Combining Stereotactic Body Radiation Therapy With Immunotherapy

Current Data and Future Directions

Alexander J. Lin; Michael Roach; Jeffrey Bradley; Clifford Robinson

Disclosures

Transl Lung Cancer Res. 2019;8(1) 

In This Article

Abstract and Introduction

Abstract

Stereotactic body radiation therapy (SBRT) offers excellent local control of early-stage non-small cell lung cancer (NSCLC), but there currently is a need for tolerable systemic therapy to address regional and distant disease progression. One potential option is immunotherapy, which in metastatic NSCLC has shown promise for sustained disease control in a subset of patients. There is also growing evidence for a clinical synergy between radiation and immunotherapy, with several ongoing trials studying the abscopal effect. This review summarizes the current data in the fast-changing field of immuno-radiation therapy, highlighting updates from recent clinical trials.

Introduction

Stereotactic body radiation therapy (SBRT) combines conformal radiation dose-shaping, tumor motion management, and on-board daily imaging to deliver high doses of radiation in five or fewer treatments.[1,2] These technological advances in radiation delivery over the last decade have allowed safer and more effective dose escalation to patients with non-small cell lung cancer (NSCLC). For early-stage, medically non-operable NSCLC, SBRT has become the standard of care.[3] RTOG 0236 established SBRT could achieve an impressive 5-year tumor control rate of 93%,[4,5] with minimal pulmonary toxicity.[6]

However, systemic progression remains problematic. Regional and distant failure rates occur in at least 30% of patients, with even higher rates with increasing tumor size.[5,7–11] Medically inoperable patients often cannot safely receive adjuvant chemotherapy to help with distant control. Immunotherapy, which is better tolerated than chemotherapy,[12] has recently been heralded as the "fourth pillar" of oncologic treatment.[13] Food and Drug Administration (FDA)-approved antibody drugs currently target cytotoxic T-lymphocyte protein 4 (CTLA-4), programmed cell-death protein 1 (PD-1), and programmed death-ligand 1 (PD-L1). Activation of CTLA-4 and PD-1 receptors on T cells downregulates the adaptive immune response. This prevents auto-immunity, but checkpoint inhibition can also be hijacked by tumors seeking to avoid immune surveillance.[14] By targeting these checkpoint inhibitors, immunotherapy has the potential to take the brakes off one's own immune system to seek out and destroy cancer cells.

Immunotherapy has had mixed success in the locally advanced and metastatic NSCLC setting. Nivolumab, a PD-1 inhibitor, was compared in a phase 3 trial to platinum-based chemotherapy for metastatic or recurrent NSCLC with PD-L1 expression ≥5%.[15] There was no difference in progression-free survival (PFS) or overall survival (OS), but patients tolerated nivolumab better (grades 3–4 adverse event 18% vs. 51%). Similarly, ipilimumab, a CTLA-4 inhibitor, did not improve PFS or OS when added to carboplatin/paclitaxel in metastatic NSCLC.[16] In contrast, KEYNOTE 24 tested pembrolizumab, a PD-1 inhibitor, compared to platinum-based chemotherapy in metastatic NSCLC patients with tumor PD-L1 expression ≥50%, and both PFS and OS were significantly improved with a 45% response rate.[17] The PACIFIC trial tested adjuvant durvalumab, a PD-L1 inhibitor, against placebo after definitive chemoradiation for stage III NSCLC.[18] Durvalumab significantly improved median PFS from 5.6 to 16.8 months. The PFS benefit was seen even when the tumor had PD-L1 expression <25%. Atezolizumab, also a PD-L1 inhibitor, improved OS compared to docetaxel in metastatic NSCLC regardless of PD-L1 expression.[19] The overall success of checkpoint inhibitors is tempered by the variable response rate, which may be improved upon when combined with radiation therapy. Several excellent reviews on this subject have been recently published and we refer you to them for additional references.[20–24] In this fast-changing field of immuno-radiation therapy, we will highlight updates from ongoing clinical trials and offer our perspective for future trials.

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