alisertib + osimertinib

Based on the search results, I can provide the following information about the drug combination alisertib + osimertinib: The combination of alisertib and osimertinib is being studied for the treatment of EGFR-mutated non-small cell lung cancer (NSCLC) that has progressed on osimertinib monotherapy. This combination targets two different pathways involved in cancer growth and resistance mechanisms. ## Mechanism of Action Alisertib is an oral, selective, small-molecule inhibitor of Aurora Kinase A (AURKA)[1]. AURKA activation has been identified as a mechanism of resistance to osimertinib[1]. By inhibiting AURKA, alisertib may help overcome resistance to osimertinib treatment. Osimertinib is a third-generation Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) that is effective for the treatment of advanced EGFR-mutated lung adenocarcinoma (LUAD)[1]. It works by blocking the action of mutant EGFR proteins that drive cancer growth[2]. ## Clinical Development A phase I/Ib study (NCT04085315) evaluated this combination in patients with advanced EGFR-mutated lung cancer who experienced disease progression on prior osimertinib monotherapy[1][2]. The study enrolled 21 evaluable patients, with 10 patients in the dose escalation phase and 11 patients in the dose expansion phase[3]. In the dose escalation phase, alisertib was administered using an intermittent dosing strategy of either 30 mg (n=6) or 40 mg (n=4) twice daily on days 1-3, 8-11, and 15-17 of a 28-day cycle, in combination with osimertinib 80 mg daily[1][3]. The maximum tolerated dose (MTD) and recommended phase II dose (RP2D) was determined to be alisertib 30 mg BID with the intermittent dosing schedule in combination with osimertinib 80 mg daily[3][6]. ## Safety Profile The most common treatment-related adverse events included: - Neutropenia (42.9%) - Anemia (42.9%) - Diarrhea (38.1%) - Lymphopenia (33.3%) - Fatigue (60%) - Alopecia (50%)[3][6] Grade 3 or higher adverse events included neutropenia (4.8%), anemia (4.8%), diarrhea (14.3%), and lymphopenia (4.8%)[3]. ## Efficacy In the phase I portion of the trial, the objective response rate (ORR) was 10% (1/10) and the disease control rate (DCR) was 70% (7/10), with 60% (6/10) of patients achieving stable disease[6]. The median progression-free survival (PFS) was 9.4 months[6]. Interestingly, the study found promising efficacy signals in patients who are TP53 wild type, as TP53 is known to be involved in the aurora kinase pathway[3]. Based on these findings, the protocol was modified to limit further enrollment to patients who are TP53 wild type[3]. The combination of alisertib and osimertinib appears to demonstrate an acceptable toxicity profile and may result in clinically meaningful disease control in EGFR-mutated lung adenocarcinoma patients whose disease is resistant to osimertinib monotherapy[6].