A phase 2 clinical trial investigating a novel immunotherapy approach for locally advanced non-small cell lung cancer (NSCLC) was halted early due to concerning safety and efficacy results. The single-arm study, conducted at the University of Texas Southwestern Medical Center, examined the use of durvalumab (an anti-PD-L1 immune checkpoint inhibitor) given concurrently with and after thoracic radiation therapy, without chemotherapy.
The study was published in the International Journal of Radiation Oncology, Biology, Physics in 2025. It was funded by AstraZeneca and the National Center for Advancing Translational Sciences of the National Institutes of Health.
The purpose of the trial was to evaluate a potentially less toxic, chemotherapy-free regimen for stage III NSCLC patients. Standard treatment typically involves concurrent chemotherapy and radiation followed by consolidation durvalumab. The investigators hypothesized that earlier exposure to durvalumab combined with radiation alone might improve outcomes while reducing side effects associated with chemotherapy.
The study enrolled 10 patients with previously untreated, medically inoperable stage IIIA or IIIB NSCLC before being closed prematurely. Eligibility criteria included ECOG performance status 0-1, adequate pulmonary function (FEV1 >1.2L and DLCO ≥50% predicted), and adequate organ function. Notably, any level of tumor PD-L1 expression was permitted. Patients with prior radiation therapy overlapping the planned field, prior immunotherapy, active autoimmune disease, interstitial lung disease, or recent immunosuppressive medication use were excluded.
The median age of participants was 65.5 years (range 56-74). The majority were white (90%), male (60%), and former smokers (80%). Most patients had nonsquamous histology (60%) and N2 nodal involvement (60%). PD-L1 expression was <1% in 40%, ≥1% in 40%, and unknown in 20% of cases.
Treatment consisted of 2 cycles of durvalumab 1500 mg IV every 4 weeks given concurrently with thoracic radiation (60 Gy in 30 fractions), followed by up to 13 cycles of consolidation durvalumab. The primary endpoint was 12-month progression-free survival (PFS).
Results were disappointing, with a 12-month PFS rate of only 20% overall (50% for PD-L1 ≥1% vs 0% for PD-L1 <1% or unknown). At a median follow-up of 12 months, 5 patients had disease progression and 8 patients had died. Median overall survival was not reached for PD-L1 ≥1% patients, but was only 10.5 months and 7 months for PD-L1 <1% and unknown cases, respectively.
Toxicity was also concerning. Six patients (60%) experienced a total of 15 treatment-related grade ≥3 adverse events. This included two fatal pulmonary events - one during the concurrent phase in an active smoker, and another shortly after starting consolidation therapy. Half of the patients developed grade ≥3 pulmonary toxicity.
The study had several important limitations. Most notably, the small sample size of only 10 patients limits the ability to draw definitive conclusions. The single-arm design also precludes direct comparison to standard chemoradiation approaches. Additionally, the inclusion of PD-L1 unselected patients may have contributed to the poor outcomes, as other studies suggest greater benefit of immunotherapy in PD-L1 positive cases.
The authors concluded that in a PD-L1 unselected population with stage III NSCLC, thoracic radiation plus concurrent and consolidation durvalumab without chemotherapy is associated with both disappointing efficacy and concerning toxicity. They noted that all but one case of disease progression occurred outside the radiation field, suggesting inadequate systemic control without chemotherapy.
These results contrast sharply with outcomes seen in trials incorporating chemotherapy. For example, the PACIFIC trial of chemoradiation followed by consolidation durvalumab showed a 2-year overall survival rate of 67%. Similarly, the NICOLAS trial of chemoradiation with both concurrent and consolidation nivolumab had a 2-year survival of 64%.
Interestingly, high-grade toxicities appeared more common in PD-L1 negative cases in this study, though the small numbers preclude definitive conclusions. The authors speculated this could potentially relate to persistent tumor bulk in non-responding cases or greater inflammatory activity in the absence of PD-L1 expression.
The potential clinical impact of this study is significant, as it suggests caution is warranted with chemotherapy-free immunotherapy and radiation approaches for unselected stage III NSCLC patients. While other ongoing trials are examining similar strategies, these results indicate additional research is needed before such regimens could be considered for routine clinical use.
The findings also highlight the importance of chemotherapy in this setting, both for enhancing local radiation effects and providing systemic disease control. The counterintuitive observation that adding chemotherapy to immunotherapy and radiation may actually reduce toxicity (as seen in trials like NICOLAS) also merits further investigation.
Finally, this study underscores the potential value of PD-L1 selection for immunotherapy approaches in stage III NSCLC. Other trials examining concurrent immunotherapy and radiation, such as the DOLPHIN study, have shown more promising results in PD-L1 positive populations.
In conclusion, while the small sample size limits definitive conclusions, this phase 2 trial raises important safety and efficacy concerns about concurrent immunotherapy and radiation without chemotherapy in unselected stage III NSCLC patients. Further research is needed to identify optimal combinations and sequencing of these modalities, as well as biomarkers to guide patient selection.
References
Zhang Y, Iyengar P, Montalvo S, et al. Concerning Safety and Efficacy of Concurrent and Consolidative Durvalumab With Thoracic Radiation Therapy in PDL1-Unselected Stage III Non-Small Cell Lung Cancer: Brief Report. Int J Radiat Oncol Biol Phys. 2025;121(1):68-74. doi:10.1016/j.ijrobp.2024.07.2333
