Should We Target Oligometastatic EGFR-Mutated Non-Small Cell Lung Cancer With Radiotherapy Before Administering Targeted Systemic Therapy?

In this issue of the Journal, Wang et al. (1) report results of the SINDAS trial, randomizing patients with previously untreated EGFR-mutated non-small cell lung cancer (NSCLC), with 1-5 oligometastases, to receive first-generation tyrosine-kinase inhibitors (TKI) alone vs TKI following upfront radiotherapy to the primary tumor, involved regional nodes, and all oligometastases. Compared with TKI alone, upfront radiotherapy followed by TKI was associated with statistically significant, clinically meaningful benefits in progression-free survival (PFS) and overall survival (OS). The phase III SINDAS trial joins a growing list of randomized phase II studies (2-7) investigating the addition of metastasis-directed therapy to standard systemic therapy for oligometastatic disease, showing benefits in PFS and, in 2 studies, OS (3,7). We commend and congratulate the authors for this landmark work.

How does the SINDAS trial fit in with these other studies? Importantly, it is not only the first published phase III study of radiotherapy for oligometastatic disease but also the first randomized study investigating patients with previously untreated oligometastatic disease, specifically selected by similar tumor biology. Prior studies specific to oligometastatic NSCLC have included diverse histologies, with few [16% of patients with driver mutations in study by Gomez and colleagues (2,3)] or no (4) patients amenable to TKI therapy. Furthermore, prior reports on the role of metastasis-directed radiotherapy in EGFR-mutated NSCLC have focused on oligoprogressive disease (8,9).

Improvements in both median PFS (12.5 vs 20.2 months) and OS (17.4 vs 25.5 months) with radiotherapy prior to TKI is meaningful (1) and seemingly obtained with less considerable toxicity than would have been anticipated (7). These favorable results arose despite more than half of patients presenting synchronously with oligometastases and clinical N2-3 lymph nodes, which a pooled analysis showed to be an adverse prognostic factor (10). More patients in the radiotherapy vs control arm had more than 2 oligometastases (53% vs 41%), which has also been associated with worse outcomes (11). Additionally, the SINDAS trial did not require positron emission tomography for initial staging; untreated occult oligometastases could potentially adversely affect PFS (5). The favorable toxicity profile may be attributable to relatively moderate radiotherapy dosing, albeit with variable radiotherapy techniques. Although radiotherapy dose escalation is associated with greater tumor control probability for oligometastases (12), the more than 90% crude local control rate after radiotherapy plus TKI (vs 55% after TKI alone), with a median follow-up of approximately 2 years, suggests that cancer-specific radiobiology and/or possible synergistic or additive effects of TKI and radiotherapy afford acceptable control without need for radiotherapy dose escalation.

Should the SINDAS trial change standard of care? This is challenging because of 2 main factors: the unplanned stopping of the trial and the changing landscape for EGFR-mutated NSCLC.

The SINDAS trial protocol specified an interim analysis at 68% of planned accrual; however, statistical-based stopping rules were not prespecified (1). Instead, the ethics committee was given discretion and closed the trial early because of the marked survival benefit with radiotherapy. Although this reflects the protocol intent, it differs substantially from most other phase II-III trials where clear prespecified statistical conditions guide trial closure. For example, 2 recent randomized phase II studies (2–4) closed early after interim analysis showed that PFS, with consolidative radiotherapy for the primary NSCLC sites and oligometastases (in contrast to upfront radiotherapy in SINDAS trial), exceeded prespecified boundaries. Despite this shortcoming, the separation of survival curves in the SINDAS trial is impressive. Yet, for the trial’s primary endpoint of 6-month PFS, the difference is negligible, with few events. The SINDAS trial investigators reasonably chose to follow patients for an additional year prior to data analyses. Conceding that cross-trial comparisons are limited by a multitude of factors, at less than 12-month timepoints, the OS for both SINDAS trial arms was comparable with that seen after stereotactic body radiotherapy for medically inoperable stage I NSCLC (13,14); at less than 18-month timepoints, the OS for both arms was markedly superior to those reported after concurrent chemoradiotherapy and adjuvant immunotherapy for stage III NSCLC (15,16). With early trial closure without formal stopping rules, coupled with unexpectedly favorable survival outcomes in both arms without meeting the study’s primary endpoint, the interpretation of the SINDAS trial is clouded.

Applying SINDAS trial results (1) to modern clinical practice has additional challenges, including the adoption of more effective TKI for first-line and salvage therapy (as opposed to cytotoxic chemotherapy as used in SINDAS trial) (17,18). It remains unclear whether the benefit of radiotherapy with first-generation EGFR TKI therapy applies to current regimens, particularly with survival rates in both trial arms numerically superior to those reported with osimertinib (third-generation TKI) for EGFR-mutated stage IV NSCLC (18), again acknowledging cross-trial comparisons fraught with confounding factors.

One confounder in the SINDAS trial is the number of bone metastases (73% of metastases) (1). In contrast, among 121 registry patients with EGFR-mutated NSCLC (not accounting for oligometastatic status), only 36% had bone metastases (similar to those with EGFR wild-type NSCLC) (19). Additionally, the applicability of SINDAS trial results to patients with brain metastases, who were not eligible for the study, is unknown, particularly in the era with more central nervous system–penetrant TKI.

The SINDAS trial data (1) do not address optimal timing of radiotherapy (20), a particularly relevant question for patients undergoing prolonged courses of systemic therapy. Whereas delaying radiotherapy can help select outpatients destined to develop widespread disease, upfront radiotherapy may slow metastatic progression. Notably, even palliative radiotherapy for NSCLC can prolong survival in some settings (21). Accounting for patients undergoing palliative radiotherapy in the control arm of the SINDAS trial, most received radiotherapy at some point in their disease course, suggesting that the treatment arm’s survival benefit derived from upfront radiotherapy reducing or eliminating tumor burden. In the randomized phase II study by Gomez and colleagues (2,3), consolidative radiotherapy after chemotherapy was associated with lower likelihood of developing new metastases and improved OS.

Finally, SINDAS trial data do not address the role of upfront radiotherapy and targeted therapy for patients with other NSCLC mutations (ie, ALK rearrangement; ROS1 mutation) or the role of radiotherapy for oligometastatic NSCLC in patients without targetable mutations. Among ongoing studies randomizing standard of care vs consolidative radiotherapy for oligometastases from NSCLC, NRG LU002 (NCT03137771) excludes patients with targetable mutations amenable to TKI and, in recent updates, stratifies by receipt of immunotherapy; SARON (NCT02417662) excludes patients receiving vascular endothelial growth factor inhibitors; and OMEGA (NCT03827577) stratifies by oncogene addiction (EGFR, ALK, ROS-1 driven, or PDL1 > 50% vs <50% vs wild type). The randomized phase II NORTHSTAR trial (NCT03410043) plans to enroll 143 patients with stage IIIB-IV EGFR-mutated NSCLC to upfront osimertinib with or without local consolidative radiotherapy or resection.

In summary, for oligometastatic EGFR-mutant NSCLC treated with first-generation TKI, PFS and OS can seemingly be improved with a 5-fraction course of modest-dose radiotherapy. More work is needed to answer clinically relevant questions on optimal treatments for oligometastatic NSCLC. The promising results from the SINDAS trial demonstrate that the field is making strides in the right direction.

Funding

None.

Notes

Role of the funder: Not applicable.

Disclosures: The authors have no relevant conflicts of interest. Michael T. Milano reports: Employment: University of Rochester. Outside of submitted work: Royalties from Wolters Kluwer (UpToDate). Honorarium from Galera Therapeutics (October 2019); Speaker fee from AstraZeneca (lecture Oct 2020). Joseph K. Salama reports: Self: Employment: Duke University, Royalties: UpToDate; Payment for development of educational presentations: Oakstone; Grants/grants pending or contracts (Research funding paid to institution): Exact Sciences, AbbVie. Spouse: Employment: Duke University, Grants/grants pending or contracts (Research funding paid to institution): BMS, Immunocore, Merck, Dynavax; Board Membership (advisory boards): Regeneron, Iovance, Pfizer, Array, Novartis. Steven J. Chmura reports: Employment: University of Chicago. Outside of submitted work: Royalties from Wolters Kluwer (UpToDate).

Author contributions: Writing—original draft: MTM; Writing—review and editing: MTM, JKS, SJC.

Data Availability

No data were generated or presented in this editorial.