Thoracic / Lung
Phase III data against adding IO to SBRT in medically inoperable early-stage NSCLC, contradicting the earlier randomized phase II signal.
SWOG/NRG S1914 NCT04214262
ForT1-3N0M0 NSCLC ≤7cm, medically inoperable or declined surgery, ≥1 risk factor
HR 1.15
95% CI 0.65-2.01, p=0.63; primary endpoint not met
TL;DROS HR 1.15 (0.65-2.01), p=0.63: atezolizumab added to SBRT failed, with more local failures (13% vs 7%) and G≥3 AEs (12% vs 2%).
The RT read is that adding IO did not just fail to help, it tracked with MORE local failure (13% vs 7%), inside a BED ≥100 Gy 3-8 fraction regimen that is already delivering >90% in-field control. Central review of those events is pending, so treat the local signal as unconfirmed. This closes the question of routinely sequencing atezolizumab around definitive SBRT off-protocol.
In medically inoperable T1-3N0M0 NSCLC with high-risk features (size ≥2 cm, SUV ≥6.2, or poorly differentiated histology), this supports SBRT alone at BED ≥100 Gy without added checkpoint blockade; it does not address IO for node-positive or operable early-stage disease.
SBRT alone at BED ≥100 Gy in 3-8 fractions remains the standard, and adding atezolizumab tracked with MORE local failure (13% vs 7%) rather than better in-field durability. Central review of those events is pending. Regional (2% vs 3%) and distant (4% vs 5%) failure were unchanged, so the out-of-field rationale also went unrewarded.
Neoadjuvant/concurrent/adjuvant atezolizumab 1200 mg Q3W × 8 cycles bought no OS or PFS benefit and cost a six-fold rise in G≥3 AEs (12% vs 2%) including a G5 respiratory failure. This argues against porting PACIFIC-style consolidation logic into node-negative early-stage disease pending the PD-L1 analysis.
11 details
Randomized phase III SWOG/NRG cooperative-group trial, accrual 8/13/20 to 9/6/24, 417 randomized / 403 eligible (201 SBRT alone, 202 atezolizumab + SBRT) against an accrual goal of 432. Closed at the first interim analysis for futility on both OS and PFS. Median follow-up in living pts was 12 months (range 0.03-49).
T1-3N0M0 NSCLC ≤7 cm, medically inoperable or declined surgery, with ≥1 recurrence risk factor: tumor diameter ≥2 cm, ≥6.2 (SUV), or moderately/poorly/undifferentiated histology. Median age 73 (41-91), 89% ECOG 0-1, median tumor diameter 2.3 cm. Stratified by location (central vs peripheral), size (<4 vs ≥4 cm) and PS.
SBRT in 3-8 fractions to a BED ≥100 Gy in both arms, i.e. standard definitive dosing rather than a de-escalated backbone. In the experimental arm SBRT began with cycle 3, so radiation was delivered after two neoadjuvant atezolizumab cycles and concurrently with the third.
Atezolizumab 1200 mg IV Q3W for 8 cycles, given neoadjuvantly, concurrently and adjuvantly around SBRT. No protocol treatment was received by 6 pts on S and 8 on AS.
Primary: overall survival, compared by 1-sided stratified log-rank at the 2.5% level. Secondary: PFS, failure patterns, toxicity, QoL.
Neither OS nor PFS favored the IO arm, and local failure ran higher with atezolizumab. See the failure-pattern table and primary endpoint above.
| Failure site | SBRT alone | Atezo + SBRT |
|---|---|---|
| Local | 7% | 13% |
| Regional | 2% | 3% |
| Distant | 4% | 5% |
G≥3 AEs 12% on AS vs 2% on S (21 G3, 1 G4, and 1 G5 respiratory failure with atezolizumab; 3 G3 and 1 G4 with SBRT alone). A six-fold excess of high-grade toxicity with no efficacy return is the safety read.
The prior randomized phase II (PMID 37478883) suggested benefit from adding immunotherapy to SBRT; this larger phase III does not reproduce it. It also sits against PACIFIC-era logic, where consolidation IO helps after chemoRT for stage III, and shows that result does not port down to node-negative disease treated with ablative SBRT.
Follow-up is short (median 12 mo alive) and central review of local recurrence events is not complete, so the local-failure imbalance is provisional. The smoker subgroup harm signal was not multiplicity-controlled, and PD-L1 status, QoL and correlative blood/tissue analyses are all still pending.
A negative primary endpoint with a directionally worse PFS, worse local control and six-fold more high-grade toxicity is stronger than a null result: it argues against the abscopal/radiosensitization rationale in this setting. It does not exclude benefit in a biomarker-selected subset, which the pending PD-L1 analysis will test.
CONSORT flow
Phase III, primary OS endpoint not met, closed at interim for futility. Reaffirms SBRT alone as SoC and refutes the earlier phase II IO signal.
- Does a PD-L1-defined subset benefit from IO added to SBRT?
- Will central review confirm the excess local failures with atezolizumab?
- Is the worse outcome in former/never smokers real or chance?