Immunotherapy Without Chemotherapy for Advanced Lung Cancer Patients With High PD-L1 Levels

NCT07360743 | Not Yet Recruiting Phase 2 DMC

• 2 other identifiers: UC-IMM-25122025-522655-26-00
• Study Type: interventional
• Target: 275
• Locations: 0 countries
• Sites: N/A

Brief Summary

Anti-PD-1 monotherapy has demonstrated significant clinical efficacy in advanced or metastatic non-small cell lung cancer (NSCLC) with high PD-L1 expression (tumor proportion score \[TPS\] \>50%), outperforming platinum-based chemotherapy in terms of objective response rate (ORR) and overall survival (OS). Pivotal randomized trials such as KEYNOTE-024 and EMPOWER-Lung 1 established the superiority of PD-1 blockade in this patient population, leading to regulatory approvals by both the FDA and EMA for first-line treatment. These studies confirmed that a subset of patients can achieve deep and durable responses with immunotherapy alone, highlighting the potential of immune checkpoint inhibition to provide long-term clinical benefit without the toxicities associated with cytotoxic chemotherapy. Despite these successes, accumulating clinical evidence has revealed a clinically significant risk of hyperprogressive disease (HPD) in a subset of patients treated with anti-PD-1 monotherapy. HPD is characterized by an unexpected and rapid acceleration of tumor growth following treatment initiation and is associated with early clinical deterioration and increased mortality. This phenomenon likely contributes to the early crossover of survival curves frequently observed when comparing immunotherapy alone with chemotherapy in first-line NSCLC trials. In contrast, such early survival crossover is not observed in trials comparing chemotherapy-immunotherapy combinations with chemotherapy alone, including CheckMate-227, CheckMate-9LA, KEYNOTE-189, and KEYNOTE-407. These results have led many thoracic oncologists to favor combined chemo-immunotherapy regimens as first-line treatment, as they reduce the risk of HPD and increase initial ORR. However, while chemotherapy combined with immunotherapy effectively mitigates the risk of hyperprogression and improves early response rates, it also appears to compromise the durability of antitumor immune responses. Clinical data indicate that the median duration of response with chemo-immunotherapy combinations is approximately 10-11 months, compared with more than 22 months for anti-PD-1 monotherapy alone. This difference is likely attributable to the cytotoxic effects of chemotherapy on immune effector cells, which may limit the persistence and depth of immune-mediated tumor control. Consequently, there remains a strong clinical need to identify patients who could safely and effectively benefit from anti-PD-1 monotherapy while avoiding unnecessary exposure to chemotherapy. Multiple early-phase translational studies have independently identified soluble plasma biomarkers associated with response or resistance to PD-1 blockade in advanced NSCLC. Building on this body of evidence, translational analyses conducted at Gustave Roussy Cancer Center have identified a composite signature of circulating soluble factors, including interleukin-6 (IL-6), interleukin-8 (IL-8), soluble CD14 (sCD14), soluble CD25 (sCD25), and growth differentiation factor-15 (GDF-15). Together, these biomarkers define a Pro-Tumoral Inflammation (PTI) signature that is strongly associated with primary resistance to anti-PD-1 monotherapy. Elevated PTI scores reflect a systemic inflammatory state that promotes tumor progression and immune dysfunction, and have been linked to poor clinical outcomes, including non-response and hyperprogressive disease. Within the META-1 sub-protocol of the METAREM master protocol, the investigators propose to integrate these soluble biomarkers into a single PTI score generated through baseline PORTRAIT immunoprofiling. The primary objective of this approach is to prospectively validate the predictive value of the PTI score for anti-PD-1 monotherapy efficacy in advanced NSCLC. By enabling early identification of patients at high risk of resistance or hyperprogression, this strategy aims to refine patient stratification and guide first-line treatment selection. Ultimately, the use of the PTI score could allow clinicians to identify patients most likely to benefit from anti-PD-1 monotherapy, preserving the potential for durable responses while sparing others from ineffective treatment and optimizing the overall therapeutic strategy in advanced NSCLC.

Conditions

Non Small Cell Lung Cancer (Squamous or Non Squamous)

Keywords

anti-PD1 monotherapy; non-small cell lung cancer (NSCLC); Tumor Proportion Score (TPS) >50%; without EGFR/ ALK/ ROS1 mutations; Pro-tumoral inflammatory score (PTI); Advanced metastatic cancers; Personalized immunotherapy

Outcome Measures

Primary Outcomes (1)

• The primary objective is to evaluate the rate of patients without early progression upon anti-PD1 monotherapy by selecting patients with a baseline plasma PTI score of 0 in patients with advanced/metastatic NSCLC with PD-L1 TPS >50%.

  The primary endpoint is the rate of patients without disease progression at 12 weeks.

  12 weeks

Study Arms (1)

Single Arm Anti-PD1 monotherapy in 1L advanced NSCLC patients with PD-L1 TPS > 50% and PTI=0

EXPERIMENTAL

Pembrolizumab or cemiplimab (anti-PD1) will be considered as investigational medical products (IMP) and will be used in accordance with their marketing authorization for the trial population.

Drug: Pembrolizumab; Drug: Cemiplimab

Interventions

Cemiplimab DRUG

350 mg every 3 weeks (Q3W) Intravenous (IV) infusion of 30 minutes

Also known as: Libtayo®

Single Arm Anti-PD1 monotherapy in 1L advanced NSCLC patients with PD-L1 TPS > 50% and PTI=0

Pembrolizumab DRUG

200 mg every 3 weeks (Q3W) Intravenous (IV) infusion of 30 minutes

Also known as: KEYTRUDA ®

Single Arm Anti-PD1 monotherapy in 1L advanced NSCLC patients with PD-L1 TPS > 50% and PTI=0

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with age ≥18 years
• Patients in first-line therapy for advanced metastatic NSCLC with PD-L1 Tumor Proportion Score (TPS) \>50%, without EGFR/ ALK/ ROS1 mutations and irrespective of their histological subtype (squamous or non-squamous).
• Patients with a PTI score of zero in plasma on the baseline PORTRAIT report. Note: Patients with PTI score ≥ 1 who meet all other criteria will be followed up to 36 months or death according to standard of care.

You may not qualify if:

• Patients who have previously received an anti-PD(L)1 or anti-CTLA4 or anti-LAG-3 or anti-TIM3 immunotherapy.
• Patients with any Hypersensitivity to the active ingredient or to any of the excipients of Pembrolizumab or Cemiplimab.

Sponsors & Collaborators

• UNICANCER: lead

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

pembrolizumab; cemiplimab

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Study Officials

• David PLANCHARD, MD, PHD

  Gustave Roussy, Cancer Campus, Grand Paris

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Priyanka DEVI-MARULKAR, PhD, MBA

CONTACT

+33 (0) 06 62 53 60 43; p-devi-marulkar@unicancer.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: META-1 is an academic, open label, multicentric, phase II, proof-of-concept clinical trial designed to evaluate whether a PTI score threshold of 1 could set apart patients at risk of hyperprogression from those who will benefit from long-term anti- PD1 monotherapy while chemotherapy-related toxicities.

Study Record Dates

• First Submitted: January 13, 2026
• First Posted: January 22, 2026
• Study Start: April 1, 2026
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): April 1, 2032
• Last Updated: February 10, 2026

Record last verified: 2026-01