Immunotherapy Fails to Improve Survival in Two Cancer Trials
Two recent clinical trials found that adding immunotherapy to standard chemoradiation did not improve survival for patients with limited-stage small-cell lung cancer or high-risk HPV-positive oropharyngeal cancer, though both studies revealed important insights about treatment delivery and radiation scheduling.
A clinical trial led by NRG Oncology in collaboration with the Alliance for Clinical Trials in Oncology found that adding the immunotherapy agent atezolizumab to chemoradiation did not significantly improve survival for patients with limited-stage small-cell lung cancer (SCLC). However, the study did find that twice-daily radiation therapy was associated with improved survival in this population.
The LU005 study enrolled 544 patients between May 2019 and December 2023 across 218 sites in the U.S. and Japan. Participants were assigned to receive either standard concurrent chemoradiation alone or chemoradiation plus atezolizumab. Thoracic radiation was delivered using either a twice-daily or once-daily schedule. The addition of atezolizumab did not improve progression-free or overall survival. However, the study found that twice-daily radiation therapy was associated with substantially better survival than once-daily radiation, regardless of immunotherapy use.
The study findings suggest that further research is needed to determine the optimal use of immunotherapy and radiation therapy in the management of limited-stage small-cell lung cancer. While the addition of immunotherapy did not improve survival in this study, the findings highlight the potential benefits of twice-daily radiation therapy for patients with limited-stage small-cell lung cancer, a regimen that remains underutilized in clinical practice.
In a separate trial, the phase 2 IMMUNEBOOST-HPV trial (NCT03838263) investigated whether adding nivolumab (Opdivo) immunotherapy before standard chemoradiation could improve outcomes for patients with high-risk oropharyngeal cancer. Administering induction immunotherapy before standard chemoradiation (CRT) in patients with high-risk HPV-positive oropharyngeal cancer proved effective for the majority of patients but narrowly missed the trial's prespecified feasibility threshold due to cisplatin dosing challenges.
The study evaluated patients with HPV-positive oropharyngeal cancer who faced elevated risk of relapse due to either advanced stage disease with T4 or N2/N3 classification or a significant smoking history exceeding 10 pack-years. A total of 62 patients were randomly assigned in a 1:2 fashion to receive either standard chemoradiation with 70 Gy and cisplatin as the control arm (n = 20) or 2 infusions of nivolumab followed by the same chemoradiation regimen in the experimental arm (n = 41).
The primary end point focused on feasibility, measured by a composite end point. This required patients to successfully receive both nivolumab infusions on schedule, initiate chemoradiation within a specific window, avoid prolonged radiotherapy breaks, achieve adequate radiotherapy dose delivery, and receive at least 200 mg/m2 of cisplatin. The primary end point was not met because 4 of the 41 patients in the experimental arm received less than 200 mg/m2 of cisplatin.
The 36-month overall survival rate was 95% (95% CI, 76.4%-99.1%) in the control arm and 90.1% (95% CI, 77.1%-96.1%) in the experimental arm. The stratified HR for death was 2.53 (95% CI, 0.29-21.64). With a median follow up of 37.5 months, the 2-year cumulative incidence of relapse was 7.3% (95% CI, 1.9-18.0) in the experimental arm compared with 15.0% (95% CI, 3.6-34.0) in the control arm.
Grade 4/5 acute adverse events (AEs) occurred exclusively in the experimental arm—2 nivolumab-related grade 4 adverse events (hepatic cytolysis and diabetic ketoacidosis), 3 grade 4 AEs were related to radiotherapy and/or cisplatin, 2 cancer-related grade 4 AEs, and 1 grade 5 AE (septic shock occurring 2.5 months after random assignment), for which it could not be determined if this was due to nivolumab, cisplatin, or radiotherapy.
The authors noted that although induction nivolumab proved deliverable for most patients, the increased rate of high-grade acute toxicities and the specific challenge of delivering full cisplatin dosing underscore the need for careful patient selection and toxicity management if this approach moves forward. The authors concluded that induction nivolumab before chemoradiation did not meet the feasibility threshold due to reduced cisplatin dosing after toxicity in 10% of patients, though the lower relapse incidence in the experimental arm warrants confirmation in future studies.