Abstract
PURPOSE
NRG Oncology/Alliance LU005 (ClinicalTrials.gov identifier: NCT03811002) tested the addition of atezolizumab to concurrent chemoradiation (CRT) in this open-label, phase III international trial.
METHODS
Patients with limited-stage small cell lung cancer (LS-SCLC), stage Tx-IV, N0–3, and M0 with Eastern Cooperative Group performance status (PS) 0–2 received one cycle of chemotherapy (platinum/etoposide) before study registration and were randomly assigned to CRT alone versus CRT plus concurrent and adjuvant atezolizumab, 1,200 mg once daily, every 3 weeks until investigator-assessed progression or intolerable side effects for a maximum of 17 cycles. Patients were stratified by choice of chemotherapy (cisplatin ν carboplatin), radiation fractionation schedule (66 Gy once daily ν 45 Gy twice daily), sex, and PS (0/1 ν 2). The primary end point was overall survival (OS). Secondary end points included investigator-assessed progression-free survival (PFS), objective response rate, local control, and distant-metastasis-free survival (DMFS).
RESULTS
patients were randomly assigned from May 2019 to December 2023. The median OS was 36.1 months (95% CI, 28.1 to 42.5) for the CRT-alone arm and 31.1 months (95% CI, 28.5 to 44.7) for the CRT + atezolizumab arm, respectively (hazard ratio [HR], 1.03 [95% CI, 0.80 to 1.32]). The median PFS was 11.4 months (95% CI, 10.3 to 13.2) for the CRT-alone arm and 12.1 months (95% CI, 10.9 to 15.2) for the CRT + atezolizumab arm, respectively (HR, 0.98 [95% CI, 0.79 to 1.22]). The median DMFS was 13.0 months (95% CI, 11.3 to 18.2) for the CRT-alone arm and 16.8 months (95% CI, 12.1 to 21.6) for the CRT + atezolizumab arm (HR, 0.96 [95% CI, 0.76 to 1.21]). No unexpected safety signals with concurrent atezolizumab were observed.
CONCLUSION
Concurrent and adjuvant atezolizumab with chemoradiation did not improve survival in patients with LS-SCLC.
INTRODUCTION
Until recently, small cell lung cancer (SCLC) management has seen limited therapeutic advances and overall survival (OS) improvements that lag behind non–small cell lung cancer.1 Major advances came in 2019 and 2020, when the US Food and Drug Administration approved atezolizumab and durvalumab, respectively, when added to chemotherapy for extensive-stage small cell lung cancer, on the basis of the IMpower 1332 and Caspian3 trials that demonstrated OS and progression-free survival (PFS) benefits.
NRG Oncology and the Alliance for Clinical Trials in Oncology (hereafter referred to as the Alliance), as part of the National Cancer Institute’s National Clinical Trials Network, designed NRG/Alliance LU005, a randomized clinical trial to test the concept of moving immunotherapy into earlier, curable stages of SCLC. The standard of care for limited-stage small cell lung cancer (LS-SCLC) had remained concurrent chemoradiation ± prophylactic cranial irradiation (PCI), with a 5-year survival of approximately 30%.4–6
NRG/Alliance LU005 was designed to test whether concurrent and adjuvant administration of atezolizumab, a monoclonal antibody to PD-L1, with chemoradiation would improve OS compared with chemoradiation alone. This trial concept was developed in 2017 and activated for enrollment in May 2019 in the United States and Japan.
METHODS
Participants
Patients with cytologically confirmed SCLC were eligible, with a central review of pathology performed by the NRG Oncology pathology chair. Patients were required to have Tx or T1–4, N0-N3, M0 disease per American Joint Committee on Cancer (AJCC) 8th edition, with positron emission tomography/computed tomography (CT), CT of the chest and abdomen with IV contrast, and brain magnetic resonance imaging (MRI) with contrast to exclude metastatic disease. Patients with Eastern Cooperative Group performance status (ECOG PS) of 0–2 were eligible. Patients received one cycle of chemotherapy with carboplatin/etoposide or cisplatin/etoposide before study registration. This design was intentional to capture patients who were diagnosed during hospital admission and were not able to undergo full staging workup before the administration of the first cycle of chemotherapy. If patients received their first cycle of chemotherapy without a complete staging workup, diagnostic imaging studies were obtained after this first cycle of preregistration chemotherapy.
Procedures
Thoracic radiation could be given either once per day to 66 Gy over 6.5 weeks (33 fractions) or twice per day to 45 Gy (30 fractions) over 3 weeks. Either carboplatin or cisplatin was allowed with etoposide during radiation and to complete chemotherapy. PCI was recommended for patients with a complete or near complete response after chemoradiation to a dose of 25 Gy in 10 fractions but was not required. High-grade toxicities (Common Terminology Criteria for Adverse Events, version 5 [CTCAE] grade 3 or higher) were to be resolved before receipt of PCI.
A robust radiation therapy quality assurance program was incorporated into this trial; the first three cases for every enrolling institution were reviewed before radiation therapy commencing by the radiation oncology co-chairs. Radiation therapy could consist of either 3-dimensional conformal radiation or intensity-modulated radiation therapy (IMRT).
This trial was sponsored by the National Cancer Institute (NCI) and conducted through the NRG Oncology cooperative group in collaboration with the Alliance. Atezolizumab was provided by the NCI via a Cooperative Research and Development Agreement. The protocol and all subsequent amendments were approved by the Central Investigational Review Board (CIRB), with all patients required to provide written consent to participate.
Random Assignment and Treatment Allocation
Patients were randomly assigned in a 1:1 ratio to receive either concurrent chemoradiation with atezolizumab followed by adjuvant atezolizumab (1,200 mg once daily every 3 weeks for up to 1 year) or concurrent chemoradiation followed by observation. Random assignment was implemented using a permuted block design7 ensuring balance across key stratification factors: radiation fractionation regimen (66 Gy once daily ν 45 Gy twice daily), chemotherapy choice (cisplatin ν carboplatin), sex (male ν female), and ECOG PS (0–1 ν 2). To maintain integrity, the allocation sequences were generated centrally at the NRG Oncology SDMC and participating centers had no access to the random assignment sequences. The study is registered with ClinicalTrials.gov (identifier: NCT03811002).
End Points and Assessments
The primary end point was OS. Secondary end points included PFS (investigator-assessed), time to local failure, distant-metastasis-free survival (DMFS), and objective response rate (ORR) (according to RECIST, version 1.1), as well as safety. Other secondary objectives not reported here include quality of life, fatigue, and the association of SCLC molecular subtypes with clinical outcomes.
Adverse events were graded according to the CTCAE, version 5. Patients were assessed weekly throughout chemoradiation and every 3 weeks after completion of chemoradiation for patients receiving atezolizumab until completed. Diagnostic imaging consisting of a CT of the chest with contrast (through the adrenals) was required every 3 months for 2 years, every 6 months in year 3, and annually thereafter. Brain MRI with contrast was obtained every 3 months for the first 2 years, followed by every 6 months if clinically indicated.
Statistical Considerations
The study was designed with 85% power to detect an improvement in median OS from 27 to 38 months (hazard ratio [HR] = 0.71) at a one-sided significance level of 0.025, requiring 545 patients and approximately 315 deaths for final analysis. Two interim analyses were planned at 40% and 70% information (127 and 222 deaths, respectively). Efficacy monitoring followed Lan-DeMets implementation of the O’Brien-Fleming boundary; an inefficacy (futility) boundary per Freidlin et al8 allowed early reporting if results indicated the trial was unlikely to achieve the targeted benefit.
Efficacy analyses followed the intent-to-treat principle. OS was defined from random assignment to death, PFS from random assignment to progression or death, and DMFS from random assignment to distant metastasis or death. Survival was estimated by Kaplan-Meier methods, with treatment comparisons by stratified log-rank tests and stratified Cox models using random assignment strata. Local control was assessed using competing-risks methods. ORR was compared between arms using a stratified Cochran-Mantel-Haenszel test. Exploratory sensitivity analyses of twice a day versus daily RT and PCI were also conducted (Appendix 1, online only).
Safety analyses used the as-treated population, defined as all patients who initiated protocol therapy, analyzed according to treatment received. Adverse events were graded per CTCAE v5.0. Additional details are provided in Appendix 1.
RESULTS
Between May 2019 and June 2022, 506 patients were enrolled. Enrollment then closed in the United States but continued in Japan until December 31, 2023, resulting in a total accrual of 544 patients (500 in the United States and 44 in Japan) across 218 sites, 270 randomly assigned to chemoradiation (CRT) and 274 to CRT + atezo arm (Fig 1). The median follow-up is 23.8 months for the entire population and 32.4 months for surviving patients.
FIG 1.
CONSORT diagram. CRT, chemoradiation; SCLC, small cell lung cancer.
Patient characteristics are shown in Table 1. The median age of the study population was 66 (20–85). Fifty-one percent of patients were female and 49% were male. Most patients were ECOG PS 0–1 with fewer than 5% of patients with ECOG PS 2. Most patients were current or former tobacco users, with 2% of patients never using tobacco. Eighty percent of patients were White, 9% were Black, and 9% were Asian. AJCC stage was well balanced between treatment groups. Most patients were stage IIIA-IIIC, 81% in the control arm and 82% in the experimental arm. There were slightly more stage IIIC patients in the atezolizumab (atezo) arm, 13% compared with 10% in the control arm.
TABLE 1.
Patient, Tumor, and Treatment Characteristics
| Patient Characteristic | CRT Only (n = 270), No. (%) | CRT + Atezolizumab (n = 274), No. (%) | Total (N = 544), No. (%) |
|---|---|---|---|
| Age, years | |||
| Median (minimum-maximum) | 67 (20–85) | 66 (44–84) | 66 (20–85) |
| ≤49 | 11 (4.1) | 5 (1.8) | 16 (2.9) |
| 50–59 | 49 (18.1) | 49 (17.9) | 98 (18.0) |
| 60–69 | 115 (42.6) | 127 (46.4) | 242 (44.5) |
| ≥70 | 95 (35.2) | 93 (33.9) | 188 (34.6) |
| Sexa | |||
| Male | 133 (49.3) | 134 (48.9) | 267 (49.1) |
| Female | 137 (50.7) | 140 (51.1) | 277 (50.9) |
| ECOG performance statusa | |||
| 0 | 121 (44.8) | 120 (43.8) | 241 (44.3) |
| 1 | 136 (50.4) | 142 (51.8) | 278 (51.1) |
| 2 | 13 (4.8) | 12 (4.4) | 25 (4.6) |
| Cigarette use | n = 269 | n = 273 | n = 542 |
| Current | 78 (29.0) | 88 (32.2) | 166 (30.6) |
| Former | 184 (68.4) | 180 (65.9) | 364 (67.2) |
| Never | 7 (2.6) | 5 (1.8) | 12 (2.2) |
| Race | |||
| American Indian or Alaska Native | 1 (0.4) | 0 (0.0) | 1 (0.2) |
| Asian | 19 (7.0) | 28 (10.2) | 47 (8.6) |
| Black or African American | 22 (8.1) | 24 (8.8) | 46 (8.5) |
| Native Hawaiian or other Pacific Islander | 1 (0.4) | 0 (0.0) | 1 (0.2) |
| White | 221 (81.9) | 215 (78.5) | 436 (80.1) |
| Multiple races | 2 (0.7) | 0 (0.0) | 2 (0.4) |
| Unknown | 4 (1.5) | 7 (2.6) | 11 (2.0) |
| Ethnicity | |||
| Hispanic or Latino | 9 (3.3) | 7 (2.6) | 16 (2.9) |
| Not Hispanic or Latino | 257 (95.2) | 261 (95.3) | 518 (95.2) |
| Unknown | 4 (1.5) | 6 (2.2) | 10 (1.8) |
| Tumor characteristics | |||
| T stage | |||
| T0 | 3 (1.1) | 2 (0.7) | 5 (0.9) |
| T1 | 95 (35.2) | 89 (32.5) | 184 (33.8) |
| T2 | 59 (21.9) | 60 (21.9) | 119 (21.9) |
| T3 | 57 (21.1) | 61 (22.3) | 118 (21.7) |
| T4 | 46 (17.0) | 53 (19.3) | 99 (18.2) |
| TX | 10 (3.7) | 9 (3.3) | 19 (3.5) |
| N stage | |||
| N0 | 20 (7.4) | 26 (9.5) | 46 (8.5) |
| N1 | 43 (15.9) | 40 (14.6) | 83 (15.3) |
| N2 | 147 (54.4) | 148 (54.0) | 295 (54.2) |
| N3 | 58 (21.5) | 59 (21.5) | 117 (21.5) |
| NX | 2 (0.7) | 1 (0.4) | 3 (0.6) |
| AJCC stage | |||
| IA-IIB | 50 (18.5) | 49 (17.9) | 99 (18.2) |
| IIIA | 107 (39.6) | 112 (40.9) | 219 (40.3) |
| IIIB | 87 (32.2) | 77 (28.1) | 164 (30.1) |
| IIIC | 26 (9.6) | 36 (13.1) | 62 (11.4) |
| Treatment characteristics | |||
| Chemotherapya | |||
| As randomized | |||
| Carboplatin | 111 (41.1) | 111 (40.5) | 222 (40.8) |
| Cisplatin | 159 (58.9) | 163 (59.5) | 322 (59.2) |
| As delivered | |||
| Carboplatin | 116 (43.0) | 123 (44.9) | 239 (43.9) |
| Cisplatin | 154 (57.0) | 151 (55.1) | 305 (56.1) |
| RT schedulea | |||
| As randomized | |||
| Twice a day (3 weeks) | 128 (47.4) | 129 (47.1) | 257 (47.2) |
| Daily (6.5 weeks) | 142 (52.6) | 145 (52.9) | 287 (52.8) |
| As delivered | |||
| Twice a day (3 weeks) | 128 (47.4) | 129 (47.1) | 257 (47.2) |
| Daily (6.5 weeks) | 142 (52.6) | 145 (52.9) | 287 (52.8) |
| RT technique | n = 249 | n = 264 | n = 513 |
| IMRT | 231 (92.8) | 241 (91.3) | 472 (92.0) |
| 3D | 18 (7.2) | 23 (8.7) | 41 (8.0) |
| PCI Delivery | |||
| No PCI | 151 (55.9) | 148 (54.0) | 299 (55.0) |
| PCI | 119 (44.1) | 126 (46.0) | 245 (45.0) |
| Unknown | 1 (0.4) | 6 (2.2) | 7 (1.3) |
Stratification factor.
Abbreviations: AJCC, American Joint Committee on Cancer; CRT, chemoradiation; ECOG, Eastern Cooperative Group; IMRT, intensity-modulated radiation therapy; PCI, prophylactic cranial irradiation; RT, radiation therapy.
Treatment characteristics are shown in Table 1. Most patients received cisplatin chemotherapy (59%). Twice daily radiation to 45 Gy was delivered in 47% of patients. Fifty-three percent of patients received daily radiation to 66 Gy. Ninety-three percent of patients received IMRT in the control arm, compared with 91% in the experimental arm. Overall, 97% of patients in both arms had acceptable radiation plans. PCI was given in 45% of patients (44% in the CRT-alone arm and 46% in the CRT + atezo arm).
Figure 2A demonstrates OS for the CRT alone arm versus CRT + atezo. The 1-, 2-and 3-year OS rates were 82.6% (95% CI, 77.2 to 86.9), 63.0% (95% CI, 56.4 to 68.8), and 50.5% (95% CI, 43.5 to 57.2) in the CRT alone arm, and 80.5% (95% CI, 75.2 to 84.8), 59.2% (95% CI, 52.8 to 65.1), and 45.8% (95% CI, 39.0 to 52.4) in the CRT + atezo arm, respectively. The median OS was 36.1 months (95% CI, 28.1 to 42.5) in the CRT-alone arm and 31.1 months (95% CI, 28.5 to 44.7) on the CRT + atezo arm, respectively. The stratified HR between CRT alone (reference level) and CRT + atezo is 1.03 (95% CI, 0.80 to 1.32), with a one-sided stratified log-rank test P value of .58.
FIG 2.
Kaplan-Meier estimates of (A) OS, (B) progression-free survival, and (C) DMFS by treatment arm. HRs with 95% CIs are from stratified Cox proportional hazards models, stratified by as-randomized radiation schedule (BID v daily), chemotherapy regimen (cisplatin v carboplatin), and sex. Stratified log-rank tests provided P values for treatment comparisons. CRT, chemoradiation; DMFS, distant metastasis–free survival; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.
PFS was not significantly different between the two arms, with Figure 2B showing the Kaplan Meier (KM) estimates. The median PFS was 11.4 months (95% CI, 10.3 to 13.2) in the CRT-alone arm and 12.1 months (95% CI, 10.9 to 15.2) on the CRT + atezo arm. The stratified HR between CRT + atezo and CRT alone (reference level) is 0.98 (95% CI, 0.79 to 1.22), with a two-sided stratified log-rank test P value of .87.
As shown in Figure 2C, there was no difference in DMFS, with a median of 13.0 months (95% CI, 11.3 to 18.2) for the CRT-alone arm and 16.8 months (95% CI, 12.1 to 21.6) for the CRT + atezo arm, with the corresponding stratified HR of 0.96 (95% CI, 0.76 to 1.21). The cumulative incidence of local failure and objective response information is summarized in Table 2, and the corresponding stratified cause-specific HR is 0.88 (95% CI, 0.53 to 1.44), with a two-sided stratified log-rank test P value of .61. For objective response, there were 59.6% and 60.2% complete response/partial response (PR) in each arm (difference −0.59%, [95% CI, −8.83 to 7.65]), with a 2-sided Cochran-Mantel-Haenszel test P value of .40.
TABLE 2.
Summary of Secondary Efficacy End Points
| Cumulative Incidence of Local Failure | CRT Only (n = 270) | CRT 1 Atezolizumab (n = 274) | Treatment Effect HR (95% CI) | P |
|---|---|---|---|---|
| 1 year (95% CI) | 10.1% (6.6 to 14.4) | 8.1% (5.0 to 12.0) | 0.88a (0.53 to 1.44)b | .61a |
| 2 years (95% CI) | 14.3% (10.1 to 19.3) | 12.8% (8.8 to 17.5) | ||
| Objective Response | n (%) | n (%) | Difference (95% CI) | P |
| CR/PR | 161 (59.6) | 165 (60.2) | −0.59% (–8.83 to 7.65) | .40c |
| No CR/PR | 109 (40.4) | 109 (39.8) |
Abbreviations: CR, complete response; CRT, chemoradiation; HR, hazard ratio; PR, partial response.
Log-rank test and cause-specific hazard Cox model stratified by as-randomized radiation schedule, as-randomized chemotherapy, and sex.
Referent = CRT only.
Cochran-Mantel-Haenszel test stratified by as-randomized radiation schedule, as-randomized chemotherapy, and sex.
A summary of the safety and AEs is shown in Table 3 on the basis of the actual treatment received. Overall, 94.2% of patients who received CRT alone and 95.8% who received CRT + atezo experienced any grade 3 or 4 AEs without regard to attribution. Grade 3–4 immune-related AEs were 6.6% of those who received CRT alone and 17.8 of those who received CRT + atezo. Grade 5 immune-related AEs were 0% of those receiving CRT alone and 1.5% of receiving CRT + atezo, with four deaths occurring; causes of death included one patient with myocarditis, two with pneumonitis, and a fourth with respiratory failure possibly related to immunotherapy. There were 8 (3.1%) and 16 (6.1%) patients who experienced grade 3+ pneumonitis when treated with CRT alone and CRT + atezo, respectively. There were 18 (7.0%) and 28 (10.6%) patients with grade 3+ esophagitis in each group. Two grade 2 pericarditis and one grade 3 encephalitis infection was also reported in the CRT + atezo group (data not shown).
TABLE 3.
AEs (safety population)
| Received CRT and No Atezolizumaba (n = 257), No. (%) | Received CRT and Atezolizumaba (n = 264), No. (%) | |||
|---|---|---|---|---|
| Adverse Event | Any grade | Grade 3 or 4 | Any grade | Grade 3 or 4 |
| Any AE | 253 (98.4) | 242 (94.2) | 264 (100) | 253 (95.8) |
| Any AE with outcome of death | 4 (1.6) | — | 24 (9.1) | — |
| Any Grade | Grade 3–5 | Any Grade | Grade 3–5 | |
| Protocol-specified AEs | ||||
| Pneumonitisb | 31 (12.1) | 8 (3.1) | 73 (27.7) | 16 (6.1) |
| Esophagitisb | 147 (57.2) | 18 (7.0) | 161 (61.0) | 28 (10.6) |
| Encephalitis | 0 (0.0) | 0 (0.0) | 1 (0.4) | 1 (0.4) |
| Myocarditis | 0 (0.0) | 0 (0.0) | 1 (0.4) | 1 (0.4) |
NOTE. The safety population included all patients who received ≥1 dose of systemic therapy or ≥1 fraction of radiation. For the CRT + atezolizumab arm, protocol therapy continued for up to 12 months with adverse events collected through 455 days from enrollment; for the CRT + no atezolizumab arm, reporting extended through 72 days from enrollment. No statistical comparisons were performed for other AEs.
Abbreviations: AE, adverse event; CRT, chemoradiation.
Patients on the CRT + atezolizumab arm who received no atezolizumab are grouped with the CRT + no atezolizumab patients. No patient on the CRT + no atezolizumab arm received atezolizumab as part of their definitive therapy.
P values for grade 3 or higher events (Fisher exact test): any immune-mediated AE: P = .0001; pneumonitis: P = .11; esophagitis: P = .098.
For grade 5 AEs, 1.6% were reported among those who received CRT alone, compared with 9.1% among those who received CRT + atezo. Of note, the observation windows for AE reporting (adjuvant atezolizumab for 1 year ν none) serious AEs, including grade 5 AEs, occurring between the start of treatment and 30 days after the end of treatment were required to be reported for all patients treated with CRT alone, whereas for those who received CRT + atezo, the window for reporting ended 90 days after the end of treatment, including atezolizumab. Appendix Tables A1 and A2 further report the distribution all grade AEs and of patient-level highest-grade AEs by system organ class and specific AE term for selected AEs, regardless of attribution. All grade 5 AEs are reported in Appendix Table A3. Of note, statistical comparisons of toxicity rates between arms were not made because of multiplicity testing concerns. The distribution of patient-level highest-grade immune-mediated AEs, regardless of attribution, is summarized in Appendix Table A2. In terms of treatment compliance (Table 4), 254 (94.1%) patients in the CRT-alone arm and 267 (97.4%) patients in the CRT + atezo arm received at least some protocol treatment. The median number of atezolizumab cycles were 17, 8, 6, and 5 among those who completed treatment (n = 99), terminated treatment because of progressive disease (n = 73), experienced an AE (n = 41), or all other reasons (n = 51), respectively. Overall, 92.9% and 92.5% of patients completed their prescribed course of radiation therapy on the CRT-alone arm and CRT plus atezolizumab arms, respectively.
TABLE 4.
Treatment Compliance
| Treatment Factor | CRT Only (n = 270), No. (%) | CRT + Atezolizumab (n = 274), No. (%) |
|---|---|---|
| Treatment delivery | ||
| Received any treatment | 254 (94) | 267 (97.4) |
| Received radiation therapy | 254 (94) | 267 (97.4) |
| Received chemotherapy | 251 (93.0) | 266 (97.1) |
| Received any atezolizumab | — | 264 (98.9) |
| Received maintenance atezolizumab | — | 261 (95.3) |
| No. of atezolizumab doses (median) | — | 8 |
| Reason for early atezolizumab discontinuation | ||
| Disease progression | — | 73 (27.7) |
| Adverse event | — | 41 (15.5) |
| Patient withdrawal | — | 16 (6.1) |
| Physician decision | — | 15 (5.7) |
| Death | — | 13 (4.9) |
| Other | — | 7 (2.7) |
| Adherence to protocol requirementsa | ||
| Radiation therapy | 248 (97.6) | 253 (95.1) |
| Chemotherapy | 227 (90.4) | 252 (97.1) |
| Atezolizumab—concurrent phase | — | 250 (94.7) |
| Atezolizumab—maintenance phase | — | 203 (77.8) |
Abbreviation: CRT, chemoradiation.
Adherence was defined as treatment delivered per protocol requirements or with acceptable variations.
Figure 3 presents an exploratory subgroup analysis of OS by RT schedule (twice a day ν daily RT), receipt of PCI, and chemotherapy regimen (cisplatin ν carboplatin) actually received. The treatment effect of CRT + atezo versus CRT alone remains consistent across RT fractionation schedules and PCI use, with interaction P values of .63 and .89, respectively.
FIG 3.
Overall survival by treatment arm according to (A) RT schedule (twice daily v daily, stratification factor), (B) PCI use (not randomized, exploratory analysis), and (C) chemotherapy regimen (cisplatin v carboplatin, stratification factor). Kaplan-Meier curves are shown for each treatment arm by factor level. Insets display HRs with 95% CIs for (1) the effect of atezolizumab within each factor level and (2) the effect of each factor within treatment arms. Interaction P values were estimated from Cox models including treatment arm, the factor of interest, and their interaction, stratified by the remaining random assignment strata. These analyses are exploratory and hypothesis-generating. CRT, chemoradiation; HR, hazard ratio; OS, overall survival; PCI, prophylactic cranial irradiation; RT, radiation therapy.
Regardless of atezolizumab receipt (Fig 3A), twice a day RT was associated with longer OS compared with daily RT, as indicated by a HR of 1.51 (95% CI, 1.05 to 2.18) in the CRT alone group, with a similar trend observed in the CRT + atezo group (HR, 1.37 [95% CI, 0.97 to 1.94]). For PCI (Fig 3B), the KM curves are shown for the intention-to-treat population, while the inset displays results from a 180-day landmark analysis among patients alive at the landmark. PCI was associated with improved OS in the CRT-alone arm (HR, 0.68 [95% CI, 0.46 to 0.99]), with a similar but nonsignificant trend in the CRT + atezo arm (HR, 0.77 [95% CI, 0.53 to 1.11]). The results of unstratified multivariable Cox models are provided in Appendix Tables A4 and A5.
By contrast, the treatment effect of CRT + atezo versus CRT alone varies by chemotherapy regimen, with an interaction P value of .06. Among patients receiving cisplatin, the HR for CRT + atezo versus CRT alone is 1.31 (95% CI, 0.93 to 1.87), whereas for carboplatin, it is 0.83 (95% CI, 0.58 to 1.17). Additionally, cisplatin was associated with significantly improved OS in the CRT-alone arm (HR, 1.65 [95% CI, 1.15 to 2.36]), but this survival benefit was not observed in the CRT + atezo arm (HR, 1.03 [95% CI, 0.73 to 1.45]).
Forest plots of OS and PFS on the basis of patient subsets are shown in Appendix Figures A1 and A2.
DISCUSSION
The standard-of-care chemoradiation backbone for LS-SCLC was established by the Turrisi trial in the late 1990’s, demonstrating improved survival when 45 Gy thoracic RT was delivered twice daily compared with once daily.9 There was more toxicity with a twice a day approach, namely esophagitis, with grade 3 esophagitis occurring in about 25% of patients9; however, at the time this trial was conducted, radiation techniques were less precise and did not spare normal tissue as well as modern day radiation techniques. A next generation of trials tested the standard of 45 Gy twice daily with concurrent chemotherapy to dose escalated, daily RT to 66–70 Gy daily. The CONVERT trial, conducted in Europe, showed that 66 Gy daily was not better than the 45 Gy twice a day standard, with a median OS of 25 versus 30 months, respectively.4 Toxicity was also not different between the once-daily versus twice-daily arms, with modern RT technologies used.4 The RTOG/CALGB 30610 trial showed essentially equivalent results, with median OS ranging from 28.5 to 30.0 months in both arms, and no improvement in OS for 70 Gy daily RT compared with 45 Gy twice daily.5
The first major improvement in decades for LS-SCLC has come with the ADRIATIC trial, which delivered adjuvant durvalumab versus placebo versus durvalumab + tremelimumab.10 This study enrolled patients only after completion of CRT without disease progression or decline in PS and with resolution of high-grade toxicities. Patients received durvalumab every 4 weeks for up to 2 years. Both OS and PFS were improved with adjuvant durvalumab with median survival increased from 33.4 months to 55.9 months.10
NRG/Alliance LU005 was conducted at the same time as the ADRIATIC trial, with a primarily US population plus 44 patients from Japan. The population was notably different in that patients were enrolled before completion of chemoradiation, after one cycle of chemotherapy. NRG/Alliance LU005 was designed this way to capture as many patients as possible for protocol therapy as well as the ability to perform quality assurance on radiation plans for all patients. Patients were also mainly from the United States, with a large portion of patients receiving twice daily RT. By contrast, the ADRIATIC trial was conducted primarily in ASIA, with the majority of patients receiving once daily RT. The most significant difference between the two trials is the timing of immunotherapy, with immunotherapy given concurrently in NRG/Alliance LU005.
NRG/Alliance LU005 failed to demonstrate an OS benefit with atezolizumab delivered concurrently with chemoradiation. Recent trials in non–small cell lung cancer reported that concurrent immunotherapy does not improve OS, including the PACIFIC 2 trial as well as the Checkmate 72L trial (press release). Taken in context, the results from NRG/Alliance LU005 suggest that the timing of immunotherapy is critically important, knowing that consolidative immunotherapy given in absence of progression after CRT on the ADRIATIC showed a strong OS benefit, in contrast to the lack of benefit of concurrent and adjuvant immunotherapy in NRG/Alliance LU005. Of note, the CRT-alone arm in NRG/Alliance LU005 sets a new benchmark for LS-SCLC, with a median survival of 36.1 months, compared with 28.5–30.0 months from the standard arms in the CONVERT and RTOG/CALGB 30610 trials. Although the median survival in the standard arm of the ADRIATIC trial was 33.4 months, the random assignment after completion of CRT with no progression and resolution of toxicities indicates a more highly selected group than NRG/Alliance LU005, CONVERT, and RTOG/CALGB 30610 trials.
There is much more to learn from a translational science perspective, to fully understand why concurrent immunotherapy and radiation do not work well in lung cancer. A likely hypothesis is that given the bulky and central location of LS-SCLC tumor volumes requiring CRT, there is significant radiation dose to the immune compartment, depleting the body of lymphocytes that are needed to create the adaptive immune response seen with immune checkpoint inhibitors. An exploratory analysis showed improved outcomes for cisplatin over carboplatin in the CRT-alone arm.
Preclinical studies of cisplatin effects on cancer related immune environment suggest several mechanisms by which cisplatin may affect anti-tumor immune response including effects on major histocompatibility complex class I expression, immune cell recruitment and function, ADCC and the tumor microenvironment.11 Importantly, this study collected baseline blood and tissue from consenting patients, as well as blood after completion of CRT. A robust translational science component to this trial is planned, including correlation of transcriptional subtypes of SCLC and clinical outcomes with concurrent immunotherapy. Immunophenotyping in peripheral blood is also planned to understand how chemotherapy and radiation may affect immune cells and response to immune checkpoint inhibitors. This work will be critical to further understand how to optimally combine radiation and immunotherapy. Another emerging treatment strategy in lung cancer is neoadjuvant chemoimmunotherapy, particularly in resectable non–small cell lung cancer. Understanding the interaction between chemotherapy, immunotherapy and radiation will be of increasing importance as novel sequencing strategies are explored in LS-SCLC.
The safety profile of atezolizumab with CRT in this study was as expected, and not likely to be contributory to the lack of OS benefit observed. Similarly, no excess rates of radiation pneumonitis or esophagitis were noted with using concurrent atezolizumab. Of note, patients receiving atezolizumab were evaluated more frequently for toxicity and for a longer time period, likely playing a role in more AEs reported. Importantly, quality-of-life data were collected in this study but will be reported in a future study.
Another important finding in NRG/Alliance LU005 is that 45 Gy twice daily RT, a stratified variable, was associated with improved OS compared with 66 Gy once daily in both arms on exploratory analysis. Other trials have shown that once-daily approaches to a total dose of 66–70 Gy are not better than 45 Gy twice daily; however, twice-daily RT schedules have not been widely adopted in the United States, with concerns over logistical challenges and patient inconvenience. The American Society for Radiation Oncology (ASTRO) clinical practice guidelines, published in 2020, recommend 45 Gy twice daily as the preferred fractionation choice for LS-SCLC.12 However, recent data show that fewer than 20% of patients with LS-SCLC in the United States receive twice-daily RT.13 Given the previous findings of the CONVERT and CALGB 30610/RTOG 0538 trials, along with NRG/Alliance LU005, 45 Gy twice daily should be considered the preferred thoracic RT schedule for patients with LS-SCLC. Additionally, patients who did not receive PCI, an unstratified factor, had worse survival in both arms compared with those who did. Although this analysis was exploratory, it is nonetheless intriguing, but should be interpreted with caution until randomized data become available. Many patients with LS-SCLC forego PCI, largely because of concerns arising from the negative findings of a randomized trial showing no survival benefit to PCI in lieu of regular brain MRIs in extensive stage SCLC.14 The role of PCI in LS-SCLC is currently being studied in the SWOG S1827 MAVERICK trial (ClinicalTrials.gov identifier: NCT04155034), which may provide further clarity on its clinical utility. Of note, side effects from PCI can be mitigated with hippocampal sparing techniques such as those used in NRG Oncology CC00315 and neuroprotective agents such as memantine.
In conclusion, although concurrent and adjuvant atezolizumab did not improve survival for patients with LS-SCLC compared with standard CRT alone, NRG/Alliance LU005 sets a new survival benchmark for CRT alone in LS-SCLC, and exploratory analyses suggests benefits of twice-daily radiation and the use of PCI. This study refines the use of immunotherapy in LS-SCLC, demonstrating the importance of sequence of immunotherapy when incorporating with CRT.
CONTEXT.
Key Objective
Does concurrent and adjuvant atezolizumab when added to chemoradiation improve survival in patients with limited-stage small cell lung cancer (LS-SCLC)?
Knowledge Generated
Concurrent and adjuvant atezolizumab did not improve survival compared with chemoradiation alone. Patients receiving twice daily radiation had better survival compared with patients receiving daily radiation.
Relevance (R.G. Maki)
While immunotherapy provides benefit in relapsed disease, atezolizumab did not improve outcomes for patients with LS-SCLC. While this study confirms the standard of care, hope continues that novel agents active in relapsed disease such as delta-like ligand 3 (DLL3)-based treatment will be pursued in earlier stage disease.*
*Relevance section written by JCO Associate Editor Robert G. Maki, MD, PhD, FACP, FASCO.
SUPPORT
Supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), UG1CA189867 (NCORP), U24CA196067 (NRG Specimen Bank), U24CA180803 (IROC) from the National Cancer Institute (NCI) and Genentech. The contribution of S.G.C. was supported by the National Cancer Institute of the National Institutes of Health under Award Number R50CA275822.
APPENDIX 1. SUPPLEMENTARY METHODS: STATISTICAL CONSIDERATIONS
The study was designed with 85% power to detect an improvement in median overall survival (OS) from 27 to 38 months (hazard ratio [HR], 0.71) at a one-sided significance level of 0.025. An accrual target of 545 patients was set to observe approximately 315 deaths for the final OS analysis. Two interim analyses were planned at 40% and 70% information (127 and 222 deaths, respectively). Efficacy monitoring used the Lan-DeMets implementation of the O’Brien–Fleming boundary. An inefficacy (futility) boundary, as described by Freidlin et al,8 was applied to allow early reporting if interim results provided convincing evidence that the trial was unlikely to achieve the targeted treatment benefit. This approach minimizes patient exposure to an ineffective regimen with minimal power loss under the alternative. The trial was initially activated in 2019 as a seamless phase II/III design; following the positive results of IMpower133 and CASPIAN, the phase II component was removed in Amendment 6 (June 2021).
Efficacy Analyses
All efficacy analyses followed the intention-to-treat principle, with patients analyzed according to randomized assignment.
OS: defined from random assignment to death from any cause; surviving patients were censored at last known follow-up.
Progression-free survival: defined as time from random assignment to disease progression (per RECIST v1.1) or death, whichever occurred first; patients without events were censored at the last evaluable tumor assessment or at random assignment if no assessment was performed.
Distant metastasis–free survival: defined as time from random assignment to development of distant metastasis or death; patients experiencing local progression before distant failure were censored at the date of local progression.
Survival distributions were estimated by the Kaplan-Meier method, with 95% CIs calculated using Greenwood’s formula. Median survival times were reported with 95% CIs derived using the Brookmeyer-Crowley method.
Treatment comparisons were performed using stratified log-rank tests, with HRs and 95% CIs estimated from stratified Cox proportional hazards models on the basis of random assignment strata (radiation therapy [RT] fractionation, chemotherapy regimen, sex, and Eastern Cooperative Group performance status [ECOG PS]). Sensitivity analyses included unstratified Cox models and exclusion of strata with sparse events. Because of the small sample size for ECOG PS = 2, stratified analyses excluded ECOG PS as a stratification factor.
Local control was defined as time to intrathoracic progression (primary lobe or mediastinal nodes). Competing events (distant metastasis or death without local progression) were accounted for using the Aalen-Johansen estimator of cumulative incidence. Treatment comparisons were performed using stratified log-rank tests and stratified cause-specific Cox models.
Objective response rate (ORR): defined as the proportion of patients achieving confirmed complete or partial response on two consecutive assessments ≥4 weeks apart (per RECIST v1.1). Treatment arms were compared using a stratified Cochran-Mantel-Haenszel test. Arm-specific 95% CIs for ORR were estimated using the Clopper-Pearson method, and 95% CIs for differences between arms were calculated using the normal approximation to the binomial distribution.
Exploratory Sensitivity Analyses: Twice a Day RT and Prophylactic Cranial Irradiation
Because twice a day RT and prophylactic cranial irradiation (PCI) were not randomized, exploratory analyses were performed to contextualize these signals while avoiding over-interpretation.
Twice a day versus daily RT:
A multivariable Cox model for OS was performed, including only treatment arm, RT fractionation (as randomized), and their interaction, stratified by chemotherapy regimen and sex (inset of Fig 3)
Unstratified multivariable Cox model, including treatment arm, RT fractionation, chemotherapy regimen, and sex, was also performed (Appendix Table A4).
PCI use:
To mitigate immortal-time bias, a landmark analysis at 180 days post-random assignment was performed among patients alive at the landmark (all but three patients who received PCI did so within 180 days). HRs on the basis of landmark population were reported for (1) the effect of atezolizumab by PCI use status, and (2) the effect of PCI use before landmark within each treatment arm. A landmark multivariable Cox model for OS was also performed, including only treatment arm, PCI use status and their interaction, stratified by RT schedule, chemotherapy regimen, and sex. These results are provided in the inset of Figure 3.
Unstratified landmark multivariable Cox model, including treatment arm, RT fractionation, chemotherapy regimen, sex, and PCI use before landmark, was also performed (Appendix Table A5).
All exploratory analyses are post hoc and hypothesis-generating; findings are presented as associations, not causal effects, and do not alter the trial’s primary conclusions.
Safety Analyses
Safety analyses were conducted in the as-treated population, defined as all patients who received ≥1 dose of systemic therapy or ≥1 fraction of radiation therapy, analyzed according to treatment received. This approach ensures accurate attribution of AEs.
Adverse events (AEs) were graded according to Common Terminology Criteria for Adverse Events v5.0. AEs were summarized descriptively by grade and type. Protocol-specified events of special interest—including pneumonitis, pericarditis, esophagitis, encephalitis, and myocarditis—were reported separately.
Interim Monitoring and Early Reporting
At the second interim analysis in July 2024, the prespecified inefficacy boundary was crossed. After reviewing all available data, the NRG Oncology Data Monitoring Committee recommended early reporting, as the study had met its accrual target and interim results indicated that continued follow-up was unlikely to demonstrate the targeted survival benefit.
Statistical Software and Significance Level
All analyses were performed using SAS version 9.4. Unless otherwise specified, two-sided P values are reported for secondary and exploratory end points. The primary OS analysis was conducted using a one-sided test at the 0.025 significance level, per the study design.
FIG A1.
Forest plot of overall survival. AJCC, American Joint Committee on Cancer; BID, twice a day; CRT, chemoradiation; ECOG, Eastern Cooperative Group; HR, hazard ratio; RT, radiation therapy.
FIG A2.
Forest plot of progression-free survival. AJCC, American Joint Committee on Cancer; BID, twice a day; CRT, chemoradiation; ECOG, Eastern Cooperative Group; HR, hazard ratio; RT, radiation therapy.
TABLE A1.
As-Treated Distribution of Patients by Highest Grade Adverse Event by System Organ Class for All Reported Adverse Events Without Regard to Attribution
| Received No Atezolizumab (n = 257), No. and (%) of Patients by Grade | Received Atezolizumab (n = 264), No. and (%) of Patients by Grade | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| System Organ Class | 1 | 2 | 3 | 4 | 5 | Any Grade | 1 | 2 | 3 | 4 | 5 | Any Grade |
| Overall highest grade | 3 (1.2) | 8 (3.1) | 56 (21.8) | 182 (70.8) | 4 (1.6) | 253 (98.4) | 0 (0.0) | 9 (3.4) | 63 (23.9) | 168 (63.6) | 24 (9.1) | 264 (100.0) |
| Blood and lymphatic system disorders | 47 (18.3) | 61 (23.7) | 99 (38.5) | 8 (3.1) | 0 (0.0) | 215 (83.7) | 36 (13.6) | 71 (26.9) | 105 (39.8) | 12 (4.5) | 0 (0.0) | 224 (84.8) |
| Cardiac disorders | 40 (15.6) | 13 (5.1) | 12 (4.7) | 2 (0.8) | 0 (0.0) | 67 (26.1) | 55 (20.8) | 21 (8.0) | 13 (4.9) | 3 (1.1) | 6 (2.3) | 98 (37.1) |
| Ear and labyrinth disorders | 54 (21.0) | 8 (3.1) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 62 (24.1) | 41 (15.5) | 13 (4.9) | 2 (0.8) | 0 (0.0) | 0 (0.0) | 56 (21.2) |
| Endocrine disorders | 5 (1.9) | 5 (1.9) | 1 (0.4) | 0 (0.0) | 0 (0.0) | 11 (4.3) | 33 (12.5) | 40 (15.2) | 1 (0.4) | 1 (0.4) | 0 (0.0) | 75 (28.4) |
| Eye disorders | 34 (13.2) | 5 (1.9) | 1 (0.4) | 0 (0.0) | 0 (0.0) | 40 (15.6) | 52 (19.7) | 8 (3.0) | 2 (0.8) | 0 (0.0) | 0 (0.0) | 62 (23.5) |
| GI disorders | 61 (23.7) | 132 (51.4) | 41 (16.0) | 0 (0.0) | 0 (0.0) | 234 (91.1) | 44 (16.7) | 137 (51.9) | 65 (24.6) | 1 (0.4) | 0 (0.0) | 247 (93.6) |
| General disorders and administration site conditions | 85 (33.1) | 98 (38.1) | 24 (9.3) | 1 (0.4) | 1 (0.4) | 209 (81.3) | 84 (31.8) | 113 (42.8) | 29 (11.0) | 0 (0.0) | 9 (3.4) | 235 (89.0) |
| Hepatobiliary disorders | 0 (0.0) | 1 (0.4) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.4) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Immune system disorders | 2 (0.8) | 1 (0.4) | 6 (2.3) | 0 (0.0) | 0 (0.0) | 9 (3.5) | 1 (0.4) | 2 (0.8) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 3 (1.1) |
| Infections and infestations | 8 (3.1) | 43 (16.7) | 35 (13.6) | 4 (1.6) | 1 (0.4) | 91 (35.4) | 7 (2.7) | 73 (27.7) | 46 (17.4) | 6 (2.3) | 3 (1.1) | 135 (51.1) |
| Injury, poisoning, and procedural complications | 48 (18.7) | 27 (10.5) | 3 (1.2) | 0 (0.0) | 0 (0.0) | 78 (30.4) | 69 (26.1) | 31 (11.7) | 8 (3.0) | 0 (0.0) | 0 (0.0) | 108 (40.9) |
| Investigations | 7 (2.7) | 8 (3.1) | 51 (19.8) | 181 (70.4) | 0 (0.0) | 247 (96.1) | 4 (1.5) | 14 (5.3) | 67 (25.4) | 174 (65.9) | 0 (0.0) | 259 (98.1) |
| Metabolism and nutrition disorders | 91 (35.4) | 69 (26.8) | 44 (17.1) | 5 (1.9) | 0 (0.0) | 209 (81.3) | 72 (27.3) | 97 (36.7) | 59 (22.3) | 8 (3.0) | 0 (0.0) | 236 (89.4) |
| Musculoskeletal and connective tissue disorders | 49 (19.1) | 48 (18.7) | 13 (5.1) | 0 (0.0) | 0 (0.0) | 110 (42.8) | 72 (27.3) | 60 (22.7) | 14 (5.3) | 0 (0.0) | 0 (0.0) | 146 (55.3) |
| Neoplasms benign, malignant, and unspecified (incl cysts and polyps) | 1 (0.4) | 2 (0.8) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 3 (1.2) | 2 (0.8) | 2 (0.8) | 1 (0.4) | 0 (0.0) | 0 (0.0) | 5 (1.9) |
| Nervous system disorders | 102 (39.7) | 44 (17.1) | 15 (5.8) | 0 (0.0) | 0 (0.0) | 161 (62.6) | 100 (37.9) | 64 (24.2) | 31 (11.7) | 1 (0.4) | 0 (0.0) | 196 (74.2) |
| Psychiatric disorders | 43 (16.7) | 33 (12.8) | 2 (0.8) | 0 (0.0) | 0 (0.0) | 78 (30.4) | 61 (23.1) | 45 (17.0) | 4 (1.5) | 0 (0.0) | 0 (0.0) | 110 (41.7) |
| Renal and urinary disorders | 17 (6.6) | 11 (4.3) | 13 (5.1) | 0 (0.0) | 0 (0.0) | 41 (16.0) | 33 (12.5) | 13 (4.9) | 7 (2.7) | 2 (0.8) | 0 (0.0) | 55 (20.8) |
| Reproductive system and breast disorders | 2 (0.8) | 4 (1.6) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 6 (2.3) | 4 (1.5) | 2 (0.8) | 1 (0.4) | 0 (0.0) | 0 (0.0) | 7 (2.7) |
| Respiratory, thoracic, and mediastinal disorders | 90 (35.0) | 70 (27.2) | 25 (9.7) | 3 (1.2) | 1 (0.4) | 189 (73.5) | 76 (28.8) | 107 (40.5) | 28 (10.6) | 11 (4.2) | 6 (2.3) | 228 (86.4) |
| Skin and subcutaneous tissue disorders | 60 (23.3) | 63 (24.5) | 0 (0.0) | 1 (0.4) | 0 (0.0) | 124 (48.2) | 89 (33.7) | 78 (29.5) | 5 (1.9) | 1 (0.4) | 0 (0.0) | 173 (65.5) |
| Surgical and medical procedures | 0 (0.0) | 0 (0.0) | 1 (0.4) | 0 (0.0) | 0 (0.0) | 1 (0.4) | 0 (0.0) | 1 (0.4) | 1 (0.4) | 0 (0.0) | 0 (0.0) | 2 (0.8) |
| Vascular disorders | 19 (7.4) | 49 (19.1) | 29 (11.3) | 1 (0.4) | 1 (0.4) | 99 (38.5) | 17 (6.4) | 51 (19.3) | 41 (15.5) | 3 (1.1) | 0 (0.0) | 112 (42.4) |
NOTE. Adverse events were graded with Common Terminology Criteria for Adverse Events version 5.
TABLE A2.
As-Treated Distribution of Patients by Highest Grade Adverse Event by System Organ Class for All Reported Immune-Mediated Adverse Events Without Regard to Attribution
| Received No Atezolizumab (n = 257), No. and (%) of Patients by Grade | Received Atezolizumab (n = 264), No. and (%) of Patients by Grade | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| System Organ Class | 1 | 2 | 3 | 4 | 5 | Any Grade | 1 | 2 | 3 | 4 | 5 | Any Grade |
| Overall highest grade | 19 (7.4) | 11 (4.3) | 14 (5.4) | 3 (1.2) | 0 (0.0) | 47 (18.3) | 29 (11.0) | 63 (23.9) | 31 (11.7) | 12 (4.5) | 4 (1.5) | 139 (52.7) |
| Blood and lymphatic system disorders | 1 (0.4) | 2 (0.8) | 4 (1.6) | 0 (0.0) | 0 (0.0) | 7 (2.7) | 3 (1.1) | 4 (1.5) | 3 (1.1) | 2 (0.8) | 0 (0.0) | 12 (4.5) |
| Cardiac disorders | 1 (0.4) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.4) | 3 (1.1) | 3 (1.1) | 1 (0.4) | 0 (0.0) | 1 (0.4) | 8 (3.0) |
| Ear and labyrinth disorders | 1 (0.4) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.4) | 0 (0.0) | 0 (0.0) | 1 (0.4) | 0 (0.0) | 0 (0.0) | 1 (0.4) |
| Endocrine disorders | 0 (0.0) | 1 (0.4) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.4) | 15 (5.7) | 23 (8.7) | 1 (0.4) | 1 (0.4) | 0 (0.0) | 40 (15.2) |
| Eye disorders | 1 (0.4) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.4) | 1 (0.4) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.4) |
| GI disorders | 7 (2.7) | 3 (1.2) | 1 (0.4) | 0 (0.0) | 0 (0.0) | 11 (4.3) | 9 (3.4) | 18 (6.8) | 9 (3.4) | 0 (0.0) | 0 (0.0) | 36 (13.6) |
| General disorders and administration site conditions | 1 (0.4) | 1 (0.4) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (0.8) | 11 (4.2) | 7 (2.7) | 6 (2.3) | 0 (0.0) | 0 (0.0) | 24 (9.1) |
| Infections and infestations | 0 (0.0) | 0 (0.0) | 2 (0.8) | 0 (0.0) | 0 (0.0) | 2 (0.8) | 0 (0.0) | 8 (3.0) | 4 (1.5) | 1 (0.4) | 0 (0.0) | 13 (4.9) |
| Injury, poisoning, and procedural complications | 1 (0.4) | 2 (0.8) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 3 (1.2) | 0 (0.0) | 3 (1.1) | 2 (0.8) | 0 (0.0) | 0 (0.0) | 5 (1.9) |
| Investigations | 3 (1.2) | 0 (0.0) | 5 (1.9) | 3 (1.2) | 0 (0.0) | 11 (4.3) | 8 (3.0) | 9 (3.4) | 4 (1.5) | 9 (3.4) | 0 (0.0) | 30 (11.4) |
| Metabolism and nutrition disorders | 4 (1.6) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 4 (1.6) | 11 (4.2) | 9 (3.4) | 1 (0.4) | 1 (0.4) | 0 (0.0) | 22 (8.3) |
| Musculoskeletal and connective tissue disorders | 1 (0.4) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.4) | 4 (1.5) | 2 (0.8) | 3 (1.1) | 0 (0.0) | 0 (0.0) | 9 (3.4) |
| Nervous system disorders | 1 (0.4) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.4) | 4 (1.5) | 0 (0.0) | 3 (1.1) | 1 (0.4) | 0 (0.0) | 8 (3.0) |
| Psychiatric disorders | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (0.8) | 1 (0.4) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 3 (1.1) |
| Renal and urinary disorders | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.4) | 1 (0.4) | 1 (0.4) | 0 (0.0) | 0 (0.0) | 3 (1.1) |
| Reproductive system and breast disorders | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.4) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.4) |
| Respiratory, thoracic, and mediastinal disorders | 4 (1.6) | 2 (0.8) | 1 (0.4) | 0 (0.0) | 0 (0.0) | 7 (2.7) | 7 (2.7) | 26 (9.8) | 6 (2.3) | 1 (0.4) | 3 (1.1) | 43 (16.3) |
| Skin and subcutaneous tissue disorders | 4 (1.6) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 4 (1.6) | 22 (8.3) | 10 (3.8) | 3 (1.1) | 0 (0.0) | 0 (0.0) | 35 (13.3) |
| Vascular disorders | 0 (0.0) | 1 (0.4) | 1 (0.4) | 0 (0.0) | 0 (0.0) | 2 (0.8) | 0 (0.0) | 2 (0.8) | 1 (0.4) | 0 (0.0) | 0 (0.0) | 3 (1.1) |
NOTE. Adverse events were graded with Common Terminology Criteria for Adverse Events version 5.
TABLE A3.
As-Treated Grade 5 Adverse Events
| Received Treatment | System Organ Class | Term | Relationship to Treatment | Days From First Treatment | Days From Last Treatment |
|---|---|---|---|---|---|
| Received no atezolizumab | General disorders and administration site conditions | Death NOS | Possible | 39 | 14 |
| Infections and infestations | Sepsis | Possible | 11 | 4 | |
| Respiratory, thoracic, and mediastinal disorders | Respiratory failure | Unlikely | 37 | 17 | |
| Vascular disorders | Thromboembolic event | Unrelated | 43 | 13 | |
| Received atezolizumab | Cardiac disorders | Myocarditisa | Definite | 179 | 31 |
| Respiratory, thoracic, and mediastinal disorders | Pneumonitisa | Definite | 132 | 55 | |
| Infections and infestations | Sepsis | Probable | 13 | 11 | |
| Respiratory, thoracic, and mediastinal disorders | Respiratory failure | Probable | 45 | 8 | |
| Cardiac disorders | Cardiac arrest | Possible | 31 | 8 | |
| Cardiac disorders | Myocardial infarction | Possible | 202 | 12 | |
| Respiratory, thoracic, and mediastinal disorders | Pneumonitisa | Possible | 162 | 56 | |
| Respiratory, thoracic, and mediastinal disorders | Respiratory failurea | Possible | 25 | 14 | |
| Respiratory, thoracic, and mediastinal disorders | Respiratory failure | Possible | 125 | 40 | |
| Cardiac disorders | Myocardial infarction | Unlikely | 39 | 16 | |
| General disorders and administration site conditions | Death NOS | Unlikely | 66 | 16 | |
| Infections and infestations | Infections and infestations—other | Unlikely | 217 | 27 | |
| Respiratory, thoracic, and mediastinal disorders | Respiratory failure | Unlikely | 430 | 79 | |
| Cardiac disorders | Cardiac arrest | Unrelated | 48 | 20 | |
| Cardiac disorders | Cardiac arrest | Unrelated | 214 | 67 | |
| General disorders and administration site conditions | Death NOS | Unrelated | 146 | 26 | |
| General disorders and administration site conditions | Disease progression | Unrelated | 310 | 79 | |
| General disorders and administration site conditions | Disease progression | Unrelated | 191 | 36 | |
| General disorders and administration site conditions | Disease progression | Unrelated | 197 | 69 | |
| General disorders and administration site conditions | Disease progression | Unrelated | 224 | 69 | |
| General disorders and administration site conditions | Multiorgan failure | Unrelated | 243 | 26 | |
| General disorders and administration site conditions | Sudden death NOS | Unrelated | 117 | 19 | |
| General disorders and administration site conditions | Sudden death NOS | Unrelated | 34 | 3 | |
| Infections and infestations | Sepsis | Unrelated | 292 | 25 |
NOTE. Adverse events were graded with Common Terminology Criteria for Adverse Events version 5. Abbreviation: NOS, not otherwise specified.
Immune-mediated adverse event.
TABLE A4.
Overall Survival Multivariable Analysis
| Parameter | Comparison | Fail/Total RL | Fail/Total Comparison | HR (95% CI) | P |
|---|---|---|---|---|---|
| Treatment arm | No atezolizumab (RL) v atezolizumab | 120/270 | 132/274 | 1.05 (0.82 to 1.34) | .72 |
| Sex | Male (RL) v female | 119/267 | 133/277 | 1.10 (0.85 to 1.41) | .47 |
| RT schedule | Twice a day (RL) v once daily | 95/257 | 157/287 | 1.69 (1.30 to 2.18) | <.0001 |
| Platinum agent | Cisplatin (RL) v carboplatin | 133/322 | 119/222 | 1.42 (1.10 to 1.82) | .0061 |
Abbreviations: HR, hazard ratio; RL, referent level; RT, radiation therapy.
TABLE A5.
Landmark Analysis: Landmark = 180 Days Post-Random Assignment Overall Survival Multivariable Analysis
| Parameter | Comparison | Fail/Total RL | Fail/Total Comparison | HR (95% CI) | P |
|---|---|---|---|---|---|
| Treatment arm | No atezolizumab (RL) v atezolizumab | 110/233 | 114/246 | 0.99 (0.76 to 1.28) | .91 |
| Sex | Male (RL) v female | 107/241 | 117/238 | 1.09 (0.83 to 1.42) | .54 |
| RT schedule | Twice a day (RL) v once daily | 90/233 | 134/246 | 1.50 (1.14 to 1.97) | .0035 |
| Platinum agent | Cisplatin (RL) v carboplatin | 118/284 | 106/195 | 1.40 (1.08 to 1.83) | .012 |
| PCI prior to landmark | No PCI prior (RL) v PCI prior | 123/241 | 101/238 | 0.77 (0.59 to 1.01) | .055 |
Abbreviations: HR, hazard ratio; PCI, prophylactic cranial irradiation; RL, referent level; RT, radiation therapy.
Footnotes
DISCLAIMER
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
PRIOR PRESENTATION
Presented at the Annual American Society of Radiation Oncology (ASTRO) Meeting, Washington DC, September 30, 2024.
CLINICAL TRIAL INFORMATION
NCT03811002 (NRG-LU005)
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Disclosures provided by the authors are available with this article at DOI https://doi.org/10.1200/JCO-25-01569.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Chemoradiation ± Atezolizumab in Limited-Stage Small Cell Lung Cancer: Results of NRG Oncology/Alliance LU005
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
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Kristin A. Higgins
Employment: city of hope
Stock and Other Ownership Interests: Picture Health
Consulting or Advisory Role: AstraZeneca, Reflexion Medical, Janssen, Daiichi Sanyko
Research Funding: Reflexion Medical, Jazz Pharmaceuticals
Travel, Accommodations, Expenses: AstraZeneca
Chen Hu
This author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.
Consulting or Advisory Role: Johnson & Johnson Enterprise Innovation Inc, Belay Diagnostics LLC, Health Catalyst
Helen J. Ross
Consulting or Advisory Role: GlaxoSmithKline, AstraZeneca, IDEOlogy Health
Research Funding: Roche (Inst)
Salma K. Jabbour
Consulting or Advisory Role: Merck Sharp & Dohme, AstraZeneca, Radialogica, Advarra
Research Funding: Merck Sharp & Dohme (Inst), NCI (Inst), Beigene (Inst), Guardant Health (Inst), Haystack Oncology (Inst)
Expert Testimony: deichert
Travel, Accommodations, Expenses: Merck, AstraZeneca
David E. Kozono
Consulting or Advisory Role: Genentech
Taofeek K. Owonikoko
Stock and Other Ownership Interests: Cambium Medical Technologies, Taobob LLC, GenCart, Coherus Biosciences
Consulting or Advisory Role: Novartis, Abbvie, Eisai, G1 Therapeutics, Takeda, Bristol Myers Squibb, MedImmune, BerGenBio, Lilly, Amgen, AstraZeneca, PharmaMar, Boehringer Ingelheim, EMD Serono, Bayer, Merck, Jazz Pharmaceuticals, Ipsen, Eisai, Roche/Genentech, Janssen, Exelixis, BeiGene, Triptych Health Partners, Daichi, Coherus Biosciences, Heat Biologics, Puma Biotechnology, Xcovery, Meryx Pharmaceuticals, Gilead Sciences
Research Funding: Novartis (Inst), Bayer (Inst), Regeneron (Inst), AstraZeneca/MedImmune (Inst), Abbvie (Inst), G1 Therapeutics (Inst), Bristol Myers Squibb (Inst), Corvus Pharmaceuticals, Amgen (Inst), Loxo/Lilly (Inst), Pfizer (Inst), Incyte (Inst), Merck (Inst), Oncorus (Inst), GlaxoSmithKline (Inst), Calithera Biosciences (Inst), Roche/Genentech (Inst), Meryx Pharmaceuticals (Inst), Boehringer Ingelheim (Inst), Bayer (Inst), Cardiff Oncology (Inst), Puma Biotechnology (Inst), Daiichi Sankyo/Astra Zeneca (Inst), Ymabs Therapeutics Inc (Inst)
Patents, Royalties, Other Intellectual Property: Overcoming Acquired Resistance to Chemotherapy Treatments Through Suppression of STAT3 (Inst), Selective Chemotherapy Treatments and Diagnostic Methods Related Thereto (Inst), DR4 Modulation and its Implications in EGFR-Target Cancer Therapy Ref:18089 PROV (CSP) United States Patent Application No. 62/670,210 June 26, 2018 (Co-Inventor) (Inst), Soluble FAS ligand as a biomarker of recurrence in thyroid cancer; provisional patent 61/727,519 (Inventor) (Inst)
Travel, Accommodations, Expenses: AstraZeneca, Janssen
Other Relationship: Roche/Genentech, EMD Serono, Novartis
Uncompensated Relationships: Reflexion Medical
Open Payments Link: https://openpaymentsdata.cms.gov/physician/253457
Timothy A. Ritter
Employment: VCU
Terence M. Williams
Employment: City of Hope
Honoraria: Reflexion Medical
Speakers’ Bureau: Reflexion Medical
Research Funding: RefleXion Medical (Inst)
Patents, Royalties, Other Intellectual Property: Albumin-bound chemotherapies developed at the Ohio State University (patent pending)
Travel, Accommodations, Expenses: Reflexion Medical
James Welsh
Employment: MD Anderson Cancer Center
Stock and Other Ownership Interests: MolecularMatch, Alpine Immune Sciences, Checkmate Pharmaceuticals, Nanorobotix, Oncoresponse, Reflexion Medical, Reflexion Medical, Welsh DV8, OligoImmune
Honoraria: Nanobiotix, Reflexion Medical, Alpine Immune Sciences, Varian Medical Systems
Consulting or Advisory Role: Reflexion Medical, Checkmate Pharmaceuticals, Nanorobotix, Oncoresponse, Nanobiotix, Genentech, Kezar Life Sciences, Novocure, McKesson
Speakers’ Bureau: Accuray, Taiwan Lung Cancer Society, The Radiosurgery Society, Roche Molecular Diagnostics, McKesson/US Oncology Network
Research Funding: Bristol Myers Squibb, Nanobiotix, Artidis, Reflexion Medical, Takeda, Hotspot Therapeutics, Gilead Sciences, Kiromic, Novocure, Genentech, Bayer, Varian Medical Systems, SciClone, Nurix
Patents, Royalties, Other Intellectual Property: MolecularMatch, MP470 (amuvatinib), MRX34 regulation of PDL1, XRT technique to overcome immune resistance
Travel, Accommodations, Expenses: IASLC, AACR, Shandong Cancer Hospital, Turkish Society of Lung Cancer, Aileron Therapeutics, MedAustron, Reflexion Medical, Gustave Roussy Cancer Center, Radiation Research Society, Nanobiotix, The Korean Society for Radiation Oncology, American Society for Radiation Oncology, Ventana Medical Systems, Artidis
Jeffry P. Simko
Stock and Other Ownership Interests: Protean Biodiagnostics, Alpenglow biosciences, Triopsy Medical Inc
Consulting or Advisory Role: Uro-1
Research Funding: Intuitive Surgical (Inst)
B Movsas
Employment: Henry Ford Hospital
Stock and Other Ownership Interests: biolife, Abbvie, Acrivon Therapeutics, metlife, United Therapeutics
Research Funding: Philips Healthcare (Inst), Siemens/Varian (Inst)
Patents, Royalties, Other Intellectual Property: Lung phantom for image guidance, MR-CT imaging related patent for radiation oncology
Travel, Accommodations, Expenses: Alpha Tau, Siemens Healthineers
Kyoichi Kaira
Speakers’ Bureau: AstraZeneca, Ono Pharmaceutical, Bristol-Myers Company, Chugai Pharma
Research Funding: AstraZeneca/Daiichi Sankyo (Inst)
Amit K. Gupta
Stock and Other Ownership Interests: Moderna Therapeutics, Revolution Medicines
Pranshu Mohindra
Employment: University Hospitals Cleveland Medical Center, University Hospitals Cleveland Medical Center (I)
Travel, Accommodations, Expenses: IBA Proton Therapy, Inc
Open Payments Link: https://openpaymentsdata.cms.gov/physician/942373
Jeremy Brownstein
Honoraria: AstraZeneca, DAVA Pharmaceuticals, MDoutlook
Consulting or Advisory Role: Varian Medical Systems
Stephen Chun
Honoraria: AstraZeneca
Consulting or Advisory Role: AstraZeneca
Research Funding: Nektar, National Cancer Institute
Travel, Accommodations, Expenses: AstraZeneca
Rupesh Kotecha
Honoraria: Elekta, BrainLAB, Novocure, Telix Pharmaceuticals, InSightec, GT Medical Technologies
Consulting or Advisory Role: Novocure, GT Medical Technologies
Speakers’ Bureau: Novocure, GT Medical Technologies (I)
Research Funding: Medtronic (Inst), Blue Earth Diagnostics (Inst), Novocure (Inst), GT Medical Technologies (Inst), AstraZeneca (Inst), Exelixis (Inst), ViewRay (Inst), BrainLAB (Inst), Cantex Pharmaceuticals, Inc (Inst), IBA (Inst), Kazia Therapeutics (Inst)
Travel, Accommodations, Expenses: Elekta, Novocure, BrainLAB, GT Medical Technologies
Other Relationship: GT Medical Technologies Data Safety Monitoring Board, Plus Therapeutics Data Safety Monitoring Board, InSightec Advisory Board
Thomas E. Stinchcombe
This author is an Associate Editor for Journal of Clinical Oncology. Journal policy recused the author from having any role in the peer review of this manuscript.
Consulting or Advisory Role: Takeda, Gilead Sciences, Coherus Biosciences, Boehringer Ingelheim, Pfizer, Janssen Oncology
Research Funding: Seagen (Inst), Mirati Therapeutics (Inst), Nuvalent, Inc (Inst), Boehringer Ingelheim (Inst)
Travel, Accommodations, Expenses: Pfizer
Other Relationship: GlaxoSmithKline, Genentech, Merck, Pfizer
Jeffrey D. Bradley
Employment: University of Pennsylvania Abramson Cancer Center
Honoraria: Mevion Medical Systems
Consulting or Advisory Role: Mevion Medical Systems
Travel, Accommodations, Expenses: AstraZeneca
Uncompensated Relationships: Genentech, IBA
No other potential conflicts of interest were reported.
DATA SHARING STATEMENT
A data sharing statement provided by the authors is available with this article at DOI https://doi.org/10.1200/JCO-25-01569.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
A data sharing statement provided by the authors is available with this article at DOI https://doi.org/10.1200/JCO-25-01569.