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Brain Metastases in EGFR- and ALK-Positive NSCLC: Outcomes of Central Nervous System-Penetrant Tyrosine Kinase Inhibitors Alone Versus in Combination With Radiation

Open AccessPublished:August 26, 2021DOI:https://doi.org/10.1016/j.jtho.2021.08.009

      Abstract

      Introduction

      Management of central nervous system (CNS) metastases in patients with driver-mutated NSCLC has traditionally incorporated both tyrosine kinase inhibitors (TKIs) and intracranial radiation. Whether next generation, CNS-penetrant TKIs can be used alone without upfront radiation, however, remains unknown. This multi-institutional retrospective analysis aimed to compare outcomes in patients with EGFR- or ALK-positive NSCLC who received CNS-penetrant TKI therapy alone versus in combination with radiation for new or progressing intracranial metastases.

      Methods

      Data were retrospectively collected from three academic institutions. Two treatment groups (CNS-penetrant TKI alone versus TKI + CNS radiation therapy) were compared for both EGFR- and ALK-positive cohorts. Outcome variables included time to progression, time to intracranial progression, and time to treatment failure, measured from the date of initiation of CNS-penetrant TKI therapy.

      Results

      A total of 147 patients were included (EGFR n = 94, ALK n = 52, both n = 1). In patients receiving radiation, larger metastases, neurologic symptoms, and receipt of steroids were more common. There were no significant differences between TKI and CNS radiation therapy plus TKI groups for any of the study outcomes, including time to progression (8.5 versus 6.9 mo, p = 0.13 [EFGR] and 11.4 versus 13.4 mo, p = 0.98 [ALK]), time to intracranial progression (14.8 versus 20.5 mo, p = 0.51 [EGFR] and 18.1 versus 21.8 mo, p = 0.65 [ALK]), or time to treatment failure (13.8 versus 8.6 mo, p = 0.26 [EGFR] and 13.5 versus 23.2 mo, p = 0.95 [ALK]).

      Conclusions

      These results provide preliminary evidence that intracranial activity of CNS-penetrant TKIs may enable local radiation to be deferred in appropriately selected patients without negatively affecting progression.

      Keywords

      Introduction

      Several oncogenic driver alterations in NSCLC have been identified in recent years as predictors of response to targeted therapy. In patients with metastatic NSCLC harboring EGFR mutations or ALK rearrangements, first-generation tyrosine kinase inhibitors (TKIs) improve progression-free survival (PFS) compared with platinum-doublet chemotherapy.
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      Although this confirmed the ongoing importance of radiotherapy for CNS disease, 98% of patients in this study received erlotinib, which has limited intracranial activity. The emergence of next-generation TKI therapies with improved CNS activity raises the question of whether these previous findings continue to be applicable. In the case of EGFR-targeted therapies, for example, the distribution of osimertinib within the brains of in vivo mouse models has been found to be greater than that of gefitinib, rociletinib, or afatinib in preclinical studies.
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      Despite these improvements, it is unclear whether the use of CNS-penetrant TKI therapy alone, with radiation reserved for intracranial progression, results in sufficient intracranial control and comparable outcomes relative to upfront radiation combined with TKI therapy. This remains an important clinical question as providers attempt to balance long-term cancer-related outcomes with the toxicities of TKI therapies and CNS radiation. Therefore, in this retrospective, multicenter cohort, we aimed to compare intracranial and overall outcomes in patients with EGFR-mutated or ALK-rearranged NSCLC metastatic to the CNS receiving CNS-penetrant TKI therapy alone versus in combination with upfront radiotherapy (WBRT or SRS).

      Materials and Methods

      Patients and Data Collection

      Three academic medical centers (University of California San Francisco, Stanford University, University of Colorado) participated in this retrospective multicenter cohort study. According to distinct institutional review board–approved protocols at each center, patient data was collected by chart review. Inclusion criteria included any patient with EGFR-mutated or ALK-rearranged NSCLC with new or progressing parenchymal CNS metastases at the time of starting single-agent, CNS-penetrant TKI therapy. For the purpose of this analysis, CNS-penetrant TKI therapy included osimertinib or rociletinib (non–Food and Drug Administration approved, withdrawn) for EGFR-mutated NSCLC and alectinib, brigatinib, lorlatinib, or ensartinib (non–Food and Drug Administration approved, in study) for ALK-rearranged NSCLC. Exclusion criteria included stable CNS metastases at the time of TKI initiation; receipt of TKI therapy in combination with other systemic therapy (e.g., bevacizumab, platinum-doublet chemotherapy); previous exposure to CNS-penetrant therapy before the onset of new or progressing CNS metastases; presence of calvarial, dural, or leptomeningeal metastases alone without parenchymal disease; or insufficient follow-up (e.g., lack of imaging or follow-up after starting TKI therapy, discontinuation of TKI therapy for toxicity or death before first radiographic response assessment).
      Patients with EGFR-mutated and ALK-rearranged NSCLC were analyzed separately. In each case, eligible patients were categorized according to the treatments they received: either (1) CNS-penetrant TKI alone or (2) CNS-penetrant TKI plus CNS radiotherapy (WBRT or SRS) administered within 8 weeks of TKI initiation as summarized in Figure 1. In one case, a patient received consolidation CNS radiotherapy beyond 8 weeks of TKI initiation but did not have evidence of progression at that time and was therefore included in the combination treatment subgroup.
      Figure thumbnail gr1
      Figure 1Consort diagram. CNS, central nervous system; RT, radiation therapy; SRS, stereotactic radiosurgery; TKI, tyrosine kinase inhibitor; WBRT, whole-brain radiation therapy.
      The following baseline variables were collected: age, sex, ethnicity, race, smoking history, tumor histopathology, and type of EGFR or ALK alteration. Additional variables at the time of initiation of CNS-penetrant TKI therapy were also collected, including performance status (Eastern Cooperative Oncology Group), number and location of new or progressing brain metastases, size of largest brain metastasis, presence or absence of neurologic symptoms, and receipt of steroids. Treatment-related data included the name and duration of all systemic and localized (e.g., surgery or radiation) therapies received before and through the initiation of CNS-penetrant TKI therapy. For CNS-penetrant TKI therapy, note was made of any changes in dose owing to toxicity or progression. Duration of therapy was calculated as the time in months from the start date of any given therapy to its date of discontinuation as reflected in the patient records. Dates of diagnosis, initial metastases, radiographic CNS progression at the start of CNS-penetrant TKI therapy, progression on therapy, most recent follow-up, and death, if applicable, were collected for progression and survival analyses.

      Outcome Variables

      Outcome variables assessed in the entire cohort were time to progression at any site (intracranial or extracranial), time to intracranial progression (local or distant), and time to treatment failure. OS was calculated in the subset of patients who received CNS-penetrant TKI therapy in the first-line setting. Time measurements were calculated in months beginning from the initiation date of CNS-penetrant TKI therapy. Treatment failure was defined as an increase in dose of CNS-penetrant TKI therapy owing to progression, initiation of new systemic therapy owing to intracranial or extracranial progression, change in therapy owing to toxicity, addition of radiation for oligoprogressive disease, or death. Progression was defined according to radiographic imaging reports rather than strict Response Evaluation Criteria in Solid Tumors (RECIST) criteria and relied on the interpretation of institutional radiologists to define time and site of progression. Magnetic resonance imaging of the brain; positron emission tomography–computed tomography of the body; and computed tomography of the chest, abdomen, and pelvis were monitored on a schedule defined by individual institutions and providers. OS was defined as time from TKI start to date of death (or last follow-up).

      Statistical Analysis

      Baseline characteristics were analyzed using unpaired two-sample Wilcoxon test for continuous variables and Fisher’s exact tests for categorical variables. The Kaplan-Meier method was used to estimate time to any progression, time to intracranial progression, and time to treatment failure. A log-rank test was used to evaluate between-group differences for each of the outcome variables. Hazard ratios (HRs) and associated 95% confidence intervals were calculated with the use of a multivariable Cox proportional hazards model. Variables for which p value is less than 0.20 by a univariate log-rank test were included in multivariate regression. These included gender, age (<60, ≥60 y), smoking status (never, former or current), pretreatment with any systemic therapy (including non-CNS-penetrant TKI), previous CNS radiation exposure, therapy group (combination of radiation + TKI versus TKI alone), steroid use before CNS-penetrant TKI, number of brain metastases at CNS-penetrant TKI initiation, maximum dimension of largest brain metastasis at CNS-penetrant TKI initiation, and presence of symptoms from brain metastases. A prespecified p value threshold of less than 0.05 was used throughout the analysis unless otherwise stated. Statistical analysis was conducted with R (Version 3.4.1, R Foundation for Statistical Computing, Vienna, Austria).

      Results

      Inclusion Cohort

      A total of 147 patients with new or progressing CNS metastases at the time of initiating CNS-penetrant TKI between March 2014 and January 2020 were identified (Fig. 1). The patients were distributed across the three treatment centers as follows: Stanford University (n = 81), University of California San Francisco (n = 46), and University of Colorado (n = 20). This included 94 patients with cancer harboring EGFR mutations, 52 with ALK rearrangements, and one with both. The distribution of specific EGFR and ALK mutations is illustrated in Supplementary Table 1.

      Patient Characteristics

      Patient characteristics are summarized in Table 1 according to treatment groups and mutation status. The median follow-up time from the date of original diagnosis was 16.8 months (range: 0.9–45.7 mo) and 27.8 months (range: 2.5–64.7 mo) for the EGFR and ALK cohorts, respectively. Consistent with the known demographic patterns for these mutations, patients in both cohorts were relatively young (EGFR median age = 59 y, range: 35.3–92.7 and ALK median age = 52 y, range: 42.4–61.2), and most were never smokers (75%). Most patients at the time of CNS-penetrant TKI initiation also had an Eastern Cooperative Oncology Group performance status of 0 to 1 (91%). The characteristics of the new or progressing brain metastases identified at the time of starting CNS-penetrant TKI therapy varied by treatment received. Although not significantly different, patients receiving TKI therapy alone trended toward having fewer brain metastases at presentation compared with those receiving TKI therapy plus radiation in the EGFR cohort (p = 0.173), whereas in the ALK cohort, those receiving TKI therapy plus radiation trended toward having fewer brain metastases at presentation (p = 0.143). Patients receiving TKI therapy alone were more likely to have smaller brain metastases relative to those receiving TKI therapy plus radiation when comparing the radiographic dimension of the largest lesions identified at the time of CNS-penetrant TKI initiation (EGFR p = 0.027 and ALK p = 0.078).
      Table 1Patient Demographics and Clinical Characteristics
      CharacteristicsEGFR: TKI Alone, n = 52EGFR: Rad + TKI, n = 43p ValueALK: TKI Alone, n = 32ALK: Rad + TKI, n = 20p Value
      Duration of follow-up0.4940.756
       Median (range)16.6 (0.9–36.0)mo17.3 (2.5–45.7)mo30.2 (2.5–64.7)mo25.9 (5.0–55.4)Mo
       IQR(9.2–23.2)mo(11.8–24.0)mo(16.5–35.9)mo(14.0–37.1)Mo
      Age at diagnosis0.9500.461
       Median (range)59.9 (35.3–92.7)y59.8 (36.8–84.0)y50.6 (22.0–72.1)y54.7 (37.1–76.9)Y
       IQR(51.6–67.6)y(51.1–66.4)y(42.4–60.9)y(45.5–61.2)Y
      GenderNo.%No.%0.660No.%No.%0.404
       Female3567.33172.11753.1840.0
       Male1732.71227.91546.91260.0
      Ethnicity0.007
      p < 0.05.
       Non-Hispanic/Latino4484.643100.03196.91894.7
       Hispanic/Latino815.400.013.115.3
      Race(n = 50)(n = 42)0.966(n = 31)(n = 19)1.000
       White2040.01638.12064.51368.4
       Asian2142.02047.6825.8526.3
       Black/African American12.000.013.200.0
       Hawaiian/Pacific Islander12.012.400.000.0
       American Indian/Alaskan Native00.000.013.200.0
       Other/multiple races714.0511.913.215.3
      Smoking status(n = 51)0.3320.401
       Never3772.53479.12681.31365.0
       Former1427.5818.6515.6630.0
       Current00.012.313.115.0
      Histopathology1.0001.000
       Adenocarcinoma5198.14297.73093.81995.0
       Adenosquamous carcinoma11.912.313.115.0
       Squamous cell carcinoma00.000.013.100.0
      ECOG performance status at CNS-penetrant TKI initiationNo.No.0.083No.No.0.689
       0–14693.93583.32996.71789.5
       2–336.1716.713.3210.5
      Number of brain mets at CNS-penetrant TKI initiation0.1730.143
       1–32446.21227.9618.81050.0
       4–6917.3614.0618.8315.0
       7–935.8614.0412.515.0
       ≥101630.81944.21546.9630.0
      Max dimension of brain mets at CNS-penetrant TKI initiation0.027
      p < 0.05.
      0.078
       <1.0 cm3470.81842.91860.0735.0
       1.0–1.9 cm1122.91433.31136.7840.0
       2.0–2.9 cm24.2716.713.3315.0
       ≥3.0 cm12.137.100.0210.0
      Leptomeningeal disease at CNS-penetrant TKI initiation611.8511.60.98913.100.00.453
      Symptomatic from brain mets at CNS-penetrant TKI initiation612.02050.00.0001
      p < 0.05.
      721.9844.40.179
      Steroids before CNS-penetrant TKI initiation815.42048.80.0005
      p < 0.05.
      39.7631.60.055
      CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; IQR, interquartile range; Max, maximum; Mets, metastases; Rad, radiation; TKI, tyrosine kinase inhibitor.
      a p < 0.05.
      A higher percentage of patients in the EGFR cohort receiving TKI therapy plus radiation were also symptomatic from their brain metastases relative to those receiving TKI therapy alone (12% EGFR TKI alone versus 50% RT + EGFR TKI, p < 0.001). Congruently, they were also more likely to have received steroids before TKI initiation (15.4% EGFR TKI alone versus 48% RT + EGFR TKI, p < 0.001). The ALK cohort revealed a similar trend, though this difference did not reach statistical significance.
      Because many patients did not have brain metastases emerge until late in their disease course, treatment histories varied before CNS-penetrant TKI initiation (Table 2). CNS-penetrant TKI was the first-line therapy received in 44% of patients in the EGFR cohort and 37% of patients in the ALK cohort. With respect to previous therapies, the most common previous therapy received by patients with EGFR in both treatment groups was first-generation, non-CNS-penetrant TKIs. In the ALK cohort, previous first-generation TKI use was more common among those patients receiving TKI therapy alone (p = 0.008), whereas those receiving TKI therapy plus radiation were more likely to have received CNS-penetrant TKI therapy as first-line treatment (TKI alone 21.9% versus RT + TKI 63.2%). None of the groups differed significantly with respect to previous CNS radiation exposure, although it is important to note that across all groups, 28% of patients had received some form of CNS radiation before CNS-penetrant TKI. With respect to CNS-penetrant TKI therapy, most patients with an EGFR mutation received osimertinib (95%) with the remaining few receiving rociletinib. Among those with ALK rearrangements, most patients (80%) received alectinib with a minority receiving brigatinib, ensartinib, or lorlatinib.
      Table 2Patient Treatment and Clinical Response
      VariableEGFR: TKI Alone (n = 52)EGFR: Rad+TKI (n = 43)p ValueALK: TKI Alone (n = 32)ALK: Rad+TKI (n = 20)p Value
      No.%No.%No.%No.%
      Treatment prior to CNS-penetrant TKI
       1st generation TKI2751.9%2046.5%0.6042475.0%735.0%0.005
      p < 0.05.
       Other systemic therapy1630.8%1330.2%0.9591340.6%420.0%0.130
       Platinum-based chemotherapy1528.8%1330.2%1340.6%420.0%
       Anti-VEGF therapy59.6%49.3%39.4%15.0%
       Checkpoint inhibitor35.8%511.6%26.3%210.0%
       Any CNS radiation1528.8%1125.6%0.7271031.3%525.0%0.640
       SRS1426.9%920.9%928.1%315.0%
       WBRT23.8%49.3%515.6%420.0%
      CNS-penetrant TKI
       Osimertinib4892.3%4297.7%00.0%15.0%
       Rociletinib47.7%12.3%00.0%00.0%
       Alectinib00.0%00.0%2681.3%1680.0%
       Brigatinib00.0%00.0%26.3%15.0%
       Ensartinib00.0%00.0%39.4%210.0%
       Lorlatinib00.0%00.0%13.1%00.0%
      CNS radiation at time of CNS-penetrant TKI
       SRS00.0%3479.1%00.0%1680.0%
       WBRT00.0%920.9%00.0%420.0%
      Line of therapy(n = 19)
       1st2140.4%2148.8%721.9%1263.2%
       2nd1732.7%920.9%1031.3%210.5%
       3rd713.5%49.3%1237.5%210.5%
       4th47.7%49.3%13.1%15.3%
       5th23.8%37.0%26.3%210.5%
       6th11.9%24.7%00.0%00.0%
      Best response
       Complete response00.0%00.0%39.4%00.0%
       Partial response3873.1%3274.4%2887.5%1995.0%
       Stable disease59.6%511.6%00.0%15.0%
       Progressive disease917.3%614.0%13.1%00.0%
      Site of first progression(n = 44)(n = 22)
       Intracranial1227.3%719.4%1150.0%642.9%
       Extracranial1943.2%2363.9%836.4%750.0%
       Both1329.5%616.7%313.6%17.1%
      Number of new brain mets at time of CNS progression(n = 24)(n = 13)
       1-31354.2%753.8%430.8%466.7%
       4-628.3%430.8%323.1%233.3%
       7-900.0%00.0%00.0%00.0%
       ≥10312.5%00.0%00.0%00.0%
       Leptomeningeal disease625.0%215.4%646.2%00.0%
      Reason for TKI discontinuation(n = 44)(n = 21)
       Progressive disease - TKI dose increase511.4%513.9%314.3%00.0%
       Progressive disease - intracranial radiation818.2%616.7%628.6%541.7%
       Progressive disease - extracranial radiation613.6%1027.8%419.0%216.7%
       Progressive disease - new systemic therapy1943.2%925.0%523.8%541.7%
       Progressive disease - hospice49.1%12.8%14.8%00.0%
       Toxicity00.0%411.1%14.8%00.0%
       Death24.5%12.8%14.8%00.0%
      ALK, anaplastic lymphoma kinase; CNS, central nervous system; EGFR, epidermal growth factor receptor; SRS, stereotactic radiosurgery; TKI, tyrosine kinase inhibitor; WBRT, whole brain radiotherapy.
      a p < 0.05.

      Outcomes

      In unmatched, unadjusted Kaplan-Meier univariate comparisons, there was no significant difference in outcomes between patients receiving EGFR CNS-penetrant TKI alone versus TKI plus radiation with respect to median time to any progressive disease (TKI 8.5 mo versus RT + TKI 6.9 mo, p = 0.13), intracranial progression (TKI 14.8 mo versus RT + TKI 20.5 mo, p = 0.51), or time to treatment failure (TKI 13.8 mo versus RT + TKI 8.6 mo, p = 0.26) (Figs. 2A and B and 3A). Similarly, in the ALK cohort, there was no significant difference between time to any progressive disease (TKI 11.4 mo versus RT + TKI 13.4 mo, p = 0.98), intracranial progression (TKI 18.1 mo versus RT + TKI 21.8 mo, p = 0.65), or time to treatment failure (TKI 13.5 mo versus RT + TKI 23.2 mo, p = 0.95) (Figs. 2C and D and 3B).
      Figure thumbnail gr2
      Figure 2Unmatched, unadjusted, univariate Kaplan-Meier estimate of time to any progression (A, C) and time to intracranial progression (B, D), calculated from date of CNS-penetrant TKI initiation in patients treated with CNS-penetrant TKI alone versus TKI plus Rad. CI, confidence interval; CNS, central nervous system; NR, not reached; Rad, radiation; TKI, tyrosine kinase inhibitor.
      Figure thumbnail gr3
      Figure 3Unmatched, unadjusted, univariate Kaplan-Meier estimate of time to treatment failure in patients with an EGFR mutation (A) or ALK rearrangment (B) calculated from the date of CNS-penetrant TKI initiation in patients treated with CNS-penetrant TKI alone versus TKI plus Rad. CI, confidence interval; CNS, central nervous system; NR, not reached; Rad, radiation; TKI, tyrosine kinase inhibitor; TTTF, time to treatment failure.
      A subset analysis was conducted among patients receiving CNS-penetrant TKI as first-line therapy. Findings remained similar, with no statistically significant difference in the EGFR cohort for either time to any progressive disease (TKI 11.5 mo versus RT + TKI 8.8 mo, p = 0.12) or time to treatment failure (TKI 14.2 mo versus RT + TKI 9.9 mo, p = 0.48). Similarly, in the ALK cohort, there was no significant difference for time to any progressive disease (TKI 15.8 mo versus RT + TKI 23.7 mo, p = 0.73) or time to treatment failure (TKI NR versus RT + TKI 24.6 mo, p = 0.57) (Supplementary Fig. 1). In addition, for the CNS-penetrant TKI as first-line therapy subgroup, there was no statistically significant difference in OS for the EGFR cohort (TKI NR mo versus RT + TKI 44.0 mo, p = 0.92) or the ALK cohort (TKI NR mo versus RT + TKI NR mo, p = 0.5) (Supplementary Fig. 2).
      In a multivariate analysis of the EGFR cohort, pretreatment with any systemic therapy was significantly associated with increased risk of time to any progression (HR = 1.85 [1.12–3.06], p = 0.015), time to intracranial progression (HR = 2.28 [1.24–4.20], p = 0.008), and time to treatment failure (HR = 1.75 [1.06–2.88], p = 0.027) (Fig. 4AC and Supplementary Table 2). All other variables including gender, age, smoking status, previous CNS radiation, therapy group (combination radiation + TKI versus TKI alone), steroid use before CNS-penetrant TKI, number of brain metastases, maximum dimension of largest brain metastasis, and presence of symptoms from brain metastases at TKI initiation were not significant (p > 0.05). In a similar multivariate analysis of the ALK cohort, there were no significant predictors of any of the three outcome variables (Supplementary Table 3).
      Figure thumbnail gr4ab
      Figure 4Multivariate analysis Cox proportional hazards for time to any progression (A), time to treatment failure (B), and time to intracranial progression (C) in patients with an EGFR mutation. There were no significant predictors in the ALK group. ∗Indicates p values < 0.05. AIC, Akaike information criterion; CI, confidence interval; Mets, metastases; Rad, radiation; TKI, tyrosine kinase inhibitor.
      Figure thumbnail gr4c
      Figure 4Multivariate analysis Cox proportional hazards for time to any progression (A), time to treatment failure (B), and time to intracranial progression (C) in patients with an EGFR mutation. There were no significant predictors in the ALK group. ∗Indicates p values < 0.05. AIC, Akaike information criterion; CI, confidence interval; Mets, metastases; Rad, radiation; TKI, tyrosine kinase inhibitor.

      Discussion

      To best of our knowledge, this is the largest study to date revealing similar outcomes in patients with EGFR-mutated or ALK-rearranged NSCLC who received CNS-penetrant TKI therapy alone versus TKI plus intracranial radiation for new or progressing CNS metastases.
      In this study, median time to progression was similar in the TKI alone and TKI plus radiation groups in both the EGFR- (8.5 versus 6.9 mo) and ALK-positive (11.4 versus 13.4 mo) cohorts. Because progression was defined in this analysis by retrospective evaluation of radiographic reports rather than Response Evaluation Criteria in Solid Tumors criteria, time to treatment failure was also assessed as an alternative end point that (1) is less subject to interobserver variability and (2) has been previously found to correlate with PFS in patients with NSCLC receiving TKI therapy.
      • Blumenthal G.M.
      • Gong Y.
      • Kehl K.
      • et al.
      Analysis of time-to-treatment discontinuation of targeted therapy, immunotherapy, and chemotherapy in clinical trials of patients with non-small-cell lung cancer.
      Although numerically longer with combination therapy in the ALK-rearranged cohort, time to treatment failure was not statistically different between the two treatment groups. Furthermore, the multivariate analysis found that treatment group (TKI alone versus TKI plus radiation) was not associated with outcomes. In contrast, pretreatment with any systemic therapy before CNS-penetrant TKI was associated with increased risk of progression and treatment failure, which likely reflects more advanced, resistant disease in patients who have already experienced progression on previous therapies. Collectively, these results provide initial evidence that it may be safe to defer upfront Rad without negatively affecting disease control.
      These results differ from previous analyses of older, first-generation TKI therapies, which revealed improved outcomes with the combination of TKI therapy plus radiation. As previously mentioned, Magnuson et al.
      • Magnuson W.J.
      • Lester-Coll N.H.
      • Wu A.J.
      • et al.
      Management of brain metastases in tyrosine kinase inhibitor–naïve epidermal growth factor receptor–mutant non–small-cell lung cancer: a retrospective multi-institutional analysis.
      reported significantly longer OS (46 [SRS] versus 30 [WBRT] versus 25 mo [TKI alone]) in patients receiving SRS or WBRT plus erlotinib compared with erlotinib alone. In addition, median time to intracranial progression was 23 and 24 months, respectively, for patients receiving SRS or WBRT plus erlotinib versus 17 months for patients receiving erlotinib alone (log-rank p = 0.025). Similar results were confirmed in a large meta-analysis of 13 studies wherein Du et al.
      • Du X.-J.
      • Pan S.M.
      • Lai S.Z.
      • et al.
      Upfront cranial radiotherapy vs. EGFR tyrosine kinase inhibitors alone for the treatment of brain metastases from non-small-cell lung cancer: a meta-analysis of 1465 patients.
      reported a statistically significant improvement in survival for upfront radiation plus TKI therapy (erlotinib, gefitinib, or icotinib) compared with TKI therapy alone (HR = 0.71, confidence interval: 0.58–0.86, p = 0.0005). Despite these findings, other studies investigating WBRT in particular have suggested that this modality may not have the same added survival benefit.
      • Jiang T.
      • Su C.
      • Li X.
      • et al.
      EGFR TKIs plus WBRT demonstrated no survival benefit other than that of TKIs alone in patients with NSCLC and EGFR mutation and brain metastases.
      • Chen Y.
      • Yang J.
      • Li X.
      • et al.
      First-line epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor alone or with whole-brain radiotherapy for brain metastases in patients with EGFR-mutated lung adenocarcinoma.
      • Yang J.J.
      • Zhou C.
      • Huang Y.
      • et al.
      Icotinib versus whole-brain irradiation in patients with EGFR-mutant non-small-cell lung cancer and multiple brain metastases (BRAIN): a multicentre, phase 3, open-label, parallel, randomised controlled trial.
      Although the use of SRS with TKI therapy has therefore remained standard, next-generation TKI therapies, such as osimertinib, are known to better penetrate the CNS.
      • Ballard P.
      • Yates J.W.
      • Yang Z.
      • et al.
      Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity.
      ,
      • Yang J.C.H.
      • Kim S.W.
      • Kim D.W.
      • et al.
      Osimertinib in patients with epidermal growth factor receptor mutation–positive non–small-cell lung cancer and leptomeningeal metastases: the BLOOM study.
      This is likely a contributing factor to the superior CNS response rates (91% versus 68%) found with osimertinib compared with first-generation inhibitors (erlotinib or gefitinib) in patients with measurable CNS disease.
      • Reungwetwattana T.
      • Nakagawa K.
      • Cho B.C.
      • et al.
      CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non–small-cell lung cancer.
      With respect to next-generation ALK inhibitors, alectinib, brigatinib, lorlatinib, and ensartinib all have favorable intracranial activity as well, with both alectinib and lorlatinib achieving intracranial response rates greater than 80% in patients with measurable CNS disease.
      • Peters S.
      • Camidge D.R.
      • Shaw A.T.
      • et al.
      Alectinib versus crizotinib in untreated ALK-positive non–small-cell lung cancer.
      • Camidge D.R.
      • Kim H.R.
      • Ahn M.J.
      • et al.
      Brigatinib versus crizotinib in advanced ALK inhibitor–naive ALK-positive non–small cell lung cancer: second interim analysis of the phase III ALTA-1L trial.
      • Shaw A.T.
      • Bauer T.M.
      • de Marinis F.
      • et al.
      First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer.
      • Selvaggi G.
      • Wakelee H.A.
      • Mok T.
      • et al.
      Phase III randomized study of ensartinib vs crizotinib in anaplastic lymphoma kinase (ALK) positive NSCLC patients: eXalt3.
      ,
      • Yang Y.
      • Zhou J.
      • Zhou J.
      • et al.
      Efficacy, safety, and biomarker analysis of ensartinib in crizotinib-resistant, ALK-positive non-small-cell lung cancer: a multicentre, phase 2 trial.
      Although the CNS activity of next-generation TKI therapies is thereby well established, to our knowledge, few studies before this one have evaluated the added benefit of intracranial radiation in patients receiving CNS-penetrant TKI therapies. One small study from one of our institutions previously evaluated patients with EGFR-mutated NSCLC who experienced CNS progression at the time of starting osimertinib and found that time to treatment failure (15.1 versus 7.7 mo), PFS (8.8 mo versus NR), and OS (NR versus 16.2 mo) were not statistically different in patients receiving osimertinib alone (n = 11) versus those receiving osimertinib plus radiation (n = 9).
      • Xie L.
      • Nagpal S.
      • Wakelee H.A.
      • Li G.
      • Soltys S.G.
      • Neal J.W.
      Osimertinib for EGFR-mutant lung cancer with brain metastases: results from a single-center retrospective study.
      Although eight patients from this previous study are included in the present analysis, our findings expand on those early exploratory results by reporting outcomes from a larger cohort, drawing on data from multiple centers, and including patients with ALK-rearranged NSCLC. Although we await further confirmation from randomized studies, such as the OUTRUN clinical trial (NCT03497767), the results reported in our analysis here provide preliminary insights that can guide therapeutic decision-making in patients with EGFR- or ALK-positive NSCLC starting CNS-penetrant TKI therapy for intracranial metastases.
      • gov ClinicalTrials.
      A randomised phase II trial of osimertinib with or without SRS for EGFR mutated NSCLC with brain metastases (OUTRUN).
      Whether certain patients receiving CNS-penetrant TKI therapy still benefit from upfront radiation remains possible. Given the retrospective nature of this study, the decision to add intracranial radiation was made on a case-by-case basis per clinician discretion, with larger size of CNS metastases, symptomatic disease, and the need for steroid pretreatment being more common among patients who received radiation. Despite these imbalances favoring the TKI alone cohort, outcomes did not differ between the TKI alone and TKI plus radiation groups in our study, suggesting early CNS radiation may have provided additive disease control among patients with unfavorable or more aggressive CNS disease features. Furthermore, factors such as number of CNS metastases and the presence of symptoms have been reported to affect survival in NSCLC, but this study was not powered to isolate the benefit of early CNS radiation among patients with matched baseline CNS disease characteristics.
      • Sperduto P.W.
      • Yang T.J.
      • Beal K.
      • et al.
      Estimating survival in patients with lung cancer and brain metastases: an update of the graded prognostic assessment for lung cancer using molecular markers (lung-molGPA).
      ,
      • Steindl A.
      • Yadavalli S.
      • Gruber K.A.
      • et al.
      Neurological symptom burden impacts survival prognosis in patients with newly diagnosed non-small cell lung cancer brain metastases.
      Therefore, future studies should aim to clarify what local CNS factors, if any, should be used to (1) prognosticate CNS metastases in the era of CNS-penetrant TKI therapies and (2) guide individual patient selection with respect to the use or deferral of upfront radiation.
      As the role of upfront local ablative therapy gains more attention, it is also possible that deferral of intracranial radiation may not apply to patients with oligometastatic disease. In a recent phase 3 trial of patients with oligometastatic EGFR-mutated NSCLC, the combination of local ablative therapy plus first-line TKI therapy (erlotinib or gefitinib) was associated with improvement in both PFS and OS.
      • Wang X.
      • Bai Y.F.
      • Zeng M.
      First-line tyrosine kinase inhibitor with or without aggressive upfront local radiation therapy in patients with EGFRm oligometastatic non-small-cell lung cancer: interim results of a randomized phase III, open-label clinical trial (SINDAS) (NCT02893332).
      Although patients with brain metastases before the time of randomization were excluded from this analysis, other retrospective studies have reported favorable outcomes in patients with oligometastatic disease within the brain who received radiation after starting EGFR TKI therapy.
      • Xu Q.
      • Zhou F.
      • Liu H.
      • et al.
      Consolidative local ablative therapy improves the survival of patients with synchronous oligometastatic NSCLC harboring EGFR activating mutation treated with first-line EGFR-TKIs.
      Although this represents an intriguing approach, only a few patients will present with oligometastases. In addition, time to intracranial progression was longer than time to any progression in both the EGFR- and ALK-positive cohorts of our study, regardless of whether intracranial radiation was received. This suggests that extracranial disease burden may be a more important driver of survival in the setting of next-generation, CNS-penetrant TKI use. Furthermore, although it may be safe, on the basis of our results, to reserve intracranial radiation for the time of progression, regular surveillance imaging to monitor for CNS oligoprogression will remain important to enable timely use of local RT in this setting.
      There are multiple strengths and limitations associated with this present analysis. Strengths include its multi-institutional design, inclusion of both EGFR- and ALK-positive cohorts, and focus on next-generation, CNS-penetrant TKI therapies, which reflects current standard-of-care practice. Limitations include the small, underpowered sample size and the baseline imbalances between the two treatment groups, which reflect the nonrandomized, retrospective nature of this study. Although factors such as number of CNS metastases, symptomatic CNS metastases, and use of pretreatment steroids were not significantly predictive of time to progression or treatment failure in multivariate analyses, small sample size and heterogeneity may limit our ability to detect real effects associated with these variables. For these reasons, propensity score matching was also unable to be performed, and primary analyses of disease control outcomes between the TKI and TKI plus radiotherapy arms were univariable in nature without controlling for baseline differences between the cohorts. In addition, heterogeneity with respect to the timing of CNS-penetrant TKI use (i.e., first-line versus later-line) limits the analysis of OS, which will be better assessed in larger prospective studies. Given the retrospective nature of this study, the data are also limited by chart documentation and lack of standardization with respect to the frequency of imaging, which diminishes our ability to detect differences between study groups because failure scoring is not continuous.
      In conclusion, we present initial evidence for the safe use of next-generation, CNS-penetrant TKI therapies alone without upfront radiation in patients with EGFR- or ALK-positive NSCLC metastatic to the brain. Although randomized studies are forthcoming, these results offer preliminary suggestion that the intracranial activity of osimertinib, alectinib, and other similarly CNS-penetrant agents may enable local radiation to be deferred in appropriately selected patients. Given the baseline differences between the cohorts in this study with respect to size and symptoms of CNS lesions and need for steroids, future analyses should aim to evaluate whether upfront radiation may have a beneficial role in subsets of patients presenting with higher-risk CNS disease factors.

      CRediT Authorship Contribution Statement

      Nicholas J. Thomas, Nathaniel J. Myall: Conceptualization, Data Curation, Formal Analysis, Writing – original draft, Project Administration.
      Fangdi Sun: Formal Analysis, Writing - review & editing.
      Tejas Patil, Rao Mushtaq, Chandler Yu, Sumi Sinha: Data curation.
      Erqi L. Pollom, Seema Nagpal, Chad G. Rusthoven, Steve E. Braunstein: Supervision, Writing - review & editing.
      D. Ross Camidge, Heather A. Wakelee, Caroline E. McCoach: Conceptualization, Supervision, Writing - review & editing.

      Supplementary Data

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