Introduction
Advanced non-squamous non-small-cell lung cancer (NSCLC) remains one of the leading causes of cancer-related mortality worldwide. For many years, platinum-based doublet chemotherapy represented the standard first-line treatment for patients without actionable genetic mutations such as EGFR or ALK alterations. Although the addition of anti-angiogenic agents like Bevacizumab improved clinical outcomes, long-term survival rates remained limited, with median overall survival generally ranging between 10 and 24 months. These limitations highlighted the urgent need for more effective and durable therapeutic strategies for advanced NSCLC management.
Recent advances in cancer immunotherapy have transformed the treatment landscape of lung cancer. In particular, immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) demonstrated substantial improvements in progression-free survival and overall survival when combined with chemotherapy. Several international clinical trials confirmed that combining anti-PD-1 or anti-PD-L1 agents with platinum-based chemotherapy could significantly improve outcomes in advanced non-squamous NSCLC regardless of PD-L1 expression status. However, evidence specifically focused on Chinese patients remained limited, despite known racial and ethnic differences in tumour biology, genomic alterations, immune microenvironment, and treatment response.
Camrelizumab is a humanized monoclonal antibody directed against the PD-1 receptor. Previous phase 1, 2, and 3 clinical studies demonstrated promising antitumour activity and a manageable safety profile across multiple malignancies. Earlier investigations in previously treated advanced NSCLC showed that camrelizumab produced encouraging objective response rates, progression-free survival, and overall survival outcomes compared with historical second-line chemotherapy data. Furthermore, platinum agents and pemetrexed are known to enhance antitumour immune responses, providing a strong biological rationale for combining chemotherapy with PD-1 blockade.
Based on these observations, researchers conducted a randomized, open-label, multicentre phase 3 clinical trial to evaluate the efficacy and safety of camrelizumab combined with carboplatin and pemetrexed compared with chemotherapy alone in chemotherapy-naive Chinese patients with advanced non-squamous NSCLC lacking EGFR and ALK alterations. The interim analysis aimed to determine whether adding camrelizumab could improve progression-free survival, overall survival, tumour response, and disease control while maintaining an acceptable safety profile.
Study Design and Patient Population
This multicentre phase 3 trial was conducted across 52 hospitals in China and enrolled patients aged 18 to 70 years with histologically or cytologically confirmed stage IIIB–IV non-squamous NSCLC. Eligible participants had no previous systemic chemotherapy and did not harbor EGFR or ALK genetic alterations. Additional inclusion criteria included measurable disease according to RECIST 1.1 criteria, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and an expected survival of at least three months.
Patients with untreated brain metastases or recent corticosteroid use were excluded from participation. Tumour tissue samples were collected for biomarker analysis, including PD-L1 testing and tumour mutational burden assessment.
Participants were randomly assigned in a 1:1 ratio to receive either:
- Camrelizumab plus carboplatin and pemetrexed
- Carboplatin and pemetrexed chemotherapy alone
Randomization was stratified according to sex and smoking history to ensure balanced patient characteristics between treatment groups.
Treatment Protocol
Patients in the experimental arm received:
- Camrelizumab 200 mg
- Carboplatin (AUC 5 mg/mL per minute)
- Pemetrexed 500 mg/m²
Treatment was administered intravenously every three weeks for four to six cycles, followed by maintenance therapy with camrelizumab plus pemetrexed.
Patients in the control arm received:
- Carboplatin
- Pemetrexed
followed by pemetrexed maintenance therapy alone.
Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, or completion of the study. Patients assigned to chemotherapy alone were allowed to cross over to camrelizumab monotherapy after disease progression based on investigator assessment.
Primary and Secondary Endpoints
The primary endpoints of the study were progression-free survival (PFS) in:
- The overall patient population
- Patients with PD-L1-positive tumours
Secondary endpoints included:
- Overall survival (OS)
- Objective response rate (ORR)
- Disease control rate (DCR)
- Duration of response
- Time to response
- Safety and tolerability
Tumour imaging was performed every six weeks during the first year and every twelve weeks thereafter.
Clinical Efficacy Results
Progression-Free Survival
The interim analysis demonstrated a significant improvement in progression-free survival with camrelizumab plus chemotherapy compared with chemotherapy alone.
Median progression-free survival reached:
- 11.3 months in the camrelizumab combination group
- 8.3 months in the chemotherapy-alone group
The hazard ratio of 0.60 indicated a 40% reduction in the risk of disease progression or death with the addition of camrelizumab.
Patients with PD-L1-positive tumours experienced even greater benefit:
- 15.4 months median PFS with camrelizumab plus chemotherapy
- 9.9 months with chemotherapy alone
Subgroup analyses consistently favored the immunotherapy combination across most patient categories.
Overall Survival
Although overall survival data remained immature during the interim analysis, a strong trend toward survival improvement was observed.
Estimated 12-month overall survival rates were:
- 74.9% with camrelizumab plus chemotherapy
- 67.1% with chemotherapy alone
After adjusting for crossover treatment, the survival benefit became more pronounced, suggesting that camrelizumab contributed significantly to prolonged survival.
Longer follow-up further demonstrated:
- Median overall survival of approximately 27.9 months in the combination group
- 20.5 months in the chemotherapy-alone group
These findings indicated durable clinical benefit associated with first-line PD-1 blockade combined with chemotherapy.
Objective Response and Disease Control
The addition of camrelizumab significantly improved tumour response outcomes.
Objective response rates were:
- 60.5% with camrelizumab plus chemotherapy
- 38.6% with chemotherapy alone
Disease control rates also improved substantially:
- 87.8% in the combination group
- 74.4% in the chemotherapy group
Responses occurred rapidly and lasted considerably longer with camrelizumab-based therapy.
Biomarker Analysis
PD-L1 Expression
Consistent with previous immunotherapy studies, patients with higher PD-L1 expression appeared to derive greater benefit from camrelizumab plus chemotherapy. Nevertheless, clinical improvements were observed across different PD-L1 subgroups, supporting broader applicability of chemoimmunotherapy combinations.
Tumour Mutational Burden
The study also explored tumour mutational burden (TMB) as a predictive biomarker using whole-exome sequencing and next-generation sequencing panels. However, no significant correlation was identified between TMB and therapeutic efficacy in either treatment group.
These findings suggest that the predictive role of TMB in chemoimmunotherapy combinations remains uncertain and requires additional investigation.
Safety and Adverse Events
The safety profile of camrelizumab plus chemotherapy was generally manageable and consistent with previously reported checkpoint inhibitor toxicities.
The most common treatment-related adverse events included:
- Neutropenia
- Leukopenia
- Anaemia
- Thrombocytopenia
Grade 3 or higher adverse events occurred more frequently in the camrelizumab combination group compared with chemotherapy alone.
Immune-Related Adverse Events
Immune-mediated toxicities were expected with PD-1 inhibition and included:
- Reactive cutaneous capillary endothelial proliferation
- Immune-related hepatitis
- Hypothyroidism
- Elevated liver enzymes
Most immune-related adverse events were mild to moderate and manageable with supportive care, corticosteroids, or temporary treatment interruption.
Reactive cutaneous capillary endothelial proliferation represented the most characteristic adverse event associated with camrelizumab therapy and occurred predominantly as low-grade skin lesions.
Importantly, no unexpected safety signals were identified during the study.
Clinical Significance and Future Perspectives
This phase 3 study demonstrated that camrelizumab combined with carboplatin and pemetrexed significantly improved progression-free survival, tumour response, and disease control in chemotherapy-naive Chinese patients with advanced non-squamous NSCLC lacking EGFR and ALK mutations.
The findings provided strong evidence supporting the integration of PD-1 inhibitors into first-line treatment strategies for advanced NSCLC in Chinese populations. Furthermore, the study highlighted important ethnic and biological considerations that may influence treatment outcomes across different populations.
Although the trial had limitations, including its open-label design and focus on Chinese patients, the overall clinical benefit observed with camrelizumab-based chemoimmunotherapy was substantial and clinically meaningful.
Continued follow-up will further clarify long-term overall survival benefits and the role of biomarkers such as PD-L1 expression and tumour mutational burden in predicting therapeutic response.
Conclusion
The combination of camrelizumab, carboplatin, and pemetrexed represents a highly promising first-line therapeutic strategy for advanced non-squamous NSCLC without EGFR or ALK alterations. Compared with chemotherapy alone, this chemoimmunotherapy regimen significantly improved progression-free survival, objective response rates, disease control, and overall survival trends while maintaining an acceptable and manageable safety profile.
These results reinforce the growing importance of immune checkpoint inhibitors in lung cancer treatment and support the continued development of personalized immunotherapy approaches for advanced NSCLC patients worldwide.