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Chong-Kin Liam
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MS 13 - How to Deal with CNS Metastases (ID 535)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Martin Schuler, Nir Peled
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 502
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MS 13.04 - The Role of Chemotherapy in the Management of CNS Metastasis (ID 7705)
11:45 - 12:00 | 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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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-088h - Resistance Mechanisms Causing First-line Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Treatment Failure (ID 9990)
09:30 - 09:30 | Presenting Author(s): Chong-Kin Liam
- Abstract
Background:
Patients with epidermal growth factor receptor (EGFR) mutant advanced non-small cell lung cancer receiving first-line EGFR-tyrosine kinase inhibitor (TKI) inevitably developed disease progression after 9-13 months.
Method:
Before 1[st] January 2017, patients were investigated for resistance mechanisms upon failure of first-line EGFR-TKI by tissue re-biopsy. Liquid biopsy to detect secondary T790M mutation in plasma cell free tumor-DNA (cfDNA) was only performed if tissue re-biopsy was not feasible. Starting 2017, liquid biopsy was the first-choice of investigation. Tumor re-biopsy was only perfomed when cfDNA was negative for T790M mutation or if the patients had rapidly enlarging tumors.
Result:
Of 45 patients who were tested, 31(68.9%) underwent tissue re-biopsy and 14 (31.1%) underwent liquid biopsy as the first investigation to determine the presence of T790M mutation. For the latter group, 4 (8.9%) patients subsequently also had tumor re-biopsy. T790M mutation was detected in 30 (66.7%) of the 45 patients. C-Met amplification was tested in 7 T790M mutation-negative patients for possible recruitment into a clinical trial with 4 of them showing c-Met amplification. Small cell lung cancer transformation and ALK rearrangement were detected in 2 (5.7%) and in 1 (2.9%) of the re-biopsy tissue specimens, respectively. The resistance mechanisms in 8 patients (17.8%) was unknown. In short, two-third (66.7%) of our patients had T790M mutation upon first-line EGFR-TKI failure; while another one-third (33.3%) failed first-line EGFR-TKI due to other resistance mechanisms. The demographic, clinical and treatment characteristics were equally distributed among these 2 groups of patients. (Table 1)Table 1. Demographic, clinical and treatment characteristics of 45 patients with first-line EGFR-TKI treatment failure
Characteristic Total patients (n = 45) T790M mutation (n = 30) Other resistance mechanims (n =15) p value of univariate analysis Gender, No (%). Male Female 18 (40.0) 27 (60.0) 13 (43.3) 17 (56.7) 5 (33.3) 10 (66.7) 0.780 Smoking history, No (%). Never Ex or current smoker 36 (80.0%) 9 (20.0%) 22 (73.3) 8 (26.7) 14(93..3) 1 (6.7) 0.963 EGFR mutation subtype, No (%) Exon 19 deletion Exon 21 L858R Others Unknown 26 (57.8) 16(35.6) 2 (4.4) 1(2.2) 17 (56.7) 12 (40.0) 1 (3.3) 0 9 (60.0) 4 (26.7) 1 (6.7) 1 (6.7) 0.999 Treatment received, No (%) EGFR-TKI EGFR-TKI followed by chemotherapy 34 (75.5) 11 (24.5) 22 (73.3) 8 (26.7) 12 (80.0) 3 (20.0) 0.484 Best tumor response, No (%) Partial response Stable disease Disease progression 38 (84.4) 6 (13.3) 1 (2.2) 27 (90.0) 2 (6.7) 1 (3.3) 11 (73.3) 4 (26.7) 0 0.419 Initial progression free survival, months Median 13.0 13.0 11.7 0.538
Conclusion:
T790M mutation is the commonest acquired resistance mechanism causing first-line EGFR-TKI treatment failure. There was no difference in the clinical and treatment characteristics between patients with and without acquired T790M mutation as causes of resistance to first-line EGFR-TKI treatment.
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P3.15 - SCLC/Neuroendocrine Tumors (ID 731)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.15-014 - Case Series of Small Cell Lung Cancer Transformation as Resistance Mechanism to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor (ID 9940)
09:30 - 09:30 | Presenting Author(s): Chong-Kin Liam
- Abstract
Background:
Patients with epidermal growth factor receptor (EGFR) mutant advanced non-small cell lung cancer (NSCLC) developed resistance to first- or second-generation EGFR-tyrosine kinase inhibitor (TKI) after 9-13 months and third-generation EGFR-TKI after 10 months, respectively. Small cell lung cancer (SCLC) transformation is a rare resistance mechanism in these patients.
Method:
Tissue re-biopsy was performed in 35 patients with EGFR mutant advanced NSCLC who failed first-line EGFR-TKI; and 4 patients with acquired T790M mutant advanced NSCLC who failed third-generation EGFR-TKI, to look for SCLC transformation
Result:
SCLC transformation was identified in 2 out of 35 (5.7%) patients who failed first-line EGFR-TKI and 1 out of 4 (25.0%) patients who failed third-generation EGFR-TKI. The first patient was a 70-year-old never-smoker male who was diagnosed with stage IV lung adenocarcinoma harboring exon 19 deletion mutation in April 2014. He had partial response (PR) to gefitinib 250 mg daily but developed symptomatic progressive disease (PD) after 26 months. Re-biopsy of his enlarging primary lung lesion showed SCLC transformation. The second patient was a 43-year-old never-smoker male who was diagnosed with stage IV lung adenocarcinoma harboring exon 19 deletion mutation in November 2015. He had PR to gefitinib 250 mg daily but developed symptomatic PD after 15 months. Re-biopsy of his rapidly enlarging primary lung lesion showed SCLC transformation. His plasma cell-free tumour DNA (cftDNA) was positive for T790M mutation. The third patient was a 62-year-old never-smoker female who was diagnosed with stage IV lung adenocarcinoma harboring exon 21 L858R mutation in November 2015. She had PR to gefitinib 250 mg daily but experienced symptomatic PD after 8 months’ of gefitinib therapy. Re-biopsy of her primary lung tumor revealed the presence of T790M mutation and her treatment was switched to osimertinib 80 mg daily. After an initial PR, she developed PR in the 12[th] month of osimertinib treatment. Biopsy from a metastatic inguinal lymph node showed SCLC. The first and second patients were given standard SCLC chemotherapy with carboplatin and etoposide but did not respond. The third patient sought treatment in another hospital.
Conclusion:
Re-biopsy is recommended in all patients with symptomatic PD while on EGFR-TKI treatment. SCLC transformation under the pressure of first, second and third-generation EGFR-TKI is an emerging challenge to the management of advanced NSCLC. Other than conventional carboplatin and etoposide chemotherapy, new treatment strategies should be explored to improve the outcome of patients who develop SCLC transformation.
