Radiotherapy for Oligometastatic Non–Small Cell Lung Cancer: Past, Present, and Future

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Oncology, ONCOLOGY Vol 35, Issue 6,

McCall and Higgins examine local ablative therapy for oligometastatic NSCLC and implications for future treatment of the disease.

Abstract

Historically, patients with stage IV non–small cell lung cancer (NSCLC) have been treated with chemotherapy alone, reserving local therapies for symptom palliation. However, evidence has accumulated that a subset of patients with oligometastatic NSCLC (OM-NSCLC) may benefit from local ablative therapies (LATs). In this article, we review the data that have formed the rationale for LAT, specifically radiotherapy, and the prospective trials that support its use in this population. Finally, we examine the evolving role of LAT in patients with OM-NSCLC in the context of immunotherapy and targeted therapies, as well as discuss ongoing clinical trials incorporating LAT in these patients.

Keywords: Non–small cell lung cancer, oligometastatic, stereotactic body radiotherapy, local ablative therapy.

Introduction

Non–small cell lung cancer (NSCLC) is the leading cause of cancer-related death in the United States, with approximately 57% of patients presenting with distant metastases at the time of diagnosis.1,2 Until recently, the prognosis for these patients had been dismal, with 5-year overall survival (OS) rates of just 5%.3 Historically, stage IV NSCLC had been regarded as a disseminated, fundamentally incurable disease. As such, chemotherapy alone formed the prevailing treatment paradigm; local therapies were reserved to palliate symptoms, rather than alter disease trajectory. However, as stereotactic body radiation therapy (SBRT), improved diagnostics, and dramatic improvements in systemic therapy have all emerged, ablative local therapies are being increasingly employed for patients with oligometastatic (ie, limited metastatic) disease (OMD).

Hellman and Weichselbaum first coined the term oligometastatic in 1995, referring to a subset of patients with limited metastases from solid tumors.4 They proposed that such a state could be associated with more indolent disease biology that had not yet acquired the ability to develop diffuse metastases. The clinical implication of the oligometastatic state is that treatment with aggressive LAT, most often either surgery or radiotherapy, may eliminate resistant clones that are responsible for the transition to a polymetastatic state—this would prolong survival in patients, if not cure them. Notably, they proposed that the OMD state would be increasingly prevalent and relevant with increasing efficacy of systemic therapy in controlling micrometastatic disease.5

Since the introduction of this theory, considerable efforts have been made to both prove the existence of the OMD and to establish a role for LAT. The first proof of concept of the OMD theory, among all solid tumors, came from long-term follow-up of patients who had undergone surgical metastectomies. Among patients with colorectal cancer, Tomlinson et al6 demonstrated that 10-year disease control and survival had been achievable in 16.7% of patients who had undergone liver metastectomy between 1985 and 1994. Similarly, a report of 5206 cases from the International Registry of Lung Metastases described an actuarial survival rate of 22% at 15 years following lung metastectomy.7 These studies, along with others, collectively proved that long-term survival or cure was possible with aggressive LAT, even in patients with metastatic disease. With advances in treatment techniques, radiotherapy has become increasingly used as a LAT, with several early randomized trials supporting its use in patients with oligometastatic NSCLC (OM-NSCLC).8-10

A fundamental challenge associated with introducing LAT into the management of patients with OM-NSCLC has been patient selection, as metastatic disease exists on a spectrum.4-5 In 2017, the American Joint Committee on Cancer adopted the M1b designation for patients with a single site of extrathoracic metastatic disease.11 Organizational guidelines, in general, currently consider 1 to 5 metastatic lesions to constitute OMD, although a number of important nuances exist.12 Joint American Society for Radiation Oncology and European Society for Radiotherapy and Oncology guidelines, for example, emphasize the importance of the method used to count lesions as well as consideration of the time course of OMD, distinguishing between patients with metachronous OMD or oligorecurrence vs synchronous OMD.

In this review, we will summarize the rationale for LAT, specifically radiotherapy, in OM-NSCLC, as well as discuss prospective trials that have begun to establish this paradigm. We will also present nuances of OMD for which data are limited, including the precise definitions of OMD.12 Finally, we will discuss the dramatic improvements in the efficacy of systemic therapy13-17 and how these will affect future research into LAT for patients with OM-NSCLC.

Rationale for LAT in OM-NSCLC

For patients with OM-NSCLC, patterns of failure analyses formed the rationale for employing LAT. In the era before immunotherapy, upon receiving 4 to 6 cycles of a platinum-doublet regimen, about 70% to 80% of patients with stage IV NSCLC would have either a partial response or stable disease.18-20 Adding maintenance chemotherapy provided minimal OS benefit of 1 to 2 months at most.18,19,21 Further, after first-line chemotherapy, 64% of patients progressed locally or at sites of initial disease involvement, 27% progressed both locally and distantly, and 9% of patients progressed distantly only.22 The rational implication of these data is that LAT may prolong time to progression and potentially OS.

Early reports of LAT for patients with OM-NSCLC came primarily from the surgical literature, most often regarding patients with a single site of OMD. Downey et al23 conducted a phase 2 trial of induction chemotherapy and radical resection in 23 patients with NSCLC who had a solitary extrathoracic metastatic lesion. Median OS was 11 months, and 2 of the 8 patients who underwent resection were alive at 5 years. By the early 2000s, however, SBRT was being increasingly utilized for the treatment of stage I NSCLC among patients who were medically inoperable.24 SBRT utilizes high-quality image guidance, immobilization, and target motion management along with nonoverlapping beams to safely deliver ablative doses of radiation with steep dose gradients, often over 5 fractions or less. The tolerability and convenience of SBRT made it an attractive alternative to surgical metastectomy.

A series of phase 1/2 dose-escalation studies demonstrated that standard SBRT doses for patients with stage I NSCLC were also safe for patients with OMD from all solid tumors.25,26 Single-arm, nonrandomized phase 2 trials of radiotherapy for patients with OM-NSCLC are summarized in Table 1.

De Ruysscher et al27 conducted a phase 2 trial of metastasis-directed radiotherapy (or chemoradiotherapy) for patients with 5 or fewer sites of synchronous OMD, in addition to treatment of the primary tumor and regional lymph nodes. Median OS was 13.5 months with 3 patients alive at 5 years on long-term follow up without evidence of disease.28 Another phase 2 study treated patients with 5 or fewer metastatic lesions (inclusive of primary tumor and regional lymph nodes) with a dose of 50 Gy in 10 fractions, either alone or following induction cytotoxic chemotherapy, delivered to all sites of disease.29 While the primary end point in this study was metabolic response rate, median OS with this approach again appeared favorable at 23 months. Iyengar and colleagues30 completed another phase 2 study of SBRT with erlotinib in patients with limited metastatic disease (≤6 metastases) whose disease had progressed after at least 1 line of systemic therapy. Median OS was 20.4 months, impressive results for a heavily pretreated population. None of these 3 studies reported any cases of grade 4 or 5 toxicities. Finally, Blake-Cerda et al31 reported results of their phase 2 trial of SBRT (45-60 Gy in 3-5 fractions) to only the primary and pulmonary metastatic disease sites in patients with 5 or fewer total lesions. Despite not treating extrapulmonary metastases, median progression-free survival (PFS) was 34.1 months, and median OS was not reached.

Ashworth et al32 published a systematic review of studies in the literature that described surgery (55%), stereotactic radiosurgery (SRS; 35%), and SBRT (10%) as definitive local therapy in patients with NSCLC and 1 to 5 sites of OMD. Five-year OS rates ranged between 8.3% and 86.0% (median, 42%). In another meta-analysis of data on individual patients, Ashworth et al33 reported the outcomes of patients with NSCLC, primarily with 1 to 2 sites of OMD, who were treated with LAT for both the primary and metastatic disease. More recently, data were reported from a large United Kingdom–based prospective registry of 1422 patients with OMD (defined as 1-3 sites of extracranial disease), including 64 patients with OM-NSCLC, who were treated with SBRT to doses of 24 to 60 Gy in 3 to 8 fractions.34 Median 2-year OS was 65.4% among patients with OM-NSCLC, and no treatment-related deaths were reported in the entire cohort. Despite the heterogeneity of patients on which these analyses were based, the results reinforce the potential for long-term survival following LAT in select patients with OM-NSCLC.

Randomized Trials of LAT

Despite the accumulated data for LAT in OM-NSCLC, immortal time bias and other selection biases could easily account for favorable outcomes with LAT in comparison with historical or retrospective controls.35 To date, 3 published phase 2 randomized trials have included OM-NSCLC; they are summarized in Table 2 and their outcomes are depicted in the Figure. The landmark SABR-COMET study randomized 99 patients (18 with NSCLC) with or fewer metastatic lesions to receive either standard palliative therapy or SBRT in a 1:2 ratio with an end point of OS.36 The experimental group received SBRT immediately after registration followed by standard-of-care systematic therapy. Median OS in the SBRT group was 50 months, compared with 28 months in the control group (P = .006); 42.3% of patients in the SBRT group survived 5 years.9 However, this came at the cost of 3 (4.5%) treatment-related deaths.

Another trial conducted by Gomez et al10,37 randomized patients with 3 or fewer metastatic lesions after 4 cycles of first-line, standard-of-care systemic therapy to receive either maintenance therapy alone or maintenance therapy plus local consolidative therapy, which was either hypofractionated RT, SBRT, or surgery (Table 2). The primary end point was PFS, and the trial was halted early after an interim analysis demonstrated improved median PFS with local consolidative therapy (18.7 vs 11.9 months; P = .005; Figure). On long-term follow-up, this translated to a significant OS benefit (41.2 vs 18.9 months; P = .017).

Finally, a trial was conducted by Iyengar et al8 in patients with NSCLC who had 6 or fewer sites of extracranial metastatic disease (including primary tumor) prior to therapy, who then had received 4 to 6 cycles of induction systemic therapy. The patients were randomized either to consolidative radiotherapy (SBRT or hypofractionated RT) plus maintenance therapy or to maintenance therapy alone (Table 2). This trial also was terminated early after meeting its primary end point at interim analysis: The median PFS was 9.7 months in the group receiving consolidative radiotherapy compared with 3.5 months in the group receiving maintenance therapy alone (P = .01; Figure). OS results are not yet mature.

Despite each of these 3 trials having convincingly met their primary end points, subtle differences in their designs disclose clinically relevant questions. The majority of patients in the 3 trials had 3 or more sites of distant metastatic disease. For example, only 7 patients on the SABR-COMET trial had 4 or 5 sites of OMD.36 The Iyengar trial reported a median of 3 sites of OMD in each group, but it did not report additional descriptive data.8 The number of metastatic lesions has been shown to be inversely associated with survival in retrospective series.33,38 Consequently, it is unclear how generalizable the results of these trials are to patients with 4 or 5 sites of OMD.

Further, definitions of OMD and how metastatic lesions were counted varied significantly among trials. For example, brain metastases were considered sites of OMD in the SABR-COMET and Gomez trials.10,36 Conversely, the Iyengar study permitted treatment prior to enrollment but did not include intracranial lesions as OMD, as the role for SRS for limited brain metastases is already well established.8,39-41 The burden of thoracic, especially mediastinal, lymph node involvement introduces another layer of complexity in extrapolating these studies to real-world patients, as hilar and mediastinal nodal involvement has been correlated with worse OS in several retrospective analyses of patients receiving LAT for OMD.33,38 One explanation for this finding is that central location tends to be the dose-limiting factor with respect to lung SBRT, and attenuated or more fractionated courses may be needed to safely treat the hila or mediastinum.42 Indeed, central thoracic metastases were SBRT targets in both of the patients who developed grade 5 pulmonary toxicity on the SABR-COMET study.36 The Iyengar trial did not specify how involved lymph nodes were counted.8 However, patients receiving consolidative radiation to the hilum or mediastinum received either lower-dose SBRT (30 Gy in 5 fractions) or hypofractionated radiotherapy (45 Gy
in 15 fractions). In the Gomez trial, each nodal group (ie, left or right hilar [N1], mediastinal [N2], or supraclavicular [N3]) was counted as a site of OMD.10 These patients were treated with either hypofractionated radiotherapy or concurrent chemoradiation. Despite the majority of patients in the Iyengar and Gomez trials having nodal involvement, the absence of high-grade toxicities in these trials, in contrast with the SABR-COMET trial, argues for greater fractionation and/or dose reduction for nodal oligometastases.

Also, the disease presentations of the patients included in these 3 trials also had fundamental differences. For example, the SABR-COMET study population included only patients with metachronous OMD, rather than synchronous, as the protocol mandated that the primary tumor be controlled for at least 3 months prior to randomization. While the Gomez and Iyengar trials did not exclude patients with metachronous presentation, they were both more representative of patients with synchronous disease presentation (Table 2). Retrospective studies have demonstrated the improved outcomes among patients with metachronous OMD, and the duration of the of preceding disease-free interval further determines prognosis.33

Additionally, the timing of LAT in these trials varied considerably. The SABR-COMET trial treated patients prior to any maintenance/systemic therapy, whereas Gomez and Iyengar both delivered LAT following 4 to 6 cycles of systemic therapy, most often cytotoxic chemotherapy. Such an approach allows for chemoselection, assuming that patients who are nonresponders to first-line therapy would be less likely to benefit from local consolidative therapy.43 Patients enrolled on the Iyengar trial had 6 or fewer sites of OMD, but this was determined prior to induction systemic therapy. The OMD burden on the Gomez study, however, was determined following 4 cycles of systemic therapy. While the burden of disease prior to induction therapy was not reported, this study may be most notable for its proof of concept that OMD is inducible with systemic therapy.5

It should be noted that the 2 trials for OM-NSCLC were conducted prior to the FDA approvals for multiple immunotherapeutic agents that have now become the standard of care for frontline therapy in stage IV NSCLC. Given the improvements in OS seen in the era of immunotherapy, LAT for OM-NSCLC may have potential even greater than what has been seen in published trials thus far.

OMD and Immunotherapy

The prevalence of OMD, as hypothesized by Hellman and Weichselbaum, is directly related to the effectiveness of systemic therapy in controlling or eliminating micrometastatic disease.5 In recent years, immunotherapy and targeted therapies have dramatically improved the efficacy of systemic therapy for patients with metastatic NSCLC. Indeed, the induction and maintenance regimens used in the Gomez or Iyengar trials are no longer considered standard-of-care first-line therapy by today’s standards.8,10 The PD-L1/PD-1 axis is the most well-characterized pathway of immune evasion, and PD-1/PD-L1 inhibitors have drastically increased the survival of patients with advanced NSCLC. For example, immunotherapies such as pembrolizumab (Keytruda) have replaced chemotherapy among patients with PD-L1 >50%, and pembrolizumab has been added to standard chemotherapy regimens among patients without PD-L1 expression or EGFR/ALK mutations.13,44-46

How to best integrate LAT, specifically radiotherapy, with immunotherapy is an active area of investigation. Interestingly, progression outside of initial sites of disease involvement may be more common with immunotherapy in comparison with cytotoxic chemotherapy, although results of patterns-of-failure analyses have been mixed.47 Nevertheless, preclinical evidence suggests that radiotherapy may enhance responses to PD-1/PD-L1 inhibitors by acting as an in situ vaccine, garnering out-of-field (ie, abscopal) responses.48-50 The clinical implication of this synergy in patients with OMD is that SBRT could enhance a patient’s response to immunotherapy both locally and systemically. While clinical data on this phenomenon have been mixed, a secondary analysis of the KEYNOTE-001 trial found improved OS among patients treated with pembrolizumab who had received prior radiotherapy.51 Bauml and colleagues52 reported results from a phase 2, single-arm study in which patients with ≤4 oligometastatic foci received pembrolizumab for 4 to 12 weeks following LAT (Table 1). The majority of patients received a combination of LAT modalities, including resection, chemoradiation, and radiofrequency ablation, although treatment details such as dose and fractionation were not reported. Median PFS from LAT and OS both compared very favorably with historical controls at 19.1 and 41.6 months, respectively. Finally, the phase 2 PEMBRO-RT trial randomized patients with metastatic (not necessarily oligometastatic) NSCLC to receive pembrolizumab with or without SBRT (24 Gy in 3 fractions) to a single site.53 SBRT numerically improved response rates (18% without SBRT; 36% with SBRT; P = .07), although the predefined threshold of clinical significance was not reached. Notably, the dose and fractionation of radiotherapy has been hypothesized to play a role in whether systemic immune responses are generated; higher doses may cause obliteration of the immune infiltrates that are responsible for generating antitumor immunity.54 It is therefore possible that the optimal dose-fractionation of SBRT or hypofractionated radiotherapy may depend upon the systemic therapy received.

OMD and Targeted Therapy

Cases of NSCLC with genetic driver mutations or alterations, including those with EGFR mutations or ALK rearrangements, exhibit unique disease biology. These alterations confer sensitivity to targeted tyrosine kinase inhibitors (TKIs), which can induce profound and durable responses. Despite this, resistance to targeted therapy invariably develops, with few effective salvage or second-line options. Similar to patients without targetable genetic alterations, progression most often occurs in the sites of initial disease involvement in patients with EGFR variants.55-57 Further, complete responses are uncommon, and nearly all patients have residual disease at the time of best response. This has led some investigators to hypothesize that LAT, either upfront or at the time of best response, may eliminate resistant clones and prolong responses, if not survival.

Among the oncogene-driven subtypes of NSCLC, EGFR mutations have been the most closely studied with respect to OMD. The nonrandomized phase 2 ATOM trial studied the effect of consolidative SBRT on oligoresidual (defined as ≤4 sites of OMD) EGFR-mutant NSCLC after 3 months of induction TKI.58 Median OS was 43.3 months among the 16 patients enrolled and analyzed, and no grade 3 or greater toxicities were observed. When the enrolled patients were compared with a cohort of patients who had failed screening for inclusion on this trial, consolidative SBRT reduced the risk of progression (HR, 0.41; P = .0097; Table 1). At the 2020 American Society of Clinical Oncology Virtual Annual Meeting, Wang et al presented results of the phase 3 SINDAS trial that randomized patients with untreated oligometastatic (≤5 sites of OMD) EGFR-mutated NSCLC without brain metastases to TKI alone (gefitinib [Iressa], erlotinib [Tarceva], icotinib) or TKI plus SBRT. The addition of SBRT prolonged PFS (20.2 vs 12.5 months; P < .001) and OS (25.5 vs 17.4 months; P < .001).59 Notably, EGFR 20 insertion, an alteration that confers TKI resistance, was more frequent in the TKI-alone arm, and full publication of results are forthcoming. Despite the low overall rates of toxicity on the SINDAS trial, LAT to sites of residual OMD (as on the ATOM trial) rather than de novo OMD would reduce treatment volumes and potentially reduce toxicity without compromising disease control, as few patients progress within the first few months of therapy.58,60 Further studies are needed to define the optimal timing of LAT in patients with EGFR-mutated OM-NSCLC.

Another challenge of defining a role for LAT in patients with EGFR-mutant NSCLC is the rapidly evolving landscape of first-line therapies. Osimertinib (Tagrisso), a third-generation EGFR TKI with activity against the T790M resistance mutation, was shown to improve PFS and OS in the FLAURA trial.17,61 Interestingly, nearly 80% of patients still have residual disease at the time of best response, and initial sites of disease involvement remain the most common sites of progression.17,60,61 To date, no prospective trials of LAT in combination with osimertinib have been reported. Osimertinib is distinguished from earlier-generation TKIs by its robust intracranial activity, with central nervous system (CNS) response rates of 64% and CNS disease control rates of 90%.62,63 With osimertinib’s intracranial disease control rates approaching those of extracranial disease control, up-front intracranial radiotherapy is being increasingly deferred for patients with asymptomatic EGFR-mutant brain metastases. This shifting paradigm calls into question whether there could be a role for stereotactic radiosurgery to oligoresidual brain metastases after induction osimertinib.

While EGFR remains the most common and best studied mutational subtype in the setting of OM-NSCLC, others deserve mention. Patients with ALK-rearranged NSCLC have also seen recent dramatic improvements in therapy. The next-generation ALK inhibitors—alectinib (Alecensa), ceritinib (Zykadia), lorlatinib (Lorbrena), and brigatinib (Alungbrig)—have all outperformed crizotinib in the first-line setting.16,64,65 Data for LAT in patients with ALK-rearranged OM-NSCLC are much more limited, although retrospective studies suggest a potential role for LAT in these patients as well. Furthermore, targeted therapies are now approved for patients with sensitizing BRAF, ROS1, NTRK, MET, and RET alterations.3,15 As these therapies are increasingly being utilized, further research regarding a role for LAT in patients receiving these agents will be warranted.

Ongoing Clinical Trials and Future Directions

Based on the data available, multiple groups have recommended delivery of radical LAT for patients with OM-NSCLC when it is safe and feasible, typically in the setting of 1 to 5 sites of OMD.12 Several prospective, randomized clinical trials that are under way to confirm these findings are summarized in Table 3. Among patients with all solid tumor histologies, SABR-COMET-3 is a phase 3 trial designed to confirm the findings of the initial SABR-COMET trial in patients with ≤3 sites of OMD.66,67 The NRG-LU002 trial randomizes patients with OM-NSCLC who have 1 to 3 sites of OMD to receive either maintenance therapy or local consolidative therapy (surgery or radiotherapy) plus continued maintained therapy.68 While patients receiving first-line targeted therapy are excluded, all FDA-approved first-line regimens containing immunotherapy are permitted. Given the success of LAT in OM-NSCLC, studies are under way to understand if LAT can improve outcomes in polymetastatic disease. Radiation technologies have improved over time, making treatment of multiple lesions more feasible in the clinic. The ongoing SABR-COMET-10 trial is evaluating SBRT in patients with 4 to 10 sites of OMD.

Aside from confirming a benefit with LAT in patients with OM-NSCLC, these trials may also provide additional guidance on the optimal dose and fractionation for LAT. As previously noted, the importance of balancing local control with safety was highlighted by the grade 5 toxicities seen on the SABR-COMET trial.36 The SABR-COMET-3 and SABR-COMET-10 trials are employing the same SBRT regimens as their phase 2 predecessor; however, the NRG LU-002 trial, for example, is using attenuated radiation doses: 24 Gy in 1 fraction, 30 Gy in 3 fractions, or 34 Gy in 5 fractions.66-68 For the treatment of primary and regional nodal disease, hypofractionated radiation (45 Gy in 15 fractions) is recommended. To date, the SAFFRON-II trial is the only randomized study to directly compare SBRT dosing schedules (28 Gy in 1 fraction vs 48 Gy in 4 fractions) for patients with OMD who have peripheral lung metastases. No differences in local control or safety were identified in SAFFRON-II.69 Following the publication of the results of the trials listed in Table 3, further studies of this type will likely be needed.

Finally, ongoing translational research is also needed to better define OMD biology, and the importance of translational end points in these ongoing trials should not be overlooked. Some investigators hypothesize that the presence of circulating tumor cells (CTCs) or mutational burden detected by circulating tumor DNA (ctDNA) may be better than conventional imaging in approximating metastatic disease burden and responses to systemic therapy.70 In 2 small studies, detection of CTCs has tended to correlate with shorter OS and PFS after SBRT for patients with OMD.71,72 The NRG LU002 trial will be correlating ctDNA in each arm after induction therapy with PFS and OS. Among patients with stage I to III NSCLC, ctDNA mutation burden has been shown to predict relapse up to 5 months before conventional imaging.70,73 In a correlative translational analysis of the Gomez trial,74 there was no association between ctDNA mutation kinetics and outcome, although the analysis was limited by a small sample size. Local consolidative therapy, however, did appear to numerically decrease ctDNA mutations. Interestingly, ctDNA burden appeared to increased 6 months prior to radiographic progression, also suggesting that ctDNA may indeed reflect tumor burden. These early results offer a glimpse into the potential of how blood-based biomarkers could better identify and quantify OMD, and how they could either supplement or replace conventional imaging as a tool for counting the number of metastatic sites in a patient.

Conclusions

In summary, the accumulated evidence indicates that LAT may improve outcomes for patients with OM-NSCLC. Several early randomized clinical trials have demonstrated improved PFS or even OS with its use. Nevertheless, larger, well-powered phase 3 trials are needed to confirm these findings in the context of modern systemic therapies. Subgroup and correlative translational analyses will help to better define both the oligometastatic state in patients with OM-NSCLC and the optimal timing for LAT.

Financial Disclosure: KH, PrecisCa (honorarium), AstraZeneca (advisory board), RefleXion (funded research); NM, PrecisCa (honorarium).

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