The success of BRAF/MEK combinations has led to the discovery of safety and preliminary activity with an investigational pan-RAF/MEK combination.
The investigational combination of lifirafenib (BGB-283) and mirdametinib (PD-0325901) has shown a favorable safety profile, as well as few dose-limiting toxicities (DLTs) and treatment discontinuations in patients with advanced or refractory solid tumors harboring MAPK pathway aberrations.1
Results come from a phase 1b, open-label, dose-escalation, and -expansion study (NCT03905148) and were presented during the AACR Annual Meeting 2023 by Benjamin M. Solomon, MBBS, PhD, FRACP.
“Attempts to target downstream RAS effectors at single nodes in cancer have resulted in limited efficacy in part due to feedback loops, which result in pathway reactivation. In contrast, the strategy of vertical pathway blockade as exemplified by the use of BRAF and MEK inhibitors in BRAF V600-mutant melanoma have resulted in more sustained and clinically effective pathway and inhibition,” said Solomon, medical oncologist in the Lung Service and the Head & Neck service at Peter MacCullum Cancer Centre, in Victoria Australia, during the presentation.
Based on prior success in BRAF V600-mutant melanoma, investigators of the phase 1b study combined the pan-RAF inhibitor, lifirafenib with the MEK inhibitor mirdametinib to investigate the safety, pharmacokinetics, and anti-tumor activity of the combination. Further rationale for the study comes from preclinical data showing the synergistic effect of combing lifirafenib plus mirdametinib. The combination achieved a 100% objective response rate (ORR) when lifirafenib was dose at 1.25 mg/kg and mirdametinib at 5 mg/kg.
During the dose-escalation phase of the study, 9 dose levels were explored to determine the maximum-tolerated dose of lifirafenib plus mirdametinib, the recommended phase 2 dose, and the pharmacokinetics. This was a coprimary end point of the study along with the incidence and severity of adverse events (AEs), the incidence of DLTs, and ORR.
Treatment with lifirafenib plus mirdametinib occurred in 28-day cycles. In the level 1 dose cohort, patients received 2 mg of mirdametinib once daily (QD) with lifirafenib 15 mg QD. Patients in the level 2 cohort received mirdametinib 2mg QD plus lifirafenib 20 mg QD. Dosing in levels 1 and 2 was continuous.
At levels 3a and 4a, patients were treated on a 5 days on and 2 days off basis. Mirdametinib was dosed at 3 mg QD in level 3 and administered with lifirafenib 20 mg QD. Patients in the level 4a cohort received mirdametinib 4 mg QD plus lifirafenib 20 mg QD.
Patients in cohorts 3b through 5c where administered lead-dosing on the 5 days on and 2 days off scheduled for 14 days followed by 5 days on and 2 days off for each intermittent 28-day cycle. The dose of treatment with mirdametinib across cohorts 3b through 5c ranged from 2 mg to 4 mg and was dose twice daily in all cohorts except 3b, which received the QD mirdametinib. The dose of lifirafenib treatment in cohorts 3b through 5c ranged from 15 mg QD to 20 mg QD.
Those treated with lifirafenib plus mirdametinib had a median age of 55.9 years (range, 23-78). The study population was 75% female and 79% of patients were White. Patients had an ECOG performance status of either 0 or 1, and had received a median of 1 (range, 1-18) prior lines of therapy. In terms of primary cancer type, the majority of patients had ovarian cancer (44%), followed by non–small cell lung cancer (NSCLC; 18%), colorectal cancer (13%), endometrial cancer (6%), melanoma (3%), pancreatic cancer (1%), and other (16%). Mutation types varied, but the majority had either KRAS mutations (57.7%), BRAF mutations (18.3%), or NRAS mutations (11.3%).
Confirmed objective responses to lifirafenib plus mirdametinib were observed in 22.6% of patients in the study. Solomon noted during his AACR presentation that the responses observed were durable and lasting more than 12 months and even 24 months, in some cases. Results were reported by tumor type and mutation type.
“Across the study responses were seen in patients with low-grade serious or ovarian cancer, NSCLC, and endometrial cancer. No responses were seen in patients with colorectal cancer. Looking across responses, according to mutations, responses was seen in patients with BRAF mutations, KRAS and NRAS mutations,” explained Solomon. “A tumor type that appeared to be particularly sensitive was low-grade serous ovarian cancer. Seventeen patients with low-grade serous ovarian cancer were enrolled on study,” he added.
In terms of safety, the most commons any-grade AEs observed were dermatitis acneiform (42.3%), fatigue (32.4%), and diarrhea (26.8%). The most common grade ≥3 AE was thrombocytopenia and platelet count decrease (5.6%).
Overall, 87.3% of the treatment-related AEs were from lifirafenib and 88.7% were from mirdametinib. Serious AEs related to lifirafenib treatment were seen in 42.3% of patients and SAEs from mirdametinib were observed in 14.1%. DLT TEAEs occurred in 9.9% of patients overall. These TEAEs lead to dose modification in 57.7%, discontinuation of treatment in 5.6%, and death in 5.6%.
Based on these findings, Solomon concluded that the low-grade serous ovarian cancer, NSCLC, and endometrial cancer patient population who harbor BRAF and KRAS mutations may be sensitive to the combination of lifirafenib and mirdametinib. Further study on the benefit-risk profile of the combination is warranted.
The study will be advancing to the dose-expansion phase during the second half of 2023. This portion of the study will take a tumor agnostic approach to investigations a biomarker-selected group of patients, Solomon announced.
Solomon, B, Gao B, Subbiah V, et al. Safety, pharmacokinetics, and antitumor activity findings from a phase 1b, open-label, dose-escalation and expansion study investigating RAF dimer inhibitor lifirafenib in combination with MEK inhibitor mirdametinib in patients with advanced or refractory solid tumors. Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, FL. Abstract CT033.