Durvalumab and tremelimumab with or without stereotactic body radiation therapy in relapsed small cell lung cancer: a randomized phase II study

Abstract

BackgroundImmune checkpoint blockade (ICB) targeting programmed cell death protein 1 and cytotoxic T lymphocyte-associated protein 4 has achieved modest clinical activity as salvage therapy in relapsed small cell lung cancer (SCLC). We conducted this signal-finding study to assess the efficacy of ICB with or without radiation in relapsed SCLC.MethodsPatients with relapsed SCLC and ≤2 previous lines of therapy were randomized to (1) arm A: durvalumab (D) 1500 mg/tremelimumab (T) 75 mg (intravenously every 4 weeks without stereotactic body radiation therapy (SBRT)) or (2) arm B: immune-sensitizing SBRT to one selected tumor site (9 Gy × 3 fractions) followed by D/T. Treatment continued until progression or a maximum of 12 months. The co-primary endpoints of the study were overall response rate (ORR) and progression-free survival (PFS). We evaluated circulating lymphocyte repertoire in serial peripheral blood samples and tumor infiltrating lymphocytes (TILs) from on-treatment biopsies as pharmacodynamic markers.ResultsEighteen patients were randomized to arms A and B (n=9 each): median age 70 years; 41.2% women. The median PFS and ORR were 2.1 months and 0% in arm A and 3.3 months and 28.6% in arm B. The median overall survival (OS) was 2.8 months in arm A and 5.7 months in arm B (p=0.3772). Pooled efficacy of D/T±SBRT in 15 Response evaluation criteria in solid tumors (RECIST) evaluable patients across both arms showed the best ORR in terms of partial response in 13.3%, stable disease in 26.6% and progressive disease in 60.0%; the overall median PFS and OS were 2.76 and 3.9 months. The most common adverse events were grade 1 fatigue (66%) and grade 1 elevated amylase (56%) in arm A, and grade 1 fatigue (56%) and pain (44%) in arm B. There was a significant increase in activated CD8(+)ICOS+ T cells (p=0.048) and a reduction in naïve T cells (p=0.0454) in peripheral blood following treatment, along with a significant amount of activated CD8+ICOS+ T cells in TILs from responders.ConclusionsThe D/T combination with and without SBRT was safe but did not show sufficient efficacy signal in relapsed SCLC. Changes in peripheral blood lymphocyte and TILs were consistent with an immunologic response.Trial registration numberNCT02701400.

A Real-World Evaluation of Atezolizumab Plus Platinum-Etoposide Chemotherapy in Patients With Extensive-Stage SCLC in Canada

“… 13 , 14 Because of the observed synergy between radiotherapy and ICI in the preclinical studies, several clinical trials are now evaluating the safety and efficacy of radiation with immunotherapy in lung cancer, most in the postprogressive disease settings. 13 , 14 , 15 , 16 , 17 , 18 , 19 Early studies suggest that tRT and ICI are safe and effective in limited-stage SCLC, but this has not yet been found in extensive-stage disease. 13 , 14 , 15 , 18 , 20 , 21 , 22 …”

“… 13 , 14 , 15 , 16 , 17 , 18 , 19 Early studies suggest that tRT and ICI are safe and effective in limited-stage SCLC, but this has not yet been found in extensive-stage disease. 13 , 14 , 15 , 18 , 20 , 21 , 22 …”

Dynamic serum biomarkers to predict the efficacy of PD-1 in patients with nasopharyngeal carcinoma

“…However, this study is not just for patients who underwent anti-PD-1 therapy. The same group also established an immune score model that estimates the risk of disease progression in NPC patients [ 38 ]. Nevertheless, our model focuses on the dynamic changes of existing serum parameters in NPC patients, avoids additional costs, and provides a novel predictive model for patients who have undergone expensive anti-PD-1 therapy.…”

Durvalumab Plus Tremelimumab in Solid Tumors: A Systematic Review

“…The electronic search identified 267 articles; after exclusion of duplicates, irrelevant articles, reviews, and papers not in English or with missing data, 19 articles were finally included for revision [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32]. Figure 1 depicts a flowchart describing the details of the document screening process, while Table 1 reports the principal details of the articles finally selected.…”

“…Pakkala et al performed a study with the aim to evaluate the efficacy of ICIs with or without radiation in patients with SCLC [ 19 ]. In particular, the primary objective of this phase II study was to determine the efficacy of the combination of durvalumab and tremelimumab with or without stereotactic body radiation therapy (SBRT) in relapsed SCLC, using as primary endpoints the PFS and ORR.…”