Phase IB Study of Osimertinib in Combination with Navitoclax in EGFR-mutant NSCLC Following Resistance to Initial EGFR Therapy (ETCTN 9903)

Abstract

Purpose: Osimertinib is an effective therapy in EGFR-mutant non–small cell lung cancer (NSCLC), but resistance invariably develops. Navitoclax is an oral inhibitor of BCL-2/BCL-xL that has exhibited synergy with osimertinib in preclinical models of EGFR-mutant NSCLC. In hematologic malignancies, BCL-2 family inhibitors in combination therapy effectively increase cellular apoptosis and decrease drug resistance. Patients and Methods: This single-arm phase Ib study evaluated safety, tolerability, and feasibility of osimertinib and navitoclax, including dose expansion in T790M-positive patients at the recommended phase II dose (RP2D). Eligible patients had advanced EGFR-mutant NSCLC with prior tyrosine kinase inhibitor exposure. Five dose levels were planned with osimertinib from 40 to 80 mg orally daily and navitoclax from 150 to 325 mg orally daily. Results: A total of 27 patients were enrolled (18 in the dose-escalation cohort and nine in the dose-expansion cohort): median age 65, 67% female, 48% exon 19 del, and 37% L858R, median one prior line of therapy. The most common adverse events were lymphopenia (37%), fatigue (22%), nausea (22%), and thrombocytopenia (37%). No dose-limiting toxicities were seen in dose-escalation cohort; osimertinib 80 mg, navitoclax 150 mg was chosen as the RP2D. Most patients (78%) received >95% of planned doses through three cycles. In expansion cohort, objective response rate was 100% and median progression-free survival was 16.8 months. A proapoptotic effect from navitoclax was demonstrated by early-onset thrombocytopenia. Conclusions: Oral combination therapy with navitoclax and osimertinib was safe and feasible at RP2D with clinical efficacy. Early thrombocytopenia was common, supporting an target engagement by navitoclax. Further study of BCL-2/BCL-xL inhibition to enhance osimertinib activity is warranted.

Resistance mechanisms to osimertinib and emerging therapeutic strategies in nonsmall cell lung cancer

“…A phase II trial of gefitinib with chemotherapy or antiangiogenesis as front-line therapy is no-going in BIM-del EGFR-mutant NSCLC patients (NCT03267654). Other potential drugs like selective BCL-2/BCL-xL inhibitors, as proapoptotic agents, could re-sensitize resistant cell lines to osimertinib in vitro and improve PFS in pretreated T790M patients [33][34][35]. Clinical trials are needed in EGFRmutant patients with BIM-del.…”

Senolytic-Mediated Elimination of Head and Neck Tumor Cells Induced Into Senescence by Cisplatin

“…One concern regarding ABT-263 in the clinic is the thrombocytopenia that has been a predominant dose limiting toxicity as both a monotherapy and in combination. This has been managed successfully in several recent trials, allowing for tolerated and biologically active combinations with kinase inhibitors such as Osimertinib (Bertino et al, 2021) and ruxolitinib (Harrison et al, 2019). However, neutropenia has been reported as a dose limiting toxicity when navitoclax was administered with chemotherapy (Puglisi et al, 2011); this toxicity has been particularly limiting for these combinations, none of which have progressed beyond Phase 1.…”

Preclinical Models for Acquired Resistance to Third-Generation EGFR Inhibitors in NSCLC: Functional Studies and Drug Combinations Used to Overcome Resistance

“…Clinical trials studying oral combination therapy with navitoclax and osimertinib in advanced EGFR-mutant NSCLC with prior TKI treatment have reported an ORR of up to 100% and a median PFS of 16.8 months. However, thrombocytopenia and lymphopenia were the most common adverse events (37%) observed in the study ( 110 ). Finally, it was found that C-FLIP knockdown restored osimertinib-induced apoptosis in resistant cells ( Table 1 ), suggesting that C-FLIP depletion may be an effective strategy to overcome osimertinib resistance in NSCLC ( 44 , 111 ).…”