Phase 2 Randomized Trial of Durvalumab Followed by Chemotherapy Versus Chemotherapy Followed by Durvalumab in Elderly Patients with Advanced NSCLC

Primary objective: evaluate the preliminary efficacy of the experimental sequencing strategy, measured as 12‑month overall survival, compared with standard sequencing in elderly patients with advanced non‑small cell lung cancer (NSCLC) and PD‑L1 ≥ 25 % or unknown, and assess safety by determining death rate within 4 months of randomization.

Secondary objectives: compare the two treatment arms regarding first progression‑free survival, health‑related quality of life (EORTC QLQ‑C30 + LC13), toxicity profile (CTCAE v5.0 and PRO‑CTCAE), objective response rate (RECIST v1.1 and iRECIST), and second progression‑free survival; explore the predictive value of baseline tumor mutation burden in blood; evaluate the prognostic and predictive significance of comprehensive geriatric assessments (ADL, IADL, G8, CIRS, gait speed); and investigate additional clinical, tumor‑derived, or circulating biomarkers and their interaction with treatment.

The trial enrolled elderly individuals (≥70 years) of both sexes with histologically confirmed advanced NSCLC, stage IV or IIIC with supraclavicular metastases, and tumor PD‑L1 expression ≥25 % or unknown. Participants were required to have an ECOG performance status of 0–1, life expectancy greater than three months, and adequate renal, hepatic, and bone‑marrow function as defined by laboratory thresholds. Selection was based on these clinical and laboratory criteria, and all subjects provided written informed consent prior to screening. The population was characterized as vulnerable due to advanced age and disease stage. The sponsor did not provide the total number of participants.

The MILES 5 study is a randomized, controlled phase 2 trial evaluating first‑line durvalumab followed at progression by standard chemotherapy versus standard chemotherapy followed at progression by durvalumab in elderly patients (≥70 years) with advanced non‑small cell lung carcinoma, PD‑L1 expression ≥25 % or unknown. Eligible participants undergo a screening visit to confirm eligibility criteria, after which they are randomized 1:1 to one of the two treatment sequences. The investigational arm receives durvalumab 1500 mg intravenously every 4 weeks; upon disease progression, patients receive investigator‑selected chemotherapy (pemetrexed, carboplatin, cisplatin, paclitaxel, vinorelbine, or gemcitabine) according to standard dosing. The comparator arm receives standard chemotherapy from the outset, followed by durvalumab 1500 mg at progression. Treatment cycles are administered every 3–4 weeks, with clinical and radiologic assessments performed at baseline, every 8 weeks during therapy, and at each progression event. Follow‑up visits continue every 12 weeks after treatment discontinuation to capture survival status, quality‑of‑life outcomes, and safety data up to at least 12 months post‑randomization, culminating in an end‑of‑study visit. Participant involvement therefore extends from screening through the end‑of‑study assessment, typically spanning 12–18 months. Early termination may occur due to death, withdrawal of consent, unacceptable toxicity (grade ≥ 3 adverse events per CTCAE v5.0), or clinical decisions to pursue alternative therapy. Primary efficacy endpoints are 12‑month overall survival and 4‑month mortality rate; secondary endpoints include progression‑free survival, quality of life (EORTC C30 + LC13), toxicity profile, objective response rate, and second progression‑free survival.

Durvalumab is supplied in the pharmaceutical form PHF00230MIG for intravenous use. The administered dose is 1500 mg per infusion. In the experimental arm, durvalumab is given as first‑line therapy; in the comparator arm it is administered after disease progression on standard chemotherapy. Infusions are performed according to the protocol‑defined schedule, and adherence to the dosing regimen is verified by review of infusion records and drug accountability logs.

Pemetrexed disodium is provided as PHF00200MIG for intravenous administration at a dose of 500 mg/m² per infusion. It is used as part of the standard chemotherapy regimen in the comparator arm. The drug is administered on the designated treatment day of each chemotherapy cycle, with compliance monitored through documented administration times and dosage calculations based on body surface area.

Carboplatin is supplied in the pharmaceutical form PHF00230MIG for intravenous use at a fixed dose of 450 mg per infusion. It is incorporated into the standard chemotherapy combinations used in the comparator treatment sequence. Dosing is recorded in the case report form, and infusion completion is confirmed by nursing staff.

Cisplatin is presented as PHF00015MIG for intravenous injection at a dose of 60 mg/m² per infusion. It may be employed as an alternative platinum agent within the standard chemotherapy regimen. Administration details, including infusion duration and any dose modifications, are captured in the trial database to ensure protocol compliance.

Paclitaxel is available in the pharmaceutical form PHF00230MIG for intravenous infusion at a dose of 90 mg/m² per administration. It is used in combination with other chemotherapeutic agents in the comparator arm. Dosing schedules are adhered to as specified in the protocol, with compliance verified by infusion logs.

Vinorelbine is provided as PHF00230MIG for intravenous use at a dose of 30 mg/m² per infusion. It forms part of the chemotherapy options permitted in the standard‑of‑care comparator treatment. Each infusion is documented, and any deviations from the planned schedule are recorded for safety monitoring.

Gemcitabine hydrochloride is supplied in the pharmaceutical form PHF00230MIG for intravenous administration at a dose of 1200 mg/m² per infusion. It is included among the permissible chemotherapy agents in the comparator treatment pathway. Administration timing and dosage are tracked to ensure adherence to the protocol‑defined regimen.

Efficacy will be evaluated primarily by the proportion of patients alive at 12 months (overall survival) and by the proportion of deaths occurring within 4 months of randomization (mortality rate). Survival status will be determined from clinical follow‑up data and analyzed using standard time‑to‑event methods.

Secondary efficacy assessments include first and second progression‑free survival, measured from randomization to disease progression or death, and the objective response rate assessed according to RECIST version 1.1 and iRECIST criteria. Health‑related quality of life will be captured with the EORTC QLQ‑C30 questionnaire supplemented by the lung‑cancer module LC13. The safety and tolerability profile will be characterized using the CTCAE version 5.0 and patient‑reported outcomes collected via PRO‑CTCAE. All efficacy parameters will be recorded at scheduled study visits, entered into the trial database, and subjected to predefined statistical analyses as outlined in the protocol.