The systemic therapy of metastatic melanoma recently underwent considerable changes due to the introduction of antibodies blocking the immune checkpoints CTLA-4 and PD-1.1 2 Both CTLA-4 (ipilimumab) and PD-1 (nivolumab, pembrolizumab) immune checkpoint inhibitors (ICIs) have been shown to induce durable tumor responses and long-term survival in a subset of patients.3–5 Immunological conditions reflecting an inflamed state of a patient’s tumor such as expression of PD-L1 or presence of tumor-infiltrating lymphocytes were identified as predictive markers of ICI treatment response.6 7 Due to the high proportion of patients with melanoma presenting a primary resistance to ICI therapy, various strategies have been considered to enhance the tumor’s upfront ICI sensitivity. Herein, one promising approach that has been discussed vigorously is the enhancement of tumor immunogenicity by radiation. For various cancer entities including non-small-cell lung cancer (NSCLC),8 9 head-and-neck cancer,10 colon carcinoma11 and sarcoma,12 it has been demonstrated that radiotherapy of tumor lesions generates immune-related abscopal antitumor effects. These effects have been assumed to be mediated by the modulation of the tumor and its microenvironment toward an increased antigen presentation and recognition, leading to an overall improvement of antitumorous immune responses.13 14 In this regard, radiation and ICI therapy were shown to act synergistically in mouse models as well as in clinical trials.9 15–17 A subgroup analysis of the KEYNOTE-001 trial cohort investigating pembrolizumab in metastatic NSCLC showed prolonged survival times in patients who received a radiotherapy of tumor lesions at any time preceding the start of pembrolizumab.8 In melanoma, a variety of small studies and case series led to contradictory results with regard to an effect of radiotherapy on ICI treatment outcome (for review see Ref. 18 and tables 1 and 2). Statistical analyses of larger patient populations that address confounding are lacking, and randomized controlled trials (RCTs) on this topic are difficult to implement.

The present study aimed at investigating the impact of a preceding therapeutic radiation of metastatic lesions on ICI treatment outcome in terms of response and survival on CTLA-4 or PD-1 inhibition in a large multicenter cohort of patients with metastatic melanoma. Since radiotherapy for melanoma is mainly applied to prognostically poor patient groups with advanced metastatic disease such as metastasis to the brain or bone, this study carefully addressed confounding by the use of directed acyclic graphs (DAGs) and inverse probability treatment weighting (IPTW).

We performed a PubMed search for articles published from January 2011 until April 2019. Our search focused on clinical studies investigating a combination or sequencing of radiotherapy and ICI in patients with metastatic melanoma. We selected studies which investigated at least 20 patients, and which reported tumor response, progression-free survival (PFS) or overall survival (OS) as a study endpoint. The used search terms were “melanoma” AND “radiotherapy”, “radiation”, “radiosurgery” AND “PD-1”, “CTLA-4”, “ipilimumab”, “nivolumab”, and “pembrolizumab”. The hereby found reported evidence on radiotherapy combined or sequenced with ICI in melanoma was based on a variety of small clinical studies with low patient numbers (tables 1 and 2). The study results were contradictory, and multivariable adjustments to confounders were lacking in the majority of studies. Data from retrospective studies led to heterogeneous results with some studies finding a beneficial effect of radiotherapy on the outcome of ICI and others do not. Data from RCTs comparing patients treated with immune checkpoint inhibitors with and without radiotherapy were missing. Thus, the clinical impact of a preceding radiotherapy on the treatment outcome of ICI in metastatic melanoma was unclear.

Radiation is a common treatment modality in metastatic melanoma, primarily aimed at the control of difficult to treat or symptomatic metastatic sites such as brain or bone. Since there are no detrimental side effects of interaction described, radiotherapy is often combined or sequenced with immunotherapy in these patients. This combination or sequencing approach gained additional attention from the hypothesis of radiation to act as means of converting immunologically “cold” into “hot” tumor microenvironments, herein functioning as a sensitizer for ICI therapy.16 23 Whether the radiation of tumor lesions prior to the start of ICI can increase ICI treatment efficacy in patients with melanoma currently is a matter of ongoing investigation and intense debate.

For both CTLA-4 and PD-1 inhibition, several case reports exist on patients with melanoma who experienced impressive tumor responses to ICI when combined or sequenced with radiotherapy.24 25 The current evidence on ICI and radiotherapy in melanoma provided by clinical studies on cohorts of >20 patients differs between the two types of inhibitors, anti-CTLA-4 and anti-PD-1 (tables 1 and 2). For anti-CTLA-4, out of 15 studies, 7 did not compare cohorts with and without radiation. Of the remaining eight studies, five demonstrated a prolonged OS (n=5) or an increased BOR (n=3) in patients treated with radiotherapy and ICI combined or sequenced, whereas three studies did not detect such a beneficial effect. For anti-PD-1 ICI combined or sequenced with radiation, out of 10 published studies only 1 compared patient cohorts with and without radiation, revealing a positive impact on BOR but no relevant differences in PFS or OS. The other nine studies investigated different timings and modalities of radiation in relation to anti-PD-1. Notably, approximately half of all studies on radiation and ICI (8/15 anti-CTLA-4; 4/10 anti-PD-1) investigated brain metastases as the only target of radiation, with the majority of these studies focusing on stereotactic radiosurgery. Additionally important, of these 25 clinical studies all but 2 were retrospective. The remaining two prospective studies included small patient numbers only and had no comparator arms. Statistical analyses addressing the important issue of confounders are lacking, mainly due to the small patient numbers analyzed in most of these studies. Taken together, the current clinical data comparing ICI with or without combined or sequenced radiotherapy rely on relatively small retrospective studies, with no implementation of multivariable adjustment for confounders. Results from RCTs adressing this subject are completely missing.

Our present study comprises by far the largest patient cohorts on ICI plus or minus radiation in melanoma to date. In contrast to some of the abovementioned smaller studies, we detected no relevant impact of a preceding radiotherapy on ICI treatment outcome, neither in patients treated with anti-CTLA-4 nor in patients treated with anti-PD-1. In patients treated with anti-PD-1 with no pretreatment with anti-CTLA-4, a possible survival benefit of a previous radiotherapy could not be excluded, while in patients treated with anti-CTLA-4 prior to anti-PD-1, a precedent radiotherapy led to no relevant difference in survival. Regarding tumor response in terms of BOR, our results revealed broad CIs indicating a wide range of potential effects of a preceding radiation. In contrast, for survival in terms of PFS and OS, the narrow CIs found by us showed no evidence that radiotherapy relevantly influenced the rate of progression or death.

The observed discrepancy between published data showing a beneficial impact of a preceding radiation on ICI treatment outcome at least in some clinical studies, and our own data revealing no evidence for such an effect can be primarily explained by the small patient numbers investigated within the previously reported studies (see tables 1 and 2). The largest study comprised 127 patients with only 45 thereof receiving radiotherapy; the majority of the remaining studies investigated cohorts of 10 to 30 patients only. These small patient numbers probably led to unreliable results and hampered the application of multivariable adjustment for confounders. Confounder adjustment is of essential importance to obtain valid effect estimates, as it was applied in our present study. Additionally, the multicenter design of our present study reduces center-induced bias, rendering the present study results superior to those emerging from the previously reported oligocentric or monocentric studies. However, the conclusions drawn by us require validation in RCTs. This is particularly true for the further investigation of sequencing and timing of radiotherapy, since the present study included patients with radiotherapy before ICI therapy only, herein excluding patients with radiotherapy concurrent to ICI.

Notably, different from other cancer entities, melanoma has been demonstrated to react to irradiation not only with unrestricted immune activation leading to beneficial abscopal tumor regressions but also with rapidly evolving resistance mechanisms. Thus, Twyman-Saint Victor and coworkers demonstrated that irradiation of melanoma metastases led to an upregulation of PD-L1 expression of tumor cells and to an increased exhaustion of tumor-infiltrating lymphocytes within these lesions, which both are mechanisms enabling the escape of tumor cells from immune recognition.26

ICI therapy of melanoma has recently been shown to exert high efficacy also in patients with brain metastases.27 28 Our present study cohort comprised a relevant number of patients with brain metastases with or without radiotherapy prior to ICI, allowing us to perform separate analyses of this clinically highly relevant patient population using appropriate adjustment sets of confounders. We did not find a relevant impact of a preceding intracranial radiation on response and survival outcomes of ICI therapy. Moreover, subgroup analyses with regard to the type of preceding intracranial radiotherapy, in terms of conventional whole brain radiation compared with stereotactic radiation, revealed no relevant differences in ICI therapy outcome. However, the wide CIs resulting from our analysis suggest that a possible advantage of a preceding radiotherapy for this patient subgroup cannot be excluded.

Notably, the conclusions drawn from our study results are limited because of its observational nature. The groups of patients with and without previous radiotherapy compared by us differed markedly in their patient and treatment characteristics, which we tried to compensate by multivariate adjustment for confounders. Also, nearly half of the investigated patients who received a preceding radiotherapy had this radiation applied not immediately before start of ICI therapy, but earlier in stage IV disease with at least one intermittent treatment line. However, a comparison of both groups did not show a benefit in ICI treatment outcome for those patients who were irradiated immediately before ICI, but rather revealed that these patients had a poorer ICI therapy outcome. Additionally, it is apparent that the patient cohorts investigated by us are characterized by a shorter PFS and OS compared with survival rates from landmark clinical trials. This can mainly be explained by the inferior treatment outcomes in real-world patient populations compared with the highly selected populations investigated in RCTs.29

The results of the present study indicate no relevant impact of a preceding radiotherapy of metastatic lesions on the therapy outcome of anti-CTLA-4 or anti-PD-1 ICI in metastatic melanoma. Based on our data, the intended use of radiation as a sensitizer for ICI therapy of melanoma can currently not be recommended for routine clinical use. Instead, patients should be preferentially treated within prospective clinical trials adressing the question of synergistic beneficial effects of radiotherapy and ICI, either simultaneously or sequentially applied. There are various RCTs planned or already activated investigating this effect (for overview see Refs 15–17 and https://clinicaltrials.gov/). However, recruitment of patients into these trials is difficult, leading to a slow trial progress with results pending for a longer term. Until data from RCTs become available, the results of our present multicenter cohort study is the most valid information to guide clinicians toward the sequencing of radiotherapy and ICI in metastatic melanoma.