Key Trial Results
| Outcome | Nivolumab (n=221) | Placebo (n=111) |
|---|---|---|
| Median overall survival | 10.2 months | 6.9 months |
| Overall survival HR | 0.69 (95% CI 0.52 to 0.91; p=0.0090) | reference |
| 1-year overall survival | 43.4% | 30.1% |
| Median progression-free survival | 3.0 months | 1.8 months |
| Progression-free survival HR | 0.67 (95% CI 0.53 to 0.85; p=0.0012) | reference |
| Objective response rate | 11% | 1% (p=0.00086) |
CONFIRM was a Phase 3, multicentre, double-blind, placebo-controlled trial that tested nivolumab (Opdivo) as a single agent in people with relapsed malignant pleural or peritoneal mesothelioma after at least one prior line of platinum-based chemotherapy. The final results were published by Fennell and colleagues in The Lancet Oncology in 2021.
Why CONFIRM Mattered
Before CONFIRM, people whose mesothelioma progressed after first-line platinum chemotherapy had no standard second-line option. CONFIRM was designed to test whether single-agent PD-1 blockade could extend survival in that setting.
How CONFIRM Was Designed
| Characteristic | Detail |
|---|---|
| Phase | 3 (randomised, double-blind, placebo-controlled) |
| Patients enrolled | 332 |
| Randomisation | 2:1 nivolumab (n=221) to placebo (n=111) |
| Nivolumab dose | 240 mg IV every 2 weeks |
| Population | Relapsed pleural or peritoneal mesothelioma after at least one prior line of platinum chemotherapy |
| Co-primary endpoints | Investigator-assessed PFS and OS |
| Recruitment window | May 10, 2017 to March 30, 2020 |
| Location | UK multicentre |
| Sponsor | University of Southampton |
| Funder | Cancer Research UK |
| Registration | NCT03063450; ISRCTN79814141 |
Detailed Results
Overall and Progression-Free Survival
In the final Lancet Oncology 2021 analysis, nivolumab extended median overall survival from 6.9 months on placebo to 10.2 months, with an adjusted hazard ratio of 0.69 (95% CI 0.52 to 0.91; p=0.0090). At one year, 43.4% of people on nivolumab were alive compared with 30.1% on placebo.
Progression-free survival also favoured nivolumab: median 3.0 vs 1.8 months, HR 0.67 (95% CI 0.53 to 0.85; p=0.0012).
Response
Objective responses were infrequent in both arms but clearly separated: 11% on nivolumab vs 1% on placebo (p=0.00086).
Biomarker Analysis
PD-L1 Expression
CONFIRM pre-specified a PD-L1 tumor proportion score (TPS) cutoff of 1%. In the final analysis, PD-L1 expression was not predictive or prognostic: there was no evidence that PD-L1 TPS identified who would benefit from nivolumab.
In CONFIRM, PD-L1 tumor proportion score did not predict benefit from nivolumab. PD-L1 testing alone should not determine immunotherapy eligibility in relapsed mesothelioma.
Histological Subtype
The subgroup picture for histology was not symmetrical.
| Subgroup | HR | 95% CI | p-value |
|---|---|---|---|
| Epithelioid | 0.71 | 0.53 to 0.95 | 0.021 |
| Non-epithelioid | 0.79 | 0.35 to 1.79 | 0.572 |
The overall survival benefit was statistically significant only in the epithelioid subgroup. In the non-epithelioid subgroup, the confidence interval crossed 1.0 and the result was not statistically significant. The trial was not powered to establish benefit in non-epithelioid histology.
Safety
| Metric | Nivolumab | Placebo |
|---|---|---|
| Treatment-related deaths | 0 | 0 |
| Serious adverse events | 41% | 44% |
The most frequent grade 3 or 4 treatment-related adverse events in the nivolumab arm were diarrhea (3%) and infusion-related reactions (3%).
Comparison to Other Immunotherapy Data
CONFIRM vs CheckMate-743
| Trial | Setting | Regimen | Median OS |
|---|---|---|---|
| CONFIRM | Relapsed after platinum chemo | Nivolumab alone | 10.2 months |
| CheckMate-743 | First-line | Nivolumab + ipilimumab | Reported separately |
CheckMate-743 tested dual checkpoint blockade in previously untreated patients. CONFIRM tested single-agent PD-1 blockade in the relapsed setting. They address different treatment lines and cannot be compared head to head.
What CONFIRM Did and Did Not Establish
CONFIRM established that single-agent nivolumab improves overall and progression-free survival compared with placebo in people with relapsed pleural or peritoneal mesothelioma after prior platinum chemotherapy. PD-L1 expression did not identify who benefited. The statistically significant overall survival benefit was confined to the epithelioid subgroup.
CONFIRM did not evaluate tumor mutational burden, BAP1 loss, NF2 alterations, or inflammatory gene signatures as predictive biomarkers in its primary publication. Any biomarker-guided treatment selection beyond what CONFIRM tested should be based on other sources of evidence.
Questions for Your Oncologist
- Am I a candidate for single-agent nivolumab or for the combination regimen studied in CheckMate-743?
- My histology is epithelioid or non-epithelioid. How should that shape the conversation about immunotherapy?
- What relapsed-setting clinical trials are currently open?
What did the CONFIRM trial show?▼
CONFIRM was a Phase 3, double-blind, placebo-controlled trial of 332 people with relapsed pleural or peritoneal mesothelioma. Nivolumab improved median overall survival to 10.2 months vs 6.9 months on placebo (HR 0.69; 95% CI 0.52 to 0.91; p=0.0090) and progression-free survival to 3.0 vs 1.8 months (HR 0.67; 95% CI 0.53 to 0.85; p=0.0012). Objective response rate was 11% vs 1% (p=0.00086).
Did PD-L1 testing predict response in CONFIRM?▼
No. PD-L1 tumor proportion score was not predictive or prognostic in CONFIRM. People with mesothelioma benefited regardless of PD-L1 status, which is different from what has been observed in some other cancers.
Did both epithelioid and non-epithelioid subtypes benefit?▼
The statistically significant overall survival benefit was confined to the epithelioid subgroup (HR 0.71; 95% CI 0.53 to 0.95; p=0.021). In the non-epithelioid subgroup the hazard ratio was 0.79 (95% CI 0.35 to 1.79; p=0.572), a result that was not statistically significant. The trial was not powered to establish benefit in non-epithelioid histology.
How does CONFIRM relate to CheckMate-743?▼
They tested different regimens in different settings. CheckMate-743 tested nivolumab plus ipilimumab in previously untreated patients. CONFIRM tested single-agent nivolumab after prior platinum chemotherapy. They address different treatment lines and cannot be compared head to head.