BGB-3245 Displays Early Antitumor Activity in Advanced/Refractory Solid Tumors With MAPK Pathway Mutations

Alison Schram, MD

The RAF dimer inhibitor BGB-3245 generated early efficacy signals with a tolerable safety profile in patients with advanced or refractory solid tumors harboring MAPK pathway mutations, according to findings from a phase 1a/1b trial (NCT04249843) that were presented at the 2023 AACR Annual Meeting.¹

In the first-in-human study, investigators aimed to determine the highest dose of BGB-3245 that can be safely administered to patients with metastatic cancers that continue to grow despite treatment and contain a mutation in a protein in a molecular pathway, MAPK.

The MAPK pathway plays a role in the control of cell growth and cell survival. Changes, including mutations, in the MAPK pathway can cause the spread of cancer in patients. Researchers are hopeful that treatment with BGB-3245 may provide an effective option for patients with advanced solid tumors who have a MAPK pathway mutation.

“BGB-3245 has activity against a broad spectrum of class 1,2, and 3 mutations and fusions, as evidenced by cellular proliferation assays and patient derived xenograft models,” said Alison Schram, MD, medical oncologist, assistant attending physician, Memorial Sloan Kettering Cancer Center, New York, New York, in a presentation of data at the 2023 AACR Annual Meeting. “Given the unmet clinical need and promising preclinical data for BGB-3245, we initiated a phase 1 dose-escalation and -expansion study in adult patients with refractory tumors harboring mutations in the MAP kinase pathway.”

In the open-label, dose-escalation and dose-expansion study, investigators are assessing the safety, pharmacokinetics, and antitumor activity of BGB-3245. In both part 1a and 1b, the dose-escalation and -expansion portions of the trial, BGB-3245 was evaluated as an oral medication.²

The study followed a modified toxicity probability interval design with a starting dose of 5 mg once daily. A total of 6 dose levels were explored and the maximum tolerated dose was defined as 40 mg once daily.

To be eligible for the study, patients must have been aged 18 years or older with a histologically confirmed advanced or metastatic solid tumor, have had disease progression during or after at least 1 line of prior systemic anticancer therapy, or have no treatments available. Patients must also have a mutation in the MAPK pathway, such as in the BRAF or KRAS proteins, have recovered from the serious adverse events (AEs) of prior therapies before receiving the study treatment, and be physically well enough that they are fully ambulatory, capable of all self-care, and capable of all but physically strenuous activities.

In phase 1a, primary end points of the trial included number of patients with AEs, severity of AEs, number of patients experiencing AEs meeting protocol defined dose-limiting toxicity (DLT) criteria, and maximum tolerated dose. Secondary end points include overall response rate (ORR), duration of response (DOR), clinical benefit rate, best overall response, duration of stable disease (SD), progression-free survival, pharmacokinetics, and more.

The phase 1b portion of the trial is assessing the primary end point of ORR, and secondary end points of DOR, disease control rate, duration of SD, clinical benefit rate, overall survival, AEs, and pharmacokinetics.

As of the data cutoff date of September 1, 2022, 42 patients were enrolled, and 9 patients were ongoing treatment. Approximately half of the patients were male (55%), the median age was 60 years old (range, 31-83), and patients were heavily pretreated with a median of 3 prior lines of therapy (range, 1-9). Patients with a variety of tumor types were enrolled, with the most common consisting of melanoma (29%), non–small cell lung cancer (12%), and colorectal cancer (10%). Additionally, 11 (26%) patients had RAS mutations, including KRAS (14%), NRAS (10%), and HRAS (2%) mutations. BRAF mutations were seen in 31 patients (74%).

The median time on treatment was 154 days, and many patients continued treatment beyond 1 year. The confirmed ORR was 18% with stable disease seen in 61% of those patients. An additional 24% of patients had stable disease for greater than 24 weeks, and the DCR was 79%.

For pharmacokinetics, the median T max was about 2 hours and exposures were generally dose proportional, with a long terminal half-life and significant accumulation observed. When given doses of 25 mg daily and above, the pharmacokinetics were consistent with what was previously noted in preclinical models as treatment led to tumor growth inhibition.

The safety of BGB-3245 was manageable and the agent had encouraged antitumor activity. Treatment-emergent AEs were consistent with other inhibitors of the MAP kinase pathway, and the most common included rash, fever, thrombocytopenia, and ALT elevation. Toxicity was generally low-grade and manageable with about 12% of patients requiring dose reductions. Further, anti-tumor activity was observed across disease types, mutations, and dose levels.

Patients are actively being recruited and assessed at locations in Massachusetts, New York, Texas, and Australia, and the study has an estimated completion date of June 1, 2024. Additionally, BGB-3245 is being evaluated in combination with the MEK inhibitor mirdametinib (PD-0325901) for patients with advanced solid tumors (NCT05580770).

“BGB-3245 has a manageable safety profile and encouraging anti-tumor activity was observed in heavily pretreated heterogeneous patients. These data support ongoing investigation of BGB-3245 in defined cohorts during the dose-expansions,” Schram said.

References

1. Schram AJ. A first-in-human, phase 1a/1b, open-label, dose-escalation and expansion study to investigate the safety, pharmacokinetics, and antitumor activity of the RAF dimer inhibitor BGB-3245 in patients with advanced or refractory tumors. Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, FL. Abstract CT031.
2. Study of safety, pharmacokinetics, and antitumor activity of BGB-3245 in participants with advanced or refractory tumors. ClinicalTrials.gov. Updated October 27, 2022. Accessed April 17, 2023. https://clinicaltrials.gov/ct2/show/NCT04249843