients experienced a DLT. Subsequently, the RP2D was determined from the dose levels that were tolerated in the dose-exploration phase. Patients received CPX-351 at 20 units/m² (daunorubicin 8.8 mg/m² and cytarabine 20 mg/m²; dose level 1), 40 units/m² (daunorubicin 17.6 mg/m² and cytarabine 40 mg/m²; dose level 2), or 30 units/m² (daunorubicin 13.2 mg/m² and cytarabine 30 mg/m²; dose level 1b; RP2D) IV on days 1 and 3 of each cycle. For each dose level, patients also received venetoclax 400 mg orally on days 2 to 21 of each cycle except cycle 1, during which the dose of venetoclax was ramped up (see below). A cycle was defined as lasting a minimum of 28 days or until count recovery was achieved. During cycle 1, to mitigate the risk of tumor lysis syndrome, the dose of venetoclax was ramped up from 100 mg/d on day 2 to 200 mg/d on day 3 and then 400 mg/d (target dose) on days 4 to 21. For subsequent cycles, venetoclax was administered at the full target dose on days 2 to 21. Risk mitigation for tumor lysis was also the rationale for starting venetoclax on day 2 rather than day 1. DLTs were defined as treatment-related (to CPX-351, venetoclax, or both) AEs occurring during cycle 1, with an observation period of 1 to 49 days (minimum of 28 days) of study treatment. Further information on the DLT criteria is included in the supplemental Methods.

In the expansion phase, an additional 20 patients received CPX-351 plus venetoclax at the identified RP2D. Patients who achieved CR, CRi, or partial response (PR) after 1 or 2 induction cycles could receive additional cycles of CPX-351 and venetoclax at the discretion of the treating physician. Patients may have received up to 4 cycles of CPX-351 and venetoclax in the dose-exploration phase or up to 12 cycles (at dose level 1) or 8 cycles (at dose level 1b, depending on the R2PD) in the expansion phase. Patients with no response after 2 induction cycles were required to stop study treatment. Patients with CRi must have achieved hematologic recovery (absolute neutrophil count [ANC] ≥0.5 x 10⁹/L and platelets ≥50 x 10⁹/L) before progressing to the next cycle. For patients without active disease who required >14 days after completion of any 28-day cycle to achieve hematologic recovery, the duration of venetoclax was reduced by 7 days in the subsequent cycle. Patients who discontinued the study treatment were permitted to receive alternative treatment at the discretion of the treating physician. Bone marrow aspirate and biopsy were performed at the time of diagnosis and on day 28 of each cycle, with additional bone marrow evaluations performed as clinically indicated until a response (CR, CRi, PR, or no response) could be evaluated. If not already performed, all patients also had a final bone marrow evaluation after their last cycle of therapy, with assessment for measurable residual disease (MRD) if in CR/CRi.

Based on a previous PK study,²⁵ concomitant treatment with a strong cytochrome P450 3A (CYP3A) inhibitor was only permitted after the venetoclax dose ramp-up, with a dose reduction by 75%, whereas concomitant treatment with a moderate CYP3A inhibitor could be administered during or after venetoclax dose ramp-up, with a dose reduction by 50%.

The study period was from 9 October 2019 (first patient signed informed consent), to 24 September 2022 (last date of survival follow-up). The study was conducted in accordance with the protocol and consensus ethical principles derived from international guidelines, including the Declaration of Helsinki, applicable International Council for Harmonisation Good Clinical Practice Guidelines, and other applicable laws and regulations. Written informed consent was obtained from all patients before enrollment.

Eligible patients included those with newly diagnosed AML, histologically confirmed by the World Health Organization 2016 criteria,²⁶ characterized as unfit to receive intensive chemotherapy before the first day of therapy. Patients were deemed to be unfit if they were aged ≥75 years and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 or if they were aged ≥18 to 74 years and fulfilled at least 1 of the following criteria associated with lack of fitness for intensive chemotherapy: ECOG performance status 2 to 3; history of congestive heart failure requiring treatment or left ventricular ejection fraction ≤50%; diffusing capacity of the lung for carbon monoxide ≤65% or forced expiratory volume in 1 second ≤65%; creatinine clearance ≥30 mL/min to <45 mL/min as calculated by the Cockcroft-Gault formula; moderate hepatic impairment with total bilirubin >1.5× to ≤3.0× the upper limit of normal; or other comorbidity incompatible with conventional intensive chemotherapy. Key exclusion criteria included ECOG performance status >3, prior treatment for AML with the exception of hydroxyurea, prior treatment with HMA for an antecedent hematologic disorder, favorable risk cytogenetics, and cardiovascular disability status of New York Heart Association class >2. There were no exclusions based on prior anthracycline exposure.

The primary end point was to determine the RP2D and the safety and tolerability of the combination of CPX-351 plus venetoclax. AEs were coded using the Medical Dictionary for Regulatory Activities version 21.0 and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

Secondary end points included the proportion of patients who achieved CR, CRi, PR, and composite CR rate (defined as CR + CRi); the proportion of patients who achieved overall response rate (defined as CR + CRi + PR); and the proportion of patients who achieved CR/CRi with MRD status negative/positive (based on local laboratory results). MRD-negative status was defined as the achievement of CR/CRi and <0.1% leukemic cells at any measurement, as detected by multicolor flow cytometry (or equivalent threshold by another assay per institutional practice) of a bone marrow aspirate. Responses were assessed according to the 2017 European LeukemiaNet criteria.²⁷ PK parameters were also assessed, with blood collection for PK analysis conducted during the first and second cycles of therapy for all dose cohorts in the dose-exploration phase. Exploratory end points included OS and duration of remission at 1 year.

All analyses were completed using Statistical Analysis System version 9.4 or higher, except for PK, which was conducted using PK software (Phoenix WinNonlin version 6.4 or higher). All analyses were conducted in the safety analysis set, which included all patients who received at least 1 dose of CPX-351 or venetoclax. The Kaplan-Meier (KM) method was used to estimate OS. A post hoc analysis investigated whether the presence of a TP53 mutation affected the efficacy of lower-intensity CPX-351 plus venetoclax.

Overall, 35 patients were enrolled in the study and received dose level 1 (n = 4), dose level 2 (n = 7), or dose level 1b (n = 24). Patient characteristics are presented in Table 1. Most patients were male (sex assigned at birth) and White with de novo AML (n = 27 [77.1%]); more than half of the patients had poor-risk disease by the 2017 European LeukemiaNet disease risk classification (n = 19 [54.3%]); and almost one-quarter of patients had secondary AML (n = 8 [22.9%]). Mutational analysis demonstrated several gene mutations; the most common were TP53 (n = 8 [22.9%]) and ASXL1 (n = 7 [20.0%]). The median age across dose levels was 74.0 years (range, 59-90). A protocol deviation resulted in 1 patient with prior HMA therapy being included in the study. Of the 35 patients included in the study, 32 completed at least 1 treatment cycle. Three patients (8.6%) discontinued treatment before the completion of cycle 1 (1 each due to transition to hospice care, AE of respiratory failure and withdrawal of consent, and AE of liver injury).

No evaluable patients treated at dose level 1 (CPX-351 20 units/m² [daunorubicin 8.8 mg/m² and cytarabine 20 mg/m²] plus venetoclax 400 mg/d; 1 unit of CPX-351 is daunorubicin 0.44 mg plus cytarabine 1 mg) experienced a DLT. One of 6 evaluable patients treated at dose level 2 (CPX-351 40 units/m² [daunorubicin 17.6 mg/m² and cytarabine 40 mg/m²] plus venetoclax 400 mg/d) experienced 2 DLTs (a grade 3 serious AE of tumor lysis syndrome and a grade 3 nonserious AE of liver injury), and review of the overall safety profile led to a protocol amendment, which permitted de-escalation to dose level 1b (CPX-351 30 units/m² [daunorubicin 13.2 mg/m² and cytarabine 30 mg/m²] plus venetoclax 400 mg/d). Three patients subsequently received dose level 1b with no DLTs and a safety profile comparable with that of dose level 1. Together, these data established dose level 1b as the RP2D. Twenty-one additional patients were enrolled in the expansion phase at dose level 1b and were included in the safety and efficacy analyses.

Among patients who achieved CR/CRi, the median time to ANC recovery (≥0.5 × 10⁹/L; 30 days [interquartile range, 28-52], 32.5 days [interquartile range, 21-44], and 31 days [interquartile range 21-36]) and platelet recovery (≥50 × 10⁹/L; 21 days [interquartile range, 21-52], 22 days [interquartile range, 12-28], and 21 days [interquartile range, 21-28]) was generally similar across patients receiving dose levels 1, 2, and 1b, respectively.

Overall, 7 of 35 patients (20.0%) experienced treatment-emergent AEs (TEAEs) that led to treatment discontinuation, including treatment-related TEAEs of cardiac failure (related to CPX-351 only), decreased ejection fraction, liver injury, sinusitis, and tumor lysis syndrome (n = 1 [2.9%], each) and non–treatment-related TEAEs of disease progression, myocardial infarction, and respiratory failure (n = 1 [2.9%] each). In patients who achieved CR/CRi, AEs were an infrequent reason for treatment discontinuation (3/17 [17.6%]). A total of 2 patients (5.7%) experienced TEAEs related to venetoclax that led to a reduced duration of venetoclax by 7 days in the subsequent cycle: 1 patient experienced events of neutropenia and thrombocytopenia (of note, this patient had a protocol deviation, receiving 8 additional days of venetoclax during cycle 1), and 1 patient experienced an event of neutropenia. There were 10 patients (28.6%) who experienced TEAEs that led to treatment interruption, with the most frequent TEAE (experienced by 4 patients) that led to treatment interruption being febrile neutropenia.

The most common TEAEs (occurring in ≥20% of all patients) by dose level are shown in Table 2. The most frequently reported TEAEs by preferred term were nausea (15/35 [42.9%]), thrombocytopenia (14/35 [40.0%]), febrile neutropenia (13/35 [37.1%]), and neutropenia (12/35 [34.3%]. Nausea events were grade 1 or 2, but the events of thrombocytopenia, febrile neutropenia, and neutropenia were all grade ≥3.

There were no deaths on or before day 30. The incidence of early mortality by day 60 was 11.4% due to 1 death in the dose level 1 cohort (non–treatment-related myocardial infarction) and 3 deaths in the dose level 1b cohort (worsening lung infection, which was considered related to both CPX-351 and venetoclax [n = 1]; disease relapse/disease progression [n = 2]).

In the overall population, CR/CRi was achieved by 17 of 35 patients (48.6%), all after cycle 1. Four patients in the study had an unknown/missing response because they discontinued before completing cycle 1 either due to AEs or patient/physician decision and, therefore, were not evaluable for response. Overall, CR/CRi was achieved by 17 of 31 evaluable patients (54.8%). Of those with CR/CRi, most achieved a best response of CR (16/17 [94.1%]; Table 3). One patient had a PR; therefore, the overall response rate was 51.4% (18/35). MRD negativity was achieved by 14 of 17 patients (82.4%) with CR/CRi (supplemental Figure 1); of these, 9 achieved CR/CRi with MRD negativity after cycle 1, 2 after cycle 2, and 1 each after cycle 3, early termination (after cycle 2), and end of treatment (after cycle 4). The clinical course of individual patients who achieved CR/CRi is presented in the supplemental Figure 1.

Response data by dose level are presented in Table 3. Given that TP53 is associated with venetoclax resistance and poor outcomes,^16,17 we conducted a post hoc analysis by TP53 mutation status. Among patients with wild-type TP53 (n = 26), CR/CRi was achieved by 15 patients (57.7%), with most achieving CR (n = 14 [53.8%]). Among patients with mutated TP53 (n = 8), CR was achieved by 1 patient (12.5%), and 1 patient had a PR. TP53 mutation status for 1 patient was not available.

Treatment beyond 1 cycle of CPX-351 plus venetoclax was at the discretion of the treating physician; overall, 13 patients (37.1%) received 1 cycle, 9 (25.7%) received 2 cycles, 2 (5.7%) received 3 cycles, 7 (20.0%) received 4 cycles, and 1 (2.9%) received 5 cycles. Two patients proceeded to hematopoietic cell transplantation (HCT).

For the overall population, the KM estimate of OS rate at 1 year was 40%, and the median OS was 9.1 months (95% confidence interval, 6.2 to not estimable [NE]; supplemental Figure 2).

In patients who achieved CR/CRi, the KM estimate of duration of remission rate at 1 year was 71%, and the median time in remission (first quartile, third quartile) was NE (185 days, NE).

The PK data (supplemental Figures 3-5) were consistent with the known PK of the standard dose of CPX-351 and venetoclax.^28,29 

In this study, we investigated the safety, efficacy, and PK of the combination of lower-intensity CPX-351 plus venetoclax as induction therapy in adults with newly diagnosed AML considered unfit for intensive chemotherapy. An RP2D of CPX-351 30 units/m² (daunorubicin 13.2 mg/m² and cytarabine 30 mg/m²) on days 1 and 3 plus venetoclax 400 mg on days 2 to 21 of each cycle was established, which is ∼30% of the standard dose of CPX-351 administered for intensively treated AML. The PK data demonstrated that the synergistic ratio of daunorubicin and cytarabine was maintained, and the observations with lower-intensity CPX-351 were consistent with the PK of the standard dose.^28,29 

The lower-intensity CPX-351 plus venetoclax regimen only requires 2 days of IV infusion, compared with the HMA plus venetoclax regimens of 7 days with azacitidine or 5 days with decitabine,²⁴ and as such, it may be less resource intensive and more convenient for patients and their caregivers. Treatment was generally well tolerated, with patients who achieved CR/CRi experiencing prompt ANC and platelet recovery at a median of 31 days and 21 days, respectively. In contrast, hematologic recovery for patients treated with azacitidine and venetoclax typically occurs between 25 and 42 days.³⁰ The safety profile of the combination was consistent with the known safety profiles of CPX-351 and venetoclax, with the most common AEs being gastrointestinal and hematologic events.^2,5,6 Furthermore, in this study, venetoclax was administered on days 2 to 21 of each cycle, and patients rarely needed to decrease the duration of venetoclax for hematologic toxicity.

In a previous phase 2 trial investigating lower doses of CPX-351 at 32 or 64 units/m² in less fit patients with untreated AML, CR + CRi rates were modest at 29% and 20%, respectively, indicating a limited benefit as a single agent in this patient population.³¹ However, the results of this study in a population in which over half of patients (54%) had poor-risk disease and almost one-quarter of patients (23%) had secondary AML suggest that combining lower-intensity CPX-351 with venetoclax results in greater improvements. CR/CRi was achieved in 49% of patients after 1 treatment cycle, and the majority of these patients (94%) achieved a best response of CR. In a post hoc analysis, this combination therapy demonstrated particular efficacy in patients with wild-type TP53, with high rates of CR/CRi (58%). In contrast, responses in patients with mutant TP53 were poor, with only 1 of 8 patients achieving CR. The results of the TP53 population in this study were consistent with a post hoc analysis of patients with TP53 mutations in the pivotal CPX-351 phase 3 trial.³² Furthermore, in CPX-351 real-world studies, although remission rates and survival were poorer among patients with vs without mutated TP53 in some studies,^33-36 particularly those with concomitant complex karyotype,³⁷ CPX-351 did benefit some patients with mutated TP53.^38-40 Additionally, patients with TP53 mutations are known to be resistant to venetoclax treatment, and available data have not demonstrated a survival benefit for patients with mutated TP53 treated with venetoclax-based combination chemotherapy.^16,41 This patient subset remains a challenging population to treat, and alternative approaches continue to be required .

In contrast to patients treated with azacitidine and venetoclax in the VIALE-A study, in which there was a lower rate of CR and a much higher proportion of patients achieving CRi,⁵ nearly all observed responses in this study were true CRs. Notably, most patients (82%) who achieved a CR/CRi in this study also achieved MRD negativity, which was often reached after only 1 treatment cycle. Achievement of CR, and in particular CR with MRD negativity, in AML is associated with improved OS compared with those achieving CRi.⁴² Moreover, achievement of MRD negativity would be expected to improve outcomes after HCT.⁴³ Although CRi is typically included in response end points for clinical trials per consensus recommendations,⁴ it has not been accepted for regulatory decisions in AML based on the lack of adequate hematologic recovery, decreased likelihood of MRD, and poorer outcomes than CR.^13,42,44 

A randomized study would be needed for any direct comparisons of lower-intensity CPX-351 plus venetoclax vs HMA plus venetoclax as induction therapy, and further studies may identify additional patient subsets who would benefit from this treatment regimen, such as those with myelodysplastic syndrome or AML who have progressed after treatment with an HMA. Additionally, this combination may be considered to allow for patients to achieve MRD negativity before proceeding to HCT, although typically patients with MRD-negative status are not considered candidates for transplant,⁴³ or to maintenance therapy for patients with prior HMA and/or venetoclax treatment. This study excluded patients with prior HMA exposure, aligned with the eligibility criteria used in other clinical studies involving HMA plus venetoclax.^5,45 Although previous studies have not shown improved outcomes for patients with prior HMA exposure who were treated with CPX-351,^46,47 a lower dose of CPX-351 with venetoclax could be explored, given the continued unmet need for these patients.^5,45,48 

Several limitations exist in the interpretation of this study. MRD assessments were performed locally and lacked standardization in terms of methodology and sensitivity. Although the KM estimate of OS rate at 1 year was 40% and is less than what has been reported for azacitidine and venetoclax (74%),⁵ this study was not designed to evaluate long-term outcomes. Rather, this study was designed to evaluate the impact of lower-intensity CPX-351 plus venetoclax as initial induction therapy, and post-remission therapy was at the discretion of the treating physician, including additional cycles of CPX-351 plus venetoclax, HMA with or without venetoclax, or allogeneic HCT.

In conclusion, the results of this study suggest that the use of lower-intensity CPX-351 plus venetoclax represents a well-tolerated alternative for induction therapy to HMA plus venetoclax for AML without TP53 mutations in older patients and adults not eligible for intensive chemotherapy. The study also supports the rationale for exploring CPX-351 plus venetoclax combinations at other doses and schedules and in other patient populations, including younger adults who are candidates for intensive chemotherapy.

This study was sponsored by Jazz Pharmaceuticals. Medical writing support, under the direction of the authors, was provided by Angharad Morgan and Trina Soluta; and editorial support by Ottilie Gildea of CMC Affinity, a division of IPG Health Medical Communications, with funding from Jazz Pharmaceuticals, in accordance with Good Publication Practice (2022) guidelines.

Contribution: E.S.W., Q.W., S.F., and R.S.C. contributed to study conceptualization; Q.W. contributed to data curation; Q.W. and D.M. contributed to the formal analysis of the data; G.L.U., V.P., P.B., R.K.S., R.B.W., E.S.W., D.C., R.S.C., and T.L.L. contributed to the study investigation; G.L.U., Q.W., and R.S.C. contributed to the methodology; S.F., D.C., and R.S.C. contributed to project administration; G.L.U., V.P., P.B., and R.B.W. contributed study resources; V.P., P.B., S.F., D.M., and R.S.C. supervised the study; V.P., S.F., D.C., and R.S.C. contributed to study validation; V.P. and T.L.L. contributed to study visualization; G.L.U. and R.S.C. contributed to the writing and original draft preparation of the manuscript; D.C. and R.S.C. directly accessed and verified the underlying data reported in the manuscript; and all authors contributed to the writing, review, and editing of the manuscript and were responsible for the decision to submit the manuscript.

Conflict-of-interest disclosure: G.L.U. has received consulting fees from and has participated on a data safety monitoring board or advisory board for Jazz Pharmaceuticals. V.P. has received consulting fees and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from AbbVie and Jazz Pharmaceuticals; and has participated on a data safety monitoring board or advisory board for AbbVie. P.B. has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Bristol Myers Squibb and Rigel Pharma; and participated on a data safety monitoring board or advisory board for Kite Pharma, ONO Pharma, and Protagonist Therapeutics. R.K.S. declares no competing financial interests. R.B.W. received clinical trial support from Jazz Pharmaceuticals. E.S.W. has participated on a data safety monitoring board or advisory board for Curis and Takeda. Q.W. was an employee of Jazz Pharmaceuticals at the time of the study and holds stock ownership in Jazz Pharmaceuticals. S.F. is an employee of and holds stock ownership/options in and participated on a data safety monitoring board for Jazz Pharmaceuticals. D.C. and R.S.C. are employees of, hold stock ownership/options in, received support for meetings/conferences and travel from, and participated on a data safety monitoring board for Jazz Pharmaceuticals. D.M. was an employee of Jazz Pharmaceuticals at the time of the study and received stock options in Jazz Pharmaceuticals. T.L.L. has received funding (with payments made directly to her institution) from Jazz Pharmaceuticals; grants or contracts (with payments made directly to her institution) from Aptevo, Astellas Pharma, Biopath Holdings, Ciclomed, Cleave, Kura Oncology, Leukemia & Lymphoma Society, and Trovagene; and has participated in an advisory board with Servier.

The current affiliation for Q.W. is Enliven Therapeutics, Boulder, CO.

Correspondence: Geoffrey L. Uy, Division of Oncology, Mail Stop 8007-0029-11, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110; email: guy@wustl.edu.