Radical treatment of metastases with stereotactic body radiation therapy (SBRT) is commonly implemented in patients receiving concurrent immune checkpoint inhibition (ICI), despite limited safety and toxicity data.

Records from a single academic institution were reviewed to identify patients treated with lung SBRT and concurrent (within 30 days) ICI; a contemporaneous cohort receiving lung SBRT alone was included for reference.

All patients received RT per RTOG 0813. Patients were treated with lung SBRT between June 2012 and January 2019. Fifty-six treatment courses, corresponding to 69 target lesions across 54 patients, were identified from those receiving lung SBRT with concurrent immunotherapy. Sixty-eight courses of treatment across 63 patients (79 target lesions) were included, comprising the SBRT-alone cohort.

The incidence of acute AEs, occurring predominantly during SBRT delivery, was similar between the SBRT + ICI and SBRT-alone groups.  However, SBRT + ICI patients were more likely to have treatment-related AEs up to 90 days after SBRT; grade 3 (G3) or higher subacute toxicity was seen in 26.8% versus 2.9% of patients (P < .001). Severe (G3 or higher) pneumonitis was substantially higher when concurrent ICI was given (10.7% vs 0%, P Z .007).

The risk of any-grade pneumonitis appeared elevated with ICI/ICI combination therapy (62.5% vs 29.17%, P Z .105); however, the risk of high-grade pneumonitis was similar compared with other ICI treatment types (12.5% vs 10.42%). ICI administration between SBRT treatment days was safe; it did not appear to increase the risk of high-grade or any-grade pneumonitis over non-overlapping delivery.

The prevalence of clinically significant pneumonitis was approximately 10%, as reported here. This risk, among known risk factors, should be considered when assessing immunotherapy patients for SBRT candidacy

Reference (PubMed Link): Tian S, Switchenko JM, Buchwald ZS, et al. Lung stereotactic body radiation therapy and concurrent immunotherapy: A multicenter safety and toxicity analysis. Int J Radiat Oncol Biol Phys 2020.

Key Institution: Multi-Institutional
Keywords: SBRT, Lung, Immunotherapy, Pneumonitis 

In patients with advanced NSCLC, concurrent chemoradiation and immunotherapy with durvalumab is standard care per the PACIFIC trial.  This retrospective review of patients with stage III unresectable NSCLC highlights similar efficacy and toxicity in clinical practice as within the PACIFIC trial.  Importantly, the presentation of distant progression was oligometastatic disease in 47% which informs the use of oligometastatsis-directed therapy including SBRT.  In this subset, PD-L1 and tumor mutational burden did not predict improvement in outcomes.  This study represents an important detailed analysis of patients receiving chemoradiotherapy with durvalumab, with the important factor of oligometastatic distant metastases highlighted.

Reference (PubMed Link): Offin M, Shaverdian N, Rimner A, et al. Clinical outcomes, local-regional control and the role for metastasis-directed therapies in stage iii non-small cell lung cancers treated with chemoradiation and durvalumab. Radiother Oncol 2020;149:205-211.

Key Institution: Memorial Sloan Kettering
Keywords: Radiotherapy, immunotherapy, NSCLC, durvalumab, metastases 

RTOG 0617 compared standard-dose (60 Gy) with high-dose (74 Gy) radiation with concurrent chemotherapy and determined the efficacy of cetuximab for stage III non–small-cell lung cancer (NSCLC). This was a report of long-term outcomes. Median follow-up was 5.1 years. There were 3 grade 5 adverse events in the standard arm and 9 in the high dose arm. Treatment-related grade >=3 dysphagia and esophagitis occurred in 3.2% and 5.0% of patients in the standard arm v 12.1% and 17.4% in the high dose arm, respectively (P = .0005 and .0001). There was no difference in pulmonary toxicity, with grade >=3 AEs in 20.6% and 19.3%. Median OS was 28.7 v 20.3 months (P = .0072) in the SD and HD arms, respectively, 5-year OS and progression-free survival (PFS) rates were 32.1% and 23% and 18.3% and 13% (P = .055), respectively. Factors associated with improved OS on multivariable analysis were standard radiation dose, tumor location, institution accrual volume, esophagitis/dysphagia, planning target volume and heart V5. The use of cetuximab conferred no survival benefit at the expense of increased toxicity. 

This was a large multi-center randomized trial examining the benefit of two methods of treatment intensification for advanced NSCLC. Notably the trial preceded the PACIFIC trial, which established chemoradiation with adjuvant immunotherapy as the new standard of care for this disease state. Unfortunately, neither method of treatment intensification (cetuximab or dose-escalated radiation) succeeded in improving outcomes and these strategies may have even worsened outcomes. The exact reason for this remains uncertain, though differences in heart dose may partially explain this. 

Overall, this was a well-designed randomized trial, which importantly demonstrates the challenges of improving outcomes in NSCLC through treatment intensification. While the addition of immunotherapy to chemoradiation has been shown to be beneficial for patients with this condition, the results of RTOG 0617 suggest that efforts to make further outcome improvements should proceed with caution.  

Reference (PubMed Link): Bradley JD, Hu C, Komaki RR, et al. Long-term results of nrg oncology rtog 0617: Standard- versus high-dose chemoradiotherapy with or without cetuximab for unresectable stage iii non-small-cell lung cancer. J Clin Oncol 2020;38:706-714.

Key Institution: Multi-Institutional
Keywords: NSCLC, randomized trial, treatment intensification, dose escalation, cetuximab 

Twenty-one participants had locally advanced, unresectable, stage III NSCLC, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate hematologic, renal, and hepatic function.

Pembrolizumab was combined with concurrent chemoradiotherapy (weekly carboplatin and paclitaxel with 60 Gy of radiation in 2 Gy per d). Progression-free survival was good, with relatively few serious immune-related adverse events.

Consolidative immunotherapy following chemoradiation for locally advanced NSCLC was shown to improve survival in the PACIFIC trial. The use of concurrent immunotherapy with radiation in intriguing but there is little data regarding safety and efficacy. This Phase 1 study demonstrates that concurrent chemoimmunoradiotherapy is tolerable in this population, with further studies required to evaluate efficacy.

(Open Access)

Reference (PubMed Link): Jabbour SK, Berman AT, Decker RH, et al. Phase 1 trial of pembrolizumab administered concurrently with chemoradiotherapy for locally advanced non-small cell lung cancer: A nonrandomized controlled trial. JAMA Oncol 2020;6:1-8.

Key Institution: Multi-Institutional (Royal Marsden Hospital, Institute of Cancer Research, London, UK)
Keywords: Immunotherapy, Chemoradiotherapy, Locally Advanced Non-small Cell Lung Cancer