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Martin Schuler
Moderator of
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MS 13 - How to Deal with CNS Metastases (ID 535)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Advanced NSCLC
- Presentations: 5
- Moderators:Martin Schuler, Nir Peled
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 502
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MS 13.01 - Strategic Approach to CNS Metastasis (ID 7701)
11:00 - 12:30 | Presenting Author(s): Maurice Pérol
- Abstract
- Presentation
Abstract:
Brain metastases (BMs) concern more than 10-15% of patients with stage IV NSCLC at baseline and more than 40% during the disease course. The wider use of MRI and improvement of extra-cranial systemic disease control contribute to increase the BMs incidence. The issue of BMs is critical in the management of NSCLC patients in the perspective of the neurological consequences of brain lesions. BMs occurrence is synonymous of a poor outcome in NSCLC but reflects in fact many different situations. Establishing a therapeutic strategy needs first to assess their prognosis; the most appropriate scale is the Graded Prognostic Assessment for Lung Cancer Using Molecular Markers including as prognostic factors EGFR mutations and ALK rearrangement in addition to age, number of BMs, extra-cranial disease and Karnofsky status, with a median survival varying from 3.0 months for the worse subgroup (GPA 0.5-1) to 46.8 months for patients with oncogene addiction and good prognostic factors (GPA 3.5-4). The second step is to evaluate the indications, efficacy and side effects of available therapeutic "weapons". Corticosteroids are active against cerebral edema and improve symptoms. Whole brain radiotherapy (WBRT) has been for decades the treatment "reflex" of BMs but the emergence of stereotactic radiosurgery (SRS) or radiotherapy (SRT) and the issue of neurocognitive complications led to deferral or omission of WBRT in an increasing number of patients. WBRT remains indicated in patients with symptomatic, large (≥3 cm) and numerous BM. However, palliative WBRT did not provide any benefit in terms of survival, quality of life and QUALYs compared to supportive care alone in the Quartz trial; the subgroup analysis suggests a benefit only in patients with better prognostic factors. Neuroprotective strategies as sparing hippocampi during WBRT are currently evaluated. SRS defined by invasive contention with sub-millimeter accuracy or noninvasive SRT with millimeter accuracy are indicated in case of 1 to 3 BMs (but now up to 10 lesions) with a diameter <3 cm, alone or as a boost on the top of WBRT. SRS/SRT alone avoids neurocognitive toxicity of WBRT and provides a similar OS to that of surgical resection when using SRS/SRT for patients with operable lesions. Radionecrosis is observed in 10-17% of patients treated with SRS/SRT, making difficult the distinction with a tumor relapse. In spite of reduction in local and distant brain failures or in death from neurological causes, adjuvant WBRT after SRS/SRT does not improve overall survival and has a detrimental effect on neurocognitive functions and quality of life. Surgical resection of BMs achieves survival and functional benefit in addition to WBRT. Surgery is indicated in case of a symptomatic lesion, larger than 2 cm, with a mass effect, allowing fast improvement of symptoms. The invasive edge of BMs explains the high local recurrence rate after resection and the need for adjuvant radiotherapy. WBRT is progressively less used in favor of SRS/SRT despite a better intracranial control rate because of a higher rate of cognitive deterioration. Systemic treatment remains critical for extracranial systemic control of the disease. Brain-blood barrier limits the brain penetration of systemic agents, especially with efflux transporters as P-gp, for which many TKIs and cytotoxic agents are substrates. BMs usually cause brain-blood barrier disruption with heterogeneous drug penetration. Cytotoxic chemotherapy provides similar response rates in BMs to those of extracranial disease. Anti-PD-1 antibodies seem to be active in the brain but available data are scarce. First and second-generation EGFR TKIs have a low brain penetration but sufficient to obtain response rates similar to those achieved for systemic disease; duration of response might be inferior. Osimertinib has a better CNS penetration. For ALK+ disease, crizotinib is a P-gp substrate with a low blood/CSF concentration ratio and brain is the most frequent site of progression. Next-generation ALK TKIs have a better CNS diffusion; alectinib largely decreases the cumulative incidence of BMs compared to crizotinib. Concurrent administration of TKIs with brain radiotherapy is controversial and is not recommended outside of a clinical trial. Defining an optimal multidisciplinary strategy needs to take into account many parameters, including number, location and size of brain metastases, leptomeningeal lesions, neurological symptoms, risk factors for neurocognitive alteration, extracranial metastases and their control, primary lung tumor control, and identification of a targetable oncogenic addiction. In absence of a targetable genomic alteration, BMs at baseline can benefit from systemic treatment alone in selected patients with no neurological symptoms, small intracranial tumor burden, low risk of impending neurologic issues, on the condition that they are closely monitored; brain radiotherapy can be safely deferred to intracranial progression. Symptomatic BMs require local treatment, by favoring SRS/SRT rather than WBRT; adjuvant WBRT is not recommended but further close monitoring is mandatory to detect new intra-cranial lesions. Surgery is preferred for large lesions, posterior fossa location or diagnosis; adjuvant SRS/SRT is mandatory to avoid local recurrences. WBRT remains indicated for multiple symptomatic lesions not eligible for SRS/SRT except in poor PS patients. In case of EGFR mutations, asymptomatic patients with BMs are treated with first or second-generation EGFR TKIs but must be closely watched with repeated brain imaging. A recent retrospective study suggests that front-line SRS/SRT might improve overall survival as CNS remains a sanctuary site in oncogene-addicted disease. Symptomatic patients are locally treated, favoring SRS/SRT requiring only a short interruption of systemic treatment. For patients with ALK+ disease, the advent of alectinib as standard front-line treatment should change the management approach to BMs: the low incidence of BMs should allow spacing brain monitoring while the high intra-cranial response rate should permit to delay local treatment. For ALK+ patients developing BMs on ALK TKI, local treatment with SRS/SRT or surgery if necessary is the first option; switching to another TKI with a better brain penetration is another option for patients candidates to WBRT. The longer life expectancy of ALK+ patients leads to defer as far as possible the use of WBRT. However, improvement of intracranial control should be considered in patients at preferential risk of dying from intracranial progression, independently on mutational status.
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MS 13.02 - SBRT vs. WBRT (ID 7702)
11:00 - 12:30 | Presenting Author(s): Paul Van Houtte | Author(s): D. Devriendt
- Abstract
- Presentation
Abstract:
The management of brain metastases remains a challenging issue due to the detrimental impact on the patient quality of life and the wide range of clinical situations. The question is not a local treatment or WBRT but when and how to use the different modalities for each patient. Survival, an endpoint often used, is probably not the best way to evaluate the local efficacy: most patients will died from progressive extracranial disease. The brain tumor control (local or freedom from new brain metastases) is a better way to assess the impact of WBRT or SBRT. Another major problem is the great heterogeneity of the primary tumors and clinical situations. First, we should remember that most patients are not candidate for a local treatment (SBRT or surgery (S)) due to the number of lesions, locations, performance status, meningeal infiltration…and WBRT remains the standard treatment if a brain irradiation is needed. For patients with an “oligo metastatic disease”, many studies have clearly showed the superiority of a form of local treatment (S or SBRT) compared to WBRT at least in term of progression or control at the primary brain site (table1)(1-5). Another issue is to control the disease within the brain: new brain metastases are very common. WBRT has been tested either after S or SBRT to prevent the development of those new lesions: indeed adding WBRT let to a better brain tumor control but this did not translate in any major survival benefit. One major drawback of WBRT is its possible toxicity: the impact on the quality of life, the neurocognitive toxicity, the fatigue and the hair loss. In the EORTC trial, WBRT had a transitory negative impact on the physical or cognitive functioning and more fatigue in the early period of observation compared to the group of patients in the observation arm (6.). A current approach is to follow the patient after SBRT and in case of relapse to propose a salvage treatment which may be a new course of SBRT or even WBRT. Another question was to improve the local control after S adding SBRT. Postoperative SBRT has been proposed and several retrospective studies have shown the feasibility results. Two recently published randomized trials have compared postoperative SBRT to either WBRT or observation. The two main conclusions were less cognitive deterioration with SBRT compared to WBRT( 15% vs 48%) and less local relapse at the primary site compared to no treatment (at 1 year 43% vs 72%) but no difference in overall survival (4,5). An intriguing observation was the better local control at one year after postoperative WBRT compared to SBRT (4). Is there a group of patients benefiting from WBRT? In a new analysis of the Aoyama trial, patients with NSCLC were divided according to a graded prognostic assessment: a statistically significant benefit was observed only in the favorable group with a 6 months gain in median survival (7). A similar observation was reported in the RTOG trial testing the role of adding SBRT to WBRT with a median survival of 14 vs 21 months (8). Is it possible to reduce WBRT toxicity? The hippocampus region play an important role in the preservation of the neurocognitive functions: techniques have been developed to spare the hippocampus region keeping the dose below 7 Gy with a better quality of life and a very low risk of new brain metastases occurring in this spared regions (9). This approach should be tested in large scale phase III trial. Last but not least, the timing of the treatment should be individualized based on the patient needs, and in asymptomatic patients, SBRT may be safely postponed if a systemic treatment is to be administered.
· Estimated from figures References 1.Aoyama H., Tago M., Shirato H. for the Japanese Radiation Oncology study Group 99-1 (JROSG 99-1) investigators Stereotactic radiosurgery with or without whole-brain radiotherapy for brain metastases. Secondary analysis of the JROSG-99 randomized clinical trial JAM Oncol. 2015; 1: 457-464 2.Kocher M., Soffietti R., Abacioglu U., et al Adjuvant whole-brain radiotherapy versus observation after surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J.Clin.Oncol. 2011; 29:131-141 3.Andrews D.W., Scott C.B., Sperduto D.W. et al Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: Phase III results of the RTOG 9508 randomised trial Lancet 2004; 363:1665-72 4.Brown PD, Ballman KV, Cerhan JH,et al Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial.Lancet Oncol. 2017 Jul 4. pii: S1470-2045(17)30441-2. doi: 10.1016/S1470-2045(17)30441-2. [Epub ahead of print] 5.Mahajan A, Ahmed S, McAleer MF, et al Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017 Jul 4. pii: S1470-2045(17)30414-X. doi: 10.1016/S1470-2045(17)30414-X. [Epub ahead of print) 6.Soffietti R., Kocher M., Abacioglu U., et al A European Organiszation for Research and Treatment of Cancer phase III trial of adjuvant whole-brain radiotherapy versus observation after surgical resection of one to three cerebral metastases: quality of life results J.Clin.Oncol. 2011; 31:65-72 7.Aoyama H., Tago M., Shirato H. et al Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial JAMA 2006; 295: 2483-91 8.Sperduto P.W., Shanley R., Luo X., et al Secondary analysis of RTOG 9508, a phase 3 randomized trial of whole-brain radiation verus WBRT plus stereotactic radiosurgery in patients with 1-3 brain metastases; poststratified by the graded prognostic assessment (GPA). Int.J.Radiat.Biol.Phys. 2014; 90: 526-531 9.Gondi V., Hermann B.P., Mehta M.P., Tome W.A. Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult brain tumors. Int. J. Radiat. Oncol. Biol. Phys. 2012 ; 83 : 487–93Authors Treatment Evaluation Time Local Control Brain Tumor Control Aoyama Kocher Andrews Brown Mahajan SBRT SBRT+WBRT Surgery Surg+WBRT SBRT SBRT+WBRT WBRT WBRT+SBRT Surg+WBRT Surg +SBRT Surg SURG.SBRT 1 Y 2 Y 1Y 1Y 1 Y 72% 88% 41% 73% 69% 81% 60% 74% 78% 55% 45% 72% 23% 53% 58% 77% 52% 67% 51% 62% 69% 32% 33% 43%
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MS 13.03 - Target Therapy for ALK/ROS1 + NSCLC with CNS Metastasis (ID 7704)
11:00 - 12:30 | Presenting Author(s): Alice Shaw
- Abstract
- Presentation
Abstract not provided
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MS 13.04 - The Role of Chemotherapy in the Management of CNS Metastasis (ID 7705)
11:00 - 12:30 | Presenting Author(s): Chong-Kin Liam
- Abstract
- Presentation
Abstract:
The optimal management of patients with CNS metastases from lung cancer should be a multidisciplinary approach which encompasses supportive therapy, local CNS-directed therapies including surgery, stereotactic radiosurgery (SRS) and whole brain radiotherapy (WBRT), and most importantly systemic therapy. In the case of patients with small cell lung cancer (SCLC), both the primary tumour and systemic metastases are generally chemosensitive, at least initially. Most studies suggested that brain metastases are as sensitive to systemic chemotherapy as extracranial disease. The concept of the brain as a pharmacologic sanctuary site for established metastases is in contrast with clinical observations of frequent responses in brain metastases to systemic chemotherapy. Response rates (RRs) of brain metastases from SCLC to systemic chemotherapy in treatment naive patients have been reported to range from 27% to 85%. RRs in previously treated patients with brain metastases range from 22% to 50% and are comparable to the RRs with second-line chemotherapy observed in extracranial disease. A meta-analysis of five studies with a single chemotherapy for pretreated patients showed RRs ranging from 33% to 43%.[1] Adding WBRT to chemotherapy increases the RR of the brain metastases, but does not appear to improve survival as shown in a phase III trial by the European Organization for Research and Treatment of Cancer.[2] For patients with advanced non-small cell lung cancer (NSCLC) without molecular drivers, chemotherapy is the mainstay of treatment. Although NSCLC is less responsive to systemic chemotherapy than SCLC, results of combining platinum compounds and third generation agents are substantially better than with earlier regimens. Platinum-based doublets are the cornerstone treatment in the first-line setting for metastatic NSCLC.[3] There is a presumed lack of effectiveness of systemic chemotherapy in CNS metastases from NSCLC because of the belief that chemotherapeutic drugs cannot cross the blood-brain barrier (BBB).[4] However, there is increasing evidence that the integrity of the BBB is impaired and disrupted in the presence of macroscopic CNS metastases. Despite a low penetration of the CNS, chemotherapy drugs have demonstrated encouraging activity against CNS metastases from NSCLC. A number of phase II studies reported RRs to cisplatin-based combination chemotherapy regimens ranging from 35% to 50%. Several clinical trials with upfront platinum-based chemotherapy have shown intracranial RRs ranging from 23% to 50% which correlated with and almost comparable to systemic RRs.[5 ]These data suggest that the intrinsic sensitivity of the tumour to the cytotoxic drug is more important in predicting response to the chemotherapeutic drug than the theoretical expected ability of the drug to penetrate the BBB. There are few randomised phase III trials of advanced or metastatic NSCLC evaluating different kinds of treatment in patients with brain metastases because generally, such patients have been excluded from clinical trials because of poor prognosis. Despite a penetration of CNS of less than 5%, pemetrexed demonstrated a consistent activity against brain metastases from NSCLC. One of the first evidence of pemetrexed activity against brain metastases came from a retrospective Italian study by Bearz and colleagues on 39 NSCLC patients with CNS metastases treated with pemetrexed as second or third line.[6] Although the patients were unselected for histology, the study reported an intracranial RR of 30.8%, with clinical benefit obtained in 69% of patients. All patients who had an overall response (i.e., partial response and stable disease) to pemetrexed had a benefit over cerebral metastases as well with partial response in 11 patients (28.2%) and stable disease in 21 (53.8%), with a clinical benefit rate of 82% for CNS metastases and an overall survival (OS) of 10 months. The addition of platinum compounds to pemetrexed slightly improved the outcome as shown in subsequent studies. In a phase II trial on 43 chemotherapy naïve NSCLC with brain metastases (93% with non-squamous histology) treated with pemetrexed and cisplatin for six cycles, the intracranial RR was 41.9%.[7] A comparable intracranial RR of 40% was observed when pemetrexed was combined with carboplatin in an observational study on 30 patients with adenocarcinoma and brain metastases.[8] These clinical trials showed that platinum-based regimens are active against brain metastases from NSCLC and high RRs can be achieved with pemetrexed-containing regimens in patients with non-squamous NSCLC. A post-hoc analysis of a large prospective observational European study on 1,564 patients with newly diagnosed advanced NSCLC receiving first-line platinum-based regimens showed that in the subgroup of 263 patients with brain metastases the median OS was 7.2 months which ranged from 5.6 months for patients treated with cisplatin/gemcitabine up to 9.3 months for those treated with platinum/pemetrexed.[9] In conclusion, systemic chemotherapy is an important part of the multidisciplinary managment of CNS metastases. Patients with small asymptomatic brain metastases from SCLC and NSCLC should be treated with the most active platinum-based combination chemotherapy upfront. Radiation therapy and other CNS-directed treatment may be deferred until the effects of the systemic chemotherapy on the CNS metastases can be determined. References 1. Grossi F, Scolaro T, Tixi L, et al. The role of systemic chemotherapy in the treatment of brain metastases from small-cell lung cancer. Crit Rev Oncol Hematol 2001; 37:61-7. 2. Postmus PE, Haaxma-Reiche H, Smit EF, et al. Treatment of brain metastases of small-cell lung cancer: comparing teniposide and teniposide with whole-brain radiotherapy--a phase III study of the European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 2000; 18:3400. 3. Du L, Morgensztern D. Chemotherapy for Advanced- Stage Non-Small Cell Lung Cancer. Cancer J 2015;21:366-70. 4. Schuette W. Treatment of brain metastases from lung cancer: chemotherapy. Lung Cancer 2004; 45:S253-7. 5. Zimmermann S, Dziadziuszko R, Peters S. Indications and limitations of chemotherapy and targeted agents in non-small cell lung cancer brain metastases. Cancer Treat Rev 2014; 40:716-22. 6. Bearz A, Garassino I, Tiseo M, et al. Activity of Pemetrexed on brain metastases from Non-Small Cell Lung Cancer. Lung Cancer 2010; 68:264-8. 7. Barlesi F, Gervais R, Lena H, et al. Pemetrexed and cisplatin as first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) with asymptomatic inoperable brain metastases: a multicenter phase II trial (GFPC 07-01). Ann Oncol 2011; 22:2466-70 8. Bailon O, Chouahnia K, Augier A, et al. Upfront association of carboplatin plus pemetrexed in patients with brain metastases of lung adenocarcinoma. Neuro Oncol 2012; 14:491-5. 9. Moro-Sibilot D, Smit E, de Castro Carpeño J, et al. Non-small Non-small cell lung cancer patients with brain metastases treated with first-line platinum-doublet chemotherapy: Analysis from the European FRAME study. Lung Cancer 2015; 90:427-32.
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MS 13.05 - Targeted Therapy for EGFR Positive Mutant NSCLC with CNS Metastasis (ID 7703)
11:00 - 12:30 | Presenting Author(s): Myung-Ju Ahn
- Abstract
- Presentation
Abstract:
Central nervous system (CNS) metastases including brain metastasis (BM) and leptomeningeal metastasis (LM) are associated with poor prognosis in non-small cell lung cancer (NSCLC). The epidermal growth factor receptor (EGFR) mutations were initially reported in 2004 and currently defined the most prevalent actionable genomically classified subgroup of NSCLC, which account for 40% of Asian patients and 10-15% of White or African American patients. Patients with EGFR mutant NSCLC may have a higher incidence of CNS metastases due to prolonged survival with targeted agents and the increased quality of CNS imaging. More than 50% of NSCLC patients with EGFR mutation develop CNS metastases during their lifetime (1). The median overall survival (OS) for patients with BM is around 16 months (2) and 4.5-11 months for those with LM (3). Whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), or surgery is widely used for BM, whereas no standard therapy is available for LM. Moreover, the benefit of radiotherapy is limited due to toxicities and long term sequelae. Brain is a privileged site, sheltered from the systemic circulation by the blood-brain-barrier (BBB), which is highly specialized structure with tight junctions created by the interaction between astrocytes, pericytes and endothelium. In addition, numerous efflux transporters (e.g. P-glycoprotein) have been identified, leading to prevent many traditional drugs from the circulation into the brain parenchyma. Although the permeation of EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib or erlotinib across the BBB has been reported, the cerebrospinal fluid (CSF) concentrations of TKIs at standard doses comprise only small fraction of the plasma concentration indicating the limited ability to permeate into the CSF (4). Several small series of phase II studies reported that EGFR TKIs, gefitinib, erlotinib or afatinib show CNS response rate of 55 to 89%, median PFS of 5.8 to 14.5 months and median OS of 15.9 to 22.9 months in patients with brain metastases. Recently, new generation EGFR TKI, AZD 3759 which is designed to effectively penetrate BBB demonstrated profound anti-tumor activity in preclinical models. Phase I study showed the free plasma concentration of AZD 3759 was approximately at the same range as that in CSF and yielded K~p,uu~,~CSF~ values of 1.18 and 1.00 for 200mg and 300mg, respectively. Tumor responses were observed in 83% and 72% of the patients with CNS and extracranial disease respectively in EGFR TKI naïve NSCLC (5). Osimertinib, a third generation EGFR TKI designed to target both activating EGFR mutation and T790M but sparing wild type EGFR, distributed into mouse brain to a greater extent than gefitinib (brain/plasma ratio 3.4 for osimertinib vs 0.21 for gefitinib). Osimertinib showed significant brain exposure and tumor shrinkage in preclinical brain metastases model. In 50 of 411 evaluable for CNS response in pooled AURA phase II study, osimertinib showed 53% of response rate and the median CNS PFS has not been reached (6). Confirmatory phase III study comparing osimertinib with platinum-doublets in T790M positive patients demonstrated significant improvement of PFS regardless of CNS metastases suggesting this agent has benefit in patients with CNS metastases. Recently released press showed that first-line osimertinib comparing with gefitinib/erlotinib (FLAURA) met the primary endpoint of PFS. It would be interesting to evaluate whether upfront use of osimertinib in EGFR mutant NSCLC can delay CNS metastases. Given the relatively high response rate in brain metastasis with EGFR TKI, the upfront use of EGFR TKI can delay other local therapies such as WBRT, SRS or surgery, leading to reduced side effects related to local therapy. However, the retrospective multi-institutional analysis demonstrated that the use of upfront EGFR TKI and deferral of radiotherapy is associated with inferior OS in patients with EGFR mutant NSCLC who developed brain metastases (7). Based on the potential synergistic effects of the combination of EGFR TKIs and radiotherapy due to opening of BBB by radiotherapy, several prospective trials were conducted. A phase II study of erlotinib combined with WBRT in 40 patients with NSCLC achieved 86% of response rate, 11.8 months of overall survival, whereas 19.1 months in patients with EGFR mutation (8). The Radiation Therapy Oncology Group conducted a phase II trial of WBRT and SRS alone or with either temozolomide or erlotinib for NSCLC patients with one to three brain metastases (EGFR mutation status was not tested). This study was closed early due to slow accrual and three arms did not show any differences in terms of efficacy. However, grade 3 to 5 toxicities were 41-49% in two concurrent drug combination arms. Thus, prospective randomized trial of SRS followed by EGFR TKI vs EGFR TKI followed by SRS at CNS progression is needed. Leptomeningeal disease (LM) is a fatal manifestation and its incidence is increasing in EGFR mutant NSCLC up to 10%. The prognosis remains very poor despite systemic treatment, intrathecal chemotherapy, radiotherapy and even molecular targeted therapy. Although EGFR TKIs have shown promising efficacy in the treatment of LM, especially with high dose or pulsatile dosing, the duration of efficacy is still limited with lack of survival improvement (9). Compared to gefitinib, erlotinib showed higher CSF concentrations (28.7 vs 3.7 ng/ml) and retrospective analysis showed promising activity with erlotinib in LM. It is not clear whether combination of intrathecal chemotherapy or WBRT can be applied to EGFR mutant NSCLC patients. Given the significantly higher penetration across the BBB (K~p,uu,brain ~=0.86) of AZD 3759, AZD3759 showed 28% of response rate (5/18) in TKI pretreated LM patients and 75% (3/4) in TKI naïve patients suggesting promising efficacy. The mean osimertinib concentration in CSF was 7.5nM in the T790M unselected cohort and AZD 9291 at 160mg once daily demonstrated encouraging activity with 43% of LM disease response and manageable tolerability (10). Both agents are currently being investigated in a larger cohort of patients with brain metastasis and leptomeningeal disease. Another challenge of conducting clinical trial in patients with LM is lack of standardized response evaluation method. Combinational measurements including neurological sign, CNS imaging and CSF cytology have been proposed, but further validation is warranted. In conclusion, CNS metastases in EGFR mutant NSCLC are increasing. Although EGFR TKI has been reported to improve clinical outcome, isolated or pre-dominant progression of CNS metastases remains a major issue in patients on EGFR inhibitors due to relative low penetration to BBB. New generation EGFR TKIs with better BBB penetration might have an impact on therapeutic strategies. Further studies are required to evaluate the optimal sequence of EGFR TKI therapy and radiotherapy. References Rangachari D, , et al. Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Cancer 2015; 88: 108-11. Fan Y, Xu X, Xie C. EGFR-TKI therapy for patients with brain metastases from non-small-cell lung cancer: a pooled analysis of published data. Onco Targets Ther 2014; 7: 2075-84. Umemura S, Tsubouchi K, Yoshioka H, et al. Clinical outcome in patients with leptomeningeal metastasis from non-small-cell lung cancer: Okayama Lung Cancer Study Group. Lung Cancer 2012; 77: 134-9. Togashi Y, Masago K, Masuda S, et al. Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer. Cancer Chemother Pharmacol 70: 399-405, 2012. Ahn MJ, Kim DW, Kim TM, et al. Phase I study of AZD3759, a CNS penetrable EGFR inhibitor, for the treatment of non-small-cell lung cancer (NSCLC) with brain metastasis (BM) and leptomeningeal metastasis (LM)., ASCO Meeting Abstracts. 34 (2016) 9003. Goss G, Tsai CM, Shepherd F, et al. CNS Response to osimertinib in patients with T790M-positive advanced NSCLC: Pooled data from two phase II trials. J Thorac Oncol Vol. 12 No. 1S (MA16.11)x William J. Magnuson, Nataniel H. Lester-Coll, 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. J Clin Oncol 35:1070-1077.James Chih-Hsin Yang Welsh JW, Komaki R, Amini A, et al. Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer. J Clin Oncol 31: 895-902, 2013. Yu HA, Sima CS, Reales D, et al. A phase I study of twice weekly pulse dose and daily low dose erlotinib as initial treatment for patients (pts) with EGFR-mutant lung cancers. J Clin Oncol33(Suppl 15s): 426s, 2015. Yang J.C.-H, Kim DW, Kim, SW, et al. Osimertinib activity in patients (pts) with leptomeningeal (LM) disease from non-small cell lung cancer (NSCLC): Updated results from BLOOM, a phase I study., ASCO Meeting Abstracts. 34 (2016) 9002.Search for articles by this authorAffiliations Cancer Research Center, National Taiwan University, Taipei/Taiwan
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Author of
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OA 17 - Immunotherapy II (ID 683)
- Event: WCLC 2017
- Type: Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yuichiro Ohe, Anne Tsao
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 301 + 302
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OA 17.04 - Discussant - OA 17.01, OA 17.02, OA 17.03 (ID 10802)
14:30 - 16:15 | Presenting Author(s): Martin Schuler
- Abstract
- Presentation
Abstract not provided
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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-012 - Ceritinib in Anaplastic Lymphoma Kinase (ALK)+ NSCLC Patients Pretreated With Only Crizotinib: ASCEND-1 Subgroup Analysis (ID 8972)
09:30 - 16:00 | Author(s): Martin Schuler
- Abstract
Background:
In phase 1 ASCEND-1 study (NCT01283516), ceritinib 750 mg/day (fasted) demonstrated durable whole-body and intracranial responses in both anaplastic lymphoma kinase inhibitor (ALKi)-naïve and ALKi-pretreated patients with ALK-rearranged non-small cell lung cancer (NSCLC). Here, we report the efficacy and safety of ceritinib in patients who were pretreated with crizotinib only from the ASCEND-1 study.
Method:
Patients with ALK+ NSCLC who were enrolled globally received ceritinib 750 mg/day (fasted). Efficacy and safety were evaluated in a subset of patients who had received prior crizotinib only (no other prior antineoplastic therapy). Data cut-off was May 03, 2016.
Result:
Overall, 246 patients with ALK+ NSCLC (83 ALKi-naïve and 163 ALKi-pretreated) received ≥1 dose of ceritinib, of whom, 26 had received prior crizotinib only. Among the 26 crizotinib-pretreated patients, 11 (42.3%) had baseline brain metastases, of which, 7 received prior radiotherapy, 6 (23.1%) had an ECOG performance status of 0, and 24 (92.3%) patients had stage IV disease. The median time from initial diagnosis to ceritinib initiation was 10.5 months (range, 2.4-33.0). At data cut-off, the median duration of exposure (range) was 41.0 weeks (2.9-180.4). In the 26 crizotinib-pretreated patients, per investigator assessment, the overall response rate was 65.4% (95% confidence interval [CI]: 44.3, 82.8), and the disease control rate was 80.8% (95% CI: 60.6, 93.4) (Table). The most frequently reported grade 3/4 adverse events (AEs), regardless of study drug relationship, were ALT increased (30.8%), AST increased (15.4%), diarrhea (11.5%), nausea (7.7%), fatigue (7.7%), and blood alkaline phosphatase increased (7.7%). All 26 patients discontinued treatment due to disease progression (n=12), consent withdrawal (n=6), AEs (n=2), administrative problems (n=4), or death (n=2).
*Median value derived from summary statistics; **Median value estimated by Kaplan-Meier method.Investigator Assessment N=26 Blinded Independent Review Committee Assessment N=26 Best overall response Complete response (CR), n (%) 1 (3.8%) 1 (3.8%) Partial response (PR), n (%) 16 (61.5%) 15 (57.7%) Stable disease (SD), n (%) 4 (15.4%) 5 (19.2%) Progressive disease (PD), n (%) 2 (7.7%) 1 (3.8%) Unknown, n (%) 3 (11.5%) 4 (15.4%) Overall response rate (ORR), % [95% CI] 65.4% [44.3-82.8] 61.5% [40.6-79.8] Disease control rate (DCR), % [95% CI] 80.8% [60.6-93.4] 80.8% [60.6-93.4] Median time to response*, weeks [95% CI] 6.1 [5.1-23.6] 6.4 [5.1-14.0] Median DOR**, months [95% CI] 8.3 [4.2-11.2] 8.5 [3.0-13.6] Median PFS**, months [95% CI] 8.5 [5.3-9.9] 8.2 [4.4-15.2]
Conclusion:
Ceritinib demonstrated durable efficacy in crizotinib-pretreated patients with ALK-rearranged NSCLC. Safety was consistent with the overall ASCEND-1 study population.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-026 - Analysis of Long-Term Response to First-Line Afatinib in the LUX-Lung 3, 6 and 7 Trials in Advanced EGFRm+ NSCLC (ID 9051)
09:30 - 16:00 | Presenting Author(s): Martin Schuler
- Abstract
Background:
In patients with advanced EGFR mutation-positive (EGFRm+) NSCLC, first-line afatinib significantly improved PFS and objective response rate (ORR) versus platinum-doublet chemotherapy in the phase III LUX-Lung (LL) 3 and LL6 studies, and PFS, time-to-treatment failure (TTF) and ORR versus gefitinib in the phase IIb LL7 study. Here, we present post-hoc analyses of efficacy, safety and patient-reported outcomes (PROs) in afatinib long-term responders (LTRs) in LL3/6/7.
Method:
Treatment-naïve patients with stage IIIb/IV EGFRm+ NSCLC who were randomized to 40mg/day afatinib in LL3/6/7 and remained on treatment for ≥3 years were defined as LTRs. In these patients, we assessed efficacy and safety outcomes, as well as PROs measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) Questionnaire and the EQ-5D™ health status self-assessment questionnaire; these included scores on the EORTC Global Health [GH]/QoL scale (0–100), EORTC Performance Functioning scale (PF; 0–100), EQ Visual Analogue Scale (VAS; 0–100) and EQ-5D UK utility scale (EQ UK utility; 0–1).
Result:
In LL3/6/7, there were 24/229 (10%)/ 23/239 (10%)/ 19/160 (12%) afatinib-treated LTRs; 6/9/14 remained on treatment at time of analysis. Baseline characteristics were similar to the overall study populations, except for the proportion of women (LL3/6 only [LTRs versus overall]: 92/78% vs 64/64%) and Del19+ patients (LL3/6/7: 63–79% vs 49–58%). In LL3/6/7, 4–11% of LTRs had brain metastases at enrolment. Median (range) duration of treatment in LL3/6/7 LTRs was 50 (41–73)/56 (37–68)/42 (37–50) months. Due to few deaths, median OS could not be estimated. Median follow-up for OS in LL3/6/7 was 64.6/57.0/42.1 months. ORR among LTRs in LL3/6/7 was 70.8% (complete response: 4.2%; n=1)/78.3% (13.0%; n=3)/89.5% (5.3%; n=1). The frequency of afatinib dose reductions due to treatment-related AEs, and the frequency/duration of subsequent treatments were similar to the overall LL3/6/7 populations. In afatinib-treated LTRs in LL3/6/7, PROs appeared stable between ~Week 24 to ~Week 160, with slight improvements after ~3 years afatinib treatment versus scores at the start of treatment.
Conclusion:
In LL3/6/7, 10%–12% of afatinib-treated patients were LTRs. Afatinib was well tolerated among these patients. Long-term treatment was independent of tolerability-guided dose adjustment or presence of brain metastases at time of enrolment, and had no detrimental impact on subsequent treatment. In afatinib-treated LTRs, PROs were not negatively affected by long-term treatment, and were slightly improved after ~3 years of treatment versus scores at treatment initiation.
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P3.01-075 - Afatinib Dose Adjustment: Effect on Safety, Efficacy and Patient-Reported Outcomes in the LUX-Lung 3/6 Trials in EGFRm+ NSCLC (ID 9365)
09:30 - 16:00 | Author(s): Martin Schuler
- Abstract
Background:
Afatinib 40mg/day is approved globally for first-line treatment of EGFR mutation-positive (EGFRm+) NSCLC. Afatinib is available in several tablet strengths (20/30/40/50mg), and tolerability-guided dose adjustment schemes are well established. Here, we evaluate the impact of afatinib dose reduction on safety (AEs), pharmacokinetics, PFS and patient-reported outcomes (PROs) in the Phase III LUX-Lung (LL) 3 and 6 trials.
Method:
Treatment-naïve patients with stage IIIB/IV EGFRm+ NSCLC in LL3/6 received either 40mg/day afatinib or chemotherapy. In case of any treatment-related grade ≥3 AEs or selected prolonged grade 2 AEs, afatinib dose was reduced by 10mg decrements (minimum dose 20mg/day). In this post-hoc analysis of all afatinib-treated patients in LL3/6 (n=229/n=239), we compared incidence and severity of common AEs before and after dose reduction, afatinib plasma concentrations in patients who reduced to 30mg versus those remaining on 40mg, and PFS in patients with/without dose reductions in the first 6 months of treatment. PROs were measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire and the EQ-5D™ health status self-assessment questionnaire, and pooled data from both trials were assessed before/after dose reduction; these included scores on the EORTC Global Health/Quality of Life scale (GH/QoL; 0–100), EORTC Performance Functioning scale (PF; 0–100), EQ Visual Analogue Scale (VAS; 0–100) and EQ-5D UK utility scale (EQ UK utility; 0–1).
Result:
Dose reductions occurred in 122/229 (53.3%) patients in LL3 and 67/239 (28.0%) in LL6; >80% of dose reductions occurred in the first 6 months of treatment. Dose reductions decreased the incidence of treatment-related AEs (grade ≥3 AEs before/after dose reduction: LL3, 73%/20%; LL6, 81%/12%), and were more likely among patients who had higher afatinib plasma concentrations prior to subsequent dose reduction (Day 22). On Day 43, geometric mean afatinib plasma concentrations were comparable between patients who had dose reduced (n=59; 23.3ng/mL) and patients who remained on 40mg (n=284; 22.8ng/mL). Median PFS was comparable between patients with or without dose reductions in the first 6 months (LL3: 11.3 versus 11.0 months; HR [95% CI] 1.25 [0.91–1.72]; p=0.175; LL6: 12.3 versus 11.0 months; 1.00 [0.69–1.46]; p=0.982). There were no clinically meaningful changes in PROs following afatinib dose reduction: GH (40/30mg: 59.1/66.9; n=136); PF (79.4/83.0; n=136); EQ VAS (70.1/75.1; n=135); EQ UK utility (0.70/0.78; n=135).
Conclusion:
Tolerability-guided dose adjustments effectively reduced afatinib-related AEs without negatively affecting therapeutic efficacy and PROs.
