Oligometastasis and local ablation in the era of systemic targeted and immunotherapy

Most of the available data are retrospective experiences on patients with brain oligorecurrence treated with radiosurgery (SRS) or hypofractionated RT. Chen et al. analyzed 37 NSCLC patients treated with SRS for brain metastases in combination with different checkpoint inhibitors. Data on these patients are enclosed in a larger series analyzing also patients with melanoma and renal cancer. Interestingly, the authors demonstrated that patients receiving RT concomitantly with immunotherapy had a longer OS (24.7 months) if compared with patients receiving both treatments but not concurrently (14.5 months). No increased rates of immune-related adverse events or acute neurologic toxicity were reported [15]. No safety concerns came also from a recent study by Verma et al. of thoracic RT combined with immunotherapy. In the 60 patients treated with 50 Gy/4 fractions or 60 Gy/10 fractions and concurrent Ipilimumab or Pembrolizumab, no patient experienced grade 4 adverse events, while 34 grade 3 events in a total of 15 patients were recorded. No difference in terms of toxicity was detected in patients receiving pembrolizumab or ipilimumab. Efficacy data are pending [16].

Concerning prospective data, two phase II trials combining RT and IT were recently published.

The Pembro-RT trial [17] enrolled NSCLC patients with at least 2 metastases (upper limit was not specified). Patients were randomized to receive Pembrolizumab or Pembrolizumab + SBRT to a single metastatic site, in order to increase the likelihood of abscopal effect. The dose chosen for SBRT was 24 Gy in 3 fractions, based on preclinical data suggesting that this schedule could increase the synergism between RT and the immune system [18]. The primary endpoint of the study was not reached, however experimental arm performed better than control arm for all endpoints. Objective response rate at 12 weeks was doubled (36% vs 18%), median PFS and OS were also improved (6.6 months and 15.9 months respectively). Addition of SBRT to Pembrolizumab did not increase toxicity.

Bauml et al. [19] conducted a single arm phase II trial specifically focused on oligometastatic NSCLC (less than 4 metastatic sites) patients treated with local ablative therapies (including SBRT in 30 patients) on all sites and Pembrolizumab. Median PFS from local therapy was 19.1 months and median PFS from starting of Pembrolizumab was 18.7 months. Both results were significantly better than the historical control reporting a PFS of 6.6 months. Overall survival rate at 12 and 24 months was 90.9 and 77.5%. Again, no safety concern emerged.

A summary of the main studies combining high dose RT and immunotherapy is reported in Tables 1 and 2.

A phase II study enrolled 24 unselected NSCLC patients with six or fewer sites of extracranial progression after first line chemotherapy. All were then treated with Erlotinib and SBRT, obtaining a median PFS and OS of 14.7 and 20.4 months. Upon progression, only three of 47 measurable lesions recurred within the SBRT field [23].

Qiu et al. analyzed data from 46 patients, treated with local therapies (all but two with RT) and continuing the same TKI. Twenty-four (52.2%) patients were treated for brain metastases, 16 (34.8%) patients for lung metastases, and 6 patients for bone metastases. The median overall and progression-free survival after the local treatment were 13.0 and 7.0 months, respectively. The 2-year OS was 65.2% [24].

Borghetti et al. analyzed 106 patients treated with RT concomitant to TKIs (EGFR or ALK inhibitors). Almost half of these patients were defined as oligometastatic/oligoprogressive patients. Sites of RT were brain, bone, lung or others in 46, 27, 14 and 13%, respectively. OS at 1 and 2 years in oligometastatic/oligoprogressive patients were 79 and 61.8%, respectively [25].

Rossi et al. reported on 131 patients experiencing disease progression during first-line Afatinib or Gefitinib. Thirty of these patients received local therapy with high dose RT and continued the same drug. Median overall survival resulted longer in these patients when compared with patients continuing TT beyond progression or patients switching to another systemic therapy (p < 0.0001). There was also a trend towards a longer second progression-free survival (measured from the time of first progression until second progression) (p = 0.06) [26]. A different approach has been studied by Xu and colleagues. They anticipated the local consolidation in oncogene driven NSCLC patients after few months of TKI, without waiting for the unavoidable progression. Patients were divided into 3 groups: 51 patients received consolidative therapy to all residual disease, 55 patients received consolidative therapy to either primary tumor or oligometastatic sites, while 39 patients did not receive any local treatment. The median PFS was improved in the first group when compared to other groups, 20.6, 15.6, and 13.9 months, respectively (P < 0.001). The median OS were 40.9, 34.1, and 30.8 months in the three groups, respectively (P < 0.001). Of note, the difference was statistically significant between patients treated to all residual disease, while it was not significant between patients who receive a partial local treatment and patients who did not receive any local therapy at all [27].

Finally, concerning the safety profile of the combination between EGFR or ALK inhibitor and high dose RT, none of the available studies showed a significant increase in side effects [28].

A summary of the main studies combining high dose RT and Target Therapy is reported in Tables 3 and 4.

Different retrospective studies have demonstrated an OS and/or intracranial control benefit of immune checkpoint inhibitors when used in combination with SRS for the treatment of melanoma brain metastases. In their mono-institutional analysis, Qin and colleagues [32] found a trend toward improved OS in advanced melanoma patients receiving Ipilimumab and ablative radiotherapy. An increased response duration was observed when RT was delivered after immunotherapy, while toxicity rates did not undergo substantial changes.

A large retrospective analysis made at Johns Hopskins hospital [15] and including patients diagnosed with brain metastases from different primary tumors, who underwent SRS with and without concurrent therapy with Immunotherapy, found a lower incidence of new intracranial metastases in those who received the combined treatment, with favorable survival outcomes and limited side effects. These last results are consistent with the ones from Diao et colleagues [33], which found a substantial improvement in median OS for patients with brain metastases treated with SRS and Ipilimumab. Four cases (17%) of acute neurologic toxicity > G2 and 4 cases (17%) of late radiation necrosis were reported.

The association between SRS and the anti-PD-1 Pembrolizumab also showed its efficacy in a retrospective study from MSKCC [34], with a marked reduction in the size of melanoma brain metastases at the time of first follow-up.

Concerning extracranial disease localization, Gabani et al. [35] found that the addition of SBRT to immunotherapy in an unselected patient population does not seem to be beneficial if compared with immunotherapy alone. More specifically, irradiation to bone metastasis was found to be associated with worse OS than those treated with Immunotherapy alone. The only significant association with improved OS was found for patients who received early SBRT to soft tissue metastases (at least 30 days before starting immunotherapy).

A summary of the main studies combining high dose RT and immunotherapy is reported in Tables 5 and 6.

Wolf and colleagues [39] reported the results of one of the first prospective experiences on the association of SRS with BRAF inhibitors in the treatment of melanoma patients who developed brain metastases. Overall survival was increased in patients harboring BRAF mutation (who received both therapies) compared to BRAF-wild type patients. The combined therapy was found to be safe, with no difference in terms of intracranial hemorrhage events between patients who were treated with systemic agent and those who also received SRS.

Several retrospective experiences on the combo SRS-target therapy were reported in the recent years. In their institutional analysis, Ahmed et al. [40] describe the outcomes of melanoma brain metastases treated with SRS and various systemic and targeted agents. Patients who received BFAF/MEK inhibitors or anti-PD-1/anti-CTLA-4 therapies had improved OS over patients who were treated with conventional chemotherapy on multivariate analysis from the date of SRS; significant difference was also noted on the rate of distant metastases control.

Gaudy Marqueste [41] provided other insights on the safety of the association between SRS and BRAF inhibitors. According to their analysis, the authors suggest not to withhold concomitant administration of Vemurafenib or Dabrafenib during SRS, while this precaution can still be valid in the case of other radiotherapy techniques, including Whole Brain Radiotherapy (WBRT), which implicate larger areas of healthy brain irradiation.

However, these data are not concordant with those reported by other authors. In fact, increased hemorrhage risk was noted by Ly et al. [42] in a subgroup of melanoma patients metastatic to the brain who received SRS together with BRAF inhibitors, despite the improved local control rates. Patel et al. noticed higher rates of both symptomatic and radiographic radiation necrosis in the same setting of patients [43].

We currently have fewer data concerning the role of SBRT in patients diagnosed with extracranial metastatic melanoma and undergoing BRAF inhibitors. Franceschini et al. [44] have reported that such therapeutic strategy is feasible and well tolerated, even though survival outcomes remain insufficient; however, LC of the irradiated lesions showed a significant impact on OS.

A summary of the main studies combining high dose RT and Target Therapy is reported in Tables 7a, b.

Clinical evidences reporting on the combination of SBRT with Immunotherapy in mRCC are poor. Xie et al. [48] showed a systemic complete response to SBRT and Pembrolizumab in a patient affected by mRCC. SBRT consisted in the administration of 4 consecutive fractions up to a total dose of 32 Gy to a mediastinal enlarged lymph node compressing the esophagus. Matsushita et al. [49] recently reported on two patients with mRCC who received Nivolumab combined with external irradiation and obtained a marked reduction of metastatic diseases, including non-irradiated lesions, after being refractory to prior treatment with multiple targeted agents. Taken together, these experiences could suggest that it might be worthwhile to consider the addition of SBRT for oligometastatic RCC patients treated with checkpoint inhibitors, due to the additive or synergistic effects of this combination.

The available experiences regarding target therapies and high doses RT included both brain and extracranial mRCC. Cochran et al. [50] demonstrated a better local control for combined approach when compared to local therapy without targeted agents. In fact, the 1-year local control was 93.3 and 60% for patients treated with and without targeted agents, respectively. Contrarily, Verma et al. [51] has observed no improvement of local control with TKIs added to local brain therapy (surgery, SRS). Different patient populations across the studies [50, 51] (patients with brain metastases at relapse in the Verma series), well reflected in very different median survival rates (5.4 and 16.6 months, in Verma and Cochran series, respectively), might at least partially explain these contradictory results.

The studies on extracranial mRCC are not conclusive about the potential benefit of adding SRT to target therapy. In a recent phase I/II study including 13 patients treated with Pazopanib and SBRT local control and response rates outside the radiation field were good but seemed not to be superior when compared to SBRT or Pazopanib in monotherapy [52]. Contrarily, Dengina et al. [53] observed in a small phase 1b Volga Study (VEGFR inhibitor or mTOR inhibitor or checkpoint inhibitors and SRT) that the difference in response in the target and control metastases evaluated by a mean size of the lesions before and at 2 months after SBRT was statistically significant (p < 0.01). Miller et al. [54] demonstrated in the multivariate competing risks regression that concurrent first-line TKI treatment was independently associated with a local control benefit (HR 0.21, p = 0.04), while patients treated with TKIs alone experienced an increased rate of local failure (HR 2.43, p = 0.03). Franzese et al. [55] showed in univariate and multivariable analyses that metachronous and single metastasis but non addition of target therapy predicted better progression-free survival. However, when the analysis was restricted to cells clear RCC cases only, target therapy performed before SBRT improved local control (HR 0.15, 95% CI 0.026–0.085, p = 0.032), suggesting different biological response of cell clear RCC to the combination of SBRT and targeted agents.

There are several ongoing or just completed prospective studies on SBRT for oligometastatic RCC [56].

A summary of the main studies combining high dose RT and Target Therapy is reported in Tables 8 and 9.