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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
Division of Medical Oncology, UCSF Helen Diller Comprehensive Cancer Center, San Francisco, CaliforniaCurrently employed by Genentech Inc., South San Francisco, California
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.
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.
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.
Highly effective next-generation TKIs, such as osimertinib and alectinib, have since been found to prolong PFS and overall survival (OS) compared with their first-generation counterparts, thereby leading to their adoption as first-line therapy in patients with metastatic disease.
Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study.
Despite these therapeutic advancements, patients with EGFR- or ALK-positive NSCLC remain at high risk for developing metastases to the central nervous system (CNS). In NSCLC overall, brain metastases are present at diagnosis in 10% to 20% of patients and occur at any time during the disease course in 25% to 50% overall.
International Association for the Study of Lung Cancer Advanced Radiation Technology Committee. Brain metastases from NSCLC: radiation therapy in the era of targeted therapies.
Although the evolution of local and systemic therapies for CNS metastases has led to improvements in intracranial control and limited off-target side effects, occurrence of disease within the brain is associated with decreased quality of life and worse prognosis.
Historically, management of parenchymal brain metastases has incorporated local resection, whole-brain radiation therapy (WBRT), and stereotactic radiosurgery (SRS).
Although the addition of WBRT compared with SRS alone improves local control within the CNS, it is associated with a greater risk of neurocognitive decline and does not improve survival, except in those patients who have CNS metastases without concurrent extracranial disease.
Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial.
SRS alone, in contrast, is associated with similar survival and better tolerance compared with WBRT in patients presenting with up to 15 CNS metastases; however, it still carries a risk for complications, such as radiation necrosis.
Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial.
Single-fraction versus multifraction (3 × 9 Gy) stereotactic radiosurgery for large (>2 cm) brain metastases: a comparative analysis of local control and risk of radiation-induced brain necrosis.
Retrospective studies of EGFR- and ALK-positive NSCLC with CNS metastases suggested that the use of first-generation TKI therapies was associated with lower rates of intracranial progression compared with chemotherapy and favorable survival when used after the onset of CNS metastases.
The impact of initial gefitinib or erlotinib versus chemotherapy on central nervous system progression in advanced non–small cell lung cancer with EGFR mutations.
The effect of gene alterations and tyrosine kinase inhibition on survival and cause of death in patients with adenocarcinoma of the lung and brain metastases.
Nevertheless, in a large, retrospective study of patients with EGFR-mutated NSCLC, OS was still significantly shorter in patients receiving EGFR TKI therapy alone versus TKI therapy plus upfront WBRT or SRS.
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.
Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity.
This has translated into superior CNS response rates whereby osimertinib has been found to prolong intracranial PFS relative to erlotinib or gefitinib (not reached [NR] versus 13.9 mo) in untreated patients with EGFR-mutated CNS metastases.
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.
Similarly, alectinib, lorlatinib, brigatinib, and ensartinib have superior activity in treating CNS metastases compared with crizotinib in patients with ALK-rearranged NSCLC.
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.
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.
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
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.
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 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 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. 4A–C 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 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 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.
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.
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.
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.
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.
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.
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.
Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity.
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.
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.
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.
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).
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.
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.
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).
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.
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.
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.
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.
Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study.
International Association for the Study of Lung Cancer Advanced Radiation Technology Committee. Brain metastases from NSCLC: radiation therapy in the era of targeted therapies.
Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial.
Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial.
Single-fraction versus multifraction (3 × 9 Gy) stereotactic radiosurgery for large (>2 cm) brain metastases: a comparative analysis of local control and risk of radiation-induced brain necrosis.
The impact of initial gefitinib or erlotinib versus chemotherapy on central nervous system progression in advanced non–small cell lung cancer with EGFR mutations.
The effect of gene alterations and tyrosine kinase inhibition on survival and cause of death in patients with adenocarcinoma of the lung and brain metastases.
Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity.
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.
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.
Analysis of time-to-treatment discontinuation of targeted therapy, immunotherapy, and chemotherapy in clinical trials of patients with non-small-cell lung cancer.
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.
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.
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.
Osimertinib in patients with epidermal growth factor receptor mutation–positive non–small-cell lung cancer and leptomeningeal metastases: the BLOOM study.
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).
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).
Consolidative local ablative therapy improves the survival of patients with synchronous oligometastatic NSCLC harboring EGFR activating mutation treated with first-line EGFR-TKIs.
Mr. Thomas and Dr. Myall are co-first authors and they contributed equally to this work.
Disclosure: Dr. Myall reports having honoraria from Patient Power/Remedy Health Media. Dr. Patil reports having consulting fees from AstraZeneca, Takeda, Pfizer, and Janssen; having participation on a data safety monitoring board or advisory board for Pfizer, Sanofi, and Crestone Oncology; having leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid as president-elect of Rocky Mountain Oncology Society (unpaid); and serving as a board member of Binaytara Foundation. Dr. Mushtaq reports owning personal pharmaceutical stocks in MDT, JNJ, GILD, EW, BSX, BMY, AMGN, and ABT. Dr. Pollom reports receiving research funding from Genentech. Dr. Nagpal reports having consulting fees from SeaGen. Dr. Camidge reports having consulting fees from AbbVie, Apollomics, AstraZeneca, Blueprint, Daiichi Sankyo, Elevation, Eli Lilly, Helsinn, Kestrel, Nuvalent, Puma, Ribon, Roche, Sanofi, Seattle Genetics, Takeda, and Turning Point. Dr. Rusthoven reports receiving research funding from Takeda and having honoraria from Roche. Dr. Wakelee reports receiving research funding to institution from ACEA Biosciences, Arrys Therapeutics, AstraZeneca/ Medimmune, Bristol-Myers Squibb, Celgene, Clovis Oncology, Exelixis, Genentech/Roche, Gilead, Merck, Novartis, Pharmacyclics, Seattle Genetics, Xcovery, Pfizer, Eli Lilly. Serving on the advisory board (compensated) of AstraZeneca, Xcovery, Janssen, Daiichi Sankyo, Blueprint, Mirati, and Helsinn; advisory board (not compensated) of Merck, Takeda, Genentech/Roche, and Cellworks; and having honoraria from Novartis AstraZeneca. Dr. McCoach reports receiving funding from Novartis and Revolution Medicines; serving on the advisory board of Genentech and AstraZeneca; having honoraria from Novartis and Guardant Health; and having meetings and/or travel support from Eli Lilly. The remaining authors declare no conflict of interest.
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