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Egbert F Smit
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IBS12 - Case-Based Management of Brain Metastasis (Bm) in Advanced Lung Cancer Patients: Changing the Standards (Ticketed Session) (ID 43)
- Event: WCLC 2019
- Type: Interactive Breakfast Session
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 07:00 - 08:00, Toronto (1985)
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IBS12.02 - Questions to Be Addressed (Now Available) (ID 3352)
07:00 - 08:00 | Presenting Author(s): Egbert F Smit
- Abstract
- Presentation
Abstract
Case-Based Management of Brain Metastasis (Bm) in Advanced Lung Cancer Patients: Changing the Standards. Questions to Be Addressed
M. Guckenberger, E.F. Smit
Dept. of Radiation Oncology, USZ, Switserland, Dept. of Thoracic Oncology, NCI, The Netherlands.
Brain metastases develop in relevant numbers of patients through their courses of metastatic non-small cell lung cancer (NSCLC) and are associated with worsening of quality-of-live and survival. Traditionally, outcome was very poor due to the lack of effective treatment options, for the brain metastases but also for extracranial metastatic disease. Recent advances in imaging, local and systemic treatment options have changed the prognosis of patients with NSCLC brain metastases and have challenged traditional treatment strategies. Management of patients with brain metastases today needs a more individualized approach due to the multiple factors influencing the decision making process: patient performance status; number, location and size of brain metastases; presence of symptoms and neurological deficits; presence and extend of extracranial disease; histology and presence of activating driver mutations; available systematic treatment options and their CNS activity; patient preference.
From a local treatment perspective, radiosurgery and neurosurgical resection are treatment options, which have shown to improve survival in patients with limited brain metastases. Whole brain radiotherapy is not recommended after radiosurgery and neurosurgical resection; however stereotactic radiotherapy should be added to the resection cavity to improve local metastasis control. The value of radiosurgery without whole brain irradiation for multiple brain metastases is currently under investigation. Whole brain irradiation is today still recommended for patients with multiple and in particular symptomatic brain metastases; whether hippocampal avoidance can reduce the risk of damage to the neurocognitive system is not finally answered. The landscape is currently changing rapidly and fundamentally due to identification of activating driver mutations and the existence of effective targeted drugs. Additionally, treatment with immune checkpoint inhibition has also shown intracranial activity. Consequently, there is in particular a need to identify optimal combined modality strategies of local radiotherapy and systemic targeted drugs and immunotherapy.
From a systemic treatment perspective, it has become apparent that brain metastases may also be sensitive to tyrosine kinase inhibitors against a variety of targets and emerging data suggest that immune checkpoint inhibitors display activity as well. Therefore, in case of asymptomatic brain metastases at diagnosis when the primary lung cancer is characterized by an oncogenic driver, nowadays many would favour initial treatment with tyrosine kinase inhibitors in an effort to delay radiotherapy to the brain as long as possible. Whether symptomatic brain metastases at diagnosis may be managed in a similar manner, especially when refractory to high dose steroids, is less clear. The third generation EGFR TKI (osimertinib) and second/third generation Alk inhibitors (ceritinib, alectinib, brigatinib and lorlatinib) are associated with response rates in the brain in the relapse setting on treatment of first/second generation EGFR TKi’s or first generation Alk inhibitor that are not different from extracranial response rates. Thus, also in this clinical situation, systemic treatment plays an important role in delaying radiotherapy – in particular whole brain radiotherapy- as long as possible. It should be noted however, that there are no formal randomized comparisons available of these treatment modalities.
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P1.04 - Immuno-oncology (ID 164)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.04-12 - Tumor Uptake and Biodistribution of 89Zr-Labeled Pembrolizumab in Patients with Metastatic Non-Small-Cell Lung Cancer (Now Available) (ID 2429)
09:45 - 18:00 | Author(s): Egbert F Smit
- Abstract
Background
Pembrolizumab, a monoclonal antibody targeting PD-1, is approved as monotherapy for the treatment of advanced NSCLC, depending on tumor PD-L1 (T-PD-L1) expression level. However, T-PD-L1 expression correlates moderately with response to pembrolizumab treatment. Therefore, there is need for biomarkers that accurately discriminate between responders and non-responders. Whole body 89Zr-pembrolizumab PET/CT allows to quantify pembrolizumab uptake in tumor lesions and to study pembrolizumab biodistribution in non-malignant tissues.
Method
Patients with advanced stage NSCLC and eligible for pembrolizumab monotherapy were enrolled. Following tracer injection (standard dose: 2mg 89Zr-pembrolizumab, 37 MBq), the first 3 patients received whole body PET/CT-scans at 1h, 72h, 120h and 168h post-injection. Subsequent 10 patients were scanned at 72h and 144h post-injection. Biodistribution and tumor uptake were assessed visually by an experienced nuclear physician. Quantitative uptake was calculated as SUVpeak for delineable lesions and correlated to T-PD-L1/PD-1 IHC and response. A tumor biopsy after the last line of prior treatment was required to assess T-PD-L1/PD-1 IHC status (22C3 assay). Response was defined as partial or complete, after 6 months, according to RECIST criteria.
Result
Thirteen patients (5 ≥50%, 4 1-49%, 4 negative by PD-L1 IHC) were enrolled (6 first line, 7 second/third line treatment). One patient experienced grade 3 myalgia after tracer injection. 89Zr-pembrolizumab biodistribution was comparable to 89Zr-nivolumab biodistribution with relatively high uptake in the spleen, likely due to binding to PD-1 receptors on lymphocytes/dendritic cells, and in the liver likely due to catabolism of the tracer. Imaging revealed tumor uptake in all patients, but not in all lesions. Visual assessment confirmed 70 lesions (including non-malignant lymph nodes) at 72h post-injection (SUVpeak range 1.7-13.0). Not all tumor lesions showed tracer uptake and uptake was heterogeneous within and between patients. In 3 patients response was observed. Pretreatment T-PD-L1≥50% was predictive for response (p=0.023). SUVpeak was higher in responding patients than in non-responding patients (median SUVpeak of all visible lesions 8.0 vs 5.5, p=0.033). In line with these results, responding lesions (n=10) had a higher SUVpeak compared to non-responding lesions (n=24, median 8.1 vs 5.5, p=0.025). Tumor tracer uptake did not correlate with PD-1 expression (low PD-1 expression SUVpeak 6.0 vs high PD-1 expression SUVpeak 7.7, p=0.3).
Conclusion
89Zr-pembrolizumab injection was safe with only one grade 3 possibly related adverse event. Tumor 89Zr-pembrolizumab uptake correlated with response to pembrolizumab treatment. Further research is needed to study the value of this biomarker as standalone biomarker or as added information to T-PD-L1 expression by immunohistochemistry.
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P1.09 - Pathology (ID 173)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Pathology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.09-21 - Tumor Responses Based on Tumor Growth Rate During PD-1 Inhibitor Therapy in Advanced Non-Small-Cell Lung Cancer Patients (ID 1906)
09:45 - 18:00 | Author(s): Egbert F Smit
- Abstract
Background
Immune checkpoint inhibitors have emerged as a standard of care treatment for non-small cell lung cancer (NSCLC). However, there remains debate about the tumor growth kinetics during treatment, for instance the incidence of rapid disease progression, described as hyperprogressive disease (HPD). To get insight into variations in tumor growth kinetics and their potential predictive values for outcome we evaluated tumor growth rate (TGR) in patients receiving PD-1 checkpoint inhibitors.
Method
An analysis and radiological review of all Nivolumab treated NSCLC patients (n=196) between 06-2015 and 09-2017 in an early access program and as standard of care was performed. Differences in TGR before and after the start of treatment were calculated by entering the sum of the longest diameters from CT-scans before and after the initiation of therapy into a formula that assumes a volumetric exponential tumor growth. TGR variations, possible predictors for TGR changes and its relationship to overall survival (OS) were studied. For comparison tumor response was assessed using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST1.1).
Result
Among the 58 evaluable patients, 37 patients (64%) showed deceleration of TGR and 16 patients (27%) showed acceleration of TGR after initiation of therapy, with a significant difference in median OS of 18.0 versus 6.0 months (HR=0.35; 95%CI:0.18-0.71) between these groups. Four patients (7%) were defined as having HPD. In 5 patients (9%), the tumor growth remained stable. These TGR categories were not significantly different according to age, gender, histology, smoking or previous radiotherapy. Of the patients defined as having progressive disease by RECIST1.1 at first follow up 40% showed response to CPI by a decrease in tumor growth rate. (Figure 1)
Conclusion
Tumor growth kinetics can be used as a clinically relevant predictor for OS in anti-PD1 treated NSCLC patients, and may provide additional information to RECIST measurements.
