MARS 2
Extended pleurectomy decortication and chemotherapy versus chemotherapy alone for pleural mesothelioma (MARS 2): a phase 3 randomised controlled trial
Phase 3N = 335NCT02040272
- Population
- People aged 16 years or older with resectable pleural mesothelioma (epithelioid, sarcomatoid or biphasic) confined to one hemithorax, with adequate organ and lung function; 291 (87%) men; 288 (86%) epithelioid
- Design
- Phase 3, national, multicentre, open-label, parallel two-group, pragmatic, superiority randomised controlled trial in 26 UK hospitals (NCT02040272). After two cycles of chemotherapy, participants were randomised 1:1 (web-based system; stratified by site, minimised by age, performance status and cell type) to pleurectomy decortication or extended pleurectomy decortication followed by two to four further cycles of chemotherapy, or to two to four further cycles of chemotherapy alone. 1030 were assessed and 335 randomised between 19 June 2015 and 21 January 2021 (169 surgery plus chemotherapy, 166 chemotherapy alone). The registry record lists an estimated enrolment of 328, status unknown and phase not applicable; the paper's planned sample size was 328 (164 per group) and it reports 335 randomised, so 335 is recorded here. Primary outcome overall survival from randomisation to death from any cause; analyses by intention to treat. Because the proportional-hazards assumption was violated, the primary comparison used the difference in restricted mean survival time to 2 years.
- Primary endpoint
- OS
- Arms
- Chemotherapy alone (control, n = 166): Two to four further cycles of chemotherapy after the initial two cycles, according to local policy
- Surgery and chemotherapy (experimental, n = 169): Pleurectomy decortication or extended pleurectomy decortication followed by two to four further cycles of chemotherapy, after the initial two cycles
- People
- Lim E, MARS 2 Investigators
Δ median OS−5.5 monthsOSHR 1.28 (95% CI 1.02–1.60)Δ 24-month OS−11 pointsΔ median PFS−0.4 months
Show the numbers
| Endpoint | Analysis | Surgery and chemotherapy | Chemotherapy alone | Effect |
|---|---|---|---|---|
| OS | primarymedian follow-up 22.4 monthsLim 2024 | median 19.3 months | median 24.8 months | P=0.019Primary comparison: difference in restricted mean survival time at 2 years of -1.9 months (95% CI -3.4 to -0.3; p=0.019), negative values favouring chemotherapy alone. The intervals printed beside the medians are interquartile ranges (surgery 10.0-33.7 months; chemotherapy alone 12.6-37.4), not confidence intervals. Median follow-up 22.4 months (IQR 11.3-30.8) for the whole cohort. |
| OSITT, first 42 months of follow-up | exploratoryLim 2024 | — | — | HR 1.28 (95% CI 1.02–1.60)P=0.032Cox regression restricted to the first 42 months (the point where the Kaplan-Meier curves intersected), surgery and chemotherapy versus chemotherapy alone; a value above 1 means a higher hazard of death with surgery. Used because proportional hazards did not hold over the whole follow-up. The paper states that the 30 participants in follow-up beyond 42 months were too few for a meaningful comparison. |
| OS | finalLim 2024 | 41% at 2 y (34–49%); 14% at 5 y (8–22%) | 52% at 2 y (44–59%); 13% at 5 y (7–20%) | Survival probabilities at 24 months are read from the Figure 2 legend (0.41 and 0.52); the 5-year rates (14% and 13%) are in the text, which says most deaths were due to disease progression. |
| PFS | finalLim 2024 | median 10.6 months | median 11 months | P=0.33Prespecified secondary outcome, investigator-assessed. Interquartile ranges beside the medians: surgery 6.3-21.6 months, chemotherapy alone 5.9-19.6 (not confidence intervals). The paper also gives a hazard ratio of 0.90 (95% CI 0.72-1.11) for progression-free survival but does not say in its text which group is the reference, so it is kept here as text and not entered as a structured hazard ratio. |
| Endpoint | Analysis | Surgery and chemotherapy | Chemotherapy alone | Effect |
|---|---|---|---|---|
| OS | primarymedian follow-up 22.4 monthsLim 2024 | median 19.3 months | median 24.8 months | P=0.019Primary comparison: difference in restricted mean survival time at 2 years of -1.9 months (95% CI -3.4 to -0.3; p=0.019), negative values favouring chemotherapy alone. The intervals printed beside the medians are interquartile ranges (surgery 10.0-33.7 months; chemotherapy alone 12.6-37.4), not confidence intervals. Median follow-up 22.4 months (IQR 11.3-30.8) for the whole cohort. |
| OSITT, first 42 months of follow-up | exploratoryLim 2024 | — | — | HR 1.28 (95% CI 1.02–1.60)P=0.032Cox regression restricted to the first 42 months (the point where the Kaplan-Meier curves intersected), surgery and chemotherapy versus chemotherapy alone; a value above 1 means a higher hazard of death with surgery. Used because proportional hazards did not hold over the whole follow-up. The paper states that the 30 participants in follow-up beyond 42 months were too few for a meaningful comparison. |
| OS | finalLim 2024 | 41% at 2 y (34–49%); 14% at 5 y (8–22%) | 52% at 2 y (44–59%); 13% at 5 y (7–20%) | Survival probabilities at 24 months are read from the Figure 2 legend (0.41 and 0.52); the 5-year rates (14% and 13%) are in the text, which says most deaths were due to disease progression. |
| PFS | finalLim 2024 | median 10.6 months | median 11 months | P=0.33Prespecified secondary outcome, investigator-assessed. Interquartile ranges beside the medians: surgery 6.3-21.6 months, chemotherapy alone 5.9-19.6 (not confidence intervals). The paper also gives a hazard ratio of 0.90 (95% CI 0.72-1.11) for progression-free survival but does not say in its text which group is the reference, so it is kept here as text and not entered as a structured hazard ratio. |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| OS | 1.28 | 1.02–1.6 |
- Surgery and chemotherapy (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 | Surgery and chemotherapy | Chemotherapy alone |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 16 | 56.3% | 63.9% |
| 31 | 32.8% | 42.0% |
| 47 | 18.5% | 26.9% |
| 62 | 10.8% | 17.7% |
- Surgery and chemotherapy (experimental)
- Chemotherapy alone (control)
Data table (modelled values)
| Months | Surgery and chemotherapy | Chemotherapy alone |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 16 | 57.6% | 66.4% |
| 32 | 30.9% | 41.1% |
| 49 | 20.3% | 23.8% |
| 65 | 14.0% | 13.0% |