Deeper Dive Toxicity of Lung SBRT and Concurrent Immunotherapy Combinations: What We Know and What We Still Need to Learn

The use of stereotactic body radiation therapy (SBRT) and immune checkpoint inhibitors (ICI) is supported by Level I evidence—both extend overall survival in the randomized setting for patients with advanced NSCLC.1
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 This has led to the proliferation of SBRT use, particularly in those with oligometastatic disease.5
Utilization of the two in combination has grown in parallel and is largely implemented in the clinic off study. Combination strategies have been advocated because of SBRT’s impact on systemic therapy, favorable side-effect profile, local efficacy, and hypothesized mechanisms of synergy with ICIs.6
Immune-mediated adverse effects (AEs) unique to ICIs have been described,7
and concerns about overlapping, or perhaps even heightened, toxicity profiles are the most commonly cited reasons for radiation oncologists to withhold SBRT with concurrent immunotherapy.8
Characterizing the toxicity of SBRT + ICI combinations and developing strategies to mitigate such AEs has become areas of great interest.

The toxicity profile of lung SBRT given concurrently with ICIs is not well known. To address this, the authors of a multicenter safety and toxicity analysis9
identified 117 patients from a single academic institution who received lung SBRT. The population was composed of 54 patients who received SBRT with concurrent ICI and a reference cohort of 63 who received SBRT alone. Concurrent administration was defined in this study as being within 30 days of each other. Common SBRT doses and fractionations included 10 Gy x 5, 6 Gy x 5, and 9 Gy x 3. Patients in the SBRT + ICI cohort were typically those with lung cancer who received SBRT to a single progressive metastatic site. Notably, the majority of patients in the SBRT + ICI cohort had received prior radiation;36% had a prior history of thoracic irradiation. This differed significantly from the SBRT-alone cohort, which was largely radiation naive. Although modest in absolute terms, the risk of grade 3 or higher (G3+) pneumonitis associated with the SBRT + ICI group was increased when compared with the SBRT-alone group (10.7% vs. 0%, p < 0.01). The risk of any-grade pneumonitis was similar between the two groups.

Overall toxicity during SBRT treatment and in the immediate post-treatment period was similar between groups, but when examining the period up to 90 days after treatment, the SBRT + ICI cohort experienced higher rates of clinically relevant toxicity (27% vs. 3%, p < 0.01). An exploratory analysis within the SBRT + ICI group found that larger planning target volumes and having radiation targets in two lung lobes appeared to increase the risk of any-grade and G3+ pneumonitis, respectively. It was also suggested that ICI/ICI combinations might increase the risk of pneumonitis relative to those receiving either ICI monotherapy or ICI/chemotherapy combinations (62.5% vs. 29.2%, p = 0.10). With respect to the sequencing of ICI and SBRT administration, ICI interdigitated between SBRT fractions did not appear to increase the risk of pneumonitis when compared with all other forms of sequencing, as long as SBRT and ICI were given within 30 days of each other.

This study adds to the growing body of literature describing SBRT and concurrent ICI, a distinct treatment strategy that has seen rapid adoption without documentation of robust safety data. Due to limitations in sample size and patient and treatment heterogeneity, reaching a consensus on toxicity in this therapeutic space has proven difficult. “Real-world” institutional data have identified rates of ICI pneumonitis significantly higher than those previously reported in large phase III studies.10
Several recent randomized studies evaluating SBRT with concurrent ICI have also shed light on the potential risks of combination therapy. 

PEMBRO-RT was a phase II study in which 76 patients with advanced NSCLC were randomly assigned to receive pembrolizumab with or without single tumor-site irradiation of 8 Gy x 3 SBRT.11
 Pembrolizumab was administered within seven days of SBRT completion. Any-grade pneumonia was more common in the experimental arm (26% vs. 8%, p = 0.06), but was not significant with respect to serious, i.e., G3+ events (3% vs. 11%). G3+ pembrolizumab-related AEs occurred in 17% of patients, with no difference between arms. With the addition of SBRT, modest increases in any-grade immune-related pneumonitis (5% vs. 11%) and G3+ events (0% vs. 5%) were seen. Overall, the number of patients experiencing immune-related AEs was no different between groups, although a trend was observed for more events in the SBRT + pembrolizumab arm (68 vs. 85 events, p = 0.076).

A similar study from The University of Texas MD Anderson Cancer Center enrolled 100 patients with metastatic NSCLC (20 patients in phase I, 80 patients in phase II; NCT02444741).12
In the phase I cohort, in which all patients received pembrolizumab and concurrent radiation therapy, six total G3 events were recorded, with no grades 4 or 5 AEs observed. Radiation therapy was either SBRT of 50 Gy in 4 fractions or a hypofractionated regimen of 45 Gy in 15 fractions when SBRT was not feasible. Forty of the 80 patients in the phase II cohort were randomly assigned to receive pembrolizumab alone or in combination with SBRT. Although the SBRT + ICI combination arm had a lower incidence of G3 events (2 vs. 8 events), this arm also featured two grade 4 events that were possibly related to treatment.

A pooled analysis of the two studies showed no new safety signals.13
Moreover, in a phase II study of 18 patients with relapsed SCLC, patients were randomly assigned to receive durvalumab and tremelimumab with or without immunogenically dosed SBRT of 8 Gy x 3, and the addition of SBRT did not appear to increase the risk of pulmonary toxicity or serious AEs.14

Identifying those who may be predisposed to AEs from thoracic irradiation should also be considered in the management of patients who are candidates for combined SBRT + ICI. A history of immune-related AEs has been suggested as a unique risk factor for radiation pneumonitis after thoracic RT.15
A report of 41 patients with prior history of immune-related AEs who subsequently received either thoracic SBRT or hypofractionated RT found a 61% incidence of grade 2 or higher, and a 15% incidence of G3+ radiation pneumonitis. Both represent significantly higher risks than those estimated in the literature using conventionally fractionated radiation.

The effects of SBRT + ICI timing on safety and toxicity are the subject of active investigation; multiple randomized studies in this therapeutic arena are evaluating concurrent versus non-concurrent administration. A study in which patients with metastatic NSCLC are randomly assigned to receive SBRT to multiple sites with concurrent or sequential ipilimumab/nivolumab has a primary safety endpoint (COSINR; NCT03223155). Patients with advanced NSCLC in another study are being assigned to receive either sequential, induction, or concurrent atezolizumab with 5-fraction SBRT (NCT02400814). Other clinical trials in which the timing of SBRT and immunotherapy administration vary by randomization or parallel assignment include NCT02318771, NCT03307759, and NCT02239900. SBRT and concurrent ICI is also being actively explored in the localized setting. SWOG S1914 is a randomized study combining definitive SBRT with atezolizumab in patients with high-risk early-stage NSCLC (NCT04214262). The start of SBRT is concurrent with the third dose of atezolizumab, the timing selected based on preclinical evidence suggesting enhanced tumor kill when radiation is given after an initial loading dose of PD-L1 inhibition. Other ongoing studies testing the sequencing and timing of SBRT + ICI combinations have been recently reviewed, the results of which are eagerly awaited.16
   

SBRT + ICI combinations are an area of active investigation. New data that are expected to emerge will contribute to our understanding. The evidence collected so far suggests the combination is safe and tolerable. Whether any modest increases in toxicity seen with SBRT + ICI combinations are simply additive in nature or amplified because of such combinations remains to be seen. In the absence of any objective data suggesting significantly elevated toxicity with concurrent administration, SBRT + ICI is a reasonable strategy for the clinic as long as providers and patients are informed about the potential for overlapping toxicity, although these patients should preferably be treated in the setting of a prospective clinical study. Treatment planning should follow established principles for SBRT planning, but with the added principle of as low as reasonably achievable. Care should be taken to avoid any unnecessary or large-volume irradiation of normal organs in the thorax. While our study provides clear evidence that the concurrent SBRT + ICI combination is safe and a part of routine clinical practice, hesitancy from many in the community also suggests more robust data are needed.

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