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.

Figure 1:. Feasibility of combination therapy and progression-free survival.

Swimmers plot demonstrating progression-free survival for each subject in the expansion phase including duration of each individual therapy. 7 of 9 continued navitoclax and 9 of 9 continued osimertinib until progression. 5 of 9 patients have ongoing progression-free survival as indicated by arrows.

Figure 2:. Platelet count trends by dose level.

Graph of platelet counts from serial complete blood counts (CBC) collected at baseline, day 3, and then weekly after first dose of navitoclax. Platelet counts demonstrate pro-apoptotic effect of navitoclax on platelets across a range of doses, including dose level 1 (A), dose level 2 (B), dose level 3 (C), expansion cohort (D).

Figure 3:. Tumor response to osimertinib and navitoclax.

Waterfall plots of best tumor response as measured by percentage reduction in sum of tumor diameters relative to baseline for patients in the (A) dose escalation cohort and (B) expansion cohort treated at the recommended phase 2 dose of osimertinib and navitoclax.

Figure 4:. Circulating tumor DNA (ctDNA) analyses.

(A) Scatterplot of baseline EGFR allele frequency (AF). Of 27 patients enrolled, ddPCR detected EGFR exon 19 deletion or L858R driver mutation in 19 patients (70.4%) in pre-treatment plasma. Exon 19 deletion was detected in 12 patients (44.4%) and L858R in 7 patients (25.9%). Eight patients did not have detectable EGFR mutation by ddPCR. (B) Percent change in allele frequency (AF) from baseline to cycle 2 in all patients. In the expansion cohort, 100% (7 of 7) had clearance of detectable EGFR mutation in plasma.