Radiation therapy for augmenting the efficacy of immunotherapy in advanced non-small cell lung cancer: a case-controlled study

Abstract

Nivolumab, a human IgG4 anti-PD1 monoclonal antibody, has been shown to have promising results in patients with advanced non-small cell lung cancer (NSCLC) [1, 2]. Despite the improved outcomes compared to chemotherapy, only ∼20% of patients had a sustained favourable response, which highlights the need to identify measures that can augment the efficacy of immunotherapy in NSCLC [3]. Previous studies have demonstrated that radiation acts as an immune stimulus, facilitating immune mediators to enable antitumour responses within and outside the radiation field [4]. Multiple mechanisms have been shown to be involved in the systemic immune response from radiation therapy [5]. Preclinical studies also suggest that immune checkpoint inhibitors such as nivolumab can have a synergistic effect to radiation with enhancement of the antitumour T-cell activity [6], which should theoretically result in a greater clinical response in patients with NSCLC. There is also evidence to suggest an augmented abscopal effect from the combined treatment [7]. Despite the strong preclinical evidence, the impact of previous radiation therapy on the efficacy and safety of immunotherapy in real-world clinical practice in patients with NSCLC is less well defined. Here, we present the findings of a pilot case-controlled study investigating the impact of radiation therapy on outcomes with nivolumab in patients with advanced NSCLC in a large thoracic oncology unit in Brisbane, Australia. Consecutive patients with metastatic or progressive locally advanced NSCLC, who had previous radiation therapy to the chest and subsequently received nivolumab (RT group, n=23) were compared to a control group comprised of an age, sex, tumour histology and performance status matched cohort of patients who did not have previous radiation therapy prior to receiving nivolumab (non-RT group, n=23), between January 2015 and June 2017. Disease response was assessed with RECIST (Response Evaluation Criteria in Solid Tumours) version 1.1 [8]. The primary co-endpoints of the study were progression free survival (PFS) and overall survival (OS). The adverse effects of therapy were graded according to the CATCAE (Common Terminology Criteria for Adverse Event) classification. Ethical approval for this study was granted by the Queensland Metro South Human Research Ethics Committee (REC/17/QPAH/338). A total of 46 patients were included in the study with a median age of 62 years (IQR 55-67 years). All patients had metastatic or progressive locally advanced disease at baseline and the other clinical variables were equal between the two groups. The performance status at baseline was also very closely matched between the two groups. All patients had platinum-based chemotherapy before receiving nivolumab. The majority of patients had received one line of chemotherapy (84.8%, n/N=39/46). A total of 17.4% (n/N=4/ 23) of patients in the RT group and 13.0% (n/N=3/23) of patients in the non-RT group received more @ERSpublications This study investigated the effects of previous radiation...

Assessing Potential Factors Influencing the Efficacy of Immune Checkpoint Inhibitors with Radiation in Advanced Non-Small-Cell Lung Cancer Patients: A Systematic Review and Meta-Analysis

“…Of note, PFS may serve as an indicator of OS in patients treated with RT + ICIs. Tese were in accordance with previously reported studies that using RT with ICIs may be associated with improved PFS and OS in well-selected patients [16,31,50].…”

“…After excluding duplication and reviewing the title and abstract of the studies, 3187 studies were discarded and the remaining 78 articles were initially included for further identifcation. Among them, a total of 26 studies [15,16,18,[20][21][22][23][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] were fnally included in the systematic review and meta-analysis after reviewing the full text, with 14192 participants. Te literature screening process and results are shown in Figure 1.…”

A Mathematical Modeling Approach for Targeted Radionuclide and Chimeric Antigen Receptor T Cell Combination Therapy

“…There is recent evidence to suggest that radiation can induce changes in the immune system and can stimulate a significant immune response for a better therapeutic efficacy [21][22][23]. Radiation therapy can act as a bridging therapy for immunotherapies yielding better therapeutic efficacies with immunotherapy [24][25][26]. With a better understanding of the mechanistic basis and supporting experimental data, the interactions between radiation and immunotherapy can be better modeled and additional interaction terms can be introduced in the mathematical formulation to account for toxicity.…”