For EGFR-mutated NSCLC, EGFR-TKIs shows dramatic initial response, however, acquired resistance is inevitable, and the initiation of new systemic therapy is the next therapeutic step [2–4, 18]. Patients progressing through first-line systemic therapy exhibit poor survival and small advantage in PFS . In select cases where initial disease progression is limited to dominant thoracic disease, SBRT can derive greater benefit in lengthening PFS than a change in systemic therapy. Here, in patients with EGFR-mutated NSCLC on EGFR-TKI with intrathoracic oligoprogressive disease treated with SBRT, we demonstrated PFS of 8-months and excellent median duration of EGFR-TKI therapy of 26-months. The PFS and duration of initial systemic therapy in this series are comparable to first-line therapy published in literature, thus offer a promising treatment paradigm with comparable efficacy [12, 20].
EGFR-mutant NSCLC patients that progress through EGFR-TKIs experience initial oligoprogression predominantly (50-80%) involving lungs [9, 11, 21]. These oligoprogressive sites harbor a population of TKI-resistant and dedifferentiated subclones with the potential to re-seed systemically leading to widespread disease progression [22, 23]. Aggressive SBRT to ablate these resistant subclones can delay progression and need to switch (or discontinue) therapy. While emerging evidence from oligometastatic disease shows upfront LCT delay progression and improve survival, there is little data about SBRT in patients that progressed through modern EGFR-TKI therapy [5–7]. A retrospective study of 23 EGFR-mutant patients on 1st generation EGFR-TKIs demonstrated an initial median PFS of 10.3 months, however, in 10 patients that received subsequent LCT for oligoprogression, showed additional PFS benefit of 6.2 months . Another retrospective study of 18 patients with EGFR-mutated NSCLC that acquired resistance to 1st generation TKIs received elective LCT with continued EGFR-TKI showed a prolonged PFS of 10 months and OS of 41 months with good tolerance . Our study supports that lung SBRT in EGFR-mutated NSCLC patients progressing through EGFR-TKI can extend median PFS by additional 8 months, and median OS by 31 months [4, 24]. Despite patients in this study already had an initial progression prior to SBRT, and PFS was calculated from SBRT, results are still comparable to some studies that evaluated adjuvant EGFR-TKI alone in treatment naïve NSCLC [4, 24–26]. To put in perspective, osimertinib provides an 8-months PFS benefit compared to older generation TKIs in the FLAURA study . However, this benefit is seen in a treatment naïve patient population. The benefit of SBRT in our study is in a population that has already showed resistance to targeted therapy through progression making an 8-months additional PFS benefit significant for this treatment group.
Our results also showed that SBRT enabled patients to effectively continue on EGFR-TKI therapy for a prolonged duration with median therapy duration of 26-months (1-85 months). This figure is longer than many historical studies using EGFR-TKI alone for recurrent and even some studies in adjuvant setting [12, 20]. Recently reported ADAURA study, a phase III, randomized placebo-controlled trial that showed resected EGFR-mutated NSCLC (stage IB-IIIA), demonstrated encouraging results with median duration of adjuvant osimertinib of 22 months . This reiterate how local therapy may benefit in combination with targeted treatment.
Our study expands on the work of a recent observational study in which EGFR-mutated NSCLC patient treated with osimertinib, showed 80% patients developed progressive disease within the initially involved thoracic sites, most of which were a potential SBRT candidate . Although this study brought forth an important concept to use SBRT to delay progression, no patients were actually treated with SBRT. Our study is among largest experiences in this patient population evaluating modern EGFR-TKIs plus SBRT for intrathoracic OPD. Our results demonstrated that lung SBRT dramatically alter the typical pattern of subsequent failures. Most common sites of initial failure following SBRT were distant, and only 2 patients (8.7%) had initial recurrence within the treated site [Figure 1]. This contrasts with pattern of failure studies in literature for patients on EGFR-TKI, that showed approximately 50-80% had lungs as the initial site of progressive disease [5, 9, 21].
With maturing evidence of combination of EGFR-TKIs plus SBRT, particularly with newer-generation TKI e.g. osimertinib, it is pragmatic to explore toxicity data. A phase II study with erlotinib and SBRT in metastatic NSCLC showed 29 grade 3-5 toxicities observed in 24 patients, four of which could be attributed to SBRT (pneumonitis and vertebral fracture) . Some retrospective studies have shown higher rates of severe radiation pneumonitis with combination of radiotherapy to first-generation EGFR-TKIs . With careful patient selection (disease size and location) and precise planning and delivery of SBRT, dose to normal lung can be effectively reduced mitigating the risk of pneumonitis. Our patients tolerated treatment well with no treatment related death or dose limiting toxicity. Grade 2 pneumonitis was observed in two patients, while one developed treatment related grade 2 (rib fracture) chest wall toxicity. Patient reported ESAS outcome analysis showed good tolerance to therapy, with fatigue being most common symptom.
Given disease heterogeneity and relative rarity of presentation (EGFR-mutant, oligoprogressive on TKIs) designing a randomized trial will always be challenging and time consuming; and lack of a uniform comparator group will limit valid interpretation. Therefore, the evidence needs to be established with assemblage of data from institutional retrospective studies and small phase II trials. A single-arm phase II trial (NCT01941654) from China is evaluating preemptive LCT to residual metabolically active oligometastases in 34 patients with EGFR-mutant NSCLC who had an initial response to first-line TKI therapy. The fact that this study has only accrued 18/34 patients since 2013 underscores this difficulty with accruing large patient numbers in such study. A single arm, multicenter phase II study (NCT02314364) SBRT for stage IV oncogene-driven NSCLC receiving TKIs is ongoing. The target accrual is 30 patients between 2013-2021 (7-years), with primary outcome to study patterns of distant failures following SBRT. Preliminary report of an ongoing prospective, multicenter, randomized study (SINDAS Trial, NCT02893332) evaluating EGFR-TKIs ± upfront SBRT in therapy naïve EGFR-mutant metastatic NSCLC patients showed that SBRT significantly improved PFS and OS compared to TKI alone . The HALT trial (NCT03256981), is a randomized, multi-center, phase II/III study ongoing in UK, is the only ongoing trial directly evaluating the role of SBRT + TKI in patients with oligoprogressive oncogene-addicted NSCLC (n=110) .
There are several limitations of this study that should be acknowledged. First, this was a single institution study with relatively small number of patients. Most data evaluating role of SBRT in oligoprogressive EGFR-mutant NSCLC on TKIs is in the form of small single-institution experiences. The small target accrual of ongoing prospective studies over extended time periods emphasizes the complexity of such studies and relative rarity and heterogeneity of this clinical scenario, especially in context of newer-generation EGFR-TKIs. To the best of our knowledge, this study is still one of the largest series evaluating effectiveness of thoracic SBRT with modern EGFR-TKI in oligoprogressive EGFR-mutant NSCLC patients. Second, given the retrospective design there were no pre-defined inclusion criteria. However, at our institution we prospectively collect all data for lung cancer patients including toxicity and patient reported outcome. Last, superior outcome reported in this study could potentially be due to predominant women (n=21, 91.3%) in this study, and it has been shown that females fare better with treatment than males .
This study demonstrates the efficacy and safety of a novel therapy indication of thoracic SBRT in oligoprogressive EGFR-mutant NSCLC with EGFR-TKI prolonging PFS and OS and allowing continuation of targeted therapy longer than historic data for EGFR-TKI alone. More information will emerge after completion of ongoing prospective studies, until then retrospective evidence should be explored to establish more evidence.