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

Sponsor
Università Vita-Salute San Raffaele
Study ID
NCT07274384
Phase
PHASE2
Status
Not Yet Recruiting

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Conditions

  • Hyperprogression
  • NSCLC (Non-small Cell Lung Cancer)

Eligibility Criteria

Sex
ALL
Age
18 Years - N/A
Healthy Volunteers
Not accepted

Interventions

  • chemotherapy plus cemiplimab — COMBINATION_PRODUCT
    Combination of platinum-based chemotherapy (PCT) with ICI. PCT regimens will include both carboplatin or cisplatin plus pemetrexed (for non-squamous histology) or paclitaxel (for squamous histology) in combination with cemiplimab. PCT will be administered for three cycles.
  • Cemiplimab — DRUG
    single-agent immune-checkpoint inhibitors

Study Details

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.

Key Dates

Start date
Jan 1, 2026
Status verified
Nov 2025
Primary completion
Dec 31, 2029
Completion
Jun 1, 2030

Study Design

Enrollment
74 participants (estimated)
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT

Arms

  • Active Comparator: single-agent immune-checkpoint inhibitors
    single-agent immune-checkpoint inhibitors (SA-ICI) (Cemiplimab)
  • Experimental: PCT regimens + immune-checkpoint inhibitors
    PCT regimens will include both carboplatin or cisplatin plus pemetrexed (for non-squamous histology) or paclitaxel (for squamous histology) in combination with cemiplimab

Primary Outcome Measure

HPD rate [ Time Frame: up to HPD, end of treatment for a maximum of 108 weeks whichever comes first ]

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