MAPK Expression Does Not Drive Selumetinib Response in Refractory Pediatric and AYA Cancers

Pediatric and young adult patients with refractory cancers experienced no clinical activity with selumetinib, according to findings from the Phase 2 National Cancer Institute (NCI)-Children’s Oncology Group (COG) Pediatric MATCH Trial (NCT03155620). Cohort findings of the trial were recently presented at ASCO’s 2021 annual meeting

Although well tolerated, no objective reactions were observed with selumetinib. Three patients achieved stable disease with the drug, while 15 patients had progressive disease. One patient was not RECIST-classifiable and 1 patient was not evaluable. In addition, the progression-free survival (PFS) rate at 6 months was 15% (95% CI, 4%-34%).

“Selumetinib was generally well tolerated in this cohort of children who had several treatment-resistant cancers. Unfortunately, no objective responses were observed,” Olive S. Eckstein, MD, of Texas Children’s Hospital/Baylor College of Medicine and a trial investigator, said in a presentation at the meeting. “The most important point to discuss and think about in the future when we design these studies is histology and mutational status. We learned here that the mutational status of the MAPK pathway alone is insufficient to determine the response to selumetinib monotherapy. to predict.”

Although pediatric cancers contain targeted molecular changes that traverse multiple disease histologies, similar to adult malignancies, the low frequency of individual gene changes makes evaluating targeted agents in pediatric tumors challenging, Eckstein explained.

Several malignancies are known to have a high frequency of MAPK pathway mutations, such as RAS (hairy cell leukemia, melanoma and papillary thyroid cancer), BRAF (hairy cell leukemia, melanoma, Langerhans cell histiocytosis and papillary thyroid cancer), and MEK1/2 (colon cancer, glioma, Langerhans cell histiocytosis and ovarian cancer). Of these pathway mutations, RAS is the most commonly observed at 22%, followed by BRAF (7%), MEK1/2 (<1%) and ERK (rare).

Selumetinib is a potent, orally bioavailable selective inhibitor of MEK1/MEK2 that blunts the RAS-RAF-MEK1/2-ERK cascade, reduces cell proliferation and promotes pro-apoptotic signal transduction. The TKI has previously demonstrated efficacy in the Phase 1 Pediatric Brain Tumor Consortium study in low-grade gliomas; 2 because of this data, investigators chose not to include this patient subgroup in this screening protocol.

Selumetinib is also approved by the FDA for the treatment of patients with plexiform neurofibroma who are 2 years of age or younger.

The data presented at the ASCO Annual Meeting in 2021 was part of the NCI-COG Pediatric MATCH study (APEC1621SC), which enables molecular profiling of therapy-refractory cancers in US pediatric and young adult patients. Patients aged 1 year to 21 years with refractory solid tumors, lymphomas and histiocytosis were required to have measurable disease and adequate performance status.

Patients had their tumors biopsied before switching to the tumor sequencing screening protocol. If useful mutations in the RAS/RAF/MAPK1/2-ERK pathway were detected – NF1, NRAS, KRAS, HRAS, ARAF, MAP2K1, GNA11, GNAQ mutations or BRAF mutations or fusion – patients were enrolled on the selumetinib sub-protocol of pediatric MATCH (APEC1621E), arm E of the study, which is designed to test the tolerability and efficacy of selumetinib in children with recurrent tumors, containing molecular MAPK pathway changes.

On this sub-protocol, patients were also required to meet standard Phase 2 protocol criteria, consisting of organ function and washout periods. FFPE tumor samples were processed centrally and Targeted Oncomine was harmonized and performed in 3 laboratories.

Selumetinib monotherapy was administered orally at a dose of 25 mg/m2 twice daily, with a maximum dose of 75 mg/m2 for up to 2 years in 28-day cycles. The responses were evaluated every other cycle for 3 events and then every 3 cycles.

Eckstein noted that the study would have potential for histology-specific expansion cohorts if objective responses were observed in at least 3 patients with the same histology.

The primary endpoint of the study was ORR; secondary endpoints were PFS and tolerability.

Twenty-one patients entered the study and 20 were eligible for selumetinib treatment. One patient was ineligible because they had a low-grade glioma. The median age was 14 years (range: 5-21 years) and 50% of the patients were male. Most patients (n = 15) were Caucasian and 1 patient was each African American, Asian, and Native American. The ethnicity of two patients was not reported.

Eleven hotspot mutations were found in RAS genes: KRAS (n = 8), NRAS (n = 3) and HRAS (n = 1); 7 patients had inactivating NF1 mutations and 2 patients had activating missense mutations in BRAF V600E.

The most common tumor histology subtypes were central nervous system astrocytoma (n = 7), of which there were BRAF mutations (n ​​= 2), NF1 (n = 2), KRAS (n = 1), NF1 plus PTEN (n = 1), and KRAS plus NF1 (n = 1); and rhabdomyosarcoma, which were NRAS mutations (n ​​= 2), KRAS (n = 4), and HRAS mutations (n ​​= 1).

Additional tumor histologies were carcinoma (n = 2), neuroblastoma, plexiform neurofibroma, yolk sac tumor, and other sarcoma (n = 1) each. Carcinoma harbored 1 mutation each of KRAS and NF1, neuroblastoma of 1 NRAS mutation, plexiform neurofibroma of NF1 plus BRCA2, yolk sac tumor of 1 KRAS and other sarcoma of 1 NF1 mutation.

The median number of completed cycles was 2 (range, 1-13) and the data cutoff date was December 31, 2020.

Of the 3 patients with SD, 1 had high-grade NF1-PTEN mutated glioma and had undergone 6 cycles of treatment until disease progression, the second had high-grade KRAS mutant glioma and received 12 cycles of disease progression, and the third had NF1-BRCA2 mutant plexiform neurofibroma and was treated for 13 cycles to a grade 4 elevated creatine kinase (CPK) elevation.

Adverse reactions possibly related to selumetinib treatment included lymphopenia, uveitis and thromboembolic events (n = 1 each; all Grade 3), elevated CPK (n = 1; Grade 4), and thromboembolic events due to pulmonary embolism leading to death (n = 1; grade 5). The deceased patient had adenocarcinoma and was treated for 11 days.

Future directions should focus on identifying histological, molecular, and clinical characteristics of glioma responders and non-responders, as well as determining biologics for predictive response to MEK inhibitors as single agents and exploring synergy with selumetinib or others. MEK inhibitors in combination with targeted or cytotoxic agents, Eckstein concluded.

References

Allen CE, Eckstein O, Williams PM, et al. Selumetinib in patients with tumors with changes in the MAPK pathway: results from arm E of the NCI-COG pediatric MATCH trial. J Clin Oncol. 2021;39(suppl 15):10008. doi:10.1200/JCO.2021.39.15_suppl.10008Banerjee A, Jakacki RI, Onar-Thomas A, et al. A Phase I Study of the MEK Inhibitor Selumetinib (AZD6244) in Pediatric Patients with Relapsed or Refractory Low-Grade Glioma: A Pediatric Brain Tumor Consortium (PBTC) study. Neuro Oncol. 2017;19(8):1135-1144. doi:10.1093/neuonc/now282

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