Shawna T. Chan, BA

In recent years, preclinical studies have demonstrated the potential of radiotherapy to enhance antitumor immune responses when used in combination with checkpoint inhibition immunotherapy. Our retrospective study of 98 patients with advanced nonsmall cell lung cancer treated on the KEYNOTE-001 trial at the University of California, Los Angeles, found that patients who had received previous radiotherapy compared with those who had not received previous radiotherapy had significantly longer progression-free survival and overall survival upon treatment using the anti&ndash;PD-1 antibody pembrolizumab (Keytruda). Additionally, the safety profile of treatment with radiotherapy and pembrolizumab was determined to be acceptable, although close toxicity monitoring is important for management of pulmonary toxicity. While this finding is novel, additional studies will be necessary to translate the current findings into routine clinical use. Furthermore, investigation is underway to elucidate the mechanism behind the synergistic antitumor activities of radiotherapy and immunotherapy, as well as to find the optimal integration of radiotherapy with immunotherapy to improve clinical outcomes.

Nonsmall cell lung cancer (NSCLC) is the leading cause of cancer-related mortality both in the United States and worldwide.

Because standard first-line therapies including surgery, platinum-based chemotherapy, and radiation therapy offer suboptimal rates of disease control, immunotherapy-based approaches offer a promising treatment alternative. Certain tumors exploit the PD-1/PD-L1 pathway by upregulating PD-L1 to inhibit T-cell activity and evade immune-mediated cell death. Therapies that block PD-1/PD-L1 signaling, known as immune checkpoint blockade inhibitors, increase the endogenous antitumor immune response and have shown clinical activity in multiple tumor types, such as NSCLC, melanoma, and renal cell carcinoma.

The KEYNOTE-001 trial demonstrated the safety and efficacy of pembrolizumab (Keytruda), a monoclonal antibody against PD-1, in patients with metastatic NSCLC.

However, responses to immunotherapy, while unprecedented in advanced NSCLC, are still achieved only in less than 20% of patients, highlighting the need to enhance the efficacy of immunotherapy in these patients.

In the present study, Shaverdian et al performed a secondary analysis of 98 patients treated in the KEYNOTE-001 trial at a single institution (University of California, Los Angeles) to compare survival outcomes between patients who had previously received radiotherapy with patients who had not.

The median time of radiotherapy prior to treatment with pembrolizumab was 9.5 months (range, 1.0-106.0). It was found that previous radiotherapy improved the activity of pembrolizumab in patients with advanced NSCLC, as measured by improved progression-free survival (PFS) and overall survival (OS) in patients who had received prior radiotherapy compared with those who had not (4.4 months and 10.7 months, respectively, vs 2.1 months and 5.3 months). Moreover, it was found that patients with prior extracranial radiotherapy had a significantly improved PFS and OS compared with those without prior extracranial radiation therapy (6.3 months and 11.3 months, respectively, vs 2.0 months and 5.3 months), suggesting greater synergy with extracranial radiation therapy. The combination was also associated with an acceptable safety profile with a trend in increase of any pulmonary toxicity and a statistically significant increase in treatment-related pulmonary toxicity. However, there was no increase in grade 3 or higher treatment-related pneumonitis in patients with prior radiotherapy. These findings are consistent with previous preclinical findings that radiotherapy increases the clinical activity of checkpoint inhibition immunotherapy.

Radiotherapy has been shown to stimulate a systemic immune response and ultimately increase tumor recognition and antitumor activity by 3 basic mechanisms: 1) in situ tumor vaccination, 2) T-cell recruitment toward site of irradiated tumor, and 3) increasing tumor cell vulnerability to cytotoxic T cells.

Tumor irradiation induces immunogenic cell death through activation of dendritic cells and subsequent antitumor T-cell activity. Upon exposure to ionizing radiation, tumor cells release apoptotic bodies that act as tumor-associated antigens, as well as damage-associated molecular patterns, which function in danger signaling to the immune system. Together, these processes lead to increased priming and activation of new antitumor T cells, converting the irradiated tumor to an in situ vaccine.

Radiotherapy also triggers the release of T-cellattracting cytokines and cell surface receptors, recruiting additional effector T cells to the tumor site.

Additionally, irradiation leads to temporary overexpression of cell surface receptors apoptosis antigen 1 and major histocompatibility complex class I on the tumor cell, increasing vulnerability to T-cell mediated attack.

Radiotherapy in Combination With Immunotherapy

Preclinical studies suggest that radiation therapy and immune checkpoint inhibitors work synergistically to enhance antitumor T-cell immunity, presumably leading to greater clinical response rates than either treatment modality alone. Inhibition of the PD-1/ PD-L1 axis suppresses tumor evasion of T-cellmediated cell death, while irradiation enhances T-cell repertoire diversity, further increasing lytic activity of cytotoxic T cells.

Additionally, some studies have observed an abscopal effect (abscopus means &ldquo;away from the target&rdquo;) when combining radiotherapy and immunotherapy; sustained anti-tumor responses were observed outside the site of irradiation.

Despite the compelling evidence for a synergy in antitumor effects with the combination of radiotherapy and immunotherapy, there is currently a paucity of clinical evidence to validate these preclinical findings, and thus the combination warrants further investigations.

Results: Pembrolizumab With or Without Prior

Pembrolizumab With or Without Prior Radiotherapy

Our primary objective was to determine whether previous radiation therapy affected PFS, OS, and pulmonary toxicity in patients with advanced NSCLC on treatment with pembrolizumab. Between May 2012 and July 2014, 98 patients with metastatic NSCLC were enrolled and treated in the phase I KEYNOTE- 001 trial at the University of California, Los Angeles; 1 patient was lost to follow-up. Nine (9%) of 97 patients received 2 mg/kg pembrolizumab every 2 weeks, 35 (36%) patients received 10 mg/kg pembrolizumab every 2 weeks, and 53 patients (55%) received 10 mg/kg pembrolizumab every 3 weeks. Median patient age was 65 years (range, 32-83 years). Forty-two (43%) patients had previously received some radiotherapy for treatment of NSCLC before the first cycle of pembrolizumab. Of the 42 patients, 38 received extracranial radiotherapy and 24 received thoracic radiotherapy. Patients with prior radiotherapy had a median 25.9 months (range, 2.6-107.0 months) between initial diagnosis and treatment with pembrolizumab and had received a median of 3 (0-5 therapies) previous unique systemic therapies, while patients with no prior radiotherapy had a median of 17.3 months (range, 0.9-98.2 months) between initial diagnosis and treatment with pembrolizumab and had received a median of 2 (0-5 therapies) previous unique systemic therapies. Eight (19%) patients with prior radiotherapy had a history of central nervous system (CNS) metastases, and 0 patients with no prior radiotherapy had a history of CNS metastases. Baseline patient characteristics are in TABLE 1.

Both PFS and OS were significantly longer in patients with prior radiotherapy compared with patients who had not received any prior radiotherapy, with a median PFS of 4.4 months (95% CI, 2.1-8.6 months) versus 2.1 months (95% CI, 1.6-2.3 months) and a median OS of 10.7 months (95% CI, 6.5-18.9 months) versus 5.3 months (95% CI, 2.7-7.7 months). PFS was determined using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. In a separate analysis of non-CNS radiotherapy only, 38 (39%) of 97 patients received extracranial radiotherapy, and both PFS and OS were significantly longer in these patients compared with patients with no prior extracranial radiotherapy, with a median PFS of 6.3 months (95% CI, 2.1-10.4 months) versus 2.0 months (95% CI, 1.8-2.1 months) and a median OS of 11.6 months (95% CI, 6.5-20.5 months) versus 5.3 months (95% CI, 3.8-8.5 months). This separate analysis was done because the blood-brain barrier may isolate the CNS from the systemic immune system, masking the effect of CNS radiotherapy.

In addition to improved survival outcomes, we also found an acceptable safety profile for previous radiotherapy followed by pembrolizumab administration, with a trend in increase of any pulmonary toxicity, a statistically significant increase in treatment-related pulmonary toxicity, but no increase in serious treatment-related pulmonary toxicity defined as grade 3 or higher pneumonitis.

Fifteen (63%) of 24 patients who previously received thoracic radiotherapy experienced some pulmonary toxicity versus 29 (40%) of 73 patients with no previous thoracic radiotherapy (P = .052), and 3 (13%) patients with previous thoracic radiotherapy had treatment-related pulmonary toxicity versus 1 (1%) patient among those without (P = .046). Significant pulmonary toxicities defined as grade 3 or higher treatment-related pneumonitis occurred in 1 (4%) of 24 patients with previous radiotherapy and 1 (1%) of 73 patients with no previous radiotherapy (P = .44).

Efficacy and Safety of Pembrolizumab With Prior Radiotherapy

Our findings point to the possibility of a synergy between radiation therapy and immunotherapy, which is particularly important for therapeutic agents such as pembrolizumab that already have a relatively low response rate (approximately 20%

) in unselected patients. The level of response to antiPD-1 therapy is correlated with high PD-L1 expression, defined as PD-L1 expression on at least 50% of tumor cells

; however, high PD-L1 expression is found in only one-fourth of patients with advanced NSCLC.

Notably, in the present study, 12 (22%) patients with no previous radiotherapy had PD-L1 expression >50%, versus only 5 (12%) patients with previous radiotherapy who did. Yet patients with previous radiotherapy demonstrated significantly longer PFS and OS despite lower PD-L1 expression, suggesting that radiation may boost the response rate of pembrolizumab among traditional nonresponders. Of note, although patients with prior radiotherapy had significantly more lines of previous systemic treatments and a significantly longer time interval between initial diagnosis and receipt of pembrolizumab, neither factor predicted for PFS. These data and other predictors of PFS and OS are in Table 39 and Table 4.9 Therefore, we attributed the improved clinical outcomes among patients who received previous radiotherapy to enhanced radiation-induced priming of the antitumor immune response, which therefore allowed for greater clinical activity of immune checkpoint blockade with pembrolizumab.

These findings also demonstrate the importance of close toxicity monitoring when combining radiotherapy and immunotherapy. Patients with prior thoracic radiotherapy were found to be at greater risk for any-grade pulmonary toxicity, although the incidence of high-grade pulmonary toxicity did not differ between patients with and without previous thoracic radiotherapy. High-grade pneumonitis, a shared toxicity of antiPD-1 therapy and radiotherapy, is of particular concern for patients with advanced NSCLC whose underlying condition and tumor burden already compromise baseline lung function.

Although all-grade pneumonitis during antiPD-1 monotherapy is relatively rare in patients with NSCLC (estimated incidence of 4.1%), clinicians must be mindful of management strategies to optimize outcomes of combinatorial radiotherapy and immunotherapy.

Prospective clinical trials are necessary to find the optimal dosing and fractionation schedule for radiotherapy, as well as the timing and sequencing of the 2 treatment modalities in order to potentiate the observed effect. Some studies suggest that antiPD-1 administration concurrent with or immediately following radiotherapy maximizes the antitumor immune response

; however, in our present study, radiotherapy was administered a median of 9.5 months (range, 1.0-106.0 months) before the first cycle of pembrolizumab, suggesting the generation of a long-lived immune response. Although our study is limited by its retrospective nature, results of prospective trials would not be available for several years. Our findings urge for continued rigorous investigation in this field to accelerate our efforts at improving outcomes of cancer therapeutics. Currently, various prospective trials evaluating the combination of radiotherapy and immunotherapy are under way (Table 5). One such ongoing trial is the phase I/II NCT03148327 study, led by Lee, testing the combination of radiotherapy with durvalumab, a PD-L1 antibody, in patients with inoperable early-stage NSCLC (https://clinicaltrials.gov/ ct2/show/NCT3148327).

Extensive preclinical data have demonstrated the exciting potential for radiotherapy to enhance anti-tumor immune responses when used in combination with immunotherapy. Our study results, in which patients with previous radiotherapy experienced significantly longer PFS and OS with pembrolizumab treatment versus those with no previous radiotherapy, corroborate these findings. Further investigation is warranted and underway to better understand how radiotherapy and immunotherapy synergize. This revolutionary therapeutic approach holds great promise, and harmonizing this combination may lead to further improvements in clinical outcomes.

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7-30. doi: 10.3322/caac.21387.

Garon EB, Rizvi NA, Hui R, et al; KEYNOTE-001 Investigators. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372(21):2018-2028. doi: 10.1056/NEJMoa1501824.

Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320-330. doi: 10.1056/NEJMoa1412082.

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The investigators discuss their findings that demonstrate patients with previous radiotherapy experienced significantly longer PFS and OS with pembrolizumab treatment versus those with no previous radiotherapy.

Shawna T. Chan, BA | Authors

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