Phase 2 Study of Osimertinib + Oleclumab in Progressive T790M-Negative EGFR-Mutated NSCLC

The combination of a novel CD73 inhibitor, oleclumab, and osimertinib was well tolerated and effective in patients with advanced EGFR-mutated and T790M-negative non–small-cell lung cancer (NSCLC).

Patients with EGFR-mutated T790M-negative non–small-cell lung cancer (NSCLC) who experience progressive disease after treatment with an EGFR tyrosine kinase inhibitor (TKI) have few therapy options. CD73, which may promote immune evasion, is overexpressed in EGFR-mutated NSCLC, suggesting the potential for combining CD73 blockers with EGFR TKIs. Oleclumab (MEDI9447) disrupts immune evasion by binding to CD73. To evaluate the safety and efficacy of oleclumab plus osimertinib in locally advanced/metastatic EGFR-mutated NSCLC, a phase 1b/2, multicenter, dose-escalation, dose-expansion study was conducted.1

Patients who enrolled in this clinical trial had histologically or cytologically confirmed T790M-negative EGFR-mutated NSCLC by local testing, a TKI-sensitive EGFR mutation (ie, exon 19 del, L858R), Eastern Cooperative Oncology Group performance status score of 0 or 1, disease progression on or after a first- or second-generation TKI, and no prior osimertinib. Intravenous oleclumab 1500 mg (dose level 1) or 3000 mg (recommended phase 2 dose) every 2 weeks was combined with daily oral osimertinib 80 mg until disease progression or intolerable adverse events (AEs).1

The primary study end points included AEs, serious AEs, and overall response rate (ORR) by RECIST version 1.1. Dose-limiting toxicities were predefined and reviewed by a dose-escalation committee. Secondary end points included duration of response, disease control rate, progression-free survival (PFS), and overall survival.1

As of November 9, 2020, 5 patients received oleclumab at dose level 1 and 21 patients received the recommended phase 2 dose. Minimum patient follow-up was 44 weeks. For the 5 patients receiving dose level 1, the safety profile and response rate were generally similar to the recommended phase 2 dose. No dose-limiting toxicities occurred.1

All 21 patients who received the recommended phase 2 dose of oleclumab had ≥1 treatment-emergent AEs, with 38% experiencing severe (grade 3/4) treatment-emergent AEs. Treatment-related AEs occurred in 81% (19% grade 3/4); none was deemed serious, and there were no patient deaths. The most common treatment-related AEs were rash (33%), stomatitis (29%), diarrhea (24%), and paronychia (24%).1

At data cutoff, 38% of patients remained on treatment; 48% discontinued due to progressive disease, with death, patient decision and AE (pneumonitis) as other causes. The ORR for patients receiving the recommended phase 2 dose of oleclumab plus osimertinib was 19% (all partial responses), while median PFS was 11 months (95% confidence interval, 3.7 months-not evaluable). The disease control rate at the recommended phase 2 dose was 81%.1

Researchers concluded that the combination of oleclumab, a CD73 inhibitor, and osimertinib was well tolerated at the recommended phase 2 dose. Compared with T790M-negative EGFR-mutated NSCLC patients in a prior study of osimertinib monotherapy, the ORR was similar while median PFS was longer (11 months [oleclumab + osimertinib] vs 2.8 months [osimertinib monotherapy]).1

1. Kim D-W, Kim S-W, Camidge DR, et al. CD73 inhibitor oleclumab plus osimertinib for advanced EGFRm NSCLC: first report of a phase 1b/2 study. Presented at: American Association of Cancer Research Annual Meeting 2021; April 10-15, 2021. Abstract CT163.