Radiotherapy and Immunotherapy Combinations in the Treatment of Patients with Metastatic Disease: Current Status and Future Focus

A growing body of literature supports the hypothesis that metastasis-directed radiotherapy delays progression and confers a survival benefit to a select group of patients with metastatic cancer (1–5). Immunotherapy has also been demonstrated to improve outcomes among subsets of patients with metastatic disease and has changed the standard of care for many malignancies (6). Immunomodulatory effects of ionizing radiation are currently under investigation and therefore, combined treatment with radioimmunotherapy has been proposed as a method of optimizing outcomes in patients with metastatic disease. Here, we review clinical studies that examine the treatment of metastatic disease with radiotherapy and immunotherapy, individually and in combination, and suggest future avenues for investigating the role of radioimmunotherapy.

Radiotherapy has historically been used with palliative intent in patients with metastatic cancer; however, mounting evidence suggests that radiotherapy may play a role in the curative management of certain patients with metastasis. Several recently completed randomized phase II trials support the hypothesis that metastasis-directed radiotherapy delays progression and may confer a survival benefit in select groups of patients (1–5). Nonrandomized prospective series with extended follow-up suggest that durable disease control can be achieved following ablative radiotherapy to all sites of metastatic disease (7–9). Clinical studies supporting the benefit of metastasis-directed radiotherapy are heterogeneous, and exclusively focus on patients with few sites of disease (typically ≤ 5 metastases). Ongoing phase III trials are investigating the role of metastasis-directed radiotherapy in patients with 1–3 metastases (NCT03862911) and 4–10 metastases (NCT0372134) separately and additional phase III trials of metastasis-directed radiotherapy include burden of disease as a stratification factor (NCT02364557, NCT03137771).

Immunotherapy plays an important role in the management of a subset of patients with metastatic cancer, including patients with metastatic melanoma and non–small cell lung cancer (NSCLC), among other histologies. Among patients with metastatic melanoma treated with pembrolizumab on KEYNOTE-001, 5-year overall survival (OS) was 34% in all patients and 41% in treatment-naïve patients (10), which represents a dramatic improvement in outcomes as compared with previous systemic therapies for this disease (11). More recent data from patients with advanced melanoma treated with nivolumab and ipilimumab resulting in a 5-year OS of 52% (12) support the conclusion that immunotherapy can provide long-term disease control for a subset of metastatic patients. Likewise, in patients with metastatic NSCLC treated on KEYNOTE-189, the addition of pembrolizumab to chemotherapy (pemetrexed and platinum) resulted in a 2-year OS of 46%, compared with 30% in patients treated with chemotherapy alone [HR, 0.56 (95% confidence interval, CI: 0.45–0.70)] (13). Nonrandomized data from patients treated with pembrolizumab for metastatic NSCLC with a PD-L1 tumor proportion score ≥ 50% demonstrate 5-year OS of 30% and 25% in treatment-naïve and previously treated patients, respectively (14), further supporting the potential for durable disease control in a subset of metastatic patients treated with immunotherapy.

Analogous to the impact of metastasis-directed radiotherapy, the efficacy of immunotherapy is greatest in the setting of low-volume disease. On secondary analysis of KEYNOTE-001, patients with less than the median baseline tumor size (summed diameter < 10.2 cm) were noted to have an improved overall objective response rate (ORR; 44% vs. 23%; P < 0.001) and OS (HR, 0.38; P < 0.001; ref. 15). Further evidence that immunotherapy is most effective in low-volume disease is observed in the adjuvant setting after local therapy for nonmetastatic disease. Among patients who underwent complete resection of high-risk stage III cutaneous melanoma on KEYNOTE-054, patients treated with adjuvant ipilimumab had a significantly improved 5-year OS compared with patients receiving placebo (65% vs. 54%; P = 0.001; ref. 16). Moreover, in the IMMUNED trial, patients with advanced melanoma with no evidence of residual disease following local therapy had a significantly improved 2-year recurrence-free survival following treatment with ipilimumab and nivolumab [70% (95% CI: 61–85)] compared with patients treated with placebo [14% (95% CI: 6–26)] or nivolumab alone [42% (95% CI: 29–55)] (17). Likewise, the PACIFIC trial demonstrated that 3-year OS was significantly greater with the addition of durvalumab among patients without evidence of progression of disease following definitive chemoradiotherapy for locally advanced NSCLC [57% (95% CI: 52–61)] compared with those receiving placebo [44% (37–50)] (18). Similar results have also been seen in patients with esophageal/gastroesophageal junction cancer treated with neoadjuvant chemoradiotherapy followed by surgery on CheckMate 577, where the addition of adjuvant nivolumab significantly improved disease-free survival compared with placebo [HR, 0.69 (96.4% CI: 0.56–0.86); P < 0.001] (19). These data from the adjuvant setting represent some of the most successful demonstrated applications of immunotherapy, further supporting the idea that the efficacy of immunotherapy is highest in the setting of low-volume disease. Thus, although data supporting the treatment of patients with metastatic disease using either radiotherapy or immunotherapy are seemingly disparate, both therapies have increased efficacy in patients with low disease burden. These results are analogous to those observed with chemotherapy and radiotherapy generally.

Given the individual efficacies of radiotherapy and immunotherapy and the proposed immunomodulatory effects of radiotherapy, the combination of radiotherapy and immunotherapy has been suggested as a strategy to improve outcomes in patients with metastatic disease. Initial studies investigated whether the combination of radiotherapy and immunotherapy impacts unirradiated (abscopal) or local irradiated tumor responses. Unlike the adjuvant setting, in which immunotherapy is used as a means to increase immune surveillance to eliminate subclinical residual disease and prevent disease recurrence, in this setting immunotherapy is aimed at potentiating distant responses. Demaria and colleagues initially proposed that abscopal effects following radiotherapy are mediated by T cells (20) and accordingly later demonstrated in murine mammary carcinoma models that the combination of radiotherapy and CTLA-4 blockade inhibited development of lung metastases (21). A number of preclinical data have subsequently demonstrated the potential for abscopal responses following radioimmunotherapy. For instance, in melanoma and renal cell carcinoma mouse models, the combination of radiotherapy with programmed cell death protein 1 (PD-1) blockade resulted in a 66% reduction in the size of tumors outside of the irradiated field (22). Other studies utilizing murine carcinoma models have similarly demonstrated the potential for radioimmunotherapy to induce significant out-of-field responses (23, 24).

In contrast to preclinical models, robust abscopal responses are rarely observed in clinical metastases (25). Postow and colleagues described a case in which a patient being treated with ipilimumab for metastatic melanoma received radiotherapy to a progressing paraspinal metastasis and subsequently had an impressive response in unirradiated metastases (26). A number of subsequent prospective studies have sought to replicate these findings by combining immunotherapy with radiotherapy directed at a single metastatic site. In a study reported by Golden and colleagues, patients with solid metastatic tumors with ≥ 3 metastases were treated with radiotherapy (35 Gy in 10 fractions) to one metastasis in combination with GMCSF (27). Responses in unirradiated metastases were noted in 11 of 41 enrolled patients, with 8 of the 11 patients with out-of-field responses having three lesions at baseline and the additional 3 patients having 4–6 lesions at baseline (27). [Of note, there is no consensus definition regarding what constitutes an abscopal response though in this study a decrease in the longest diameter of any measurable nonirradiated lesion by ≥ 30% was considered an abscopal response; this differs from the summed change in index lesion diameter used for RECIST (28) or the modified response criteria used to capture later responses that are common in patients treated with immunotherapy, immune-related response criteria (29)]. As described in Table 1, comparative studies reported by McBride and colleagues (30), Moreno and colleagues (31), and Theelen and colleagues (32) similarly investigated radiotherapy targeted at one metastasis in combination with immunotherapy. In each of these of these phase II studies, patients received PD-1 blockade alone or in combination with metastasis-directed radiotherapy. Notably, none of these studies demonstrated significant improvements in ORR, progression-free survival (PFS), or OS with the addition of radiotherapy to immunotherapy. Considered together, these studies suggest that laboratory studies may not faithfully reproduce aspects of clinical interactions between radiotherapy and immunotherapy and that abscopal effects may not be as common in humans as preclinical models suggest.

In contrast to studies targeting a single metastasis with radiotherapy, a number of prospective studies have combined multi-site metastasis-directed radiotherapy with immunotherapy. In a study reported by Luke and colleagues, 73 patients with a variety of advanced solid tumors were treated with 30–50 Gy in 3–5 fractions to 2–4 metastases prior to pembrolizumab, yielding an out-of-field response (≥ 30%) in one or more metastases in 27% of patients (33). Although the authors were encouraged by the 2-year OS of patients in this study of nearly 20% (34), it is possible that these results may have been achieved with treatment with immunotherapy alone. Randomized studies by reported by Curti and colleagues (35), Mahmood and colleagues (36), and Welsh and colleagues (37) also investigated the use of multi-site metastasis-directed radiotherapy in combination with immunotherapy, as detailed in Table 1. In these studies, the addition of metastasis-directed radiotherapy did not increase ORR, PFS, or OS compared with systemic therapy with IL2 (35) or pembrolizumab alone (36, 37). It is of note that an unplanned pooled analysis of the studies by Theelen and colleagues and Welsh and colleagues demonstrated improved PFS (4.4 vs. 9.0 months, P = 0.045) and OS (8.7 vs. 19.2 months, P < 0.001) with the addition of radiotherapy to immune checkpoint blockade (ICB; ref. 38). Radioimmunotherapy has also been investigated in the context of multi-site metastasis-directed radiotherapy targeting all sites of metastatic disease. In a nonrandomized phase II study reported by Bauml and colleagues, locally ablative therapy (surgery, radiotherapy, chemoradiotherapy, or interventional ablation) to all sites of disease (≤ 4 metastases) was combined with pembrolizumab in 45 patients with metastatic NSCLC yielding 2-year PFS of 56% and 17% in patients with metachronous and synchronous metastatic disease, respectively [HR, 1.98 (95% CI: 0.87–4.52)], and a significant improvement in the primary endpoint of the study, median PFS from time of locally ablative therapy compared with historical outcomes (19.1 months vs. 6.6 months, P = 0.005), with several patients surviving greater than 3 years following the completion of locally ablative therapy (39).

Overall, the results of prospective studies investigating the use of radioimmunotherapy in patients with metastatic disease are not conclusive. Beyond the number of metastases targeted with radiotherapy, several additional variables exist in the design of currently reported studies of radioimmunotherapy in metastatic patients. Thus, data examining radioimmunotherapy in patients with metastatic cancer should be further considered in the context of a number of tumor and treatment-related factors.

Although the majority of studies of radioimmunotherapy in metastatic patients have required at least one metastasis to be unirradiated (27, 30–33, 35–37), a number of preclinical and translational data support the rationale for treating all sites of metastatic disease with radiotherapy, similar to the approach in the study reported by Bauml and colleagues (39). High doses of radiotherapy have been demonstrated to kill resistant tumor clones and increase tumor T-cell infiltration and priming without killing radioresistant tumor-reprogrammed resident T cells (40–42). In addition, radiotherapy has been demonstrated to enhance MHC class I (MHC-I) expression (43) and induce and/or upregulate the expression of genes containing immunogenic mutations and nonmutated genes that are immunogenic when overexpressed (44). Given that downregulation of MHC-I is known to be an important mechanism of tumor immune evasion (45) and that tumor neoantigens have been demonstrated to drive response to ICB (46), it is plausible that antitumor immune response may be enhanced in irradiated metastases. An interesting observation noted by Luke and colleagues was that partial irradiation of large metastases did not result in inferior local control compared with targeting the entire tumor (33). Thus, is possible that the potential benefits of using radiotherapy targeted at all sites of disease in combination with immunotherapy may be attainable even if treating the entire volume of each metastasis is not feasible. However, it should be noted that given that approximately 80% of the patients in this study had expired within 2 years of treatment, the definitive conclusions that can be derived from this observation are limited. Nonetheless, it is hoped that future technical advances in radiotherapy will increase the number of tumors that can be treated to a curative dose.

In contrast to tumor-reprogramed resident T cells, T cells in lymphoid organs are radiosensitive (41). Draining lymph nodes have been demonstrated to be essential for the accumulation and priming of T cells induced in response to ionizing radiation (47) and thus it is feasible that nodal irradiation may decrease antitumor immune response. Consistent with this finding, a study in which mice were treated with concurrent ICB and radiotherapy to either tumor alone or tumor and draining lymph nodes found that inclusion of the draining lymph nodes in the irradiated field resulted in lower levels of immunostimulatory chemokines and tumor-specific CD8⁺ T cells, as well as worse OS (48). In addition, in contrast to randomized trials that have demonstrated improved outcomes with the addition of ICB to chemoradiotherapy in patients with locally advanced NSCLC (18) and esophageal cancer (19), similar trials for patients with locally advanced head and neck cancer have not been successful (49, 50). While a number of differences in trial design and populations examined in these studies could potentially explain their disparate results, it is conceivable that this discrepancy could be explained by the immunosuppressive effects of elective nodal irradiation in the head and neck cancer studies. Similarly, given that radiotherapy-induced lymphopenia is associated with a poor prognosis and decreased response to ICB (51, 52), minimizing the volume of bone marrow irradiated may be an important consideration in patients treated with radioimmunotherapy (53).

Although several comparative studies have utilized radiotherapy doses of 24–30 Gy given in 3–5 fractions (30–32, 36) a number of other dose/fractionation schemes have been utilized in randomized studies of radioimmunotherapy in metastatic patients. Notably, the study reported by Curti and colleagues, utilized either 1 or 2 fractions of 20 Gy (35), while patients in the study reported by Welsh and colleagues were treated with 48 Gy in 4 fractions if deemed clinically feasible (n = 19) and otherwise were treated with 45 Gy in 15 fractions (n = 21; ref. 37). Dose and fractionation are similarly heterogeneous in the reported noncomparative studies of radioimmunotherapy in patients with metastatic disease (27, 33). Consistent with these varied approaches, the radiotherapy dose and fractionation scheme most likely to optimize the benefit of radioimmunotherapy remains unclear. In patients treated with metastasis-directed radiotherapy alone, ablative doses have been demonstrated to be crucial to achieve high rates of local control (54). In addition, it has been demonstrated that type 1 IFN produced in response to high doses of ionizing radiation is important for radiotherapy-mediated tumor control (40, 55). However, it is of note that large radiotherapy doses may attenuate radiotherapy-induced tumor immunogenicity via induction of the DNA exonuclease TREX1 (56), which in some instances has been correlated with decreased expression of cytolytic T-cell genes and inferior irradiated tumor local control following radiotherapy and ICB (34). Thus, further investigation is required to better delineate the ideal radiotherapy dose and fractionation scheme for metastatic patients treated with radioimmunotherapy.

Most of studies of radioimmunotherapy in metastatic patients have utilized ICB agents targeting either PD-1 (30–33, 36, 37, 39) or CTL-associated protein 4 (CTLA-4; refs. 57, 58). Among studies investigating combined radiotherapy and ICB, the sequencing of these therapies is variable. Nonrandomized series have suggested that treatment response and OS are improved with concurrent radiotherapy and ICB compared with sequential therapy (59, 60). In addition, preliminary data from a phase I trial in which patients with metastatic NSCLC treated with multi-site ablative radiotherapy were randomized to receive either concurrent or sequential ipilimumab and nivolumab suggest that concurrent ICB results in fewer dose-limiting toxicities and improved cytoreduction (61). However, the ideal sequencing of radioimmunotherapy remains largely unclear and likely depends upon a number of factors including the immunotherapy agent utilized, radiotherapy dose/fractionation, and the clinical scenario. Thus, future studies are necessary to better delineate the ideal immunotherapy modality and timing relative to radiotherapy in metastatic patients treated with radioimmunotherapy.

Antagonistic effects of radiotherapy and immunotherapy may, at least in part, account for the heterogeneous results of trials of radioimmunotherapy in patients with metastatic disease. Despite the rationale for combining radiotherapy and immunotherapy, which has been detailed previously (62), a number of potentially antagonistic effects may prevent these therapies from acting synergistically. IFN induced in response to high-dose radiotherapy has been demonstrated to result in an immune cascade that is important for tumor control (55); however, prolonged IFN signaling has also been shown to result in resistance to T cell–mediated cytotoxicity (63). Factors secreted into the tumor microenvironment following radiotherapy can also result in an efflux of immunostimulatory cells and attract immunosuppressive cell populations (20, 40). In particular, high levels of infiltrating regulatory T cells (Treg) following radiotherapy have been demonstrated to suppress antitumor immune response, resulting in poor clinical outcomes (64, 65). Moreover, Tregs enhance the function of tumor-associated myeloid cells including M2-like tumor-associated macrophages and myeloid-derived suppressor cells, both of which have been shown to negatively impact disease control following radiotherapy (66, 67). One hypothesis is that immunomodulatory effects of ionizing radiation are complex and likely simultaneously important for tumor control, but also potentially detrimental if prolonged, much the same way that acute inflammation in response to a foreign pathogen is adaptive but can also become disastrous if unabated. Thus, additional strategies aimed at negating the immunosuppressive effects of radiotherapy while preserving antitumor response require further investigation and may be important to maximize the therapeutic ratio of radioimmunotherapy in metastatic patients.

Radiotherapy and immunotherapy have been demonstrated to be effective when used together, most convincingly so in the adjuvant setting. However, the role of immunotherapy in this setting, differs from its application in the metastatic setting and these data do not necessarily imply a positive interaction between radiotherapy and immunotherapy. Some trials to date do suggest an interaction occurs in a subset of patients; however, this population seems relatively small and more work needs to be done to allow consistent identification of these patients. Radiotherapy and immunotherapy seemingly provide the largest benefit to metastatic patients with low-volume disease. Although a variety questions remain regarding the optimal strategies for combining radiotherapy and immunotherapy in metastatic patients, data seemingly support the benefit of targeting all sites of metastasis to reduce tumor burden. Given that patients with oligometastatic disease inherently have a low disease burden that is likely to be amenable to metastasis-directed radiotherapy to all sites of disease, patients with oligometastatic disease may be best suited for future studies of radioimmunotherapy.

Initially proposed by Hellman and Weichselbaum in 1995, the oligometastatic hypothesis postulates the existence of a state characterized by limited disease burden that has metastasized distantly and a slow rate of progression (68). Pending the results of ongoing phase III trials, preliminary data suggest that patients with oligometastatic disease may benefit from metastasis-directed radiotherapy. Although durable disease control can be achieved following ablative radiotherapy to all sites of metastatic disease in a subset of patients, immunotherapy may serve as a strategy to eradicate subclinical disease and improve outcomes in the remaining patients. Thus, future studies investigating the role of radioimmunotherapy in the management of metastatic patients should focus upon patients with oligometastatic disease.

In addition to the volume and rate of metastatic progression, timing of metastasis, histology, and lymph node status, among other factors, have been demonstrated to be prognostic in patients with purported oligometastatic disease (69–71). Recent work has also identified molecular factors associated with oligometastatic versus polymetastatic progression (71) and an integrated molecular classification scheme has been demonstrated to successfully stratify patients with hepatic colorectal cancer metastases by risk of failure following metastasectomy (72). Thus, these molecular and clinicopathologic factors will be important considerations in the design and interpretation of future studies of radioimmunotherapy in patients with oligometastatic disease, as will be the identification of novel biomarkers that more clearly delineate the oligometastatic state. Moreover, future work will need to delineate the ideal radiotherapy dose/fractionation, immunotherapy agents, and sequencing of radiotherapy and immunotherapy in patients with oligometastatic disease treated with radioimmunotherapy. In addition, studies are needed to investigate methods to overcome known antagonistic effects of radiotherapy and immunotherapy as well as novel targets to increase the efficacy of these therapies, such as the microbiome, which has been shown to impact both response to ICB (73) and radiotherapy-induced antitumor immune response (74, 75).

In conclusion, both radiotherapy and immunotherapy have been shown to improve outcomes in select patients with metastatic cancer. Despite rationale supporting the potential utility of treating metastatic patients with radioimmunotherapy, the design and results of preliminary investigations of this therapeutic approach have been heterogeneous. Future studies investigating the role of radioimmunotherapy in the management of metastatic patients should focus upon patients with oligometastatic disease.

R.R. Weichselbaum reports other support from Boost Therapeutics, Immvira LLC, Reflexion Pharmaceuticals, Coordination Pharmaceuticals Inc., Magi Therapeutics, Oncosenescence, Aettis Inc., AstraZeneca, Coordination Pharmaceuticals, Genus, Merck Serono S.A., Nano proteagen, NKMax America Inc, Shuttle Pharmaceuticals, and Highlight Therapeutics; grants from Varian and Regeneron; and personal fees from AstraZeneca, Boehringer Ingelheim LTD, and Merck Serono S.A. outside the submitted work. No disclosures were reported by the other authors.

We would like to acknowledge the Ludwig Cancer Research Foundation and the Foglia Family Foundation for their funding support.