First-in-class ERK1/2 inhibitor safe, shows early efficacy in patients with advanced solid tumors

December 15, 2017, American Association for Cancer Research

The novel ERK1/2 kinase inhibitor ulixertinib displayed an acceptable safety profile and had clinical activity in patients whose tumors had mutations in the MAPK cell-signaling pathway, according to data from a phase I clinical trial published in Cancer Discovery, a journal of the American Association for Cancer Research.

"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 develop resistance to current drugs," said Ryan J. Sullivan, MD, assistant professor of hematology and oncology and member of the Termeer Center for Targeted Therapies at Massachusetts General Hospital. "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."

The MAPK/ERK pathway is essential for key cellular processes, and mutations along this pathway may result in uncontrolled cellular growth, which can lead to cancer. The RAS gene, an upstream regulator within the MAPK/ERK cascade, is mutated in roughly 30 percent of human cancers. Mutations in BRAF, another gene in this pathway, often occur at codon V600 in malignant melanoma, where combined BRAF/MEK inhibition is the current standard of care. Atypical BRAF mutations (non-V600) are found in a variety of cancers. There is no targeted therapy for patients with atypical BRAF-mutant cancers, said Sullivan.

The ERK gene is the final regulator in the MAPK/ERK pathway, and when upstream inhibition of this protein cascade fails, ERK signaling is reactivated, resulting in renewed MAPK signaling, Sullivan explained. "Targeting ERK for inhibition may allow the opportunity to thwart resistance from upstream mechanisms," he noted. Preclinical studies had shown ERK inhibition to overcome resistance to BRAF and MEK inhibitors.

Sullivan and colleagues tested the ERK inhibitor ulixertinib in an open-label, first-in-human study. They enrolled 27 patients in the dose-escalation phase and 108 in the dose-expansion phase. All patients had advanced solid tumors, and more than 65 percent had BRAF-mutant cancers. Of the patients, 24 percent had received prior BRAF and/or MEK therapy and 51 percent had received prior immunotherapy.

In the dose-escalation phase, the recommended phase II dose (RP2D) of ulixertinib was determined to be 600mg twice daily. The dose-expansion portion of the trial tested the RP2D of ulixertinib in six groups of patients whose tumors had BRAF, NRAS, or MEK mutations, the majority of whom were not treated with prior MAPK-targeted therapy. Partial responses (PR) were seen in 12 percent and 14 percent of evaluable patients in the dose-escalation and dose-expansion cohorts, respectively. PR and/or disease stabilization was seen in all groups, including solid tumors with atypical BRAF mutations.

"It was exciting to see responses in some patients, especially those with non-V600 BRAF mutations," said Sullivan. "We also saw responses in some patients with BRAF V600 mutant melanoma who had progressed on prior BRAF/MEK inhibitor therapy. ERK inhibition may be a potential way forward for these populations."

Patients treated at the RP2D had near-complete inhibition of ERK as verified in blood samples. Side effects were comparable to other MAPK inhibitors, and the most common treatment-related adverse event (AE) was rash. No AEs above grade 3 were observed.

"This study shows that ulixertinib is tolerable and has activity in a subset of patients with in the MAPK pathway," said Sullivan. "The results of this study can be built upon to develop better treatment regimens for these patients."

Sullivan anticipates that ERK inhibitors will likely be used in combinatorial therapies, and they may supplement pre-existing regimens, such as BRAF/MEK inhibition. "I think we'll see very complex combinations tailored to specific subtypes, and ERK inhibitors deserve to be part of the repertoire," Sullivan said.

Based on data from this trial, ulixertinib has received the U.S. Food and Drug Administration's Fast Track designation.

Limitations of the study include a small pool of expansion cohorts, as is consistent with a phase I trial, and lack of tumor pharmacodynamic analysis.

Explore further: Preclinical study indicates potential for novel inhibitor to overcome drug resistance induced by RAF, MEK inhibitors

Related Stories

Preclinical study indicates potential for novel inhibitor to overcome drug resistance induced by RAF, MEK inhibitors

April 8, 2013
A new class of investigational medicines may help to treat patients with cancers driven by mutations in genes such as BRAF or KRAS/NRAS, including those patients who have become resistant to therapies that target BRAF directly, ...

A Braf kinase-inactive mutant induces lung adenocarcinoma

August 3, 2017
The initiating oncogenic event in almost half of human lung adenocarcinomas is still unknown, complicating the development of selective targeted therapies. Yet these tumours harbour a number of alterations without obvious ...

Studies identify cell-signaling pathway alterations responsible for melanoma drug resistance

November 22, 2013
Genomic profiling of treatment-resistant, BRAF-mutated melanomas revealed multiple gene alterations, mostly involving a cell-signaling pathway called the MAPK pathway, and more potent forms of existing drugs and drugs targeting ...

Study identifies novel treatment resistance mechanism in BRAF-mutant melanoma

August 8, 2016
A Massachusetts General Hospital (MGH) research team has identified an additional mechanism for resistance to targeted treatment for BRAF-mutant melanoma. Their paper, receiving advance online publication in Nature Medicine, ...

Enhanced treatment, surveillance needed for certain melanoma patients to prevent secondary cancers

August 14, 2013
Moffitt Cancer Center researchers suggest secondary cancers seen in melanoma patients who are being treated for a BRAF gene mutation may require new strategies, such as enhanced surveillance and combining BRAF-inhibitor therapy ...

Melanoma cells rewire to resist drug treatment

September 27, 2017
In 2014, new combination therapies to treat patients with metastatic melanoma hit the market, helping extend the lives of those with this aggressive disease. Yet unfortunately, after several months of treatment, almost all ...

Recommended for you

DNA vaccine leads to immune responses in HPV-related head and neck cancer

September 21, 2018
A therapeutic vaccine can boost antibodies and T cells, helping them infiltrate tumors and fight off human papillomavirus (HPV)-related head and neck cancer. Researchers from the Abramson Cancer Center of the University of ...

In zebrafish, a way to find new cancer therapies, targeting tumor modulators

September 21, 2018
The lab of Leonard Zon, MD, at Boston Children's Hospital has long been interested in making blood stem cells in quantity for therapeutic purposes. Looking for a way to test for their presence in zebrafish, their go-to research ...

What can salad dressing tell us about cancer? Think oil and vinegar

September 20, 2018
Researchers led by St. Jude Children's Research Hospital scientists have identified another way the process that causes oil to form droplets in water may contribute to solid tumors, such as prostate and breast cancer. The ...

Novel biomarker found in ovarian cancer patients can predict response to therapy

September 20, 2018
Despite months of aggressive treatment involving surgery and chemotherapy, about 85 percent of women with high-grade wide-spread ovarian cancer will have a recurrence of their disease. This leads to further treatment, but ...

Testing fluorescent tracers used to help surgeons determine edges of breast cancer tumors

September 20, 2018
A team of researchers with members from institutions in The Netherlands and China has conducted a test of fluorescent tracers meant to aid surgeons performing tumor removal in breast cancer patients. In their paper published ...

Cancer immunotherapy might benefit from previously overlooked immune players

September 20, 2018
Cancer immunotherapy—efforts to boost a patient's own immune system, allowing it to better fight cancer cells on its own—has shown great promise for some previously intractable cancers. Yet immunotherapy doesn't work ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.