Many patients with stage III lung cancer were ineligible for concurrent CRT, medically unsuitable or refused to chemotherapy. The prognosis of these patients received RT alone was poor. Immune checkpoint blockade is an exciting treatment option for cancer. It has been demonstrated that immune checkpoint inhibitors and radiation had a synergistic effect. The mechanisms of radiation enhancing immunotherapy include increased tumor antigen release, augmented antigen presentation, activation of innate immune pathways, increased T-cell infiltration, and modulation of immunosuppressive cells. 7,8 The safety and efficacy of this combination have also been confirmed in metastatic solid tumors. But it is still unclear how this combination can be used in the curative setting.
The case series demonstrating the effect of curative radiation and anti-PD-1 immunotherapy in patients with stage III unresectable NSCLC. Limited by the short follow-up time and small sample size, we still found the potential effect of this treatment. All patients had no local-regional recurrence. The case series only received 5 cycles of pembrolizumab treatment, but the responses maybe long-lasting. The efficacy of immunotherapy in which a significant tumor regression would translate into extension of overall survival. Previous research have demonstrated the synergistic efficacy of high-dose fractionated radiotherapy combined with anti–PD-1 therapy16. Current data from our experience showed conventionally fractionated radiotherapy also has synergistic effect with anti–PD-1 antibody. Due to lack of direct comparison, the optimal fraction scheme in combination with anti–PD-L1 therapy needs further investigation. This case series may play an important role for future clinical trial design, since most patients received conventionally fractionated radiotherapy in clinical practice.
Although the CRT was the standard treatment of NSCLC patients with stage III, the treatment toxicity was obvious, with 42% grade 3 acute toxicities, 25% grade 3 late toxicities1. About 20% patients could not complete the concurrent treatment. In the present case series, the pembrolizumab can be safely added to radiotherapy without an increase in the toxicity profiles. No patient experienced ≥ grade 3 AE, and no patient discontinued treatment because of an AE.
Immunohistochemistry assay for PD-L1 expression remains the current standard for identifying patients with NSCLC who are more likely to benefit from immunotherapy9. Many prospective trials have demonstrated a correlation between the level of tissue PD-L1 expression and clinical efficacy. However, not all patients with high PD-L1 expression respond to therapy, and some patients with low or no expression of PD-L1 also achieve benefit. In this case series, the Case #1 patient with no expression of PD-L1 still demonstrate a durable clinical benefit from the treatment of pembrolizumab plus radiation. Currently, PD-L1 still remains a controversial biomarker with some limitations: differences in testing platforms, the use of different cutoff points for different immunotherapy agents, and the heterogenous expression within tumors. Compared with monotherapy, it is more difficult to identify which patients may derive the benefit from combined immunotherapy. In addition to PD-L1 expression, high microsatellite instability (MSI), DNA mismatch repair deficiency (dMMR), and high tumor mutational burden (TMB) also approved as biomarkers of immunotherapy10. Clinical studies with larger samples are required to develop suitable biomarkers for predicting toxicity and sensitive of radiation plus immunotherapy response.