Results from the phase 1 RaDDtrial (NCT03610061) radiotherapy added to immunotherapy enhanced responses, demonstrated manageable safety, and was informed by T-cell dysregulation in patients with B-cell lymphomas. 1

The objective response rate (ORR) in patients with follicular lymphoma (FL) was 60% (n = 3/5), and 14% (n = 4/27) in patients with diffuse large B-cell lymphoma (DLBCL). Of the total patients, 32 were evaluable for response and had an ORR of 22%.]

The study examined the safety of escalating radiotherapy dose and treated volumes with durvalumab (Imfinzi) in 34 patients with relapsed/refractory DLBCL and relapsed/refractory follicular lymphoma (FL). The median age of patients was 74 (range, 28–87). Of the total patients, 29 had DLBCL and 5 had FL.

The median number of durvalumab cycles was 2 (range 1–32; DLBCL median 2 cycles, range, 1–32; FL median 11 cycles, range, 4–30). The median follow-up was 7.1 months (range, 0.17–60 months).

The median duration of response (DOR) was 3.3 months (95% CI, 2-16 months) and >12 months in 50% (n = 4/8) of patients.

“Our demonstrated safety of [radiotherapy] with PD-L1 [inhibition] has broad applicability across different tumor types and can be potentially extrapolated to [radiotherapy] combinations with newer T-cell engaging immunotherapies including bispecifc antibodies,” wrote Hawkes et al, authors of the study.

The primary end point was the recommended phase 2 dose of radiotherapy combined with durvalumab. Secondary end points were toxicity for adverse events (AEs), ORR, progression-free survival (PFS), overall survival (OS), and maximum tolerated dose of radiotherapy.

All patients experienced at least 1 AE. Treatment-related AEs grade ≥ 3 occurred in 38% of patients (n = 13). There was 1 death due to sepsis, which was considered unrelated to the study interventions. Serious AEs occurred in 8 patients, and 3 were therapy related. No dose-limiting toxicities occurred.

The most reported AEs were neutrophil count decrease, platelet count decrease, anemia, nausea/vomiting, and diarrhea.

Due to an early unrelated grade 5 AE, 2 patients with DLBCL were not evaluable.

“Our application of [radiotherapy] potentially impacts future combination trial designs by establishing the required [radiotherapy] dose to elicit FL and DLBCL in-field responses,” wrote study authors.“Conventionally, [radiotherapy] volumes applied in this context tend to be regional rather than focal. Our approach treated involved nodes only, prioritized symptomatic or dominant disease with the rationale that it could overcome protracted time-to-maximal response seen with PD-L1 [inhibition] and sites least likely to be affected by additive toxicity based on PD-L1 [inhibition] safety profiles.”

Biomarker Analysis

A preplanned, extensive biomarker program revealed a strong correlation between T-cell characteristics and treatment response across tissue, blood, and imaging analyses. An analysis of baseline tumor biopsies showed that a T-cell-inflamed microenvironment was critical for response. Responders had significantly higher levels of T-cell infiltration and cytotoxic T-cell markers (including CD8A) at baseline compared to nonresponders.T-cell activation scores were significantly higher in responders (P=.0013).

The ratio of T-cell infiltration to immune-suppressive PD-L1 expression and M2 macrophages was significantly lower in patients who progressed (P =.0051), indicating that an imbalance favoring suppression is associated with poor outcomes.

Gene expression of TCF7, a transcription factor associated with progenitor, reversibly exhausted T-cells that can be reinvigorated by immunotherapy, was significantly higher in responders (P =.0160).

Baseline PD-L1 gene expression did not correlate with response. However, a significant reduction in PD-L1 RNA levels was observed in biopsies taken at the time of progression, suggesting PD-L1 down regulation may be a mechanism of therapeutic resistance.

Patient Criteria

Patient inclusion criteria included, but were not limited to, having histologically proven CD20-positive relapsed/refractory DLBCL, either de novo or DLBCL transformed from any indolent non-Hodgkin lymphoma; receiving at least 1 line of previous treatment for lymphoma which must include a CD20 monoclonal antibody such as rituximab (Rituxan), with no curative option as determined by the investigator; and having an ECOG score of 0 or 1.2

Patient exclusion criteria included, but were not limited to, having T-cell lymphoma or Hodgkin lymphoma; receiving prior therapy with any antibody or drug targeting T-cell coregulatory proteins such as PD-1, PD-L1, or CTLA-4,; and having an active autoimmune disease that might deteriorate when receiving an immunostimulatory agent.2

About the RaDD Trial

The RaDD trial was an investigator-initiated multicenter phase 1b radiotherapy dose and treated volume-escalation trial with a standard 3+3 design. All patients received at least 5 radiotherapy fractions between 1 and 3 treated sites. The cumulative dose ranged between 2.5 Gy and 30 Gy across 6 dose cohorts. Patients received 1500 mg of durvalumab intravenously on day 2 of radiotherapy, continuing every 28 days until disease progression or unacceptable toxicities.1

All patients underwent a baselineCT–guided radiotherapy planning. The gross tumor volume was treated for each 1 to 3 sites. Cohorts 1 to 5 received doses that escalated from 2.5 Gy/5 to 20 Gy/5, the latter a typical palliative dose with response rates >80%. Cohort 6 used 30 Gy/10 to reduce the risk of potential tumor lysis with large fraction sizes in anticipation of potential heavy tumor burden.

REFERENCES1.Hawkes E, Palmer J, Khor R, et al. T-cell dysregulation informs radiotherapy-immunotherapy response in B-cell lymphoma: results from a phase 1 trial. Blood Adv (2025) 9 (20): 5263–5273. doi.org/10.1182/bloodadvances.20250165052.A trial of radiotherapy and durvalumab in DLBCL and FL (RaDD). ClincalTrials.gov. Updated April 12, 2024. Accessed November 4, 2025. https://clinicaltrials.gov/study/NCT03610061