Pattern of Recurrence Analysis in Metastatic EGFR-Mutant NSCLC Treated with Osimertinib: Implications for Consolidative Stereotactic Body Radiation Therapy

Journal Pre-proof Pattern of recurrence analysis in metastatic EGFR-mutant NSCLC treated with Osimertinib: implications for consolidative stereotactic body radiation therapy Tiantian Guo, Jianjiao Ni, Xi Yang, Yuan Li, Yida Li, Liqing Zou, Shengping Wang, Quan Liu, Li Chu, Xiao Chu, Shuyan Li, Luxi Ye, Zhengfei Zhu PII:

S0360-3016(20)30060-2

DOI:

https://doi.org/10.1016/j.ijrobp.2019.12.042

Reference:

ROB 26144

To appear in:

International Journal of Radiation Oncology • Biology • Physics

Received Date: 6 October 2019 Revised Date:

7 December 2019

Accepted Date: 21 December 2019

Please cite this article as: Guo T, Ni J, Yang X, Li Y, Li Y, Zou L, Wang S, Liu Q, Chu L, Chu X, Li S, Ye L, Zhu Z, Pattern of recurrence analysis in metastatic EGFR-mutant NSCLC treated with Osimertinib: implications for consolidative stereotactic body radiation therapy, International Journal of Radiation Oncology • Biology • Physics (2020), doi: https://doi.org/10.1016/j.ijrobp.2019.12.042. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Inc. All rights reserved.

Pattern of recurrence analysis in metastatic EGFR-mutant NSCLC treated with Osimertinib: implications for consolidative stereotactic body radiation therapy Tiantian Guo1,4#, Jianjiao Ni1,4#, Xi Yang1,4, Yuan Li3,4, Yida Li1,4, Liqing Zou1,4, Shengping Wang2,4, Quan Liu2,4, Li Chu1,4, Xiao Chu1,4, Shuyan Li1,4, Luxi Ye1,4 and Zhengfei Zhu1,4* 1

Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China;

2

Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, China;

3

Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China;

4

Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China

# These two authors contributed equally.

Running title: Pattern of recurrence to osimertinib in EGFR-mutant NSCLC Manuscript word count: 4200 (excluding references) Number of Tables: 2 Number of Figure(s): 4 Number of references: 35

Keywords: non-small cell lung cancer, EGFR, pattern of recurrence, SBRT

Authors responsible for statistical analysis: Tiantian Guo Conflicts of interest(s): none. Acknowledgments: none. Funding: This work was supported by Shanghai Science and Technology Committee (Grant No. 19411965900) and National Natural Science Foundation of China (Grant No.81903253).

*Corresponding Author: Zhengfei Zhu, MD

Department of Radiation Oncology, Fudan University Shanghai Cancer Center 270 Dong An Road, Shanghai, 200032 China Phone: +86-18017312901 Fax: +86-2164175242 E-mail: [email protected]

Summary We studied the patterns of residual disease and progression in metastatic EGFR-mutant NSCLC treated with osimertinib. Initial recurrence was predominantly limited to sites of residual disease at maximal osimertinib response. Consolidative SBRT as an addition to EGFR-TKIs holds promise for delaying disease progression, at least in subsets of patients with oligo-residual disease state.

1

Abstract Purpose: Despite the impressive response rate to osimertinib, acquired resistance remains an obstacle to achieving long-term tumor control in metastatic EGFR-mutant NSCLC. Stereotactic body radiation therapy (SBRT) plays a growing role in the management of oligometastatic disease. We investigated the patterns of residual disease and progression on osimertinib, as well as the predictors of candidates for consolidative SBRT. Methods and materials: The serial scans of metastatic EGFR-mutant NSCLC patients treated with osimertinib were retrospectively reviewed. Disease progression in residual sites, new sites, both residual and new sites were classified as RR, NR, and RNR, respectively. Logistic regression analysis was performed to identify predictors of consolidative SBRT candidates. Results: Ninety-seven patients were enrolled. The median time to maximal osimertinib response was 2.6 months. Twenty-six patients (26.8%) with oligo-residual disease were identified as candidates for consolidative SBRT at time of maximal response. Stage T1-2 before initiation of osimertinib (p=0.046) was the independent predictor of consolidative SBRT eligibility. During a median follow-up of 10.9 months, disease progression was documented in 50 (51.5%) patients, and 70% of them experienced oligo-progression. Twenty-five (50%) patients developed disease progression in originally involved sites, 11(22%) had new metastases, and 14(28%) experienced disease progression in both original and new metastatic sites. There were 46 patients with progressive disease after experiencing initial stable disease or objective response to osimertinib. RR occurred in 20 (43.5%) of these patients, NR in 14 (30.4%), and RNR in 12 (26.1%). Notably, within the subgroup of patients eligible for consolidative SBRT, RR was observed in six (54.5%) patients, RNR in three (27.3%), and NR in two (18.2%). Conclusion: The majority of progressive disease on osimertinib was within residual lesions in initially involved sites. Consolidative SBRT may potentially prolong time to progression in a selected subgroup of patients, which merits further investigation.

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Introduction In recent years, the discovery of multiple oncogenic drivers, including epidermal growth factor receptor (EGFR) mutations as the targetable oncogenes in non-small cell lung cancer (NSCLC), has shed new light on the treatment of advanced EGFR-mutant NSCLC. Emerging data from clinical trials indicate the superiority of first- or second-generation EGFR tyrosine kinase inhibitors (TKIs) over conventional chemotherapy in terms of quality of life, as well as treatment efficacy including progression-free survival (PFS) and objective response rate (ORR) (1-3). However, disease progression occurs within approximately one to two years after initiation of EGFR-TKIs therapy (1-3), with EGFR T790M mutation being the underlying mechanism driving acquired resistance in approximately 60% of cases (4). Osimertinib is a third-generation EGFR-TKI that targets both activating EGFR mutations and T790M mutation in exon 20. The phase III AURA III trial, which compared osimertinib versus platinum-pemetrexed chemotherapy in patients with T790M mutation after progression on prior EGFR-TKIs therapy, demonstrated a significant improvement in ORR (71% versus 31%) and PFS (10.1 months versus 4.4 months) in favor of osimertinib (5). Moreover, as the first-line setting for EGFR-mutant advanced NSCLC, osimertinib was associated with prolonged PFS compared to erlotinib or gefitinib in the phase III FLAURA trial (6). However, the development of resistance to osimertinib remains an obstacle to achieving durable disease control. Stereotactic body radiation therapy (SBRT) is a novel radiation technique which offers the advantage of delivering high tumoricidal doses to the target lesion within a short treatment course. Accumulating evidence has shown the potential role of SBRT in achieving high local control in patients with a limited number of metastases in a variety of sites, including the lungs, liver, spine, and adrenal glands (7-10). Growing attention has been focused on the benefit of SBRT for oligo-progressive NSCLC (11-13), and recent retrospective data demonstrated that local ablative therapy conferred a significant survival advantage in metastatic EGFR-mutant NSCLC patients with oligo-PD on osimertinib (14). Herein, we hypothesize that local ablative therapy, especially SBRT, to all of the residual sites at time of maximal response to EGFR-TKIs, could potentially delay the time to progression (TTP) or even improve OS. The hypothesis is based on two aspects. First, there is a close relationship between tumor burden and the efficacy of radiotherapy. At 3

maximal response to EGFR TKIs, the patients have the lowest tumor burden, and thus SBRT to all of the residual sites at this time point is most likely to achieve potent treatment efficacy. Second, the drug-resistant clones in the residual tumor lesions may serve as the seeds for new distant metastases. Consistent with this assumption, several studies focusing on the patterns of recurrence following first- or second-generation EGFR-TKIs therapy showed that the majority of progressive disease was within the initially involved sites of disease (15,16). However, there is a paucity of data available on whether osimertinib treatment has similar patterns of recurrence, and little is known of the proportion and disease characteristics of the subset of osimertinib-treated patients who are eligible for consolidative SBRT. It is therefore necessary to investigate the patterns of residual disease and initial progression on osimertinib. Furthermore, we sought to identify the independent predictors of potential candidates for consolidative SBRT, which is of critical importance for the selection of patients who may derive benefit from early incorporation of SBRT.

Methods and Materials Patients The medical records of metastatic NSCLC patients treated with osimertinib at XXXX from April 2017 to December 2018 were retrospectively reviewed. EGFR mutant NSCLC patients treated with osimertinib in the first-line setting and T790M mutation-positive NSCLC patients receiving osimertinib after progression on first- or second-generation EGFR-TKIs were enrolled in this study. The evaluation of EGFR mutation status was performed using ARMS (amplification-refractory mutation system) method. All of the included patients should have pathologically-confirmed NSCLC, adequate surveillance imaging, and measurable disease. The following clinical characteristics of eligible patients were retrieved from electronic medical records: age at diagnosis, sex, tumor histology, TNM stage, primary tumor size, Eastern Cooperative Oncology Group (ECOG) score, organs harboring metastatic disease, number of metastatic lesions, and prior treatment regimens. The dates of cancer diagnosis, osimertinib initiation, maximal treatment response, disease progression, last follow-up, and death were collected. Data collection was cut-off by June 30, 2019. We obtained approval from the 4

institutional review board of XXXXX.

Response assessment and pattern of recurrence analysis Surveillance contrast-enhanced computed tomography (CT) imaging was performed every six to eight weeks. Brain magnetic resonance imaging (MRI) or CT scans were not routinely performed for patients without brain metastases at baseline unless there were signs for brain metastases during osimertinib treatment. Serial scans were reviewed independently by two experienced radiologists to assess disease response to treatment based on Response Evaluation Criteria in Solid Tumor (RECIST) criteria (version 1.1). Oligo-progression referred to the disease state of being progressive disease (PD) as defined by RECIST1.1 with a limited number of sites of progression (n≤5). The pattern of initial recurrence was classified as follows: residual-site recurrence (RR), new-site recurrence (NR), and combined RR and NR (RNR). RR was defined as initial recurrence limited to residual sites at maximal osimertinib response. NR was defined as the development of new metastatic sites that were not identified at maximal response to osimertinib. Initial recurrence involving both residual and new metastatic sites was defined as RNR.

Eligibility for consolidative SBRT The last CT scan before achieving the stabilization of target lesions on at least two consecutive follow-up scans was identified as the CT scan at maximal osimertinib response. The residual disease burden on CT scan at maximal osimertinib response was assessed to identify patients eligible for SBRT. Given the lack of universally accepted criteria for judging SBRT eligibility, we adopted the eligibility criteria of the NRG-BR001 trial, which is the first National Cancer Institute (NCI) supported trial of SBRT for multiple extracranial metastases to test its safety and efficacy in treating oligo-metastases. The inclusion criteria for consolidative SBRT were as follows: (1) less than five metastatic sites, (2) extracranial metastases located within the lungs, mediastinal/cervical lymph node, liver, bone, spine, and abdominal-pelvic metastases including lymph node as well as adrenal gland, (3) complete resolution of the effusion in patients who presented with pleural effusion in the baseline CT (17). Given the controversial role of SBRT for lymph node metastases, each positive thoracic lymph node (including mediastinal, hilar, and supraclavicular node) was counted individually as one metastatic lesion. In addition, residual 5

tumor lesions which had been treated with radiotherapy were deemed ineligible for SBRT. Although all patients were evaluated for SBRT eligibility, none of them received consolidative SBRT before developing progressive disease.

Statistical analysis Differences between clinical parameters in patients with and without consolidative SBRT eligibility were compared using the χ2, and Fisher’s exact tests. The associations between clinical variables and the feasibility of consolidative SBRT were first evaluated in univariate logistic regression analysis. Variables with a P value less than 0.10 were further examined in multivariable logistic regression analysis to identify the independent predictors of candidates for consolidative SBRT and estimate the odds ratios (ORs) and 95% confidence intervals (CIs). The assessment is considered significant when two-sided P-value is less than 0.05. PFS referred to the time interval from osimertinib initiation until disease progression or death and was calculated using the Kaplan-Meier method. Differences among subgroups were evaluated by the log-rank test. SPSS 21.0 (SPSS, Chicago, IL, USA) was used to carry out all statistical analyses.

Results Baseline characteristics One hundred sixty-four patients with metastatic EGFR-mutant NSCLC received osimertinib during the period from April 2017 to December 2018. A final cohort of 97 cases with adequate follow-up and measurable disease was enrolled in this study (Figure1). Patient characteristics before initiation of osimertinib are summarized in Table1. Most patients (73.2%) had more than five metastatic sites. Main sites of metastases included bone (69.1%), lung (64.9%), brain (32.0%), liver (15.5%), and adrenal glands (10.3%). Osimertinib was used as the first-line therapy in 15 (15.5%) patients, while the remaining 82 (84.5%) patients were treated with osimertinib after progression on first- or second-generation EGFR TKIs. Eleven patients had received radiotherapy for brain metastases before commencing osimertinib therapy, with eight (72.7%) of them receiving whole-brain radiation therapy (WBRT), and three (27.3%) receiving stereotactic radiosurgery (SRS). Thirteen patients had received prior radiotherapy for lung metastases, with six (46.2%) of 6

them receiving thoracic SBRT, and seven (53.8%) receiving conventional palliative radiotherapy. Among the 22 patients who had undergone prior radiotherapy for bone metastases, 20 (90.9%) had received conventional palliative radiotherapy, and two (9.1%) had received SBRT for spinal metastases.

Patterns of residual disease at maximal osimertinib response Four patients had disease progression at the first follow-up assessment, and therefore did not achieve maximal osimertinib response. Among the remaining 93 patients, one (1.1%) achieved a complete response (CR), 63 (67.7%) a partial response (PR), and 29 (31.2%) stable disease (SD). The median time to maximal osimertinib response was 2.6 months (range: 0.5–7.1 months). As illustrated in Figure2, the most common site of residual disease at maximal response was the lung, followed by bone, lymph nodes, brain, liver, and adrenal glands. Of note, eight patients who presented with symptomatic bone metastases at baseline had negative bone scans and the disappearance of pain at maximal response to osimertinib and were considered to achieve a complete response of bone metastases. Additionally, among patients who presented with brain metastases at time of maximal response, three had fewer than five total metastases with only 1-3 intracranial metastatic sites.

Predictors of consolidative SBRT eligibility Twenty-six patients (26.8%) were considered as potential candidates for consolidative SBRT. Univariate analysis demonstrated that stage T1-2 (P=0.014) and the number of organs harboring metastases (P=0.031) were significantly associated with the feasibility of SBRT. In multivariate analysis, stage T1-2 before initiation of osimertinib (OR=2.991, 95%CI 1.021-8.762, P=0.046) was identified as the independent predictor of consolidative SBRT candidates (Table2).

Pattern of progressive disease During a median follow-up of 10.9 months, disease progression was observed in 50 patients (51.5%), with a median PFS of 12.5 months (95%CI: 10.0–14.9 months). Oligo-progression was observed in 35 patients (70%). The majority of disease progression occurred in the lungs (58%), followed by bone (22%), lymph nodes (20%), brain (14%), and liver (10%). Twenty-five (50%) 7

patients developed disease progression within initially involved sites of disease, 11(22%) had new metastatic sites that were not identified before initiating osimertinib, and 14 (28%) experienced disease progression in both original and new metastatic sites. There were 46 patients who developed disease progression after achieving PR (n=29) or SD (n=17). RR was observed in 20 (43.5%) of these patients, NR in 14 (30.4%) patients, and RNR in 12 (26.1%) patients. Moreover, the pattern of recurrence was altered by prior radiation therapy. In the subgroup of patients without prior radiotherapy (n=64), the pattern of recurrence was predominantly within residual disease sites with RR, NR, and RNR frequencies being 50%, 26.7%, and 23.3%, respectively. In contrast, among patients who received prior radiotherapy (n=33), the frequencies of RR, NR, and RNR were 31.3 %, 37.5%, and 31.3%, respectively.

Candidates for consolidative SBRT Detailed baseline characteristics of the 26 candidates for consolidative SBRT are shown in Table1. Eleven patients (42.3%) had more than five metastatic sites at time of initiation of osimertinib. Main sites of metastases included lung (61.5%), bone (53.8%), brain (19.2%), adrenal glands (7.7%), and liver (3.8%). Nineteen patients (73.1%) achieved PR, and seven (26.9%) achieved SD at maximal response to osimertinib, with a median time to maximal response of 2.6 months (range: 0.6–5.5 months). The majority (92.3%) of them had fewer than three involved organs at maximal response. Most of their residual disease was located within the lungs and bone. The residual disease burden of the 26 patients is shown in Figure3. All of the patients eligible for consolidative SBRT continued treatment with osimertinib and did not receive consolidative SBRT. At a median follow-up of 16.8 months, 11 (42.3%) patients developed PD. Sites of PD included lung (54.5%), bone (36.4%), lymph nodes (18.2%), and brain (9.1%). Oligo-progression was observed in seven (63.6%) patients. Of note, six (54.5%) of the 11 patients with PD on osimertinib experienced RR, three (27.3%) developed RNR, and two (18.2%) had NR (Figure4A). As shown in Figure4C, compared with those ineligible for consolidative SBRT, the 26 patients with oligoresidual disease burden at best response to osimertinib had a significantly longer PFS (median PFS 17.2 vs. 11.3 months, P=0.002).

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Discussion Despite the dramatic response rate and improved PFS seen with the use of osimertinib, acquired resistance remains a significant challenge to achieving long-term tumor control. SBRT is emerging as a promising treatment option with high local control and acceptable toxicity for patients with a limited number of metastases (18,19). Therefore, the appropriate integration of SBRT with osimertinib could potentially improve clinical outcomes of advanced EGFR-mutant NSCLC patients. To the best of our knowledge, this is the first study to explore the patterns of residual disease and initial progression on osimertinib. Additionally, we identified the predictors of candidates for consolidative SBRT in order to select the potential candidates for SBRT before disease progression occurs. We chose the time point of maximal response to osimertinib to evaluate consolidative SBRT eligibility, with the intent to maximize the benefit from osimertinib treatment and enhance the likelihood of SBRT-eligibility. Finally, twenty-six (26.8%) patients were considered eligible for consolidative SBRT. The majority of them had fewer than three involved organs at time of maximal response. Most (80.8%) of their residual disease was located in the lungs, which constituted targets for thoracic SBRT. Of note, we observed that more than half of patients (54.5%) eligible for consolidative SBRT developed progressive disease within the persistent disease in originally involved sites (Figure4A). This finding suggests an intriguing possibility: instead of waiting for disease progression to occur, consolidative SBRT applied to residual disease sites may play a role in prolonging time to progression, at least in the subgroup of patients with oligoresidual disease state. A recent retrospective study has shown a significant improvement in PFS and overall survival (OS) with local consolidative therapy (LCT) delivered to all metastatic lesions in patients with EGFR-mutant oligo-metastatic NSCLC (20). Similarly, another retrospective study also reported OS and PFS benefit of combining TKI therapy and LCT versus TKI monotherapy in patients with oligo-metastatic state (21). Taken together, consolidative SBRT as an addition to EGFR-TKIs treatment may hold promise for delaying disease progression and extending the duration of EGFR-TKIs therapy in oligo-metastatic EGFR-mutant NSCLC patients. Additionally, a high rate of oligo-progression (70%) was noted in our study. Although growing evidence has indicated that SBRT plays an essential role in the management of 9

oligo-progressive EGFR-mutant NSCLC (12,13), the optimal timing of integrating SBRT with EGFR-TKIs remains an unanswered question. In our study, we found that the pattern of recurrence was predominantly within original sites of disease. Approximately half of the patients who suffered from progressive disease after experiencing initial stable disease or objective response had initial progression within residual disease sites only. Similarly, a previous retrospective study of metastatic NSCLC patients treated with first-line systemic therapy reported a high rate of initial progression in previously involved sites and suggested an improved time to progression (TTP) with the incorporation of consolidative SBRT (22). Analysis of a prospective cohort of EGFR-mutant NSCLC patients receiving EGFR-TKIs (gefitinib, erlotinib, and afatinib) showed that approximately half of the initial progression on TKI therapy occurred in initially involved sites (15). Another retrospective study demonstrated that initial recurrence was limited to the existing sites of disease in 60.2% of EGFR-mutant patients who progressed on erlotinib, and intrathoracic primary disease progression accounted for 60% of initial progression (16). Moreover, a randomized, phase II trial evaluating the effect of LCT including radiotherapy and surgical resections in oligo-metastatic NSCLC patients with no disease progression, reported a significantly prolonged PFS in the LCT group compared with the maintenance therapy group (11.9 vs. 3.9 months; P=0·0054) (23). Notably, LCT prolonged the time to the appearance of new metastatic lesions. A significant OS benefit was also noted in the LCT group (41.2 vs.17 months, P = 0.017) (24). All these data raise an important hypothesis that new distant metastases may arise from the growth of drug-resistant clones at the residual tumor lesions in the initially involved sites. Therefore, compared to the salvage SBRT in patients with oligo-progressive disease, consolidative SBRT which ablates the EGFR-TKI resistant clones in all of the oligo-residual tumor sites, could have a potential advantage of altering patterns of recurrence and improving patients’ survival. Stage T1-2 was identified as the independent predictor of consolidative SBRT eligibility. The eligibility criteria utilized in our study were in accordance with the NRG-BR001 study. Less than five metastases located in extracranial sites, including lung, mediastinal/cervical lymph node, bone, liver, spine, and adrenal gland, were considered eligible for consolidative SBRT treatment with different initial doses (45–50Gy) and fractions (3-5) (17). Consolidative SBRT-eligible patients tended to have a lower rate of brain metastases before initiating osimertinib (p = 0.110). However, this trend failed to reach statistical significance. In fact, stereotactic radiosurgery (SRS) has 10

opened new avenues for durable tumor control, better quality of life (QoL), and improved preservation of neurocognitive function in the treatment of limited brain metastases(25,26). Here, we noted a subset of patients with up to four total metastases and only 1-3 intracranial metastatic sites at maximal osimertinib response, who may be candidates for consolidative SBRT and cranial SRS. Two ongoing randomized clinical trials (NCT03769103, NCT03497767) are investigating whether the combination of SRS and osimertinib will lead to improved intracranial disease control in patients with EGFR-mutant NSCLC with brain metastases compared to osimertinib alone. Encouraging results from landmark clinical trials have indicated that osimertinib has great potential to change our clinical practice in the treatment of asymptomatic brain metastases with its remarkable intracranial activity (6,27,28). Moreover, personalized treatment strategies such as the combination of osimertinib and SRS or osimertinib alone may be carefully tailored for individual patients, based on their clinical presentation as well as the size, number, and site characteristics of brain metastases. Future studies are necessary to explore the optimal management of brain metastases in the osimertinib era. While the addition of consolidative SBRT to EGFR-TKI holds promise as an effective treatment option for metastatic EGFR-mutant NSCLC, there are still challenges that need to be addressed. First, despite the impressive clinical outcomes of treatment with osimertinib, high drug acquisition costs remain an obstacle to achieving favorable economic outcomes. Recently, osimertinib has been approved as first-line therapy for metastatic EGFR-mutant NSCLC in a number of countries. However, several studies have indicated that osimertinib may not be a cost-effective treatment option in either the first- or second-line setting in the US, Canada, Brazil, or China (29-31). Second, unknown synergistic risks of combined SBRT and osimertinib are of potential concern, considering both treatment modalities carry the risk of treatment-related toxicities. In the SABR-COMET trial, three treatment-related deaths were noted in the SABR group (32). In the pre-osimertinib era, several retrospective studies have suggested a higher risk of severe radiation pneumonitis with the addition of radiotherapy to EGFR-TKI (33,34). The adverse effects of EGFR-TKI on pulmonary interstitium might contribute to the risk of synergistic toxicity of these two treatment modalities, which can manifest itself as an increase in the risk of severe radiation pneumonitis. The toxicity profile of combined osimertinib and consolidative SBRT in metastatic 11

EGFR-mutant NSCLC needs to be further investigated in randomized controlled trials. Currently, careful selection of candidates for consolidative SBRT, as well as careful evaluation of the risks and benefits, is needed to ensure the safety of this combined treatment approach. In the present study, the residual disease state at maximal response was assessed to identify patients eligible for SBRT. One potential advantage of SBRT in patients with low-burden residual disease, instead of patients with oligoprogressive NSCLC, is that it may have a lower risk of treatment-related toxicities. Third, the optimal schedule of osimertinib when delivering SBRT to all residual lesions is not well defined. On the one hand, given the potentially increased risk of pulmonary toxicity, special attention is needed for patients with a high risk of radiation pneumonitis, and osimertinib may be withheld on the days of thoracic SBRT for these patients. On the other hand, the total treatment duration of SBRT delivered to all residual sites is of potential concern in a setting in which osimertinib is withheld on the days of SBRT, as longer breaks from osimertinib may result in a higher risk of progression. Notably, the efficacy and safety of SBRT for the treatment of multiple metastases in the same treatment course is an area of ongoing clinical investigation in NRG-BR001 (17). Ultimately, future prospective randomized trials are required to elucidate these questions. Our study has some limitations indeed. First, considering the retrospective design of our study, the follow-up intervals differed among patients. Brain imaging and bone scanning were not mandatorily performed, which could delay the diagnosis of new asymptomatic bone or brain metastases. Second, only 15.5% of patients in the study received osimertinib as first-line therapy. Osimertinib is playing an increasing role in the first-line treatment of metastatic EGFR-mutant NSCLC. Further investigation is needed to determine whether first-line osimertinib has similar patterns of recurrence. Third, based on the results of this study, we hypothesize that consolidative SBRT to all residual disease sites at maximal osimertinib response could potentially delay disease progression, prolong the duration of osimertinib therapy, and improve overall survival. However, the actual benefit of consolidative SBRT in metastatic EGFR-mutant NSCLC treated with osimertinib needs to be evaluated in prospective clinical trials such as the ongoing NORTHSTAR trial (NCT03410043), which is a multicenter phase II randomized trial comparing the combination of osimertinib and consolidative SBRT versus osimertinib alone in patients with EGFR-mutant 12

NSCLC (35).

Conclusions The majority of osimertinib-treated patients developed progressive disease within the persistent lesions in initially involved sites. Patients with stage T1-2 before initiating osimertinib were particularly likely to become candidates for consolidative SBRT. The addition of SBRT to residual sites of disease at maximal osimertinib response may potentially prolong time to progression in subsets of patients with oligo-residual disease state.

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therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: A multicentre, randomised, controlled, phase 2 study. The Lancet Oncology 2016;17:1672-1682. 24. Gomez DR, Tang C, Zhang J, et al. Local consolidative therapy vs. Maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer: Long-term results of a multi-institutional, phase ii, randomized study. J Clin Oncol 2019;37:1558-1565. 25. Brown PD, Jaeckle K, Ballman KV, et al. Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: A randomized clinical trial. Jama 2016;316:401-409. 26. Suh JH. Stereotactic radiosurgery for the management of brain metastases. The New England journal of medicine 2010;362:1119-27. 27. Wu YL, Ahn MJ, Garassino MC, et al. Cns efficacy of osimertinib in patients with t790m-positive advanced non-small-cell lung cancer: Data from a randomized phase iii trial (aura3). J Clin Oncol 2018;36:2702-2709. 28. Goss G, Tsai CM, Shepherd FA, et al. Cns response to osimertinib in patients with t790m-positive advanced nsclc: Pooled data from two phase ii trials. Annals of oncology : official journal of the European Society for Medical Oncology 2018;29:687-693. 29. Wu B, Gu X, Zhang Q. Cost-effectiveness of osimertinib for egfr mutation-positive non-small cell lung cancer after progression following first-line egfr tki therapy. J Thorac Oncol 2018;13:184-193. 30. Aguiar PN, Jr., Haaland B, Park W, et al. Cost-effectiveness of osimertinib in the first-line treatment of patients with egfr-mutated advanced non-small cell lung cancer. JAMA oncology 2018;4:1080-1084. 31. Ezeife DA, Kirk V, Chew DS, et al. Economic analysis of osimertinib in previously untreated 16

egfr-mutant advanced non-small cell lung cancer in canada. Lung Cancer 2018;125:1-7. 32. Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (sabr-comet): A randomised, phase 2, open-label trial. Lancet (London, England) 2019;393:2051-2058. 33. Zhuang H, Yuan Z, Chang JY, et al. Radiation pneumonitis in patients with non--small-cell lung cancer treated with erlotinib concurrent with thoracic radiotherapy. J Thorac Oncol 2014;9:882-5. 34. Chang CC, Chi KH, Kao SJ, et al. Upfront gefitinib/erlotinib treatment followed by concomitant radiotherapy for advanced lung cancer: A mono-institutional experience. Lung Cancer 2011;73:189-94. 35. Osimertinib, Surgery, and Radiation Therapy in Treating Patients With Stage IIIB or IV Non-small Cell

Lung

Cancer

With

EGFR

Mutations.

Available

online:

https://clinicaltrials.gov/ct2/show/NCT03410043. Accessed October 29, 2019.

Figure Legends Figure1. Flowchart of patient enrollment. NSCLC, non-small cell lung cancer; EGFR: epidermal growth factor receptor. TKI, tyrosine kinase inhibitors. Figure2. The distribution of metastatic sites at time of maximal osimertinib response. The baseline distribution of disease sites is shown in the lower bars. Sites of residual disease at maximal osimertinib response are shown in the upper bars. Figure3. Patterns of residual disease at maximal osimertinib response in 26 patients eligible for consolidative SBRT. (A) patients with one involved organ (B) patients with two involved organs (C) patients with three involved organs. Figure4. Patterns of recurrence analysis. (A) Venn diagram of patterns of recurrence in patients eligible for consolidative SBRT at maximal response. (B) Venn diagram of patterns of recurrence in patients ineligible for consolidative SBRT at maximal response. (C) Kaplan-Meier curves for PFS in patients with and without consolidative SBRT eligibility. Patients eligible for consolidative 17

SBRT had significantly longer PFS (P = 0.002) than those without consolidative SBRT eligibility. RR, residual-site recurrence. NR, new-site recurrence. RNR, combined RR and NR. PFS, progression-free survival. SBRT, stereotactic body radiation therapy.

18

Table 1. Baseline characteristics of the 97 patients before initiation of osimertinib All patients

n (%)

Patients eligible for

Patients ineligible

SBRT (n=26)

for SBRT (n=71)

n (%)

n (%)

0.635

Age (years)

Median

61

61

61

Range

29-80

29-75

35-80

0.356

Sex

Male

41 (42.3)

9 (34.6)

32 (45.1)

Female

56 (57.7)

17 (65.4)

39 (54.9)

0.509

ECOG PS score

0-1

2

93 (95.9)

26 (100)

67 (94.4)

4 (4.1)

0 (0)

4 (5.6)

0.466

Histology

Adenocarcinoma

Non-adenocarcinoma

P-value

95 (97.9)

25 (96.2)

70 (98.6)

2 (2.1)

1 (3.8)

1 (1.4)

0.748

Primary size (cm)

Median

2.0

2.0

2.0

Range

0.0-9.8

0.0-9.8

0.0-7.2

T stage

0.011

T0-2

54 (55.7)

20 (76.9)

34 (47.9)

T3-4

43 (44.3)

6 (23.1)

37 (52.1)

0.653

N stage

N0

23 (23.7)

7 (26.9)

16 (22.5)

N1-3

74 (76.3)

19 (73.1)

55 (77.5)

Number

of

metastatic

<0.001

lesions

≤5

26 (26.8)

15 (57.7)

11 (15.5)

>5

71 (73.2)

11 (42.3)

60 (84.5)

Number of metastatic organs

0.019

1-2

73 (75.3)

24 (92.3)

49 (69.0)

>2

24 (24.7)

2 (7.7)

22 (31.0)

0.670

Lung metastases

Yes

63 (64.9)

16 (61.5)

47 (66.2)

No

34 (35.1)

10 (38.5)

24 (33.8)

0.104

Brain metastases

Yes

31 (32.0)

5 (19.2)

26 (36.6)

No

66 (68.0)

21 (80.8)

45 (63.4)

0.110

Liver metastases

Yes

15 (15.5)

1 (3.8)

14 (19.7)

No

82 (84.5)

25 (96.2)

57 (80.3)

0.050

Bone metastases

Yes

67 (69.1)

14 (53.8)

53 (74.6)

No

30 (30.9)

12 (46.2)

18 (25.4)

0.892

Adrenal metastases

Yes

10 (10.3)

2 (7.7)

8 (11.3)

No

87 (89.7)

24 (92.3)

63 (88.7)

0.576

Prior radiotherapy

Yes

33 (34.0)

10 (38.5)

23 (32.4)

No

64 (66.0)

16 (61.5)

48 (67.6)

0.340

Prior treatment lines

0

15 (15.5)

4 (15.4)

11 (15.5)

1

46 (47.4)

9 (34.6)

37 (52.1)

2

25 (25.8)

10 (38.5)

15 (21.1)

3

11 (11.3)

3 (11.5)

8 (11.3)

ECOG: Eastern Cooperative Oncology Group

Table 2. Results of univariate and multivariate logistic regression analysis for predictors of consolidative SBRT eligibility. Univariate Analysis

Multivariate Analysis

OR

95%CI

p

Age (≤60y vs >60y)

0.608

0.243-1.520

0.287

Sex (male vs female)

1.550

0.609-3.942

0.358

Primary tumor size (≤2.0 vs >2.0)

1.033

0.416-2.567

0.944

T stage (T1-2 vs T3-4)

3.627

1.302-10.103

0.014

N stage (N0 vs N1-3)

1.266

0.452-3.547

0.653

Number of metastatic organs (1-2 vs >2)

5.388

1.169-24.824

0.031

Lung metastases (No vs Yes)

1.224

0.483-3.104

0.670

Liver metastases (No vs Yes)

6.140

0.765-49.274

0.088

Brain metastases (No vs Yes)

2.427

0.817-7.205

0.110

Adrenal metastases (No vs Yes)

1.524

0.302-7.694

0.610

Bone metastases (No vs Yes)

2.524

0.988-6.450

0.053

Prior treatment lines (0 vs ≥1)

0.992

0.286-3.442

0.990

Prior radiotherapy (No vs Yes)

0.767

0.301-1.950

0.577

OR

95%CI

p

2.991

1.021-8.762

0.046

2.066

0.353-12.091

0.421

2.842

0.270-29.870

0.384

2.063

0.752-5.659

0.159