Hyperprogression in PD-L1 ≥ 50% NSCLC: a Biomarker Guided Phase 2 Trial

In metastatic NSCLC patients with PD-L1 expression ≥50%, a circulating immature (CD10-) LDNs level of ≥30.5% confers a high risk of hyperprogression (HPD) with first line single-agent immune-checkpoint inhibitors (SA-ICI). HPD is defined as a tumor growth rate (TGR) delta ≥50% between pre-treatment and post-treatment, and/or a TGR ratio ≥2. The combination of platinum-based chemotherapy (PCT) with ICI in this setting could prevent the occurrence of HPD and ultimately improve survival outcomes. This randomized, multicentric, open-label, phase 2 trial will include patients with stage IV NSCL, without targetable oncogene drivers, PD-L1 TPS≥50%, and measurable disease on two CT scans performed before randomization. Participants will be randomized 1:1 to SA-ICI or ICI+PCT. Radiological evaluation will be performed by CT-scan at 6-8 weeks and subsequently according to the local investigators' schedule. In the SA-ICI arm, ICI regimen will include cemiplimab. In the PCT+ICI arm, PCT regimens will include both carboplatin or cisplatin + pemetrexed (for non-squamous histology) or paclitaxel (for squamous histology) in combination with cemiplimab. PCT will be administered for three cycles. In case of stable disease or partial response according to RECIST v.1.1, cemiplimab will be performed as monotherapy from the third cycle until disease progression or unacceptable toxicity. If progression according to RECIST v.1.1 or HPD after three cycles of PCT+ICI, patients will be treated with standard second line therapy as local standard of care.

Intervention: PCT plus cemiplimab for 3 cycles followed by cemiplimab in case of absence of PD/HPD. PCT regimens will include both carboplatin (area under the concentration-time curve, 5 mg per milliliter per minute) or cisplatin (75 mg per square meter of body surface area) plus pemetrexed (500 mg per square meter) for non-squamous histology or paclitaxel (200 mg per square meter) for squamous histology. All drugs in the PCT regimens will be administered intravenously every 3 weeks. Cemiplimab 350 mg "flat dose" will be administered intravenously every 3 weeks. Treatment will continue for a maximum of 108 weeks or until progression or unacceptable toxicity. Comparator: Single-agent cemiplimab. Cemiplimab 350 mg "flat dose" will be administered intravenously every 3 weeks for 108 weeks or until progression or unacceptable toxicity. Efficacy criteria: The rate of patients experienced HPD or ED will be calculated for both treatment arms.1 HPD is defined as a delta of tumor growth rate (TGR) ≥50% and/or a TGR ratio ≥2. TGR will be computed using RECIST v.1.1 on three consecutive, centrally revised, CT scans (two CT scans before treatment start and one after 7 week ± 5 days from treatment start). Central review of CT scans will be performed before treatment start and after the first radiological evaluation (before third cycle). RECIST response after the second cycles will be decided according to central review. ED is defined as tumor-related death within 12 weeks from ICI initiation, in absence of a radiological evaluation performed during ICI. HPD rate according to definitions proposed by Lo Russo et al., Matos et al.et Saâd-Bouzid et al., will be evaluated as a secondary endpoint. Efficacy parameters: After the first radiological evaluation performed at 7 weeks ± 5 days from treatment start, subjects will be evaluated by CT scans every 12 weeks ± 28 days according to local investigators' schedule. CT scans are to be performed until disease progression or until the start of new anticancer treatment, withdrawal of consent, or death, whichever occurs first. Per RECIST 1.1, the partial and complete response should be confirmed by a repeat tumor imaging assessment not less than 4 weeks from the date the response was first documented. The enrollment period will last 48 months. The approximate duration of the active study assessments for each patient, including the screening phase, will be 3 months (the time required to confirm HPD occurrence or not). The duration of the active portion of the study will be 48 months, followed by and additional 3 months of follow-up, for a total of 51 months. In both arms, patients will receive treatment for a maximum of 108 weeks or until disease progression or unacceptable toxicity occurs. After the active portion of the study is completed, all patients will be followed for survival.