Phase Ib Study of Combination Therapy with MEK Inhibitor Binimetinib and Phosphatidylinositol 3-Kinase Inhibitor Buparlisib in Patients with Advanced Solid Tumors withRAS/RAFAlterations

Abstract

Background This multicenter, open‐label, phase Ib study investigated the safety and efficacy of binimetinib (MEK inhibitor) in combination with buparlisib (phosphatidylinositol 3‐kinase [PI3K] inhibitor) in patients with advanced solid tumors with RAS/RAF alterations. Materials and Methods Eighty‐nine patients were enrolled in the study. Eligible patients had advanced solid tumors with disease progression after standard therapy and/or for which no standard therapy existed. Evaluable disease was mandatory, per RECIST version 1.1 and Eastern Cooperative Oncology Group performance status 0‐2. Binimetinib and buparlisib combinations were explored in patients with KRAS‐, NRAS‐, or BRAF‐mutant advanced solid tumors until the maximum tolerated dose and recommended phase II dose (RP2D) were defined. The expansion phase comprised patients with epidermal growth factor receptor (EGFR)‐mutant, advanced non‐small cell lung cancer, after progression on an EGFR inhibitor; advanced RAS‐ or BRAF‐mutant ovarian cancer; or advanced non‐small cell lung cancer with KRAS mutation. Results At data cutoff, 32/89 patients discontinued treatment because of adverse events. RP2D for continuous dosing was buparlisib 80 mg once daily/binimetinib 45 mg twice daily. The toxicity profile of the combination resulted in a lower dose intensity than anticipated. Six (12.0%) patients with RAS/BRAF‐mutant ovarian cancer achieved a partial response. Pharmacokinetics of binimetinib were not altered by buparlisib. Pharmacodynamic analyses revealed downregulation of pERK and pS6 in tumor biopsies. Conclusion Although dual inhibition of MEK and the PI3K pathways showed promising activity in RAS/BRAF ovarian cancer, continuous dosing resulted in intolerable toxicities beyond the dose‐limiting toxicity monitoring period. Alternative schedules such as pulsatile dosing may be advantageous when combining therapies. Implications for Practice Because dysregulation of the mitogen‐activated protein kinase (MAPK) and the phosphatidylinositol 3‐kinase (PI3K) pathways are both frequently involved in resistance to current targeted therapies, dual inhibition of both pathways may be required to overcome resistance mechanisms to single‐agent tyrosine kinase inhibitors or to treat cancers with driver mutations that cannot be directly targeted. A study investigating the safety and efficacy of combination binimetinib (MEK inhibitor) and buparlisib (PI3K inhibitor) in patients harboring alterations in the RAS/RAF pathway was conducted. The results may inform the design of future combination therapy trials in patients with tumors harboring mutations in the PI3K and MAPK pathways.

The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling

“…Although not currently specific to patients with prostate cancer, clinical trials exploring co-inhibition of the PI3K-AKT-mTOR and MAPK cascades to treat various advanced solid cancers have also been developed (e.g., ClinicalTrials.gov identifiers: NCT01390818, NCT01347866, and NCT02583542), although response rates appear to be low and are linked to RAS and RAF mutations [ 277 ]. For example, a recent Phase Ib study of combination therapy with the MEK1/2 inhibitor binimetinib (Mektovi) and the pan-PI3K inhibitor Buparlisib (BKM120) in advanced solid tumors reported promising efficacy in patients with advanced ovarian cancer with RAS / RAF genetic alterations, however continuous dosing resulted in intolerable toxicities and an intermittent schedule is suggested for future trials [ 278 ]. Additionally, the MATCH screening trial (targeted therapy directed by genetic testing in treating patients with advanced refractory solid tumors, lymphomas, or multiple myeloma, ClinicalTrials.gov identifier: NCT02465060) will investigate the efficacy of MEK and PI3K inhibitors as monotherapies in patients with progressive disease that carries a genetic alteration in either the RAS/MAPK or the PI3K-AKT-mTOR pathways respectively.…”

MEK inhibitor resistance mechanisms and recent developments in combination trials

“…These results have led to a number of clinical trials combining PI3K pathway inhibitors with MEKi across a variety of cancers. Many of these studies have found an initial positive tumor response with cancers responding better than monotherapy alone, but these studies have run into issues regarding dose toxicity for longer-term treatment [84][85][86]. Similarly, studies targeting the Hippo pathway through YAP inhibition after MEKi treatment showed positive results in BRAF-mutant tumor cell lines, and combination treatment was able to overcome acquired resistance to MEKi [64].…”

<p>Anlotinib Exerts Anti-Cancer Effects on KRAS-Mutated Lung Cancer Cell Through Suppressing the MEK/ERK Pathway</p>

“…4,5 Mutations in KRAS constitutively activate its downstream signaling pathways 6 such as MEK/ERK, a mitogen-activated protein kinase (MAPK) pathway, this is known to promote cancer cell survival and chemoresistance. 7,8 KRAS mutations correlate significantly to poor therapeutic response in NSCLC patients. [9][10][11] Therefore, it is essential to develop novel KRAS-targeting drugs for treating recalcitrant NSCLC patients with KRAS mutations.…”