Promising Activity Seen from ERK1/2 Inhibitor in MAPK/ERK Mutations and BRAF/MEK Resistance

Ryan J. Sullivan, MD

Ulixertinib, a novel ERK1/2 inhibitor, demonstrated encouraging antitumor activity in patients with solid tumors harboring mutations in the MAPK/ERK pathway, according to the results of a phase I

study published inCancer Discovery.

Responses were even seen in patients withBRAF-mutant melanoma who were refractory to or who had progressed on prior MAPK-targeted therapy of BRAF and/or MEK inhibition, which led to the FDA granting a Fast Track designation to the first-in-class agent for patients with unresectable or metastaticBRAFV600-mutant melanoma in this setting. Activity was also seen in patients with solid tumors harboringBRAFandNRASmutations.

“A great number of cancers, including melanoma and lung cancers, have mutations in the MAPK/ERK pathway, and while current therapies target proteins in this cascade, many patients develop resistance to current drugs,” lead study author Ryan J. Sullivan, MD, assistant professor of hematology and oncology and member of the Termeer Center for Targeted Therapies, Massachusetts General Hospital, said in a statement. “The common denominator in these failed therapies is that the cancer has found a way to activate ERK. Therefore, the development of ERK inhibitors is a crucial next step to target this aberrant pathway.”

Ulixertinib is a highly potent, selective, reversible ATP-competitive ERK1/2 inhibitor. In preclinical models, the novel agent showed an ability to reduce tumor growth and induce tumor regression in BRAF- and RAS-mutant cell lines, leading to the start of the open-label, first-in-human study of ulixertinib in patients with solid tumors harboring MAPK/ERK pathway aberrations.

The phase I study enrolled 135 patients between April 2013 and March 2017. Twenty-seven patients were included in the dose-escalation phase, which gave patients oral ulixertinib at doses from 10 to 900 mg twice daily for a 21-day cycle. For the escalation phase, 108 patients were enrolled in 1 of 6 cohorts. The primary endpoint of the trial was the maximum tolerated dose (MTD) and the recommended phase II dose of ulixertinib; secondary endpoints included preliminary efficacy and pharmacokinetic and pharmacodynamic analyses.

The median patient age across the study was 62 years (range, 21-85); the majority were male (61%) and had an ECOG performance status of 1 (67%). Across the study, 51% of the patients had received prior immunotherapy and 24% had received prior BRAF and/or MEK inhibition therapy.

In the dose-escalation phase, the recommended phase II dose was determined to be 600 mg twice daily as only 1 patient experienced a dose-limiting toxicity (DLT) of grade 3 rash at that dosage. The 900-mg dosage exceeded the MTD with observed DLTs, including grade 3 pruritus, grade 3 elevated aspartate aminotransferase, and grade 3 elevated alanine aminotransferase in 1 patient. Another patient experienced grade 3 diarrhea, vomiting, dehydration, and elevated creatinine. The next dosage level of 750 mg also exceeded the MTD, with grade 3 rash and grade 2 diarrhea in 1 patient and grade 2 hypotension, grade 2 anemia, and grade 1 elevated creatinine in another patient.

The expansion phase included 3BRAFmutation— specific cohorts, including patients who had not received prior MAPK-targeted therapy. Seventeen patients were enrolled in a cohort withBRAF-mutant colorectal cancer, 16 withBRAF-mutant lung cancer, and 24 with other solid tumors who harbored aBRAFmutation. A fourth cohort included 21 patients withBRAF-mutant melanoma who were refractory to or had progressed on prior BRAF and/or MEK inhibitor therapy. The fifth and sixth cohorts included 22 patients withNRAS-mutant melanoma without prior MAPK-targeted therapy and 8 patients with aMEK-mutant solid tumor who had not received prior BRAF and/or MEK inhibitors, respectively (FIGURE).

From the overall study, 25 patients in the dose-escalation phase and 81 from the expansion cohorts were evaluable for efficacy. Fourteen partial responses (PRs) were experienced across 101 patients who were dosed at the recommended phase II dose or higher, including 3 patients from the dose-escalation phase, all of whom hadBRAFV600 mutation—positive melanoma.

Among the 3 patients, responses lasted 4.2, 12.4, and 24.9 months. Six additional patients from the dose-escalation portion of the study had stable disease.

Of the 11 patients who experienced a PR from the expansion cohorts, 3 were in the NRAS-mutant melanoma cohort, 3 hadBRAF-mutant lung cancer, 1 hadBRAFV600E-mutant melanoma that was refractory/ resistant to BRAF and/or MEK inhibition, and 4 of the responses were observed in the cohort of patients with other solid tumors harboringBRAFmutations (TABLE). Responses were also noted in patients with central nervous system metastases, including 1 patient withBRAFV600E-mutant lung cancer and another patient withBRAFV600E-mutant glioblastoma.

Across the study, 19 evaluable patients had been exposed to prior MAPK-targeted therapy and had relapsed on or had progressed following treatment. Three of these patients achieved a PR and 6 more had stable disease. “ERK inhibition may be a potential way forward for these populations,” Sullivan said in a statement.

Responses were also noted in patients with atypicalBRAFmutations, or non-V600 mutations, with significant tumor reduction observed in patients with L485W and G469A mutations. No targeted therapy currently exists for patients with these specific mutations.

“In particular, non-V600BRAFmutations, including L485W, L597Q, and G469A across a variety of solid tumors, were shown to be clinically actionable for the first time, with durable objective responses,” the study authors wrote. “This study provides the first clinical evidence that dimer-dependent atypicalBRAFnon-V600 mutations may be actionable by downstream ERK inhibition, highlighting an important new therapeutic target for future drug development in solid tumors.” They also noted that there was little efficacy seen among patients withMEKmutations, as minimal to no tumor size reduction was observed in the study.

Pharmacokinetics analysis showed that oral ulixertinib (taken without food) was slowly absorbed and reached maximum concentration typically within 2 to 4 hours and then declined slowly after. Minimal plasma accumulation of the drug and its metabolites were observed at lower dosage levels <75 mg.

Pharmacokinetics analysis showed that oral ulixertinib (taken without food) was slowly absorbed and reached maximum concentration typically within 2 to 4 hours and then declined slowly after. Minimal plasma accumulation of the drug and its metabolites were observed at lower dosage levels <75 mg.

Grade 3 events occurred in 41% and typically included rash (17%). No grade 4/5 TRAEs were observed. Thirty-eight serious TRAEs occurred, including diarrhea in 7, dehydration in 4, and acute renal failure, anemia, increased blood creatinine, maculo-papular rash, nausea, and vomiting in 2 patients each.

Treatment interruptions were needed for 85% of patients in the dose-escalation portion and 65% in the expansion cohorts, mostly related to gastrointestinal, dermatologic, or subcutaneous disorders. Nineteen percent discontinued treatment overall, including 3 patients in the dose-escalation portion who were being treated at dosages of 75, 300, and 900 mg twice daily.

The study authors noted that ulixertinib&rsquo;s toxicity profile overlapped with that of MEK inhibitors and was consistent with selective inhibition of the MAPK pathway. While the expansion cohorts did have a limited patient pool, the study authors highlighted the potential of the ERK1/2 inhibitor in patients&rsquo;BRAFandNRASmutations, even among patients who had progressed on prior BRAF and/or MEK inhibitors. They also suggested that ulixertinib could be used in combination regimens with BRAF and/or MEK inhibitors to improve responses and delay resistance in these patients.

&ldquo;ERK inhibition with ulixertinib alone or in combination with other MAPK signaling pathway inhibitors may have the potential to delay the development of resistance to existing therapies and to benefit a broader patient population,&rdquo; Sullivan et al wrote.

Reference:

Sullivan RJ, Infante JF, Janku F, et al. First-in-class ERK1/2 inhibitor ulixertinib (BVD- 523) in patients with MAPK mutant advanced solid tumors: results of a phase I dose-escalation and expansion study [published online December 15, 2017]. Cancer Discov. 2017. doi: 10.1158/2159-8290.CD-17-1119.