ALK-driven lung cancer

Radiotherapy and Oncology xxx (2017) xxx–xxx

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Original article

Treatment options for patients with brain metastases from EGFR/ALK-driven lung cancer Mark K. Doherty a,⇑, Grzegorz J. Korpanty a, Pascale Tomasini a, Moein Alizadeh b, Kevin Jao a, Catherine Labbé a, Celine M. Mascaux a, Petra Martin a, Suzanne Kamel-Reid c, Ming-Sound Tsao c, Melania Pintilie d, Geoffrey Liu a, Penelope A. Bradbury a, Ronald Feld a, Natasha B. Leighl a, Caroline Chung b, Frances A. Shepherd a a Department of Medical Oncology; Canada

a r t i c l e

b

Radiation Medicine Program; c Laboratory Medicine Program; and

i n f o

Article history: Received 11 November 2016 Received in revised form 30 January 2017 Accepted 12 March 2017 Available online xxxx Keywords: Non-small cell lung cancer Brain metastases EGFR mutation ALK translocation Whole brain radiotherapy Stereotactic radiotherapy

d

Department of Biostatistics, Princess Margaret Cancer Centre, Toronto,

a b s t r a c t Introduction: Brain metastases in EGFR/ALK-driven NSCLC frequently pose treatment dilemmas. Tyrosine kinase inhibitors (TKIs) can control extracranial disease, but radiotherapy is often required for intracranial control. We aimed to evaluate the impact of first-line whole brain radiotherapy (WBRT), stereotactic radiotherapy (SRS) or TKI alone on outcomes of patients with brain metastases from EGFR/ALK-driven NSCLC. Methods: This single center retrospective review included 184 patients with brain metastases from EGFR/ ALK-driven NSCLC, and analyzed effect of treatment choice on time to intracranial progression (TTIP) and overall survival (OS). Results: First-line treatment for brain metastases consisted of WBRT in 120 patients, SRS in 37 and TKI alone in 27. WBRT-treated patients had more brain metastases, and more baseline symptoms. Median TTIP was longer in the WBRT group at 50.5 months than SRS or TKI groups at 12 and 15 months (p = 0.0038). No significant difference was seen in median OS: 21.6 months in the WBRT group, 23.9 months in the SRS group and 22.6 months in the TKI group (p = 0.67). In multivariable analysis, age > 65 years (HR 2.2, p = 0.0014), greater number of brain metastases (HR 2.48, p = 0.0002) and greater number of extracranial metastatic sites (2 vs 0–1 HR = 2.05, p = 0.014 and 3+ vs 0–1 HR = 2.95, p = 0.0001 were associated with shorter OS. No independent effect was seen from first-line CNS treatment choice. Conclusions: First-line WBRT for brain metastases from EGFR/ALK-driven NSCLC was associated with longer TTIP than SRS or TKI alone, with no difference in OS. These results could support deferral of WBRT until intracranial progression in selected patients who are closely monitored. Ó 2017 Elsevier B.V. All rights reserved. Radiotherapy and Oncology xxx (2017) xxx–xxx

Brain metastases occur in 20–40% of patients with non-small cell lung cancer (NSCLC), and are associated with short survival and debilitating neurological symptoms [1–4]. Patients with brain metastases from lung cancer and other cancers have reduced quality of life, increased healthcare utilization and increased cost of care [5,6]. Lung cancers, with activating mutations in the epidermal growth factor receptor (EGFR) gene and echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) chromosomal rearrangements have shown sensitivity to targeted therapies. EGFR-targeting tyrosine kinase inhibitors (TKIs) have demonstrated objective response rates (ORR)

⇑ Corresponding author at: Department of Medical Oncology, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. E-mail address: [email protected] (M.K. Dohert.

of over 60%, and median survival times greater than 2 years [7,8]. Crizotinib, the most widely-studied ALK inhibitor, has an ORR of 74% and 1-year survival rate of 84% in previously untreated patients [9]. Up to 50% of patients with advanced EGFR/ALK-driven NSCLC will develop brain metastases, a higher rate than other lung cancer subtypes, and isolated central nervous system (CNS) progression is common in patients on targeted therapy [10–12]. Whole brain radiotherapy (WBRT) has long been a mainstay of treatment for brain metastases, providing symptom palliation and prolonging survival in selected patients [13]. For larger solitary metastases or metastases causing mass effect, surgical resection may be considered [4,14]. Stereotactic Radiosurgery (SRS) offers highly conformal radiation to metastases with limited dose to the remainder of the brain, and combined with WBRT has demonstrated longer

http://dx.doi.org/10.1016/j.radonc.2017.03.007 0167-8140/Ó 2017 Elsevier B.V. All rights reserved.

Please cite this article in press as: Doherty MK et al. Treatment options for patients with brain metastases from EGFR/ALK-driven lung cancerEGFR/ALKdriven NSCLC –>. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.03.007

2

Brain metastases in EGFR/ALK-driven NSCLC

survival than WBRT alone in patients with solitary small (
3 cm) tumors, and better intracranial control in those with 1–4 lesions [15]. However, with longer patient survival, there is growing concern for the neurocognitive consequences of WBRT, leading to the investigation of SRS alone for patients with limited brain disease [16,17]. This study reports the survival outcomes of patients with EGFR/ ALK-driven NSCLC after diagnosis of brain metastases at a comprehensive cancer center, based on first-line treatment choice for brain metastases: WBRT (or WBRT + SRS) and TKI, SRS and TKI or TKI alone. Materials and methods This retrospective study included all patients with brain metastases from EGFR- or ALK-driven NSCLC treated at Princess Margaret Cancer Centre up to August 2015. EGFR mutation status was established through DNA fragment analysis. Screening for ALK rearrangement was performed first by immunohistochemistry using an ALK1 antibody (Dako, Glostrum, Denmark), followed by confirmatory fluorescence in-situ hybridization [18]. Patients who did not receive any systemic therapy or brain radiotherapy were excluded. The primary outcome of this study was comparison of time to intracranial progression in patients treated with WBRT + TKI, SRS + TKI or TKI alone for brain metastases. Secondary outcomes included overall survival and ORR in these groups. Following approval from the institutional research ethics board, eligible patients were identified from the University Health Network molecular laboratory system and the Princess Margaret Cancer Registry, and data were collected from medical records. WBRT was delivered either as a course of 30 Gy in 10 fractions or 20 Gy in five fractions. SRS generally was reserved for patients with four or Ò fewer brain lesions and was delivered using Gamma Knife PerfexTM ion (Elekta, Stockholm, Sweden) to doses ranging from 15 to 21 Gy based on tumor volume. TKIs used in the EGFR cohort were gefitinib, erlotinib, afatinib, osimertinib, rociletinib and EGF-816, and in the ALK cohort were crizotinib and ceritinib. In our institutional practice, patients with symptomatic brain metastases or a large burden of intracranial disease generally would be selected for WBRT, while those with fewer lesions would be offered the choice of SBRT with close surveillance. Asymptomatic patients with very small or multiple small brain metastases generally would be offered the choice of TKI alone or up-front WBRT + TKI. Clinical outcomes included intracranial progression, intracranial radiographic response, and overall survival. Intracranial progression was defined as clear radiographic progression, or consistent clinical and radiographic changes. Radiographic response was defined as any reduction in intracranial lesions, assessed by diagnostic imaging reports and decision of the multidisciplinary brain metastases tumor board. MRI brain is the primary modality for diagnosis and surveillance of brain metastases at our institution; patients with contraindication to MRI undergo CT brain with contrast. CNS imaging was performed routinely 4– 6 weeks post SRS or following commencement of TKI; all patients, regardless of treatment choice, were followed approximately 3 monthly with CNS imaging unless earlier imaging was clinically indicated. In addition, all patients had CNS imaging at time of systemic progression.

Statistical analysis Patient demographics and clinical characteristics were summarized using descriptive methods, and differences between treatment groups at baseline were evaluated using Fisher’s exact tests

and Mann–Whitney’s tests as appropriate. The two primary event outcomes were time to intracranial progression (TTIP) and OS. The date of brain metastases diagnosis was the starting date for timeto-event analyses. The Kaplan–Meier method and log-rank tests were applied; for multivariable analyses, Cox proportional hazards model was employed. Dates of progression were determined radiologically, with the last date of radiological evaluation in the absence of progression used for censoring. In addition, competing risk specific models using the cumulative incidence method obtained the probability of progression, while Gray’s test evaluated significance of a covariate and the Fine and Gray model obtained the adjusted effect of a covariate within multivariable analysis. ORR in evaluable patients were compared between groups using Fisher’s Exact Test. Patients without follow-up CNS imaging following treatment for brain metastases, or those who underwent surgical resection, were considered non-evaluable for response. Statistical analyses were performed using SAS Software v9 (SAS Institute, Cary, NC) and R-3.2.2.

Results We identified 184 patients treated for brain metastases from EGFR/ALK-driven NSCLC. A WBRT-containing regimen was used in 120 patients: WBRT + SRS + TKI, WBRT + surgery + TKI, or WBRT + TKI. These were grouped together for the purposes of this analysis. SRS + TKI was used in 37 patients, and 27 were treated with TKI alone. More patients in the TKI alone group had metastatic disease at first diagnosis (p = 0.014) and more were of Asian ethnicity (p = 0.0063, Table 1). The EGFR cohort contained 163 patients, 21 had ALK rearrangement. In all three groups, brain metastases were most commonly diagnosed at the time patients were found to have stage IV NSCLC or during first-line systemic therapy (WBRT + TKI – 70%, SRS + TKI – 89%, TKI alone – 85%). More patients had symptomatic brain metastases in the WBRT-treated group than SRS + TKI or TKI alone groups (52% vs 16% vs 11%, p < 0.0001). In line with accepted practice, most patients (94%) treated initially with SRS had 1–4 brain metastases, whereas more of those treated with WBRT had five or more lesions (61%). In total, 18 patients had surgical excision as part of their initial treatment of brain metastases; 16 had surgery followed by WBRT, one had surgery followed by SRS and one had surgery followed by SRS boost and WBRT. Of 17 patients who underwent surgery with a defined number of brain metastases, the median was one (range 1–7). Twelve patients had one lesion, two had three lesions, one had five lesions and one had seven; two had innumerable lesions: in these patients, surgery was performed to obtain diagnostic tissue. In the six patients with > 2 lesions, surgery was performed either for confirmation of malignancy or for symptom palliation. Nine patients had subsequent intracranial progression, at a median TTIP of 19.5 months (range 3.7–50.5 months). Of these, eight had additional local therapy (SRS in 5 and WBRT in 3) and one had supportive care only due to clinical deterioration. In the whole cohort, patients treated with a WBRT regimen had significantly longer TTIP than those treated with SRS + TKI or TKI alone, with a median TTIP of 50.5 months compared with 12 and 15 months, respectively (p = 0.0038, Fig. 1A, Table 2). This pattern was similar in both the EGFR and ALK cohorts. In the EGFR cohort, median TTIP was not reached in the WBRT + TKI group, 12 months in the SRS + TKI group and 16.2 months in the TKI alone group (p = 0.0064, Fig 1B). Two-year intracranial progression rates in WBRT + TKI, SRS + TKI or TKI alone groups were 39%, 73% and 74%, respectively in the EGFR cohort. Analysis of the ALK cohort was limited by small numbers; the difference in TTIP between treatment groups was not statistically significant (p = 0.44).

Please cite this article in press as: Doherty MK et al. Treatment options for patients with brain metastases from EGFR/ALK-driven lung cancerEGFR/ALKdriven NSCLC –>. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.03.007

3

M.K. Doherty et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx Table 1 Patient characteristics and treatment details according to first-line treatment for brain metastases.

Median age (range) Sex N, (%) Female Male Ethnicity N, (%) Asian Caucasian Other Smoking status N, (%) Never Smoker Current/Former Smoker Stage at diagnosis N, (%) I II III IV ECOG PS at Diagnosis N, (%) 0 1 2–3 Molecular profile N, (%) EGFR Exon 19 Deletion** EGFR Exon 21 Mutation EGFR Exon 18** EML4-ALK rearrangement Failed Systemic therapy linesy N, (%) 0 1 2–4 Number of brain mets N, (%) 1 2–4 5 or more Leptomeningeal Only Missing Leptomeningeal diseasey N, (%) No Yes Symptoms of Brain Mets N, (%) None Headache Neurological Impairment Seizure Initial treatment for brain mets N, (%) WBRT Surgery + WBRT Surgery + WBRT + SRS SRS + WBRT SRS Surgery + SRS Systemic Therapy Alone Number of sites of extracranial diseasey 0 1 2 3 4 5 Liver metastasis Bone metastasis

Total (N = 184)

WBRT (N = 120)

SRS (N = 37)

TKI alone (N = 27)

p-Value

59 (29–86)

58 (29–84)

59 (30–78)

65 (41–86)

0.045

125 (68) 59 (32)

85 (71) 35 (29)

26 (70) 11 (30)

14 (52) 13 (48)

0.17

78(42) 81(44) 25 (14)

48 (40) 56 (47) 16 (13)

12 (32) 21 (57) 4 (11)

18 (67) 4 (15) 5 (19)

0.0063

142 (77) 42 (23)

88 (73) 31 (27)

31 (84) 6 (16)

22 (82) 5 (19)

0.46

8 (4) 10 (6) 15 (8) 151 (82)

8 (7) 6 (5) 11 (9) 95 (79)

0 4 (11) 4 (11) 29 (78)

0 0 0 27 (100)

91 (49) 84 (46) 9 (5)

52 (43) 61 (51) 7 (6)

22 (60) 14 (38) 1 (2)

17 (63) 9 (33) 1 (4)

99 (54) 63 (34) 2 (1) 21 (11)

64 38 2** 17

(53) (32) (2) (14)

19 (51) 15 (41) 0 3 (8)

16 (59) 10 (37) 0 1 (4)

140 (76) 18 (10) 26 (14)

84 (70) 17 (14) 19 (16)

33 (89) 1 (3) 3 (8)

23 (85) 0 4 (15)

46 (25) 48 (26) 82 (45) 4 (2) 4 (2)

20 (17) 22 (18) 71 (59) 3 (3) 4 (3)

16 (43) 19 (51) 2 (5) 0 0

10 (37) 7 (26) 9 (33) 1 (4) 0

169 (92) 15 (8)

107 (89) 13 (11)

37 (100) 0

25 (93) 2 (7)

0.081

113 (61) 18 (10) 44 (24) 9 (5)

58 (48) 14 (12) 40 (33) 8 (7)

31 (84) 3 (8) 2 (5) 1 (3)

24 (89) 1 (4) 2 (7) 0

<0.0001

98 (82) 16 (13) 1 (1) 5 (4) – – –

– – – – 36 (97) 1 (3) –

– – – – – – 27 (100)

4(3) 47(39) 37(31) 26(22) 6(5) 0 26(22) 52(43)

1(3) 16(43) 10(27) 9(24) 0 1(3) 5(14) 18(49)

0 12(44) 10(37) 4(15) 1(4) 0 1(4) 13(48)

0.014* 0.25

0.042

<0.0001à

0.89^ 5(3) 75(41) 57(31) 39(21) 7(4) 1(1) 32(17) 83(45)

0.06 0.78

ECOG PS – Eastern Co–operative Oncology Group performance status. * Reflects the differences in the proportion of stage IV between the three treatment groups. ** One patient had both EGFR Exon 18 and 19 mutations. à Reflects the differences between the distribution of 1 vs 2–4 vs 5+ in the three treatment groups. ^ Reflects the differences between the distribution of 0–1 vs. 2 vs 3+ in the three treatment groups. y At diagnosis of brain metastases.

Other factors associated with longer TTIP included age > 65 years (HR 0.44, p = 0.0061), no smoking history (HR 0.51, p = 0.04) and larger number of brain metastases (5 brain metastases: HR = 0.61, p = 0.036). This last covariate is possibly related

to treatment differences as most of these patients received initial WBRT (Table 1). Assessment of intracranial ORR was possible in 146 patients (Supplementary Table 1). Of 89 evaluable patients treated with WBRT + TKI, the intracranial ORR (complete/partial response) was

Please cite this article in press as: Doherty MK et al. Treatment options for patients with brain metastases from EGFR/ALK-driven lung cancerEGFR/ALKdriven NSCLC –>. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.03.007

4

Brain metastases in EGFR/ALK-driven NSCLC

Fig. 1. Competing risk analysis of time to intracranial progression (TTIP) according to first-line treatment for brain metastases: (A) all included patients and (B) patients with tumors harboring a mutation in the epidermal growth factor receptor (EGFR) gene. TKI – Tyrosine Kinase Inhibitor, WBRT – Whole Brain Radiotherapy, SRS – Stereotactic Radiosurgery.

Table 2 Time to Intracranial progression in included patients. Whole Cohort (N = 185)

WBRT SRS TKI Alone

EGFR(N = 163)

ALK (N = 21)

N

Median TTIP (months)

2-year intracranial progression

Overall p-value

N

Median TTIP (months)

2-year intracranial progression

Overall p-value

N

Median TTIP (months)

Overall p-value

120 37 27

50.5 12 15

39% 73% 74%

0.0038

103 34 26

NR 12 16.2

38% 73% 71%

0.0064

17 3 1

30.2 NR 15

0.44

TTIP – time to intracranial progression, NR – not reached.

80%; 13% had stable disease (SD) and 7% had progressive disease (PD). In SRS-treated patients, the intracranial ORR was 76%; 21% had SD and 3% had PD. The intracranial ORR was 67% in the TKI alone group; 25% had SD and 8% had PD. There was no statistically significant difference between treatment groups (p = 0.50). Fig. 2A is a swimmer plot of 27 patients (26 EGFR- and 1 ALKdriven) who had TKI alone as first-line treatment for brain metastases. Intracranial progression was observed in 12 patients (median TTIP 9.6 months). Eight patients had WBRT at some point; two received SRS for intracranial progression and two had no further treatment due to clinical deterioration. In addition, four patients died without intracranial progression, for a total of six who never received cranial irradiation. Fig. 2B is a swimmer plot

for 37 patients (34 EGFR- and 3 ALK-driven) treated with SRS + TKI for brain metastases. Twenty patients suffered intracranial progression (median TTIP 7.9 months). CNS progression was due to new brain metastases in 14, leptomeningeal carcinomatosis in three and progression of existing lesions in three. WBRT was required for 11 patients at some point in their treatment; six patients had additional SRS, one had resection for radionecrosis, and three were not fit for further treatment. Salvage treatment for 47 patients with intracranial progression in the first-line WBRT group consisted of repeat WBRT in 14, SRS in 22, and systemic therapy alone in 10. One patient declined further treatment and one had no further therapy due to rapid clinical deterioration. In this group, CNS progression was due to new lesions in 18 patients,

Fig. 2. Swimmer plot of patients treated for brain metastases from EGFR/ALK-driven NSCLC: (A) with first-line tyrosine kinase inhibitor (TKI) alone and (B) with first-line stereotactic radiosurgery (SRS) and TKI. EGFR – Epidermal Growth Factor Receptor, ALK – Anaplastic Lymphoma Kinase, NSCLC – Non-Small Cell Lung Cancer, WBRT –Whole Brain Radiotherapy.

Please cite this article in press as: Doherty MK et al. Treatment options for patients with brain metastases from EGFR/ALK-driven lung cancerEGFR/ALKdriven NSCLC –>. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.03.007

M.K. Doherty et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx

progression of existing metastases in 24, and leptomeningeal disease in six. Twenty patients had third-line CNS treatment for progressive disease: repeat WBRT in eight, SRS in nine and surgery in three. A subgroup of 39 patients in the WBRT + TKI group was identified as having CNS disease potentially eligible for SRS (1–4 metastases, no leptomeningeal involvement). Among these patients, the median TTIP was 29.1 months, significantly longer than the median for SRS-treated patients (HR 2.02, 95% CI 1.07–3.81, p = 0.031). No significant difference was noted when these patients were compared with the TKI-alone group (HR for intracranial progression 1.73, p = 0.13). Overall survival from time of diagnosis of brain metastases was not significantly different among the treatment groups: median OS was 21.6 months in the WBRT + TKI group, 23.9 months in the SRS + TKI group and 22.6 months in the TKI alone group (p = 0.67, Fig. 3A). In the group of patients treated with WBRT + TKI that were potentially eligible for SRS, median overall survival was 47.3 months. Although this was numerically longer than the SRS + TKI or TKI alone groups, the differences were not statistically significant (HR 1.63, p = 0.062 and HR 2.17, p = 0.19, respectively), due to the small number of patients in this group at risk at the median. In the EGFR cohort, median OS in the WBRT + TKI, SRS + TKI and TKI alone groups was 19.9, 23.9 and 18.5 months, respectively (p = 0.52, Fig. 3B). Analysis of the ALK cohort was limited by small numbers but no significant difference was apparent (p = 0.67): median OS was 32.4 months WBRT-treated patients, 13.7 months in those who had SRS + TKI, and one patient treated with TKI alone is alive at 23 months. Patients with EGFR exon 19 deletion had longer survival compared with those with exon 21 L858R mutation (HR 0.61, p = 0.029). In the whole cohort, additional factors associated with shorter OS on univariable analysis included age > 65 years (HR 1.92, p = 0.0035), metastatic disease at first diagnosis of NSCLC (HR 2.54, p = 0.0023), 5 brain metastases at initial brain metastasis diagnosis (HR 2.66, p < 0.0001), progression on  1 line of systemic therapy at diagnosis of brain metastases (HR 2.32, p = 0.0008), increasing number of sites of extracranial disease (3+ vs 0–1, HR 2.95, p < 0.0001) and the presence of liver or bone metastases at time of brain metastasis diagnosis (Table 3). There was no significant difference in OS between 15 patients who had leptomeningeal disease at diagnosis of brain metastasis and the 169 that did not (HR 1.61, p = 0.16). On multivariable analysis in the whole cohort, patients with age >65 years had shorter survival (HR 2.2, p = 0.0014), as well as those with greater numbers of brain metastases (HR 2.48, p = 0.0002) and with increasing number of

5

extracranial disease sites (2 vs 0–1 HR 2.05, p = 0.014 and 3+ vs 0–1 HR 2.95, p = 0.0001). Discussion In patients with EGFR- or ALK-driven metastatic NSCLC, targeted therapies offer high response rates and the potential for surviving years rather than months [7–9]. Brain metastases in this population have become a significant clinical problem, associated with morbidity and the potential for treatment-related toxicity. In this study, patients treated with first-line WBRT + TKI had significantly longer TTIP than those treated with SRS + TKI or TKI alone despite features that might be expected to result in poorer outcomes. More patients with symptomatic brain metastases had WBRT + TKI, and patients receiving SRS + TKI generally had four or fewer lesions. Some patients in the SRS-treated group had relatively rapid intracranial progression, mostly due to the development of new metastases, but small numbers in this cohort preclude identification of any prognostic factors. Despite the difference in TTIP, no difference was seen in OS among these closely followed groups, with all three groups surviving over 21 months from diagnosis of brain metastases. Most patients received some salvage therapy in the event of CNS progression, chosen according to clinical indication. Salvage SRS was used when a small number of new brain metastases were discovered, and WBRT used for progression that was more diffuse. In SRS + TKI-treated patients, 30% had salvage WBRT, which falls within the 18–32% rate reported in other studies of SRS. The choice of WBRT as salvage may be related to the development of new brain metastases rather than progression of existing lesions, which would be more likely treated with repeat SRS. It is notable that relatively few patients in the first-line TKI alone group received salvage WBRT compared with other groups. This may be due to overall lower volume of CNS disease in this cohort, or may reflect physician treatment bias. Based on the results of this study, it is clear that if first-line WBRT is deferred, patients should have close monitoring for progression of CNS metastases. The results of our study are consistent with a previous report of patients treated with either erlotinib, SRS or WBRT for EGFR-driven NSCLC, in which WBRT-treated patients had longer TTIP, but similar OS to those treated with TKI alone [19]. In that study, a small number of patients treated with SRS had longer OS (median 64 months) than those treated with WBRT or TKI alone, in contrast to our results, but the small sample size precludes further testing of this difference. These results contrast with a recent publication examining the effect of WBRT + TKI or TKI alone in Chinese patients with brain metastases from EGFR-driven NSCLC [20]. The

Fig. 3. Kaplan–Meier estimate of overall survival according to first-line treatment for brain metastases: (A) all included patients and (B) – patients with tumors harboring a mutation in the epidermal growth factor receptor (EGFR) gene. SRS – Stereotactic Radiosurgery, TKI – Tyrosine Kinase Inhibitor, EGFR – Epidermal Growth Factor Receptor, ALK – Anaplastic Lymphoma Kinase, NSCLC – Non-Small Cell Lung Cancer, WBRT –Whole Brain Radiotherapy.

Please cite this article in press as: Doherty MK et al. Treatment options for patients with brain metastases from EGFR/ALK-driven lung cancerEGFR/ALKdriven NSCLC –>. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.03.007

6

Brain metastases in EGFR/ALK-driven NSCLC

Table 3 Univariable and multivariable regression analyses of overall survival in all included patients. Univariable analysis

Age (>65 vs
65) Sex (Female vs Male) Smoking Status (Ever vs Never) Stage at Diagnosis (IV vs I–III) Number of Brain Mets (5 vs 1–4) Symptomatic Brain Mets (Yes vs No) Leptomeningeal Disease (Yes vs No) First Line Therapy for Brain Mets WBRT vs TKI Alone SRS vs TKI Alone Failed Lines of Systemic Therapy 1 vs 0 2–4 vs 0 TKI after diagnosis of Brain Mets Number of extracranial involvement 2 vs 0–1 3+ vs 0–1 Liver metastasis (Yes vs No) Bone metastasis (Yes vs No)

Multivariable analysis

HR

95%CI

p-Value

HR

95%CI

p-Value

1.92 0.74 0.94 2.54 2.66 1.41 1.61

1.24–2.98 0.48–1.12 0.56–1.58 1.39–4.63 1.70–4.15 0.93–2.11 0.83–3.11

0.0035 0.16 0.82 0.0023 < 0.0001 0.11 0.16

2.20 – – – 2.48 – –

1.36–3.57 – – – 1.55–3.97 – –

0.0014 NS NS NS 0.0002 NS NS

0.98 0.76

0.50–1.92 0.34–1.71

0.96 0.5

– –

– –

NS NS

2.22 2.41 1.33

1.13–4.35 1.3–4.46 0.72–2.48

0.02 0.005 0.37

– – –

– – –

NS NS NS

2.5 2.95 2.58 2.15

1.46–4.27 1.76–4.95 1.57–4.25 1.40–3.29

0.0008 < 0.0001 0.0002 0.0004

2.05 2.95 – –

1.16–3.62 1.69–5.13 – –

0.014 0.0001 NS NS

TKI – Tyrosine Kinase Inhibitor.

authors observed similar intracranial PFS for the two treatment approaches, but shorter OS in the WBRT + TKI group (HR 1.667, p = 0.049). There were more patients with newly diagnosed lung cancer in the TKI-alone group, which may have influenced the analysis. No patients in that study were treated with SRS, so only the effect of WBRT in addition to TKI was evaluated. A recent meta-analysis of studies comparing treatments for brain metastases in patients with EGFR-mutation positive NSCLC reported a borderline significant improvement in 2-year overall survival in patients treated with cranial irradiation (WBRT or SRS) compared with TKI alone (RR 1.33, 95% CI 1.00–1.77, p = 0.05) [21]. No significant difference was reported in intracranial progression and response rates. This study was limited by poor data quality and small sample sizes, and updated reviews are likely warranted using more recent, larger datasets, in the absence of randomized trial data. Efforts to refine the decision-making process for local therapies for brain metastases have focused on the development of prognostic scores. The Graded Prognostic Assessment (GPA) score used age, number of brain metastases, performance status and extracranial disease to stratify the prognosis of patients with any tumor histology [22]. This was further refined by separating primary tumor types, with the development of the Diagnosis-Specific GPA (DSGPA) [23]. In the NSCLC DS-GPA, patients with the best prognostic score had median survival of 14.8 months, and patients treated with SRS- or surgery-based treatment had better survival than those receiving WBRT. This is clearly in contrast to the results of the current study, as well as other studies of patients with brain metastases from EGFR/ALK-driven lung cancer. In response to this, the same group have recently published data on the Lung-mol GPA, which incorporates EGFR or ALK mutation status [24]. Using this score, the median survival for patients in the best prognostic group was 47 months. Although our results are limited by the retrospective nature of the study, our findings suggest that in selected patients, consideration may be given to deferring WBRT for first-line treatment of brain metastases with the aim of delaying potential neurocognitive toxicity. There was insufficient neurocognitive data to report for our study cohort, but the association between WBRT and leukoencephalopathy is well documented, and late neurocognitive effects have been reported in up to 49% of patients [16,25]. There is arguably greater neurocognitive deficit caused by progressive brain

metastases, as illustrated by a significantly larger drop in MiniMental Status Examination scores in patients with uncontrolled compared with controlled brain metastases on the RTOG 9104 study [26]. Although the mechanisms of neurocognitive toxicity are not understood fully, limited radiation dose to the hippocampus has been associated with functional preservation, and this may account for the lower toxicity seen with SRS [27,28]. The randomized N0574 study of SRS with or without WBRT reported more frequent cognitive deterioration in patients treated with WBRT + SRS at 3 months, despite lower rates of intracranial progression and no difference in OS [17]. These results suggest that neurocognitive toxicity may be minimized by the use of SRS without detriment to survival, but the final report of this study is awaited. The findings of this study are also consistent with those seen in our study – patients treated with WBRT have longer time to intracranial progression, but without a significant impact on survival. There is also growing evidence of the CNS activity of targeted therapies in NSCLC. Prospective studies of first-generation EGFR TKIs reported intracranial ORR of 66–88%, and patients with asymptomatic brain metastases had longer PFS with afatinib than chemotherapy from one report [29–32]. Third-generation EGFR TKIs appear to have greater intracranial activity, with early clinical data on osimertinib showing intracranial responses in 33%, and improvement in leptomeningeal disease [33,34]. In our study, patients with EGFR-positive NSCLC treated with TKI alone had an intracranial response rate of 68%, and median TTIP of 16.2 months. Nine patients received osimertinib as part of clinical trials and 13 received other investigational T790 M-specific TKIs at some point in their treatment, but variability of TKI and treatment timing precludes further assessment of this subgroup. Additionally, comparative analysis of individual TKIs was not possible due to the small number of patients treated with each agent. In ALK-positive NSCLC, targeted therapy with crizotinib has shown a modest intracranial effect, with intracranial ORR of 18%, and TTIP of 7 months [35]. Second-generation ALK-targeting TKIs have shown more promise: CNS responses to alectinib were seen in 57%, and in a randomized phase III study fewer patients experienced CNS relapse or progression on alectinib compared with crizotinib [36–38]. Ceritinib also appears to have activity in brain metastases, with CNS responses in 34–61% and intracranial PFS of 8.3 months [39,40]. We had only one patient with ALK-positive NSCLC treated with crizotinib alone as first-line therapy, a reflec-

Please cite this article in press as: Doherty MK et al. Treatment options for patients with brain metastases from EGFR/ALK-driven lung cancerEGFR/ALKdriven NSCLC –>. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.03.007

M.K. Doherty et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx

tion of the perceived lack of intracranial efficacy of this agent. No patient in our cohort received alectinib. In summary, this study showed that patients with brain metastases from EGFR- or ALK-driven lung cancer had similar overall survival regardless of first-line treatment modality for brain metastases, although time to intracranial progression was significantly longer in those treated with WBRT + TKI, despite features associated with worse prognosis in this group. With the growing data to support concerns of neurocognitive toxicity following WBRT, particularly in patients with longer expected survival, our findings could support consideration of SRS + TKI or TKI alone in selected patients with close monitoring for intracranial progression to enable timely salvage treatment.

[9]

[10]

[11]

[12]

[13]

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Sources of funding Mark K. Doherty is supported by the Princess Margaret Cancer Foundation as the Oberlander Clinical Research Fellow in Thoracic Oncology, and this study is partially supported by the Canadian Cancer Society Research Institute IMPACT grant #701595. Neither source had a role in the conduct of the study or the preparation of the manuscript.

[15]

[16]

[17]

Conflicts of interest [18]

No author declares any interest related to this study. Ming-Sound Tsao has received honoraria for advisory boards for Pfizer, AstraZeneca, Hoffman LaRoche, Bristol-Meiers Squibb and Merck Canada, and has received research grant funding from Pfizer and AstraZeneca. Geoffrey Liu has received honoraria for advisory boards for AstraZeneca, Roche, Novartis, Pfizer, Millennium and Takeda. Natasha B. Leighl has institutional funding from Novartis, and has received honoraria from AstraZeneca. Frances A. Shepherd has received honoraria for advisory boards for AstraZeneca, Boehringer Ingelheim, Bristol-Meiers Squibb, Eli Lilly, Merck Canada, Pfizer and Roche-Genentech, has received payment for consulting for Eli Lilly, and holds investments in Eli Lilly and AstraZeneca. For the remaining authors none was declared.

[19]

[20]

[21]

[22]

[23]

Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.radonc.2017.03. 007.

[24]

[25]

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Please cite this article in press as: Doherty MK et al. Treatment options for patients with brain metastases from EGFR/ALK-driven lung cancerEGFR/ALKdriven NSCLC –>. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.03.007