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. 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.
Tumor motion management
RTOG 0236 established SBRT could achieve an impressive 5-year tumor control rate of 93%, with minimal pulmonary toxicity. 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. Medically inoperable patients often cannot safely receive adjuvant chemotherapy to help with distant control.
Immunotherapy, which is better tolerate than chemotherapy, has recently been herald as the “fourth pillar” of oncologic treatment. 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 programme death-ligand 1 (PD-L1). Activation of CTLA-4 and PD-1 receptors on T cells down regulates the adaptive immune response.
Cytotoxic T-lymphocyte protein
This prevents auto-immunity, but checkpoint inhibition can also be hijack by tumors seeking to avoid immune surveillance . 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 advance and metastatic NSCLC setting. Nivolumab, a PD-1 inhibitor, was compare in a phase 3 trial to platinumbased chemotherapy for metastatic or recurrent NSCLC with PD-L1 expression ≥5% . There was no difference in progression-free survival (PFS) or overall survival (OS), but patients tolerate nivolumab better (grades 3–4 adverse event 18% vs. 51%).
Patients tolerated nivolumab
Similarly, ipilimumab, a CTLA-4 inhibitor, did not improve PFS or OS when added to carboplatin/paclitaxel in metastatic NSCLC . 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 are significantly improve with a 45% response rate.
The PACIFIC trial tested adjuvant durvalumab, a PD-L1 inhibitor, against placebo after definitive chemo radiation for stage III NSCLC. 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.
Ongoing clinical trials
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. In this fast-changing field of immuno-radiation therapy, we will highlight updates from ongoing clinical trials and offer our perspective for future trials.