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

Suchita Pakkala, Kristin Higgins, Zhengjia Chen, Gabriel Sica, Conor Steuer, Chao Zhang, Guojing Zhang, Shuhua Wang, Mohammad S Hossain, Bassel Nazha, Tyler Beardslee, Fadlo R Khuri, Walter Curran, Sagar Lonial, Edmund K Waller, Suresh Ramalingam, Taofeek K Owonikoko, Suchita Pakkala, Kristin Higgins, Zhengjia Chen, Gabriel Sica, Conor Steuer, Chao Zhang, Guojing Zhang, Shuhua Wang, Mohammad S Hossain, Bassel Nazha, Tyler Beardslee, Fadlo R Khuri, Walter Curran, Sagar Lonial, Edmund K Waller, Suresh Ramalingam, Taofeek K Owonikoko

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.

Keywords: clinical trials; immunotherapy; lung neoplasms; phase II as topic; programmed cell death 1 receptor; radioimmunotherapy.

Conflict of interest statement

Competing interests: AstraZeneca provided funding for this study and is manufacturing the products being evaluated in the research described in this paper. TKO and KH served as paid consultants to AstraZeneca and personally received compensation for these services. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Non-comparative Kaplan-Meier curves for progression-free survival (PFS) and overall survival (OS) in arm A and arm B of the study.
Figure 2
Figure 2
Kaplan-Meier curves for progression-free survival (PFS) (left) and overall survival (OS) (right) for combined data across both arms for platinum-sensitive and resistant relapse.
Figure 3
Figure 3
Kaplan-Meier curves for progression-free survival (PFS) (left) and overall survival (OS) (right) with combined data across both arms for patients treated with second-line versus third-line therapy.
Figure 4
Figure 4
(A) Representative flow cytometric gated populations of red blood cells-lysed white cells. (B) Flow cytometric gated populations of TILs from biopsy samples. (C) Comparison of lymphocyte subsets in peripheral blood samples collected at baseline versus on treatment on day 15 of cycle 1 with reduced proportion of naïve CD4+ and CD8+ T cells, increased activated CD8+ICOS+ T cells and reduced levels of CD8+CTLA-4+ cells. (D) TIL distribution in tumor biopsies showed higher proportion of activated CD8+ICOS+ T cells and lower proportion of CTLA-4+ subsets of both CD4 and CD8+ T lymphocytes; colored hatched symbols highlight the two patients with objective response by RECIST 1.1 criteria. CTLA-4, cytotoxic T lymphocyte-associated protein 4; FSC, forward scatter; SSC, side scatter; TILs, tumor infiltrating lymphocytes.

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