Durvalumab Plus Chemotherapy in Patients With -Mutated Advanced NSCLC Whose Disease Progressed on First-Line Osimertinib: ORCHARD.

[INTRODUCTION] ORCHARD (NCT03944772) was a phase II, biomarker-directed platform study designed to characterize resistance mechanisms and evaluate novel therapy combinations after progressive disease (PD) on first-line osimertinib. We report results of the module assessing durvalumab plus chemotherapy.

[METHODS] Patients with epidermal growth factor receptor ()-mutated non-small cell lung cancer (NSCLC) with PD on first-line osimertinib whose tumors did not harbor a prespecified alteration by next-generation sequencing of a post-osimertinib biopsy, or for whom a biomarker-matched treatment was not available, were eligible. Patients received 4 to 6 cycles of durvalumab 1500 mg plus carboplatin target area under the curve 5 and pemetrexed 500 mg/m. After platinum-based chemotherapy, patients without PD could continue to receive durvalumab plus pemetrexed maintenance. Primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 by investigator assessment.

[RESULTS] Overall, 25 patients received more than or equal to 1 dose of durvalumab plus chemotherapy; all had discontinued treatment at the primary analysis data cutoff. Confirmed ORR was 16% (80% confidence interval [CI]: 7-30); response was maintained for more than 6 months in the four patients with confirmed response. Furthermore, 22 patients (88%) had PD and median progression-free survival was 4.8 months (95% CI: 2.6-7.6). Ten patients (40%) had died, and median overall survival was 23.4 months (95% CI: 8.8-not calculable). Nine patients (36%) had grade 3 or higher adverse events, most often neutrophil count decreased (20%).

[CONCLUSIONS] Durvalumab plus chemotherapy demonstrated limited clinical benefit for -mutated NSCLC after PD on first-line osimertinib. Although the combination was well tolerated, the overall risk-benefit profile did not warrant further evaluation.