IND.227 / KEYNOTE-483
Pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma in Canada, Italy, and France: a phase 3, open-label, randomised controlled trial
Phase 2/3N = 440NCT02784171
- Population
- Adults aged 18 years or older with previously untreated advanced pleural mesothelioma and ECOG performance status 0 or 1
- Design
- Open-label international randomised phase 2/3 trial, sponsored and conducted by the Canadian Cancer Trials Group according to the EMA assessment. The phase 3 part ran at 51 hospitals in Canada, Italy and France: 440 patients were randomly assigned 1:1 between 31 January 2017 and 4 September 2020 to chemotherapy with or without pembrolizumab for up to 2 years, stratified by histological subtype (FDA label). The phase 2 part had three arms (chemotherapy, chemotherapy plus pembrolizumab, pembrolizumab alone) and accrual to the pembrolizumab-alone arm was stopped after an interim analysis. The registry record lists an enrolment of 520 for the study as a whole (registered as phase 2/3); the Lancet paper reports 440 randomised in the phase 3 comparison. The primary endpoint was overall survival in all randomly assigned patients.
- Primary endpoint
- OS
- Arms
- Chemotherapy alone (control, n = 218): Cisplatin 75 mg/m2 or carboplatin AUC 5 to 6 mg/mL per min with pemetrexed 500 mg/m2 every 3 weeks for up to 6 cycles
- Chemotherapy plus pembrolizumab (experimental, n = 222): The same chemotherapy plus pembrolizumab 200 mg every 3 weeks for up to 2 years
- People
- Chu Q
OSHR 0.79 (95% CI 0.64–0.98)Δ median OS+1.2 monthsΔ 36-month OS+8 pointsPFSHR 0.80 (95% CI 0.65–0.99)Δ median PFS0 monthsΔ ORR+23 points
Show the numbers
| Endpoint | Analysis | Chemotherapy plus pembrolizumab | Chemotherapy alone | Effect |
|---|---|---|---|---|
| OSAll randomly assigned patients (phase 3 part) | finalmedian follow-up 16.2 monthsChu 2023 | median 17.3 months (14.4–21.3); 25% at 3 y (20–33%) | median 16.1 months (13.1–18.2); 17% at 3 y (13–24%) | HR 0.79 (95% CI 0.64–0.98)P=0.0324Two-sided p-value. Median follow-up 16.2 months (IQR 8.3 to 27.8) per the Lancet abstract. The data cut-off is the EMA assessment's date for the same final analysis (identical medians and hazard ratio); the Lancet abstract gives a database lock of 15 December 2022 and the EMA assessment a database lock of 16 December 2022. The FDA label prints a log-rank p-value of 0.0162 without stating its sidedness; the EMA assessment gives 0.0162 as a one-sided p-value, which fits the Lancet's two-sided 0.0324. |
| PFSAll randomised patients (222 pembrolizumab with chemotherapy, 218 chemotherapy alone; FDA labelling)Progression-free survival assessed by blinded independent central review using modified RECIST for mesothelioma (label wording) | finalSource 2024 | median 7.1 months (6.9–8.1) | median 7.1 months (6.8–7.7) | HR 0.80 (95% CI 0.65–0.99)P=0.0194Stratified log-rank p-value as printed in the label, which does not state whether it is one- or two-sided; the EMA assessment report gives 0.0194 as a one-sided p-value. The Lancet abstract gives no progression-free survival result. |
| ORRAll randomised patients (222 pembrolizumab with chemotherapy, 218 chemotherapy alone; FDA labelling)Overall response rate assessed by blinded independent central review using modified RECIST for mesothelioma (label wording) | finalSource 2024 | 52% (45.5–59.0%) | 29% (23.0–35.4%) | P<0.00001Label table: 1 complete response (0.5%) and 115 partial responses (52%) with pembrolizumab plus chemotherapy; 0 complete and 63 partial responses (29%) with chemotherapy alone. |
| OSEpithelioid histology, phase 3 ITT subgroup as labelled by the EMA (176 pembrolizumab with chemotherapy, 169 chemotherapy alone)Overall survival in the epithelioid subgroup (EMA assessment, Table 30) | exploratorySource 2025 | median 19.8 months (16.0–22.2) | median 18.2 months (16.0–20.4) | HR 0.89 (95% CI 0.70–1.13)Subgroup analysis from the EMA assessment report; the report acknowledges the limited value of subgroup analyses. |
| OSNon-epithelioid histology, phase 3 ITT subgroup as labelled by the EMA (46 pembrolizumab with chemotherapy, 49 chemotherapy alone)Overall survival in the non-epithelioid subgroup (EMA assessment, Table 30) | exploratorySource 2025 | median 12.3 months (8.7–21.2) | median 8.2 months (5.8–9.8) | HR 0.57 (95% CI 0.36–0.89)Subgroup analysis from the EMA assessment report; the report acknowledges the limited value of subgroup analyses. |
| OSPhase 2 part (arm sizes are not stated in the abstract)Median survival in the phase 2 part, chemotherapy plus pembrolizumab versus chemotherapy | exploratoryPiccirillo 2023 | median 19.8 months (8.40–41.36) | median 8.9 months (5.3–12.8) | Brief report of the phase 2 part (J Thorac Oncol 2023). Progression-free survival, the comparison named in the abstract, was reported as similar between arms. The abstract does not state the arm sizes or whether these patients are included in the phase 3 analysis. |
| ORRPhase 2 part (arm sizes are not stated in the abstract)Overall response rate in the phase 2 part, chemotherapy plus pembrolizumab versus chemotherapy | exploratoryPiccirillo 2023 | 47% (24–71%) | 19% (5–42%) | Brief report of the phase 2 part (J Thorac Oncol 2023); wide intervals reflect a small sample. |
| Endpoint | Analysis | Chemotherapy plus pembrolizumab | Chemotherapy alone | Effect |
|---|---|---|---|---|
| OSAll randomly assigned patients (phase 3 part) | finalmedian follow-up 16.2 monthsChu 2023 | median 17.3 months (14.4–21.3); 25% at 3 y (20–33%) | median 16.1 months (13.1–18.2); 17% at 3 y (13–24%) | HR 0.79 (95% CI 0.64–0.98)P=0.0324Two-sided p-value. Median follow-up 16.2 months (IQR 8.3 to 27.8) per the Lancet abstract. The data cut-off is the EMA assessment's date for the same final analysis (identical medians and hazard ratio); the Lancet abstract gives a database lock of 15 December 2022 and the EMA assessment a database lock of 16 December 2022. The FDA label prints a log-rank p-value of 0.0162 without stating its sidedness; the EMA assessment gives 0.0162 as a one-sided p-value, which fits the Lancet's two-sided 0.0324. |
| PFSAll randomised patients (222 pembrolizumab with chemotherapy, 218 chemotherapy alone; FDA labelling)Progression-free survival assessed by blinded independent central review using modified RECIST for mesothelioma (label wording) | finalSource 2024 | median 7.1 months (6.9–8.1) | median 7.1 months (6.8–7.7) | HR 0.80 (95% CI 0.65–0.99)P=0.0194Stratified log-rank p-value as printed in the label, which does not state whether it is one- or two-sided; the EMA assessment report gives 0.0194 as a one-sided p-value. The Lancet abstract gives no progression-free survival result. |
| ORRAll randomised patients (222 pembrolizumab with chemotherapy, 218 chemotherapy alone; FDA labelling)Overall response rate assessed by blinded independent central review using modified RECIST for mesothelioma (label wording) | finalSource 2024 | 52% (45.5–59.0%) | 29% (23.0–35.4%) | P<0.00001Label table: 1 complete response (0.5%) and 115 partial responses (52%) with pembrolizumab plus chemotherapy; 0 complete and 63 partial responses (29%) with chemotherapy alone. |
| OSEpithelioid histology, phase 3 ITT subgroup as labelled by the EMA (176 pembrolizumab with chemotherapy, 169 chemotherapy alone)Overall survival in the epithelioid subgroup (EMA assessment, Table 30) | exploratorySource 2025 | median 19.8 months (16.0–22.2) | median 18.2 months (16.0–20.4) | HR 0.89 (95% CI 0.70–1.13)Subgroup analysis from the EMA assessment report; the report acknowledges the limited value of subgroup analyses. |
| OSNon-epithelioid histology, phase 3 ITT subgroup as labelled by the EMA (46 pembrolizumab with chemotherapy, 49 chemotherapy alone)Overall survival in the non-epithelioid subgroup (EMA assessment, Table 30) | exploratorySource 2025 | median 12.3 months (8.7–21.2) | median 8.2 months (5.8–9.8) | HR 0.57 (95% CI 0.36–0.89)Subgroup analysis from the EMA assessment report; the report acknowledges the limited value of subgroup analyses. |
| OSPhase 2 part (arm sizes are not stated in the abstract)Median survival in the phase 2 part, chemotherapy plus pembrolizumab versus chemotherapy | exploratoryPiccirillo 2023 | median 19.8 months (8.40–41.36) | median 8.9 months (5.3–12.8) | Brief report of the phase 2 part (J Thorac Oncol 2023). Progression-free survival, the comparison named in the abstract, was reported as similar between arms. The abstract does not state the arm sizes or whether these patients are included in the phase 3 analysis. |
| ORRPhase 2 part (arm sizes are not stated in the abstract)Overall response rate in the phase 2 part, chemotherapy plus pembrolizumab versus chemotherapy | exploratoryPiccirillo 2023 | 47% (24–71%) | 19% (5–42%) | Brief report of the phase 2 part (J Thorac Oncol 2023); wide intervals reflect a small sample. |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| OS | 0.79 | 0.64–0.98 |
| PFS | 0.8 | 0.65–0.99 |
| OS | 0.89 | 0.7–1.13 |
| OS | 0.57 | 0.36–0.89 |
- Chemotherapy plus pembrolizumab (experimental)
- Chemotherapy alone (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Chemotherapy plus pembrolizumab | Chemotherapy alone |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 11 | 64.4% | 62.3% |
| 22 | 41.4% | 38.8% |
| 32 | 27.7% | 25.2% |
| 43 | 17.9% | 15.7% |
- Chemotherapy plus pembrolizumab (experimental)
- Chemotherapy alone (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Chemotherapy plus pembrolizumab | Chemotherapy alone |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 4 | 67.7% | 67.7% |
| 9 | 41.5% | 41.5% |
| 13 | 28.1% | 28.1% |
| 18 | 17.3% | 17.3% |
Appears in
Sources
Chu Q, Perrone F, Greillier L, Tu W, Piccirillo MC, Grosso F, et al. Pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma in Canada, Italy, and France: a phase 3, open-label, randomised controlled trial. Lancet. 2023;402(10419):2295-2306.
U.S. Food and Drug Administration. KEYTRUDA (pembrolizumab) prescribing information enclosed with the BLA 125514/S-161 approval letter (Reference ID 5448057). Sections 1.3 and 14.3: malignant pleural mesothelioma, KEYNOTE-483.
European Medicines Agency, CHMP. Assessment report, Keytruda (pembrolizumab), procedure EMEA/H/C/003820/II/0154, 27 February 2025 (EMA/CHMP/99965/2025).
Piccirillo MC, Chu Q, Bradbury P, Tu W, Coschi CH, Grosso F, et al. Brief Report: Canadian Cancer Trials Group IND.227: A Phase 2 Randomized Study of Pembrolizumab in Patients With Advanced Malignant Pleural Mesothelioma (NCT02784171). J Thorac Oncol. 2023;18(6):813-819.