Atezolizumab Plus Concurrent Chemoradiation Fails to Improve Survival in LS-SCLC

The addition of concurrent and adjuvant atezolizumab (Tecentriq) to chemoradiation failed to demonstrate a significant improvement in overall survival (OS) compared with concurrent chemoradiation alone in patients with limited-stage small cell lung cancer (LS-SCLC), according to findings from the phase 3 NRG Oncology/Alliance LU005 trial (NCT03811002) published in the Journal of Clinical Oncology.^1,2

The median OS was 31.1 months (95% CI, 28.5-44.7) in the investigational arm vs 36.1 months (95% CI, 28.1-42.5) in the control arm (stratified HR, 1.03; 95% CI, 0.80-1.32; 1-sided P = .58).¹ The 1-, 2- and 3-year OS rates were 80.5% (95% CI, 75.2%-84.8%), 59.2% (95% CI, 52.8%-65.1%), and 45.8% (95% CI, 39.0%-52.4%) in the investigational arm, respectively, vs 82.6% (95% CI, 77.2%-86.9%), 63.0% (95% CI, 56.4%-68.8%), and 50.5% (95% CI, 43.5%-57.2%) in the control arm.

“Recent trials in non–small cell lung cancer reported that concurrent immunotherapy does not improve OS, including the [phase 3] PACIFIC-2 trial [NCT03519971] as well as the [phase 3] CheckMate[73L trial (NCT04026412)]. Taken in context, the results from NRG/Alliance LU005 suggest that the timing of immunotherapy is critically important, knowing that consolidative immunotherapy given in [the] absence of progression after chemoradiation on the [phase 3] ADRIATIC [trial (NCT03703297)] showed a strong OS benefit, in contrast to the lack of benefit of concurrent and adjuvant immunotherapy in NRG/Alliance LU005,” Kristin A. Higgins, MD, lead study author and radiation oncologist at City of Hope in Duarte, California, and coauthors reported in the publication.

What was the rationale for the LU005 trial?

Concurrent chemoradiation with or without prophylactic cranial irradiation (PCI) has been the longstanding standard of care (SOC) for patients with LS-SCLC, despite a 5-year survival rate of approximately 30%. Checkpoint inhibitors such as atezolizumab and durvalumab (Imfinzi) have shown improved OS and progression-free survival (PFS) when combined with chemotherapy for extensive-stage SCLC. As such, LU005 was designed to evaluate whether the addition of concurrent and adjuvant atezolizumab to SOC therapy could improve survival compared with SOC alone.

Who was eligible for enrollment?

Study investigators enrolled patients with cytologically confirmed SCLC per central assessment, with an ECOG performance status between 0 to 2. Patients were required to have Tx or T1-4, N0-N3, M0 disease per the American Joint Committee on Cancer’s AJCC Cancer Staging Manual, 8th edition, and to undergo PET/CT, CT of the chest and abdomen with intravenous contrast, and brain MRI with contrast to rule out metastatic disease. All patients received 1 cycle of chemotherapy with platinum and etoposide prior to enrollment.

What did the study protocol consist of?

Three-dimensional conformal or intensity-modulated radiation therapy (IMRT) was administered either once per day at a dose of 66 Gy over 6.5 weeks, totaling 33 fractions, or twice per day at a dose of 45 Gy, totaling 30 fractions over 3 weeks. PCI was encouraged but not required for patients with a complete or near-complete response following chemoradiation to 25 Gy in 10 fractions.

Patients were randomly assigned 1:1 to receive concurrent chemoradiation with atezolizumab followed by adjuvant atezolizumab at 1200 mg once daily every 3 weeks for up to 1 year, or concurrent chemoradiation followed by observation.

What were the key primary and secondary end points?

OS served as the primary end point. Secondary end points included investigator-assessed PFS, time to local failure, distant metastasis-free survival (DMFS), objective response rate (ORR) according to RECIST 1.1 criteria, and safety.

The study was designed with 85% power to identify an improvement in median OS from 27 to 38 months at a 1-sided significance level of 0.025.

What were the demographics of the study population?

A total of 506 patients were enrolled in the United States and Japan between May 2019 and June 2022, after which an additional 38 patients were enrolled in Japan. A total of 274 patients were randomly assigned to the investigational arm and 270 to the control arm.

The median patient age was 66 years (range, 20-85), with most patients falling between 60 and 69 (44.5%) or 70 or older (34.6%). Most patients were female (50.9%) and had an ECOG performance status of 1 (51.1%). Regarding cigarette use, most patients were current (30.6%) or former (67.2%) tobacco users. A total of 80.1% of patients were White, 8.5% were Black or African American, and 8.6% were Asian. Most patients had AJCC stage IIIA (40.3%) or IIIB (30.1%) disease. There was also a slightly greater representation of stage IIIC patients in the investigational arm (13.1%) than in the control arm (9.6%).

Most patients received cisplatin (59.2%), once-daily radiation (52.8%), and IMRT (92.0%). PCI was administered in the minority of cases (45.0%).

How did atezolizumab plus concurrent chemoradiation compare with the SOC?

The median follow-up was 23.8 months for the overall population and 32.4 months for surviving patients. The median PFS was 12.1 months (95% CI, 10.9-15.2) in the investigational arm vs 11.4 months (95% CI, 10.3-13.2) in the control arm (stratified HR, 0.98; 95% CI, 0.79-1.22; 2-sided P = .87).

The median DMFS was 16.8 months (95% CI, 12.1-21.6) in the investigational arm vs 13.0 months (95% CI, 11.3-18.2) in the control arm (stratified HR, 0.96; 95% CI, 0.76-1.21).

Additional efficacy results revealed that the 1-, 2-, and 3-year local failure rates were 8.1% (95% CI, 5.0%-12.0%), 12.8% (95% CI, 8.8%-17.5%), and 12.8% (95% CI, 8.8%-17.5%), respectively, in the investigational arm. These respective rates were 10.1% (95% CI, 6.6%-14.4%), 14.3% (95% CI, 10.1%-19.3%), and 14.3% (95% CI, 10.1%-19.3%) in the control arm, resulting in a corresponding stratified cause-specific HR of 0.88 (95% CI, 0.53-1.44; 2-sided stratified P = .61).

The ORRs were 60.2% and 59.6% in the investigational and control arms, respectively (difference, –0.59%; 95% CI, –8.83 to 7.65; 2-sided Cochran-Mantel-Haenszel test P = .40).

How was the regimen’s safety profile characterized?

Grade 3 or 4 adverse effects (AEs) occurred in 95.8% of patients in the investigational arm and 94.2% of those in the control arm. Grade 3 or 4 immune-mediated AEs occurred in 17.8% of patients in the investigational arm, compared with 6.6% in the control arm. Four deaths due to immune-mediated AEs occurred in the investigational arm (n = 1, myocarditis; n = 2, pneumonitis; n = 1, respiratory failure possibly related to immunotherapy).

Protocol-specified AEs that occurred in the investigational and control arms, respectively, included pneumonitis (27.7%; 12.1%), esophagitis (61.0%; 57.2%), encephalitis (0.4%; 0.0%), and myocarditis (0.4%; 0.0%).

Grade 3 or higher pneumonitis occurred in 6.1% and 3.1% of patients in the investigational and control arms, respectively. Grade 3 or higher esophagitis occurred in 10.6% and 7.0% of patients in the investigational and control arms, respectively. Two cases of grade 2 pericarditis and one case of grade 3 encephalitis infection also occurred in the investigational arm.

“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,” Higgins and her coauthors wrote. “Understanding the interaction between chemotherapy, immunotherapy, and radiation will be of increasing importance as novel sequencing strategies are explored in LS-SCLC,” the authors concluded.

References

1. Higgins KA, Hu C, Ross HJ, et al. Chemoradiation ± atezolizumab in limited-stage small cell lung cancer: results of NRG Oncology/Alliance LU005. J Clin Oncol. 2026;44(8):630-640. doi:10.1200/JCO-25-01569
2. Testing the addition of a new immunotherapy drug, atezolizumab (MPDL3280A), to the usual chemoradiation (CRT) therapy treatment for limited stage small cell lung cancer (LS-SCLC). ClinicalTrials.gov. Updated March 10, 2026. Accessed February 9, 2026. https://clinicaltrials.gov/study/NCT03811002