GI Upper
Concurrent pembro + dCRT is negative at IA2 in CPS ≥10. Consolidation-timed IO after dCRT remains untested.
KEYNOTE-975 NCT04210115
ForUntreated unresectable locally advanced ESCC/EAC/GEJ, dCRT candidates
HR 0.97
95% CI 0.77-1.23, P=0.3994; not met (boundary 0.0193)
TL;DREFS HR 0.97 (95% CI 0.77-1.23), median 15.2 vs 14.7 mo in PD-L1 CPS ≥10: no EFS gain adding concurrent pembro to dCRT in unresectable esophageal/GEJ cancer.
The trial failed in the enriched PD-L1 CPS ≥10 group, where IO was most likely to help, and the curves sat on top of each other (EFS HR 0.97, OS HR 1.00) at 47.1 mo median f/u. Grade 5 AEs ran 13% vs 10%, so concurrent pembro with 50-60 Gy dCRT adds toxicity without benefit. This leaves dCRT alone as the backbone.
In untreated unresectable esophageal or GEJ cancer going to dCRT, including PD-L1 CPS ≥10, this does not support concurrent pembrolizumab; it does not address consolidation-only IO after dCRT or the resectable trimodality setting. The longer read
Concurrent pembro with 50-60 Gy dCRT did not move EFS (HR 0.97) or OS (HR 1.00) in CPS ≥10 pts, and grade 5 AEs rose to 13% vs 10%. No local control or dose-stratified data in source, so the RT backbone stays dCRT alone with no IO-driven change to dose or volume.
PD-L1 CPS ≥10 enrichment did not rescue concurrent pembro (EFS HR 0.97, OS HR 1.00), and AE discontinuation rose to 34% vs 27%. Biomarker selection does not justify adding PD-1 blockade to dCRT; consolidation-only timing remains untested by this trial.
9 details
International phase 3, randomized 1:1, double-blind, placebo-controlled, multicenter; N=703. Results are from the second interim analysis (IA2), after which the study was stopped. Median follow-up 47.1 mo.
Previously untreated locally advanced unresectable ESCC, EAC or GEJ cancer (cTX N+ M0 or cT2-T4a NX M0), or cervical/upper thoracic EC with supraclavicular nodal M1 only. ECOG 0-1, ineligible for curative surgery but suitable for dCRT.
Pembro 200 mg or placebo Q3W for 8 cycles, then 400 mg or placebo Q6W for 5 cycles, concurrent with dCRT. Chemo backbone FP or FOLFOX by site choice.
50 Gy or 60 Gy with FP, or 50 Gy with FOLFOX, by site choice. Fractionation, technique and target volume not reported in source.
Dual primary: investigator-assessed EFS and OS, tested hierarchically in PD-L1 CPS ≥10, CPS ≥1, then all pts.
EFS not improved in CPS ≥10 (arm-level numbers in table), so every downstream comparison went untested and the study was stopped.
| Endpoint (CPS ≥10) | Pembro + dCRT | Pbo + dCRT | HR (95% CI), P |
|---|---|---|---|
| Median EFS (investigator) | 15.2 mo | 14.7 mo | 0.97 (0.77-1.23), P=0.3994; boundary 0.0193 |
| Median OS | 32.2 mo | 35.0 mo | 1.00 (0.77-1.30), nominal P=0.5003 |
| AE | Pembro + dCRT | Pbo + dCRT |
|---|---|---|
| Grade ≥3 | 100% | 100% |
| Grade 5 | 44 (13%) | 37 (10%) |
| Discontinuation for any AE | 117 (34%) | 97 (27%) |
Grade ≥3 AEs in 100% of both arms. Grade 5 AEs 44 (13%) vs 37 (10%), AE discontinuation 117 (34%) vs 97 (27%). Authors report no new safety signals.
Joins KUNLUN (durvalumab + dCRT) as a negative concurrent IO-dCRT trial in esophageal cancer. Adjuvant nivolumab per CheckMate 577 belongs to the resected trimodality setting and is untouched by this result.
RT dose and chemo backbone by site choice with no outcome breakdown, pooled histologies, and no local control or failure-pattern data in source to show whether IO changed in-field control.
A flat EFS and OS in the PD-L1-enriched group argues against a hidden benefit in the untested CPS ≥1 or all-comer groups. Whether timing (consolidation vs concurrent) or histology matters stays open.
CONSORT flow
Double-blind phase 3 stopped at IA2 after the gatekeeper EFS endpoint failed in the enriched CPS ≥10 group; reaffirms dCRT alone as standard. Downstream populations formally untested.
- Would consolidation-only IO after dCRT differ from concurrent dosing?
- Histology-specific EFS in ESCC vs EAC/GEJ
- Did pembro alter local control or failure patterns?