Purpose: Mutations in BRAF at codons other than V600 (non-V600) and BRAF fusions confer dependence on RAF-MEK-ERK pathway. Subprotocol Z1L (EAY131-Z1L) investigated the clinical activity of ulixertinib (ERK1/2 inhibitor) in patients with tumors harboring these alterations. Patients and Methods: In this single-arm study, patients with BRAF non-V600 mutation or BRAF fusion were given ulixertinib orally, at a dose of 600 mg twice daily, continuously for each 28-day cycle until progression or intolerability. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), 6-month PFS, and overall survival (OS). Results: Among 34 eligible patients, median age was 66.5; 50% were female, 88% were white, 9% black, 3% Asian. ECOG PS 1 in 74% of patients. Median number of prior therapies was 4. Tumor types included multiple gastrointestinal malignancies (n = 16), lung cancer, melanoma (n = 3 each), among others. No patients achieved CR or PR, resulting in ORR = 0%. Stable disease was the best response in 7/26 centrally confirmed cases. Median PFS was 1.7 months (90% CI: 1.1, 2.2), 6-month PFS rate was 5% (90% CI: 0.6%, 17.7%), and median OS was 3.5 months (90% CI: 1.9, 5.4). Twenty patients (57%) had grade 3 toxicities, and one patient (3%) had grade 4 toxicity as their worst toxicity; there were no grade 5 toxicities. Conclusion: Ulixertinib had no demonstrable evidence of clinical activity in this small, heavily pretreated population of patients with tumors harboring BRAF fusions, or with non-V600E, non-V600K BRAF mutations.
Vivek Subbiah, Feng-Min Zhao, R. Kudchadkar et al.· Clinical Cancer Research· 0 citations
PURPOSE Motivated by the rising incidence of cancers at younger ages, this study compares tumor genomic alterations between adolescents and young adults (AYAs; 18-39 years) and non-AYAs (40 years and older) and explores the relationship with continuous age in patients with relapsed/refractory ovarian, breast, and colorectal cancers accrued to the NCI-MATCH trial. METHODS Tumor genomic profiles generated by a next-generation sequencing 143-gene panel (NCI-MATCH assay, v2) were analyzed for association with age (AYA/total: 21/455 ovarian, 27/576 breast, 43/759 colorectal cancers). For each gene, AYA and non-AYA DNA alteration proportions were compared (Fisher exact test) and alteration association with continuous age (logistic regression) was evaluated (false discovery rate‑adjusted P value <.1 statistically significant). For colorectal cancer, sex-stratified analysis was also performed. RESULTS No significant AYA versus non-AYA differences were observed in the prevalence of gene mutations (single nucleotide variant [SNV]/indel). A significant association of gene amplification with AYAs (odds ratio [OR], 95% CI) was CCND1 (0.2, 0.1-0.4), favoring AYAs in breast cancer. Examining age as a continuous variable, significant associations of gene mutations (SNV/indel) with older age, expressed as 5-year OR (OR [95% CI]), were observed: TP53 (1.3 [1.1 to 1.4]), ovarian cancer; CDH1 (1.4 [1.2 to 1.6]) and PIK3CA (1.1 [1.1 to 1.2]), breast cancer; and BRAF (1.4 [1.2 to 1.7]), female colorectal cancer. Associations with younger age included SMAD4 (0.8 [0.7 to 0.9]), male colorectal cancer. Significant associations of gene amplification with age (continuous) were as follows: CCNE1 (1.3 [1.1 to 1.6]), older ovarian cancer, and CCND1 (0.8 [0.8 to 0.9]), younger breast cancer. CONCLUSION Comparing AYAs with non-AYAs among patients having relapsed/refractory disease, no significant differences in SNV/indel prevalence were observed, but CCND1 amplifications were more prevalent in AYA breast cancer. For several genes, DNA alterations were associated with continuous age and may depend on sex in colorectal cancer.
Hari Sankaran, Yuri Kotliarov, Ying-Dong Zhao et al.· JCO Precision Oncology· 0 citations
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