Journal Publication

Ascentage's pelcitoclax pairs with osimertinib but stalls in resistant NSCLC

A phase 1b trial found the BCL-2/BCL-xL inhibitor drove an 80.8% response rate in TKI-naive patients but only 10.7% after resistance had already set in.

By AppliedXLJuly 13, 2026Trial NCT04001777

Executive Summary

The combination produced a clear response signal in patients who had never received a TKI, but that signal narrowed sharply once patients had already progressed on a third-generation TKI.
The trial identified a recommended dose for further study after one dose-limiting toxicity emerged at a higher dose level, closing out the safety question the design was built to answer.
A BCL-xL expression subgroup showed longer progression-free survival in the resistant cohort, a result that did not reach statistical significance but points to where the drug might work best.
The findings sharpen where pelcitoclax plus osimertinib might add value, favoring earlier, treatment-naive use over deployment after resistance has already taken hold.

The trial

The phase 1b trial (NCT04001777) tested pelcitoclax, a BCL-2/BCL-xL inhibitor, alongside osimertinib in EGFR-mutated advanced non-small-cell lung cancer, enrolling patients across three cohorts defined by prior treatment history: progression after third-generation TKI plus chemotherapy, progression after first- or second-generation TKI plus chemotherapy, and TKI-naive disease. The registered primary endpoints were maximum tolerated dose and recommended phase 2 dose in the dose-escalation portion, and objective response rate and safety in the dose-expansion portion. BCL-2/BCL-xL+1

How it was done

The study was an open-label, single-arm, multicenter design run in two stages: dose-finding using a 3+3 escalation scheme, and dose-expansion across the three treatment-history cohorts. Sixty-four patients were enrolled, 13 in dose-escalation and 51 in dose-expansion, split into 29 patients previously progressed on third-generation TKI plus chemotherapy, 8 previously progressed on first- or second-generation TKI plus chemotherapy, and 27 TKI-naive. Patients received intravenous pelcitoclax weekly, at 160 mg in dose-expansion and either 160 mg or 240 mg in dose-escalation, plus oral osimertinib 80 mg daily. Response was assessed by RECIST 1.1. BCL-2/BCL-xL+1

The result

One dose-limiting toxicity occurred at the 240 mg pelcitoclax dose, and the recommended phase 2 dose was set at 160 mg weekly plus osimertinib 80 mg daily. In the cohort that had already progressed on third-generation TKI plus chemotherapy, the objective response rate was 10.7% with median progression-free survival of 2.7 months. In TKI-naive patients, the objective response rate reached 80.8% with a median progression-free survival of 16.4 months. BCL-2/BCL-xL

Biomarker signal

Within the resistant cohort, patients with high BCL-xL expression had longer median progression-free survival than those with low expression, 4.2 months versus 2.7 months, though the difference did not reach the conventional significance threshold (p=0.058). That the biomarker split moved in the expected direction, toward benefit concentrated where the target is more highly expressed, gives a mechanistic anchor for how the drug might be used going forward even though the resistant-cohort response rate overall stayed low. BCL-2/BCL-xL

Landscape

Ascentage runs pelcitoclax as its only trial pairing a BCL-2/BCL-xL inhibitor with osimertinib in NSCLC, and BCL-2-targeted trial activity generally has declined, with 63 recent trials against 290 older ones in the target's broader history. The company's other BCL-2-family programs, including lisaftoclax and alrizomadlin, run in blood cancers rather than tumors confined to a single organ, and competing NSCLC trials in this landscape target EGFR, KRAS, MET, and immune checkpoints rather than BCL-2. Osimertinib itself remains in active testing across multiple combination trials sponsored by AstraZeneca, underscoring that TKI resistance in EGFR-mutated NSCLC remains an active area without a validated combination strategy to reverse it.

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