First-Line Treatment of EGFR and ALK Wild-Type Advanced/Metastatic NSCLC: Refined Endpoints and Statistical Analysis Plan in the Phase III MYSTIC Study

China regulatory submission opportunity strengthened with the expansion of the phase III NEPTUNE study and the initiation of the new Asia-focused phase III PEARL trial

On 17 January 2017, AstraZeneca provided an update on its immuno-oncology late-stage clinical development programme in first-line non-small cell lung cancer (NSCLC), including a refinement in endpoints and statistical analysis plan in the phase III MYSTIC trial.

The MYSTIC trial was initially designed to assess the benefit of durvalumab monotherapy and durvalumab and tremelimumab combination therapy versus standard of care chemotherapy, focused on progression-free survival (PFS).

The MYSTIC trial will now assess PFS and overall survival (OS) endpoints in patients with PDL1-expressing tumours for both durvalumab monotherapy and the combination of durvalumab plus tremelimumab, as well as in ‘all comers’ for the combination of durvalumab plus tremelimumab, versus standard of care chemotherapy.

While the focus remains on exploring the benefit of durvalumab plus tremelimumab as combination therapy, the company has updated the endpoints of the MYSTIC trial to include OS and PFS in durvalumab monotherapy. According to the company statement, this is based on recent internal and external data, including durvalumab’s strong efficacy in monotherapy presented at recent medical meetings, as well as significant opportunities in the competitive landscape.

The estimated primary completion date has been updated to reflect both an increase in patient recruitment (as reported in February 2016 with the inclusion of OS as a co-primary endpoint) and the event-based nature of the trial. As a result, the company anticipates MYSTIC PFS data in mid-2017 and final OS data at the latest in 2018. MYSTIC also includes several undisclosed interim analyses for OS.

Additionally, the ongoing phase III NEPTUNE trial will be expanded with local patients to support regulatory submission of durvalumab plus tremelimumab combination therapy in China for first-line NSCLC patients without delaying the anticipated OS data readout in 2018 from the global cohort, which is approaching full recruitment. The company has also initiated the new phase III PEARL trial of durvalumab monotherapy versus standard of care chemotherapy in first-line NSCLC patients whose tumours express PD-L1. The PEARL trial focuses on Asian countries, primarily China, due to the high prevalence of NSCLC in the region.

All amendments will be reflected in updates to clinical trials websites, including clinicaltrials.gov.

The MYSTIC trial is a randomised, open-label, multi-centre, global, phase III trial of durvalumab in combination with tremelimumab or durvalumab monotherapy versus standard of care platinum-based chemotherapy in first-line treatment of patients with EGFR and ALK wild-type advanced or metastatic NSCLC.

The NEPTUNE trial is a randomised, open-label, multi-centre, global, phase III trial of durvalumab in combination with tremelimumab versus standard of care platinum-based chemotherapy in first-line treatment of patients with EGFR and ALK wild-type advanced or metastatic NSCLC.

The PEARL trial is a randomised, open-label, multi-centre phase III trial of durvalumab monotherapy versus standard of care chemotherapy in first-line treatment of patients with EGFR and ALK wild-type advanced or metastatic PD-L1-expressing NSCLC. The trial was initiated to determine the efficacy and safety of durvalumab in Asian countries, some of which have the highest current NSCLC burden, with over 1.1 million new cases projected for China alone in 2030.

Durvalumab is an investigational human monoclonal antibody directed against PD-L1. Durvalumab received US Food and Drug Administration (FDA) Breakthrough Therapy Designation in patients with PD-L1 positive inoperable or metastatic urothelial carcinoma in 2016 and Fast Track Designation in 2015 for the treatment of patients with PD-L1 positive metastatic head and neck squamous cell carcinoma. The durvalumab biological license application in second-line urothelial carcinoma has been accepted by the FDA with a PDUFA date in the second quarter of 2017.