Dataset Information

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

ABSTRACT:

Background

Immune 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.

Methods

Patients 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.

Results

Eighteen 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.

Conclusions

The 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 number NCT02701400.

SUBMITTER: Pakkala S

PROVIDER: S-EPMC7754662 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Publications

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

Pakkala Suchita S Higgins Kristin K Chen Zhengjia Z Sica Gabriel G Steuer Conor C Zhang Chao C Zhang Guojing G Wang Shuhua S Hossain Mohammad S MS Nazha Bassel B Beardslee Tyler T Khuri Fadlo R FR Curran Walter W Lonial Sagar S Waller Edmund K EK Ramalingam Suresh S Owonikoko Taofeek K TK

Journal for immunotherapy of cancer 20201201 2

<h4>Background</h4>Immune 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.<h4>Methods</h4>Patients with relapsed SCLC and ≤2 previous lines of therapy were randomized to (1) arm A: durvalumab (D) 1500 mg/tremelimumab (T) ...[more]

PMID: 33428583

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Project description:Lessons learnedDisease control with signals of response were demonstrated, which should lead to future validating clinical trials using checkpoint inhibitors in this underserved rare malignancy population. Although the study of single types of rare cancers is practically challenging, clinical trial designs that aggregate such patients into cohorts treated similarly are feasible, even in the community setting.BackgroundPatients with rare cancers are an underserved population with limited access to clinical trials aside from phase I trials in the refractory setting. Treatment of these patients is often based on collections of anecdotes and small denominator review articles. Despite broad evidence of efficacy of combined immune checkpoint blockade across multiple tumor types, patients with rare tumors have not been afforded the opportunity for these therapies.MethodsA phase II, investigator-initiated, single institution trial using durvalumab (1,500 mg every [Q]4 weeks × 13) and tremelimumab (75 mg Q4 weeks × 7, then Q12 weeks × 2) is reported. The population included 50 patients with advanced rare solid tumors (incidence <6/100,000 per year). The phase II dose and safety profile were defined in prior phase I trials. All patients had exhausted standard therapy options and all had received at least one prior line of systemic therapy (n = 49) unless a standard treatment option did not exist (n = 1).ResultsA complete response was demonstrated in one patient with anal cancer. Striking partial responses were seen in four patients. Prolonged disease stability was noted in 18 patients. Thirteen patients experienced disease progression. Patients were considered unevaluable if unable to initiate therapy (n = 6) or unable to complete two cycles of therapy (n = 8). In all cases, patients were unevaluable because of clinical deterioration. The toxicity profile paralleled prior published studies. Toxicities were manageable and without new signals. There were two events of grade 4 immune-mediated hepatitis and one death from pneumonitis.ConclusionThis single-cohort basket trial demonstrated clinical activity from combined checkpoint blockade in 23 of the 36 evaluable patients. Patients with rare cancers, not eligible for immunotherapy via conventional clinical trial mechanisms, should be considered for this therapy through compassionate use, further clinical trials, and national registry programs.

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Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

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