This groundbreaking study shows that adding nivolumab immunotherapy to chemotherapy before surgery significantly improves long-term survival for patients with operable lung cancer. After nearly 6 years of follow-up, patients receiving the combination treatment had a 65.4% 5-year survival rate compared to 55.0% with chemotherapy alone, representing a 28% reduction in risk of death. The benefits were consistent across most patient subgroups, and those achieving a complete pathological response had remarkable 95.3% survival rates at 5 years.
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New Immunotherapy Combination Before Surgery Significantly Improves Long-Term Survival in Operable Lung Cancer
Table of Contents
- Introduction: Why This Research Matters
- Study Design and Methods
- Patient Characteristics
- Key Findings: Survival Results
- Results Across Different Patient Groups
- How Treatment Response Affects Survival
- Treatment Safety and Side Effects
- What This Means for Patients
- Study Limitations
- Recommendations for Patients
- Source Information
Introduction: Why This Research Matters
Lung cancer remains one of the most common and deadly cancers worldwide, with non-small cell lung cancer (NSCLC) representing approximately 85% of all cases. For patients with early-stage, operable lung cancer, treatment typically involves surgery to remove the tumor, often followed by chemotherapy to eliminate any remaining cancer cells.
This landmark study, called CheckMate 816, investigated whether adding an immunotherapy drug called nivolumab to standard chemotherapy before surgery could improve outcomes for patients with resectable (operable) NSCLC. Nivolumab works by blocking the PD-1 protein, which helps the immune system recognize and attack cancer cells more effectively.
Previous results from this trial showed that the combination treatment significantly improved pathological complete response (meaning no detectable cancer cells remained after treatment) and event-free survival (time without cancer progression or death). However, the most important measure of cancer treatment success—overall survival—had not yet been reported until this final analysis.
Study Design and Methods
This was a phase 3, randomized, open-label clinical trial conducted at multiple medical centers worldwide. Phase 3 trials are large studies designed to confirm treatment effectiveness and monitor side effects in comparison to standard treatments.
The trial included 358 patients with stage IB to IIIA operable non-small cell lung cancer who were randomly assigned to one of two treatment groups:
- Experimental group (179 patients): Received nivolumab (360 mg) plus platinum-based chemotherapy every 3 weeks for three cycles (9 weeks total)
- Control group (179 patients): Received platinum-based chemotherapy alone every 3 weeks for three cycles
After completing neoadjuvant (pre-surgery) treatment, patients underwent surgery within 6 weeks. Some patients also received optional adjuvant (post-surgery) chemotherapy, radiotherapy, or both based on their individual situation.
The researchers followed patients for a median of 68.4 months (nearly 6 years) to assess long-term outcomes. The study was designed to detect differences in both event-free survival and overall survival between the two treatment approaches.
Patient Characteristics
The patients enrolled in this trial represented a typical cross-section of people diagnosed with operable lung cancer. The average age was mid-60s, and approximately two-thirds were men, which reflects the higher incidence of lung cancer in male populations.
Patients had varying stages of disease: 36% had stage IB-II cancer and 64% had stage IIIA cancer. The study included patients with both squamous and non-squamous cell types of NSCLC, which are the two main subtypes of this cancer.
It's important to note that the study population was diverse geographically, including patients from North America, Europe, and Asia. However, Black patients were underrepresented in the trial, which is a common limitation in cancer research that needs to be addressed in future studies.
Key Findings: Survival Results
The most significant finding from this long-term analysis is that adding nivolumab to chemotherapy before surgery substantially improved overall survival—the gold standard for measuring cancer treatment success.
At 5 years after treatment:
- 65.4% of patients receiving nivolumab plus chemotherapy were still alive
- 55.0% of patients receiving chemotherapy alone were still alive
This represents an absolute improvement of 10.4 percentage points in 5-year survival—a clinically meaningful difference that translates to many additional lives saved.
The statistical analysis showed a hazard ratio of 0.72, which means patients receiving the combination treatment had a 28% reduction in the risk of death compared to those receiving chemotherapy alone. This result was statistically significant (p=0.048), meaning there's less than a 5% probability that this finding occurred by chance.
The median overall survival—the point at which half of patients are still alive—was not reached in the nivolumab-plus-chemotherapy group (meaning more than half were still alive at the end of the study), compared to 73.7 months (just over 6 years) in the chemotherapy-alone group.
Results Across Different Patient Groups
The researchers analyzed whether the survival benefit was consistent across different types of patients. Importantly, the advantage of adding nivolumab was observed in most subgroups:
By cancer stage: Both patients with earlier stage (IB-II) and more advanced stage (IIIA) disease benefited from the combination treatment. This is particularly significant because neoadjuvant therapy has historically been used mainly for stage III disease.
By PD-L1 expression: PD-L1 is a protein that helps cancer cells evade the immune system. Patients with higher PD-L1 levels (≥1%) showed greater benefit from nivolumab, but even patients with low PD-L1 expression (<1%) derived some benefit from the combination treatment.
By cancer type: Both patients with squamous cell carcinoma and non-squamous cell carcinoma experienced improved survival with the nivolumab combination.
By geographic region: Patients from North America, Europe, and Asia all showed consistent benefits, suggesting the treatment approach works across different populations.
How Treatment Response Affects Survival
One of the most striking findings was the relationship between pathological response to treatment and long-term survival outcomes.
Patients who achieved a pathological complete response (no detectable cancer cells in the surgical specimen) had exceptional outcomes:
- 95.3% 5-year survival rate for those with complete response
- Only 3 deaths occurred among 43 patients with complete response
- None of these deaths were due to lung cancer
In contrast, patients who did not achieve a complete response had a 55.7% 5-year survival rate. This dramatic difference highlights the importance of achieving a complete response when possible.
The study also found that circulating tumor DNA (ctDNA) clearance—a blood test that measures disappearing cancer DNA—strongly predicted survival outcomes. Patients who cleared their ctDNA before surgery had:
- 75.0% survival in the nivolumab group
- 52.6% survival in those without ctDNA clearance
This suggests that ctDNA testing could help identify which patients are responding well to treatment and which might need additional therapies.
Treatment Safety and Side Effects
The safety profile of nivolumab plus chemotherapy remained consistent with previous reports, with no new safety concerns identified during the extended follow-up period.
Treatment-related side effects were manageable and similar to what has been observed in other studies of immunotherapy combined with chemotherapy. Importantly, no new treatment-related deaths occurred beyond those previously reported.
The combination treatment did not increase surgical complications or interfere with patients' ability to undergo planned surgery, which was a important consideration for this pre-surgical treatment approach.
What This Means for Patients
This research represents a significant advancement in the treatment of operable lung cancer. The demonstration of improved overall survival—the most important endpoint in cancer research—establishes neoadjuvant nivolumab plus chemotherapy as a new standard of care for eligible patients.
For patients diagnosed with stage IB-IIIA non-small cell lung cancer, these findings suggest that:
- Adding immunotherapy to chemotherapy before surgery can significantly improve long-term survival
- The treatment benefit persists for at least 5 years after treatment
- The combination is effective across different patient subgroups
- Achieving a complete pathological response is associated with excellent long-term outcomes
The 10.4% absolute improvement in 5-year survival means that for every 100 patients treated with this approach, approximately 10 additional lives are saved compared to chemotherapy alone.
Study Limitations
While these results are highly promising, several limitations should be considered:
The study population included relatively few Black patients, which limits our understanding of how this treatment works across all racial and ethnic groups. Future research should specifically address this diversity gap.
The trial compared nivolumab plus chemotherapy to chemotherapy alone, but didn't compare against other potential treatment approaches, such as immunotherapy given after surgery instead of before.
The statistical significance for overall survival was borderline (p=0.048), though the consistent results across multiple endpoints and subgroups strengthen confidence in the findings.
Long-term follow-up beyond 5 years will be important to understand if the survival benefit continues or diminishes over time.
Recommendations for Patients
Based on these findings, patients with newly diagnosed, operable non-small cell lung cancer should:
- Discuss neoadjuvant immunotherapy options with their oncology team, including the potential benefits of adding nivolumab to chemotherapy before surgery
- Understand the side effect profile of combination treatment and how it might differ from chemotherapy alone
- Consider biomarker testing including PD-L1 expression, which can help predict response to immunotherapy
- Ask about ctDNA monitoring during treatment, as this emerging technology may help assess treatment response
- Maintain follow-up care after treatment completion, as long-term monitoring is essential for detecting potential late effects or recurrence
Patients should have detailed conversations with their healthcare providers about whether this treatment approach is appropriate for their specific situation, considering factors such as overall health, cancer characteristics, and personal preferences.
Source Information
Original Article Title: Overall Survival with Neoadjuvant Nivolumab plus Chemotherapy in Lung Cancer
Authors: Patrick M. Forde, Jonathan D. Spicer, Mariano Provencio, Tetsuya Mitsudomi, Mark M. Awad, Changli Wang, Shun Lu, Enriqueta Felip, Scott J. Swanson, Julie R. Brahmer, Keith Kerr, Janis M. Taube, Tudor-Eliade Ciuleanu, Fumihiro Tanaka, Gene B. Saylors, Ke-Neng Chen, Hiroyuki Ito, Moishe Liberman, Claudio Martin, Stephen Broderick, Lily Wang, Junliang Cai, Quyen Duong, Stephanie Meadows-Shropshire, Joseph Fiore, Sumeena Bhatia, Nicolas Girard, for the CheckMate 816 Investigators
Publication: The New England Journal of Medicine, August 21/28, 2025, Vol. 393 No. 8
DOI: 10.1056/NEJMoa2502931
Note: This patient-friendly article is based on peer-reviewed research from a major clinical trial funded by Bristol Myers Squibb (ClinicalTrials.gov number NCT02998528).