Oleclumab Plus Osimertinib Show Early Activity and Tolerability EGFR-Mutant NSCLC

The combination of oleclumab (MEDI9447) and osimertinib (Tagrisso) was well-tolerated and demonstrated preliminary anti-tumor activity in patients with non-small-cell lung cancer (NSCLC) with an epidermal growth factor receptor mutation (EFGR) mutation after progression on an EGFR tyrosine kinase inhibitor (TKI), according to results from a phase 1B/2 study presented in a poster during the American Association for Cancer Research Annual Meeting 2021.

CD73 is often overexpressed in EGFR-mutant NSCLC and is a potential therapeutic target. The overexpression of CD73 is an independent indicator of poor prognosis. Inhabitation of CD73 may both inhibit tumor growth in vivo and increase sensitivity to EGFR TKIs in NSCLC tumor cells. Oleclumab is meant to bind to CD73. Osimertinib is a third-generation EGFR TKI inhibitor.

The non-randomized phase 1b/2 study (NCT03381274) enrolled 43 patients. Primary outcomes included incidence of adverse events (AEs) as a measure of safety and objective response rate as a measure of anti-tumor activity in the dose-expansion phase. Secondary outcomes included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), objective response by T790M status, disease control by TM90M status, serum oleclumab levels, serum osimertinib concentration levels, serum oleclumab concentration levels, and the development of detectable anti-drug antibody to oleclumab.

The study had 2 arms. In experimental arm A, patients received oleclumab and osimertinib. In experimental arm B, patients received oleclumab and AZD4635.

In order to participate, Patients must be 18 years old or older, weigh 35 kg or more, have an EGOG performance status of 0 or 1, and are diagnosed with histologically or cytologically confirmed locally advanced/metastatic NSCLC with EGFR mutation. Patients who were the recipients and EGFR TKI within 14 days of the first dose of the study treatment, the recipient of any conventional or investigation anticancer therapy not otherwise specified within 21 days of the planned first dose, prior receipt of any investigation immunotherapy, or concurrent enrollment in another therapeutic clinical study are not eligible to participate. 

As of November 9, 2020, 5 patients were receiving 1500 mg IV of oleclumab every 2 weeks (Q2W) and 80 mg of osimertinib once daily (QD). Additionally, 21 patients were treatment with the investigational combination at the recommended phase 2 doses (RP2D) 3000 mg IV of oleclumab Q2W and 80 mg of osimertinib QD. This group included 6 patients who were in the dose-escalation phase and 15 in the dose-expansion phase, respectively.

Treatment with oleclumab and osimertinib achieved an ORR of 40% in the 5 patients who received DL1. Responses included partial responses (PRs) and stable disease (SD) in 40% of patients each. Twenty percent of patients in the cohort were not evaluable for response. The DOR observed with the combination was not assessable (NA; range, 4.8-18.1). The DCR in this cohort was 80%.

No dose-limiting toxicities were reported in the 5 patients treated at DL1.

In the cohort of patients who received the RP2D of oleclumab plus osimertinib, the ORR was 19% and consisted of PRs in 19% of the responders, and SD in 61.9%. In addition, progressive disease was observed in 14.3% of patients, and the remaining 4.8% of the cohort was not evaluable for response. The median DOR was also NA in this cohort (range, 9.2-11.1 months). The DCR was 81%.

Investigators noted that overall, responses were similar between DL1 and the RP2D.

Survival was also assessed in the study at both dose levels. In the DL1 cohort, the median PFS observed was 6.5 months (95% CI, 1.4-19.8). The 6-month PFS rate in the DL1 cohort was 53.3% (95% CI, 6.8%-86.3%), and the 9-month PFS rate was 26.7% (95% CI, 1.0%-68.6%). The median OS seen at DL1 was 21.9 months (95% CI, 1.4 to not estimable [NE]). The 6-month and 9-month OS rate were equivalent at 80% (95% CI, 20.4%-96.9%).

The median PFS among patients who received the RP2D was 11 months (95% CI, 3.7-NE). At 6 months, the PFS rate was 63.5% (95% CI, 38.3%-80.7%), and the 9-month PFS rate was 52.9% (95% CI, 29.0%-72.1%). At the RP2D, the median OS for the combination of oleclumab plus osimertinib was NR (95% CI, 11.7-NE). The 6-month OS rate in cohort was 100% in the RP2D cohort (95% CI, 100%-100%), and the 9-month OS rate 90% (95% CI, 65.6%-97.4%).

The median age of the patients in the lower-dose arm, DL1, was 62 and 58 in the higher-dose arm, RP2D. In the lower-dose arm, 80% of participants were Asian and 20% were White. In the higher-dose arm, 90.5% were Asian and 9.5 were white. In the lower-dose arm, 100% of patients had an ECOG score of 1. In the higher-dose arm, 95.2% had an ECOG score of 1. In the low dose group, the median number of prior treatments was 5. In the higher-dose group, it was 2. The minimum follow-up was 44 weeks.

The rate of treatment-related AEs (TRAEs) was similar between the high-dose and the low-dose. In both groups, 5% or more patients had a TRAE of any severity. In the high-dose group, 33.3% of patients experienced rash, 28.6% experienced stomatitis, and 23.3% experienced diarrhea. Paronychia occurred in 60% of the low-dose group. In the high dose group 23.3% of patients experienced the AE and 4.8% experienced grade 3/4 paronychia.

The study of oleclumab plus osimertinib is ongoing. Based on the results observed, the study investigators believe that further evaluation of the combination may be warranted for patients with locally advanced or metastatic T790M-negative, EGFR-positive NSCLC.

REFERENCE:

Kim D, Kim S, Camidge D, et al. CD73 inhibitor oleclumab plus osimertinib for advanced EGFRm NSCLC: First report of a Phase 1b/2 study. Abstract presented at the AACR Annual Meeting 2021. April 9-14. Accessed April 29, 2021.