Abstract
Purpose:
The NCI-COG Pediatric MATCH trial assigns patients age 1 to 21 years with refractory malignancies to phase 2 treatment arms of molecularly-targeted therapies based on genetic alterations detected in their tumor. Patients with activating alterations in the MAPK pathway were treated with ulixertinib, an ERK1/2 inhibitor.
Methods:
As there were no prior pediatric data, ulixertinib was initially tested in a dose escalation cohort to establish the recommended phase 2 dose (RP2D) before proceeding to the phase 2 cohort. Ulixertinib was administered at 260 mg/m2/dose PO BID (dose level 1, DL1, n=15) or 350 mg/m2/dose PO BID (DL2, n=5). The primary endpoint was objective response rate; secondary endpoints included safety/tolerability and progression-free survival (PFS).
Results:
Twenty patients (median 12 years; range 5–20) were treated, all evaluable for response. CNS tumors comprised 55% (11/20) of diagnoses with high-grade glioma and low-grade glioma most common (n=5 each). All CNS tumors except one harbored BRAF fusions or V600E mutations. Rhabdomyosarcoma (n=5) was the most frequent non-CNS diagnosis. DL1 was declared the RP2D in the dose escalation cohort after dose limiting toxicities (DLTs) in Cycle 1 occurred in 1/6 patients at DL1 and 2/5 patients at DL2, including fatigue, anorexia, rash, nausea, vomiting, diarrhea, dehydration, hypoalbuminemia, and hypernatremia. No objective responses were observed. Six-month PFS was 37% (95% CI: 17%, 58%). Three patients with BRAF-altered CNS tumors achieved stable disease > 6 months.
Conclusion:
Ulixertinib, a novel targeted agent with no prior pediatric data, was successfully evaluated in a national precision medicine basket trial. The pediatric RP2D of ulixertinib is 260 mg/m2/dose PO BID. Limited single-agent efficacy was observed in a biomarker-selected cohort of refractory pediatric tumors.
Context Summary
Key Objective
The National Cancer Institute-Children’s Oncology Group Pediatric Molecular Analysis for Therapy Choice (Pediatric MATCH) trial is a national platform trial that assigns patients age 1 to 21 years with refractory malignancies to molecularly-targeted therapies based on tumor genetic testing. Treatment Arm J of Pediatric MATCH evaluated the objective response rate of ulixertinib, an oral ERK inhibitor, in children and young adults with tumors harboring activating MAPK alterations.
Knowledge Generated
As there were no prior pediatric data, Arm J established the pediatric recommended phase 2 dose of ulixertinib. No objective responses were seen; three patients with BRAF-altered brain tumors (low-grade glioma and low-grade neuroglial tumor) achieved stable disease > 6 months.
Relevance
Ulixertinib, a novel targeted agent with no prior pediatric data, was successfully evaluated in a national precision medicine basket trial. Limited single-agent activity was observed in a biomarker-selected cohort of refractory pediatric tumors.
INTRODUCTION
Aberrant activation of the mitogen-activated protein kinase (MAPK) pathway is frequently observed in cancer and is responsible for controlling multiple key physiological processes, making it an attractive therapeutic target. Components of the MAPK pathway often undergo genetic mutation, causing constitutive activation of the signaling cascade. This commonly occurs through gain-of-function mutations in genes encoding RAS and RAF family members as well as by loss of NF1.1
There is clinical evidence supporting diverse MAPK gene alterations as biomarkers for response to RAF and/or MEK inhibitors in adult malignancies, including activating RAS gene mutations (NRAS/KRAS/HRAS)2,3, activating BRAF mutations (V600E and others) and fusions4–6, GNAQ and GNA11 activating mutations7; and loss of NF1 through inactivating mutations or insertion/deletion8. MAPK pathway alterations are also observed in pediatric and young adult cancers,9–17 with evidence of clinical activity of MAPK inhibitors in several pediatric cancer types.18–21
Reactivation of ERK signaling is a common driver of resistance following treatment with BRAF and/or MEK-inhibitors and the clinical development of ERK inhibitors is of considerable interest.22,23 Ulixertinib (BVD-523) is a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and selectivity. The phase 1 dose escalation and dose expansion study of single-agent ulixertinib (NCT01781429) determined the adult recommended phase 2 dose (RP2D) to be 600 mg by mouth twice daily.24 Dose-limiting toxicities (DLT) included rash, diarrhea, elevated AST, and elevated creatinine. Evidence of clinical activity was observed, with partial responses in 11 of 81 (14%) patients with solid tumors in the expansion phase of the trial including patients with NRAS hotspot mutations and both V600 and non-V600 mutations in BRAF. Nearly 50% (9/19) of patients with BRAF-mutant melanomas that had been refractory to prior BRAF and/or MEK inhibitor treatment had either a partial response or stable disease to ulixertinib. A partial response was also observed in one patient with BRAF V600E glioblastoma multiforme, providing evidence for central nervous system (CNS) activity of the agent. There have been no prior studies of ulixertinib or other ERK inhibitors in a pediatric population.
The National Cancer Institute-Children’s Oncology Group Pediatric Molecular Analysis for Therapy Choice (NCI-COG Pediatric MATCH) trial was activated in July 2017 to provide a national framework for histology-agnostic trials of molecularly targeted therapies in biomarker-selected populations.25,26 Here, we report the results of Arm J of Pediatric MATCH in which patients with tumors harboring alterations in the MAPK signaling pathway were treated with the ERK inhibitor ulixertinib (NCT03698994).
METHODS
Patient Eligibility
Patients were eligible for participation in the NCI-COG Pediatric MATCH screening trial if they were 1 to 21 years old with treatment-refractory or recurrent solid tumors, non-Hodgkin lymphomas, or histiocytic disorders treated at US-based COG sites.26 Both the screening protocol and all treatment subprotocols were approved by the NCI Central Institutional Review Board. Written informed consent (and assent when applicable) was obtained for all patients.
Formalin-fixed paraffin-embedded tumor specimens obtained at any time of refractory/recurrent disease were required to determine treatment arm eligibility and subjected to DNA- and RNA-based testing in centralized MATCH laboratories using an Oncomine AmpliSeq cancer gene panel (Thermo Fisher Scientific, Waltham, MA) designed for detection of single-nucleotide variants, insertions and deletions, amplifications, and selected fusions as previously described.27 Blood samples were also sequenced using the same DNA panel to identify germline variants, but was not used to determine treatment regimens. If an actionable tumor genetic alteration was detected, patients were assigned to a Pediatric MATCH treatment subprotocol.26
Specific actionable alterations for all patients on Arm J (ulixertinib) were defined in ARAF, BRAF, HRAS, NRAS, KRAS, MAPK1, MAP2K1, GNA11, GNAQ, and NF1 (Appendix Table A1). Patients with tumors harboring a BRAF V600 mutation were preferentially assigned to a separate MATCH subprotocol (Arm G) evaluating the BRAF-V600E inhibitor vemurafenib. Patients with tumors harboring an actionable MAPK pathway mutation who previously had not received treatment with a MEK inhibitor were preferentially assigned to subprotocol (Arm E) evaluating selumetinib until study closure in September 2020.28
Any tumor histology was eligible for Arm J, including patients with low-grade glioma (LGG), who were excluded from assignment to Arms G and E given that prior clinical trials of vemurafenib and selumetinib for children with LGG had already demonstrated activity.28,29 Additional eligibility criteria for treatment included age ≥ 12 months and ≤ 21 years, Karnofsky or Lansky performance score ≥ 50%, radiographically measurable disease or MIBG-evaluable disease if patient had neuroblastoma, body surface area ≥ 0.54 m2, ability to swallow intact capsules, and adequate organ function. Patients were excluded if they had a history of known significant ophthalmologic conditions, uncontrolled infection, or concomitant use of CYP3A4/CYP2D6/CYP1A2-inducing or -inhibiting agents.
Treatment
As there were no prior pediatric data, ulixertinib was initially tested in a dose escalation cohort to establish the RP2D before proceeding with enrollment to the primary phase 2 cohort. Ulixertinib was administered orally twice daily (PO BID) per protocol dosing nomogram (Appendix Table A2). The pediatric starting dose was 75% of the adult RP2D. Two dose levels were evaluated: (1) 260 mg/m2/dose (max 450 mg) PO BID and (2) 350 mg/m2/dose (max 600 mg) PO BID. Each cycle lasted 28 days. Patients were eligible to receive therapy for up to 2 years if there was no evidence of progressive disease or toxicity that met protocol-defined criteria for discontinuation of therapy.
Adverse Events and Dose Modifications
Adverse events (AEs) were reported according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. All patients who received at least one dose of protocol therapy were considered evaluable for toxicity. In addition, for the dose escalation portion during Cycle 1, patients without DLT must have received at least 85% of the prescribed dose to be considered evaluable for DLT for the purpose of determining dose escalation and defining the RP2D. Patients enrolled in the dose escalation cohort who did not receive the prescribed dose during Cycle 1 were replaced for the dose escalation portion. DLT was defined differently for hematologic and non-hematologic toxicity. Of note, allergic reaction that necessitated discontinuation of study drug was not considered a DLT. Treatment could be withheld for DLTs for up to 14 days. If the DLT resolved to baseline or eligibility parameters within 14 days of discontinuing therapy, the patient could resume ulixertinib at a reduced dose; if not, the patient was removed from protocol therapy. If a recurrent or second DLT occurred at a reduced dose of ulixertinib, the patient was removed from protocol therapy.
Measurement of Response
Any eligible patient who received at least one dose of protocol therapy in either the dose escalation or the primary cohort was evaluable for response. Tumor disease evaluations were obtained every other cycle for three occurrences, and then every three cycles. For documentation of objective response (complete response [CR] or partial response [PR]), confirmatory scans were required after the next consecutive cycle. The revised RECIST version 1.1 was used to determine response, with specific criteria outlined for CNS tumors (RANO), non-CNS solid tumors, lymphomas, and histiocytoses.30,31 Central review was required for any patient who was deemed to have a CR or PR and was used to determine final assessment of response.
Pharmacokinetic Studies
Optional pharmacokinetics (PK) studies of ulixertinib were performed in subjects who consented. In Cycle 1, blood samples were drawn on day 1 (pre-dose, 1, 2, 4, 6–8, and 24 hours after dose), day 15 (pre-dose, 1, 2, 4, and 6–8 after dose), and day 22 (pre-dose). Ulixertinib plasma concentrations were determined using a validated liquid chromatography, tandem mass spectrometry method by Covance Laboratories, Inc. (Madison, WI). Ulixertinib PK parameters were estimated by standard noncompartmental analysis using the program Phoenix® WinNonlin® Version 6.4 (Certara Corporation, Princeton, NJ).
Statistical Considerations
An initial dose escalation using a Rolling 6 design was used to establish a pediatric RP2D.32 This was followed by enrollment of patients treated at the pediatric RP2D into the primary cohort of the phase 2 portion of the study. The primary endpoint was to determine the objective response rate and included patients in both the dose escalation and primary cohorts. The primary study cohort used a single-stage design with a minimum of 20 patients. The overall response rate was compared against a null benchmark value of 5%. The study design had 90% power (alpha = 10%) to detect a 20% improvement in response rates (from 5% to 25%) if the agent was sufficiently active to warrant further study.
The secondary endpoints included progression-free survival (PFS) and PK of ulixertinib. PFS was defined as time from initiation of protocol therapy until the occurrence of disease progression, disease recurrence, or death from any cause by institutional review. PFS along with the 95% confidence intervals was estimated using the Kaplan-Meier method. Chi-square tests (or Fisher’s exact tests as appropriate) were used to evaluate the association between patient’s baseline characteristics and treated/untreated cohorts. PK parameters were analyzed with summary statistics, including means, and standard deviations. All statistical analyses were done in SAS (version 9.4) or R (version 4.0).
RESULTS
Patient Characteristics
Sixty patients were matched to Arm J; twenty patients were enrolled and initiated therapy on Arm J between November 2018 and March 2021 (Figure 1). The most common reasons provided for subjects who were matched but did not enroll were: “on other treatment” (n=13) or “family/physician preference” (n=10). All 20 patients enrolled in Arm J were treated and evaluable for response and toxicity. Data as of March 31, 2022 were used in the manuscript.
Figure 1.
Patient flow diagram of NCI-COG Pediatric MATCH Arm J. Other reasons for ineligibility were age > 22 years (n=2), liver function test abnormalities, known ophthalmologic condition, and inadequate platelet count (n=1 each).
Characteristics of matched (n=60) and treated (n=20) patients, including diagnoses, are shown in Table 1. Patients receiving therapy ranged in age from 5 to 20 years (median: 12 years). No demographic differences were noted between the treated and untreated patient cohorts (Table 1). Among all matched patients, LGG (22/60, 37%), rhabdomyosarcoma (RMS; 16/60, 27%), and high-grade glioma (HGG; 9/60, 15%) were most common. In treated patients, HGG and LGG were most frequent (n=5 each), with CNS tumors overall comprising 55% (11/20) of diagnoses. RMS (5/20, 25%) was the most frequent non-CNS diagnosis. Prior treatment with BRAF and/or MEK inhibitors was reported for six (6/20, 30%) patients treated on Arm J (Appendix Table A3), all with CNS tumors, including one patient whose tumor had previously progressed on treatment with selumetinib on Pediatric MATCH Arm E.
Table 1.
NCI-COG Pediatric MATCH trial patient characteristics
| Treated | Overall | p-value | ||
|---|---|---|---|---|
|
| ||||
| Characteristics | Yes (N=20) | No (N=40) | Matched patients (N=60) | |
|
| ||||
| Sex | 0.58 | |||
| Female | 9 (45%) | 21 (52%) | 30 (50%) | |
| Male | 11 (55%) | 19 (48%) | 30 (50%) | |
| Median age, years (range) | 12 [4, 20] | 11[3, 21] | 11 [3, 21] | |
| Age categories, years | 0.36 | |||
| <5 years | 1 (5%) | 8 (20%) | 9 (15%) | |
| ≥5 years and <15 years | 13 (65%) | 21 (53%) | 34 (57%) | |
| ≥15 years | 6 (30%) | 11 (28%) | 17 (28%) | |
| Race | 0.69 | |||
| White | 16 (80%) | 30 (75%) | 46 (77%) | |
| Black or African American | 0 (0%) | 2 (5%) | 2 (3%) | |
| Asian | 0 (5%) | 2 (5%) | 2 (3%) | |
| Native Hawaiian or Other Pacific Islander | 0 (0%) | 1 (3%) | 1 (2%) | |
| Not Reported/Unknown | 4 (20%) | 5 (13%) | 9 (15%) | |
| Ethnicity | 0.72 | |||
| Not Hispanic or Latino | 14 (70%) | 30 (75%) | 44 (73%) | |
| Hispanic or Latino | 4 (20%) | 8 (20%) | 12 (20%) | |
| Not Reported/Unknown | 2 (10%) | 2 (5%) | 4 (7%) | |
| Diagnosis | 0.58 | |||
| Low grade glioma | 5 (25%) | 17 (43%) | 22 (37%) | |
| Rhabdomyosarcoma | 5 (25%) | 11 (28%) | 16 (27%) | |
| High grade glioma | 5 (25%) | 4 (10%) | 9 (15%) | |
| Othera | 2 (10%) | 2 (5%) | 4 (7%) | |
| Carcinoma | 1 (5%) | 2 (5%) | 3 (5%) | |
| Undifferentiated sarcoma | 1 (5%) | 1 (3%) | 2 (3%) | |
| MPNST | 0 (0%) | 2 (5%) | 2 (3%) | |
| Plexiform neurofibroma | 1 (5%) | 1 (3%) | 2 (3%) | |
NOTE: The table reflects data collected at screening enrollment. Data are reported as number of patients (%) unless otherwise indicated.
Abbreviations: MPNST, malignant peripheral nerve sheath tumor.
Other diagnoses in the treated cohort were glioneuronal tumor and pancreatoblastoma (n=1 each). Other diagnoses in the untreated cohort were hepatoblastoma and Wilms tumor (n=1 each).
Landscape of MAPK Pathway Alterations in Arm J
The range of actionable alterations identified in the 20 treated patients is shown in Figure 2 and Appendix Table A3. BRAF alterations were detected in 10 patients (4 fusions and 6 V600E), hotspot NRAS or KRAS mutations in 7 patients, and NF1 alterations in 4 patients. Only one tumor had two different MAPK alterations: a HGG with KRAS and NF1 mutations (variant allele fractions of 0.14 and 0.17, respectively). All other CNS tumors harbored BRAF fusions or V600 mutations. NRAS mutations were detected in 4 out of 5 RMS cases. Non-MAPK pathway tumor alterations were also detected in 7 (7/20, 35%) tumors (Figure 2, Appendix Table A3) including PIK3CA mutations in two patients with RMS. Two of the tumor mutations were also detected in patient-matched germline samples: TP53 (in a 12-year-old with undifferentiated sarcoma) and CHEK2 (in a 20-year-old with HGG).
Figure 2.
Diagnoses and MAPK pathway mutations detected in Arm J patients (20 patients, N=21 mutations). MAPK pathway alterations by gene are indicated for each patient (each column represents a patient). Actionable MAPK pathway alterations are in the top rows of the figure (KRAS mutation to BRAF fusion); other cancer gene alterations identified by the tumor panel testing are listed in the rows below.
*Tumor mutations identified in patient-matched blood (germline) samples.
**One patient each: glioneuronal tumor, plexiform neurofibroma, pancreatoblastoma, carcinoma, undifferentiated sarcoma
Abbreviations: HGG, high-grade glioma; LGG, low-grade glioma; RMS, rhabdomyosarcoma
Dose Escalation and Toxicity
Of the 20 patients evaluable for toxicity, 12 experienced a grade 3 or higher AE potentially related to ulixertinib (Table 2). Eight patients enrolled at dose level 1 (DL1), 260 mg/m2/dose PO BID; including 2 patients who did not receive 85% of the prescribed dose thus were inevaluable for DLT and replaced (due to progressive disease in one patient and an allergic reaction [Stevens-Johnson syndrome] in another patient). One out of 6 patients enrolled on DL1 had a DLT of diarrhea in Cycle 1, therefore, dose level 2 (DL2) 350 mg/m2/dose PO BID began enrollment. In DL2, Cycle 1 DLTs in 2 of 5 patients included a patient with hypernatremia and hypoalbuminemia and another with nausea, dehydration, and fatigue. The pediatric RP2D was determined to be 260 mg/m2/dose PO BID (75% of the adult RP2D). Seven additional patients received ulixertinib at the pediatric RP2D in the primary cohort; 4 patients had Cycle 1 DLTs, including: intolerable rash; prolonged nausea, vomiting, and fatigue; hypoalbuminemia; and anorexia and nausea. Overall, 38% (5/13) patients treated with ulixertinib 260 mg/m2/dose BID experienced a Cycle 1 DLT. Dose-limiting toxicities experienced by all patients during all cycles of protocol therapy are summarized in Appendix Table A4.
Table 2.
All adverse events associated with the protocol treatment (with attribution possible, probable, or definite) according to CTCAE v5.0
| Dose Level and Toxicity Grade, No. (%) | ||||||
|---|---|---|---|---|---|---|
| All Dose Level (N=20) | Dose Level 1 260 mg/m2 (N=15) |
Dose Level 2 350 mg/m2 (N=5) |
||||
| Toxicity Type | All | ≥ 3 | All | ≥ 3 | All | ≥ 3 |
| Abdominal distension | 1 (5.0) | 1 (6.7) | ||||
| Abdominal pain | 5 (25.0) | 3 (20.0) | 2 (40.0) | |||
| Alanine aminotransferase increased | 6 (30.0) | 1 (5.0) | 4 (26.7) | 2 (40.0) | 1 (20.0) | |
| Alkaline phosphatase increased | 2 (10.0) | 1 (6.7) | 1 (20.0) | |||
| Allergic reaction | 1 (5.0) | 1 (6.7) | ||||
| Alopecia | 2 (10.0) | 2 (13.3) | ||||
| Anemia | 9 (45.0) | 3 (15.0) | 7 (46.7) | 1 (6.7) | 2 (40.0) | 2 (40.0) |
| Anorexia | 4 (20.0) | 1 (5.0) | 2 (13.3) | 1 (6.7) | 2 (40.0) | |
| Arthralgia | 1 (5.0) | 1 (6.7) | ||||
| Aspartate aminotransferase increased | 8 (40.0) | 1 (5.0) | 4 (26.7) | 1 (6.7) | 4 (80.0) | |
| Blood bicarbonate decreased | 1 (5.0) | 1 (6.7) | ||||
| Blood bilirubin increased | 2 (10.0) | 2 (13.3) | ||||
| Blurred vision | 1 (5.0) | 1 (20.0) | ||||
| Cheilitis | 1 (5.0) | 1 (6.7) | ||||
| Cholecystitis | 1 (5.0) | 1 (5.0) | 1 (6.7) | |||
| Colitis | 1 (5.0) | 1 (6.7) | ||||
| Confusion | 1 (5.0) | 1 (6.7) | ||||
| Constipation | 1 (5.0) | 1 (20.0) | ||||
| Creatinine increased | 6 (30.0) | 1 (5.0) | 5 (33.3) | 1 (6.7) | 1 (20.0) | |
| Dehydration | 4 (20.0) | 2 (10.0) | 3 (20.0) | 1 (6.7) | 1 (20.0) | 1 (20.0) |
| Delirium | 1 (5.0) | 1 (20.0) | ||||
| Diarrhea | 9 (45.0) | 1 (5.0) | 7 (46.7) | 1 (6.7) | 2 (40.0) | |
| Dizziness | 5 (25.0) | 4 (26.7) | 1 (20.0) | |||
| Dry skin | 1 (5.0) | 1 (6.7) | ||||
| Dyspepsia | 1 (5.0) | 1 (6.7) | ||||
| Dyspnea | 1 (5.0) | 1 (6.7) | ||||
| Edema face | 2 (10.0) | 2 (13.3) | ||||
| Edema limbs | 2 (10.0) | 2 (13.3) | ||||
| Eosinophilia | 2 (10.0) | 1 (6.7) | 1 (20.0) | |||
| Epistaxis | 1 (5.0) | 1 (6.7) | ||||
| Erythema multiforme | 1 (5.0) | 1 (6.7) | ||||
| Eye infection | 1 (5.0) | 1 (6.7) | ||||
| Fatigue | 8 (40.0) | 2 (10.0) | 6 (40.0) | 1 (6.7) | 2 (40.0) | 1 (20.0) |
| Fecal incontinence | 1 (5.0) | 1 (20.0) | ||||
| Fever | 3 (15.0) | 2 (13.3) | 1 (20.0) | |||
| Flank pain | 1 (5.0) | 1 (20.0) | ||||
| Generalized edema | 1 (5.0) | 1 (6.7) | ||||
| Headache | 3 (15.0) | 2 (13.3) | 1 (20.0) | |||
| Hip fracture | 1 (5.0) | 1 (5.0) | 1 (20.0) | 1 (20.0) | ||
| Hyperglycemia | 5 (25.0) | 5 (33.3) | ||||
| Hypermagnesemia | 2 (10.0) | 1 (6.7) | 1 (20.0) | |||
| Hypernatremia | 1 (5.0) | 1 (5.0) | 1 (20.0) | 1 (20.0) | ||
| Hyperphosphatemia | 3 (15.0) | 1 (6.7) | 2 (40.0) | |||
| Hypoalbuminemia | 11 (55.0) | 3 (15.0) | 7 (46.7) | 2 (13.3) | 4 (80.0) | 1 (20.0) |
| Hypocalcemia | 9 (45.0) | 5 (33.3) | 4 (80.0) | |||
| Hypoglycemia | 1 (5.0) | 1 (6.7) | ||||
| Hypokalemia | 3 (15.0) | 3 (20.0) | ||||
| Hypomagnesemia | 2 (10.0) | 1 (6.7) | 1 (20.0) | |||
| Hyponatremia | 3 (15.0) | 2 (13.3) | 1 (20.0) | |||
| Hypophosphatemia | 1 (5.0) | 1 (20.0) | ||||
| Hypotension | 2 (10.0) | 1 (6.7) | 1 (20.0) | |||
| INR increased | 1 (5.0) | 1 (6.7) | ||||
| Immune system disorders - Other, specify | 1 (5.0) | 1 (6.7) | ||||
| Lipase increased | 1 (5.0) | 1 (5.0) | 1 (6.7) | 1 (6.7) | ||
| Lymphocyte count decreased | 3 (15.0) | 2 (10.0) | 2 (13.3) | 1 (6.7) | 1 (20.0) | 1 (20.0) |
| Mucositis/stomatitis (functional/symptomatic) - Oral cavity | 3 (15.0) | 3 (20.0) | ||||
| Nausea | 8 (40.0) | 4 (20.0) | 5 (33.3) | 3 (20.0) | 3 (60.0) | 1 (20.0) |
| Neutrophil count decreased | 2 (10.0) | 2 (13.3) | ||||
| Pancreatitis | 1 (5.0) | 1 (6.7) | ||||
| Papulopustular rash | 1 (5.0) | 1 (6.7) | ||||
| Paronychia | 1 (5.0) | 1 (6.7) | ||||
| Platelet count decreased | 5 (25.0) | 1 (5.0) | 4 (26.7) | 1 (6.7) | 1 (20.0) | |
| Pruritus | 2 (10.0) | 2 (13.3) | ||||
| Rash acneiform | 2 (10.0) | 1 (6.7) | 1 (20.0) | |||
| Rash maculo-papular | 8 (40.0) | 2 (10.0) | 6 (40.0) | 2 (13.3) | 2 (40.0) | |
| Respiratory, thoracic and mediastinal disorders - Other, specify | 1 (5.0) | 1 (6.7) | ||||
| Sepsis | 1 (5.0) | 1 (5.0) | 1 (6.7) | 1 (6.7) | ||
| Sinus tachycardia | 1 (5.0) | 1 (20.0) | ||||
| Skin and subcutaneous tissue disorders - Other, specify | 2 (10.0) | 2 (13.3) | ||||
| Sore throat | 1 (5.0) | 1 (6.7) | ||||
| Stevens-Johnson syndrome | 1 (5.0) | 1 (5.0) | 1 (6.7) | 1 (6.7) | ||
| Urinary retention | 1 (5.0) | 1 (5.0) | 1 (6.7) | 1 (6.7) | ||
| Urinary tract infection | 2 (10.0) | 2 (13.3) | ||||
| Vomiting | 8 (40.0) | 1 (5.0) | 6 (40.0) | 1 (6.7) | 2 (40.0) | |
| Weight loss | 2 (10.0) | 2 (13.3) | ||||
| White blood cell decreased | 3 (15.0) | 2 (13.3) | 1 (20.0) | |||
Response
There were no objective responses (PR or CR) observed in the 20 treated patients (Figure 3A). The median number of cycles completed was 2 (range: 1–26). Three patients with CNS tumors had a best overall response of prolonged stable disease (SD) (> 6 cycles); none of these patients had prior BRAF and/or MEK inhibitor therapy (Table 3). One patient with a low-grade glioneuronal tumor (BRAF V600E mutation) had SD for 9 cycles before declining additional therapy. A second patient with LGG (BRAF fusion) had SD for 15 cycles before progressing on therapy. A third patient with LGG (BRAF fusion) completed all 26 cycles of therapy on study based on institutional radiology review. However, upon re-review of the scans, the institution reported the patient had disease progression at the end of Cycle 7. Ultimately, this patient was determined to have best response of SD for 16 cycles by central review. Six-month PFS based on institutional review was 37% (95% CI, 17% to 58%; Figure 3B).
Figure 3.
(A) Swimmer plot and (B) Kaplan-Meier curve of the 20 treated Arm J patients.
Abbreviations: HGG, high-grade glioma; LGG, low-grade glioma; PFS, progression-free survival; RMS, rhabdomyosarcoma; UDS, undifferentiated sarcoma.
Table 3.
Clinical and genetic details of patients with low-grade gliomas and glioneuronal tumors
| Patient ID | Age (yrs) | Histology | Previous Cytotoxic Chemotherapy | Previous BRAF and/or MEK Inhibitor | MAPK Gene Alterationa | Other Mutations | Best Responseb | Cycles Treated | PFS (months)c | Reason Off Protocol Therapy |
|---|---|---|---|---|---|---|---|---|---|---|
| 4 | 6 | LGG | Multiple agents | None |
BRAF::KIAA1549 fusion |
None | SD, 15 cycles |
15 | 13.9 | Progressive disease |
| 20 | 7 | LGG | Multiple agents | Trametinib |
BRAF::KIAA1549
fusion |
None | ND | 1 | ND | Declined additional therapy |
| 9 | 7 | LGG | Multiple agents | None |
BRAF::KIAA1549
fusion |
None | SD, 5 cycles |
5 | 18.0 | Adverse events |
| 8d | 5 | LGG | None | None |
BRAF::KIAA1549
fusion |
None | SD, 16 cycles |
26 | 6.2 | Completed protocol therapy |
| 5 | 7 | LGG | Multiple agents | None | BRAF V600E (0.19) | None | ND | 1 | ND | Physician determination |
| 15 | 16 | GNT | Multiple agents | None | BRAF V600E (0.28) | None | SD, 9 cycles |
9 | 12.6 | Declined additional therapy |
Abbreviations: LGG, low-grade glioma; GNT, glioneuronal tumor; ND, not determined; PFS, progression-free survival; PD, progressive disease; SD, stable disease; yrs, years.
Tumor variant allele frequency is shown in parentheses.
Best response determined by central review.
PFS determined by institutional review.
Patient #8 completed all 26 cycles of protocol therapy on study based on institutional radiology review. Upon re-review of the scans, the institution reported the patient had disease progression at the end of Cycle 7. Ultimately, this patient was determined to have best response of SD for 16 cycles by central review.
Pharmacokinetic Studies
Pharmacokinetics of ulixertinib (BVD-523) are summarized in Appendix Tables A5. Overall, six patients submitted samples for the optional ulixertinib PK analysis in Cycle 1 (DL1, n=5; DL2, n=1) and 4 patients submitted follow-up PK samples on Day 15 (DL1, n=3; DL2, n=1). Concentration-time data were highly variable due to apparent differences in time and extent of absorption. The Cmax and AUC0–6h values (mean ± SD) increased from 172 ± 163 ng/mL and 534 ± 661 hr*ng/mL (n=6), respectively, on day 1 to 340 ± 231 ng/mL and 1606 ± 1215 hr*ng/mL (n=4), respectively on day 15.
DISCUSSION
The nationwide screening framework created for the NCI-COG Pediatric MATCH trial was successful in efficiently identifying children and young adults with refractory tumors harboring MAPK alterations for pathway-targeted therapy with the ERK inhibitor ulixertinib, as was reported for the MEK inhibitor selumetinib.28 Treatment Arm J of Pediatric MATCH is the first pediatric trial of an ERK inhibitor, demonstrating the feasibility of pediatric drug development and evaluation in the setting of an innovative clinical trial design. Unlike Arms E (selumetinib) and G (vemurafenib), in which patients with LGG were ineligible given the clinical activity of those agents in previous pediatric trials, Arm J was histology-agnostic.18,21 As anticipated, actionable alterations for MAPK pathway study arms have been the most frequently detected in Pediatric MATCH (11% of patients); with three histologies (RMS, LGG, and HGG) accounting for 72% of all MAPK-altered tumors.26 These tumor types were similarly represented in this 20 patient phase 2 trial of ulixertinib (75%, Table 1).
Toxicities reported in this pediatric trial were consistent with the adult ulixertinib experience as well as prior trials of targeted agents within the MAPK pathway.18–21,24 Dose level 1 at 260 mg/m2 (max 450 mg; 75% of the adult RP2D) dose was identified as the pediatric RP2D based on the statistical plan in the dose finding cohort. No unexpected AEs were seen. GI-related toxicities, especially nausea, were notable and additional supportive care measures should be incorporated in future studies.
Pharmacokinetic analysis in the small cohort of patients who participated in the PK studies showed a slow and variable absorption of ulixertinib, as was also reported for adults.24
Although no objective responses were seen to treatment with ulixertinib, prolonged stable disease was observed in 3/6 patients with BRAF-aberrant CNS tumors with LGG or low-grade glioneural tumors (Table 3, Figure 3A, Appendix Table 3). Another patient with LGG discontinued therapy for adverse events after Cycle 5 while still with stable disease; the other two had progressive disease in or after Cycle 1. Five of these six patients were reported to have previously been treated with multiple cytotoxic chemotherapy agents, with the lone exception being the LGG patient (#8) who received all 26 cycles of ulixertinib on study. This potential activity of ulixertinib in LGG patients stands in marked contrast to the results for patients with HGG (n=5) and RMS (n=5) in the trial (Figure 3A). A similar lack of activity in patients with HGG and RMS was observed for the MEK inhibitor selumetinib in Arm E of Pediatric MATCH.28
More generally, these results are consistent with the previous pediatric experience in which genomically complex and clinically aggressive tumor types such as HGG and RMS13,17 are largely resistant to single-agent MAPK pathway inhibition. Prior studies of single agents targeting MAPK signaling have shown durable responses in several pediatric cancer types whose genomes harbor few additional driver mutations (“single pathway diseases”), including progressive LGG harboring alterations in BRAF or NF118,21, Langherhans cell histiocytosis with BRAF mutations33, and inoperable plexiform neurofibromas20 (leading to FDA approval of selumetinib for neurofibromatosis patients with these tumors). In this arm of Pediatric MATCH the primary signal of single-agent ulixertinib activity noted was in patients with LGG or glioneuronal tumors, none of whom had additional alterations beyond BRAF detected by tumor screening. Combination targeted therapies (primarily BRAF and MEK inhibition) have shown promise for MAPK pathway diseases such as LGG and are currently being evaluated in clinical trials; similar combination approaches have been reported to have increased efficacy (as compared to single agents) for more complex tumors such as HGG34,35 and are also being studied (NCT04201457, NCT03919071).
In conclusion, single-agent ulixertinib administered at or above the pediatric MTD demonstrated limited anti-tumor effect in this patient population. The identification of 3 patients with periods of sustained tumor stabilization in this small cohort with LGG or low-grade glioneuronal tumor (n=6) suggests that additional studies of ulixertinib should be considered in that population. Taken together, Pediatric MATCH treatment Arms E and J demonstrate the need for alternative therapeutic strategies utilizing MAPK-targeted agents across tumor histologies, including evaluation of combination approaches. The Pediatric MATCH trial has highlighted the high burden of MAPK alterations in pediatric cancers, presenting a key opportunity for further research.
Supplementary Material
Support:
Supported by the National Cancer Institute of the National Institutes of Health (NIH) under the award numbers U10 CA180886, U10 CA180899, U24 CA196173, and by the St. Baldrick’s Foundation. KTV was also supported in part by the Alex’s Lemonade Stand Foundation, Frank A. Campini Foundation, Posey Family Foundation, and by the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), through UCSF-CTSI Grant KL2 TR001870. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Footnotes
Prior Presentation: Presented in part at the 2022 ASCO Annual Meeting, June 3–7, 2022.
Data Sharing Statement
The Children’s Oncology Group Data Sharing policy describes the release and use of COG individual subject data for use in research projects in accordance with National Clinical Trials Network (NCTN) Program and NCI Community Oncology Research Program (NCORP) Guidelines. Only data expressly released from the oversight of the relevant COG Data and Safety Monitoring Committee (DSMC) are available to be shared. Data sharing will ordinarily be considered only after the primary study manuscript is accepted for publication. For phase 3 studies, individual-level de-identified datasets that would be sufficient to reproduce results provided in a publication containing the primary study analysis can be requested from the NCTN/NCORP Data Archive at https://nctn-data-archive.nci.nih.gov/. Data are available to researchers who wish to analyze the data in secondary studies to enhance the public health benefit of the original work and agree to the terms and conditions of use. For non-phase 3 studies, data are available following the primary publication. An individual-level de-identified dataset containing the variables analyzed in the primary results paper can be expected to be available upon request. Requests for access to COG protocol research data should be sent to: datarequest@childrensoncologygroup.org. Data are available to researchers whose proposed analysis is found by COG to be feasible and of scientific merit and who agree to the terms and conditions of use.
For all requests, no other study documents, including the protocol, will be made available and no end date exists for requests. In addition to above, release of data collected in a clinical trial conducted under a binding collaborative agreement between COG or the NCI Cancer Therapy Evaluation Program (CTEP) and a pharmaceutical/biotechnology company must comply with the data sharing terms of the binding collaborative/contractual agreement and must receive the proper approvals.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The Children’s Oncology Group Data Sharing policy describes the release and use of COG individual subject data for use in research projects in accordance with National Clinical Trials Network (NCTN) Program and NCI Community Oncology Research Program (NCORP) Guidelines. Only data expressly released from the oversight of the relevant COG Data and Safety Monitoring Committee (DSMC) are available to be shared. Data sharing will ordinarily be considered only after the primary study manuscript is accepted for publication. For phase 3 studies, individual-level de-identified datasets that would be sufficient to reproduce results provided in a publication containing the primary study analysis can be requested from the NCTN/NCORP Data Archive at https://nctn-data-archive.nci.nih.gov/. Data are available to researchers who wish to analyze the data in secondary studies to enhance the public health benefit of the original work and agree to the terms and conditions of use. For non-phase 3 studies, data are available following the primary publication. An individual-level de-identified dataset containing the variables analyzed in the primary results paper can be expected to be available upon request. Requests for access to COG protocol research data should be sent to: datarequest@childrensoncologygroup.org. Data are available to researchers whose proposed analysis is found by COG to be feasible and of scientific merit and who agree to the terms and conditions of use.
For all requests, no other study documents, including the protocol, will be made available and no end date exists for requests. In addition to above, release of data collected in a clinical trial conducted under a binding collaborative agreement between COG or the NCI Cancer Therapy Evaluation Program (CTEP) and a pharmaceutical/biotechnology company must comply with the data sharing terms of the binding collaborative/contractual agreement and must receive the proper approvals.