Tocilizumab Combined With First-Line Chemo-Immunotherapy in Metastatic Non-Small Cell Lung Cancer

Lung cancer remains the leading cause of cancer-related mortality globally, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all diagnoses. For patients with metastatic NSCLC lacking actionable driver mutations (e.g., EGFR, ALK), the standard first-line therapeutic strategy involves immune checkpoint inhibitors (ICIs) targeting the programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) axis, administered either as monotherapy or in combination with platinum-doublet chemotherapy. While these regimens have significantly improved overall survival (OS), a substantial proportion of patients fail to derive durable clinical benefit, and long-term survival rates for metastatic disease remain suboptimal, often due to host-related factors that impair the anti-tumor immune response.

A critical determinant of poor therapeutic outcomes in advanced NSCLC is cancer-associated cachexia (CAC), a multifactorial paraneoplastic syndrome characterized by systemic inflammation, negative protein-energy balance, and the involuntary loss of skeletal muscle mass (sarcopenia). Primary observational studies demonstrate that nutritional derangements closely associated with cachexia - such as significant weight loss and malnutrition - are highly prevalent in lung cancer, particularly in advanced disease, with lung cancer-specific cohorts reporting rates ranging from approximately 35% - 70% depending on disease stage and assessment method. Unlike starvation, it is driven by aberrant systemic inflammation and not fully reversible via nutritional support.

Clinically, cachexia is defined by the international consensus (Fearon criteria) as weight loss >5% over 6 months, or weight loss >2% in individuals with a body mass index (BMI) < 20 kg/m2 or sarcopenia. Sarcopenia is specifically defined by a low skeletal muscle index (SMI) at the L3 vertebral level, with widely validated cutoffs of < 52.4 cm2/m2 for men and < 8.5 cm2/m2 for women.

This is a Phase 1b/2, multi-site, single-arm, open-label, non-randomized study looking at whether adding tocilizumab to standard treatment for metastatic Non-Small Cell Lung Cancer (NSCLC) is safe, possible, and effective. The study includes people with metastatic NSCLC, that is lung cancer that has spread, who have experienced significant loss of weight or muscle mass.

Primary Objective Evaluate the safety/feasibility and efficacy of adding tocilizumab to standard first-line chemo-immunotherapy in biomarker-selected patients with stage IV NSCLC, defined by weight loss ≥5% within the prior 6 months, or ≥2% if BMI < 20 kg/m².

Co-primary endpoint 1: Safety/Feasibility Proportion of patients completing four cycles of chemo-IO + tocilizumab without grade ≥3 autoimmune or non-hematological treatment-related adverse events (TRAE). Feasibility will be defined as ≥80% completion; unacceptable toxicity as >30% incidence of grade ≥3 serious AEs.

Co-primary endpoint 2: Progression-Free Survival Rate at 6 months Proportion of patients alive and progression-free at 6 months after starting therapy per RECIST v1.1, estimated by Kaplan-Meier and presented with a 95% CI.

Secondary Objectives Assess the effect of tocilizumab on body composition, inflammatory biomarkers, and treatment response.

Secondary Endpoints: change in weight/muscle mass (CT-based sarcopenia/Fearon index); Overall Response Rate (ORR); median Overall Survival Rate; and CRP levels from baseline to end of treatment.

Correlative Objectives Evaluate associations between treatment response (PFS rate at 6 months, ORR) and baseline inflammatory biomarkers (CRP) as well as molecular biomarkers (KRAS, STK11) identified by next-generation sequencing (NGS) of tumor tissue.

Exploratory Objectives Identify associations between treatment response (PFS rate at 6 months, ORR) and longitudinal measurements of CRP, IL-6, Cyclin D1 and Bcl-xL mRNA, as well as baseline PTPRT methylation.

Participants will go through the screening and baseline process to assess eligibility. If eligible, participants will attend study treatment visits every 21 days for about 3 months, an End of Treatment (EOT) visit about 30 days after the last dose of treatment, and follow up for up to 12 months after the EOT visit. Tocilizumab will be administered in addition to standard treatment regimens for NSCLC, at a dose of 8 mg/kg intravenous (IV) once every three weeks (once every 21 days); on day one of each treatment cycle. Tocilizumab is administered as a single IV drip infusion over 1 hour; it cannot be administered as bolus or push. Tocilizumab will be given for 4 doses, at the beginning of treatment, or until disease progression or unacceptable toxicities.

The study will be open at 4 VA hospitals, and planned enrollment is about 43 participants in total with about 11 participants from each site. This research study is expected to take about 4 years. Individual participation in the study will take about 18 months.

• Tocilizumab (Drug), also known as Actemra, Actemra ACTPen, Tofidence, Tyenne: Tocilizumab 8 mg/kg intravenous infusion administered once every 21 days (Day 1 of each cycle) for up to 4 doses. The drug is diluted in 0.9% or 0.45% sodium chloride and infused over 60 minutes. Tocilizumab is given in combination with pembrolizumab and platinum-based doublet chemotherapy. Dose reductions to 4 mg/kg are permitted per protocol in the setting of toxicity.
• Pembrolizumab (Drug): Pembrolizumab is administered per standard-of-care dosing every 21 days in combination with platinum-based doublet chemotherapy and tocilizumab.
• Platinum-Doublet Chemotherapy (Drug), also known as Carboplatin plus pemetrexed; carboplatin plus taxane: Standard-of-care platinum doublet chemotherapy administered every 21 days in combination with pembrolizumab and tocilizumab, using either carboplatin with pemetrexed (non-squamous NSCLC) or carboplatin with a taxane (squamous NSCLC), per institutional guidelines.

Primary outcomes

• Safety [From Day 1 of treatment through completion of Cycle 4 (approximately 12 weeks)]: Safety: Incidence of grade ≥3 non-hematological treatment-related adverse events (TRAEs) or autoimmune toxicities. Unacceptable toxicity is defined as more than 30% incidence of grade ≥3 serious adverse events (AEs), assessed by clinical and laboratory evaluation per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
• Progression-Free Survival Rate [6 months after after initiation of study treatment]: Progression-Free Survival Rate at 6 months: Time from Day 1 of treatment to documented disease progression or death, assessed at 6 months per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and calculated using Kaplan Meier statistics.
• Feasibility of Treatment Completion [From Day 1 of treatment through completion of Cycle 4 (approximately 12 weeks)]: Proportion of patients completing four cycles of treatment. Feasibility is defined as ≥80% of patients completing all four cycles.

Secondary outcomes

• Weight Change [Baseline to EOT (approximately 3 months)]: Measured from baseline to end of treatment (EOT) using objective weight data.
• Muscle Mass [at baseline and EOT (30 +/- 7 days post last dose)]: Assessed via Computed Tomography (CT) -based analysis at baseline and end of treatment.
• Overall Response Rate (ORR) [at EOT (approximately 3 months)]: Defined as complete response (CR) + partial response (PR) per RECIST 1.1 at end of treatment.
• Median Overall Survivial Rate [From Day 1 of treatment until death or last follow-up (up to 12 months post-EOT)]: Time from Day 1 of treatment to the point at which 50% of participants have died and 50% remain alive.
• Inflammatory Biomarkers [From baseline to EOT (30 +/- 7 days post last dose)]: Changes in C-Reactive Protein (CRP) levels from baseline to end of treatment.
• Sarcopenia [at baseline and EOT (30 +/- 7 days post last dose)]: Assessed via CT-based analysis at baseline and end of treatment.

Other outcomes

• Correlation between Baseline IL-6 and Overall Response Rate (ORR) [Baseline]: Evaluation of the association between baseline Interleukin-6 (IL-6) concentration and Objective Response Rate (ORR).
• Correlation between Baseline CRP and Overall Response Rate (ORR) [Baseline]: Assessment of the relationship between baseline C-reactive protein (CRP) levels and ORR.
• Correlation between Baseline PTPRT Methylation and Overall Response Rate (ORR) [Baseline]: Assessment of the association between baseline PTPRT methylation status and ORR.
• Correlation between Baseline KRAS Mutation Status and Overall Response Rate (ORR) [Baseline]: Evaluation of the correlation between KRAS tumor mutational status at baseline and ORR.
• Correlation between Baseline STK11 Mutation Status and Overall Response Rate (ORR) [Baseline]: Evaluation of the correlation between baseline STK11 tumor mutational status and ORR.
• Correlation between Baseline IL-6 and PFS [Baseline]: Evaluation of the association between baseline IL-6 concentration and Progression-Free Survival (PFS).
• Correlation between Baseline CRP and PFS [Baseline]: Assessment of the relationship between baseline CRP concentration and PFS.
• Correlation between Baseline PTPRT Methylation and PFS [Baseline]: Assessment of the association between baseline PTPRT methylation status and PFS.
• Correlation between Baseline KRAS Mutation Status and PFS [Baseline]: Evaluation of the correlation between KRAS mutation status at baseline and PFS.
• Correlation between Baseline STK11 Mutation Status and PFS [Baseline]: Evaluation of the association between baseline STK11 mutation status and PFS.
• Correlation between Longitudinal IL-6 Changes and Overall Response Rate (ORR) [Baseline through End of Treatment (30 +/- 7 days post last dose)]: Analysis of whether changes in IL-6 levels measured at Baseline, C1D1, C2D1, C3D1, C4D1, and End of Treatment correlate with ORR.
• Correlation between Longitudinal CRP Changes and Overall Response Rate (ORR) [Baseline through End of Treatment (30 +/- 7 days post last dose)]: Analysis of whether changes in CRP levels measured at Baseline, C1D1, C2D1, C3D1, C4D1, and End of Treatment correlate with ORR.
• Correlation between Longitudinal Cyclin D1 mRNA Changes and Overall Response Rate (ORR) [Baseline through End of Treatment (30 +/- 7 days post last dose)]: Assessment of whether changes in Cyclin D1 mRNA expression measured at Baseline, C1D1, C2D1, C3D1, C4D1, and End of Treatment correlate with ORR.
• Correlation between Longitudinal Bcl-xL mRNA Changes and Overall Response Rate (ORR) [Baseline through End of Treatment (30 +/- 7 days post last dose)]: Evaluation of whether changes in Bcl-xL mRNA expression measured at Baseline, C1D1, C2D1, C3D1, C4D1, and End of Treatment correlate with ORR.
• Correlation between Longitudinal IL-6 Changes and PFS [Baseline through End of Treatment (30 +/- 7 days post last dose)]: Evaluation of whether IL-6 level changes measured at Baseline, C1D1, C2D1, C3D1, C4D1, and End of Treatment correlate with PFS.
• Correlation between Longitudinal CRP Changes and PFS [Baseline through End of Treatment (30 +/- 7 days post last dose)]: Evaluation of whether CRP level changes measured at Baseline, C1D1, C2D1, C3D1, C4D1, and End of Treatment correlate with PFS.
• Correlation between Longitudinal Cyclin D1 mRNA Changes and PFS [Baseline through End of Treatment (30 +/- 7 days post last dose)]: Assessment of whether changes in Cyclin D1 mRNA measured at Baseline, C1D1, C2D1, C3D1, C4D1, and End of Treatment correlate with PFS.
• Correlation between Longitudinal Bcl-xL mRNA Changes and PFS [Baseline through End of Treatment (30 +/- 7 days post last dose)]: Assessment of whether changes in Bcl-xL mRNA measured at Baseline, C1D1, C2D1, C3D1, C4D1, and End of Treatment correlate with PFS.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Age ≥ 18 years at the time of consent
2. Histologically confirmed metastatic Non-Small Cell Lung Cancer (NSCLC)
3. No Epidermal Growth Factor Receptor (EGFR), Anaplastic Lymphoma Kinase (ALK), ROS Proto-Oncogene 1 (ROS1), or Rearranged During Transfection Proto-Oncogene (RET) mutations
4. ≥ 5% unintentional weight loss or >2% if Body Mass Index (BMI) < 20 kilograms/square meter (kg/m2) in prior 6 months
5. Candidate for platinum-doublet and Programmed Death-Ligand 1 (PD-L1) inhibitor
6. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
7. Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
8. Baseline Interleukin-6 (IL-6) and C-reactive protein (CRP) available

Exclusion Criteria:

1. Prior systemic therapy for metastatic disease
2. Autoimmune disease requiring immunosuppression
3. Active infection or high Gastrointestinal (GI) perforation risk
4. Symptomatic brain metastasis
5. Active hepatitis B infection
6. Active or untreated latent Tuberculosis (TB) infection

• Charles J Nock, MD, Principal investigator, Louis Stokes VA Medical Center, Cleveland, OH