- Email: [email protected]
MTE26.02 EGFR Targeted Therapies: Lessons Learned
January 2017
molecular predictor of effectiveness. As for prognostic evaluations, thresholds of 1%, 5%, 10%, 50% or continuous H score have been used. In addition, in a few trials, PD-L1 expression in TILs was predictive more than PD-L1 on tumor cells but the best cut off was not revealed. Conclusion: PDL1 expression predicts response to immune checkpoint inhibitors. Concordant results showing a better response if PDL1 + in several trials, using drug specific test and for Nivolumab also histology specific. We should evaluate membranous staining in tumor sample with at least 100 tumors cells and immune cells. Perspective for upgrading includes: 1) heterogeneity of the expression of PDL1 within tumor, primitive vs metastases number and size of samples; 2) surgical tissue versus biopsy and 3) archival versus new biopsy and 4) standardize the assays. Published abstracts showed high rates of concordance between primary and metastases (81%). Obtaining multiple biopsies from different areas of the tumor would enhance the validity of the results of IHC evaluation (160 patients¼48% discordance). References: 1. Sholl LM, Aisner DL, Allen TC, Beasley MB, Borczuk AC, Cagle PT, Capelozzi V, Dacic S, Hariri L, Kerr KM, Lantuejoul S, Mino-Kenudson M, Raparia K, Rekhtman N, Roy-Chowdhuri S, Thunnissen E, Tsao MS, Yatabe. Programmed Death Ligand-1 Immunohistochemistry–A New Challenge for Pathologists: A Perspective From Members of the Pulmonary Pathology Society. Arch Pathol Lab Med. 2016;140(4):341-4. 2. Couzin-Frankel J. Breakthrough of the year 2013: cancer immunotherapy. Science 2013;342:1432e1433. 3. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of nonesmall-cell lung cancer. N Engl J Med 2015;372:2018e2028. 4. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373:123e135. 5. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015;373: 1627e1639. 6. Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014;515:563e567. 7. Stewart R, Morrow M, Hammond SA, et al. Identification and characterization of MEDI4736, an antagonistic anti-PD-L1 monoclonal antibody. Cancer Immunol Res 2015;3:1052e1062. 8. Brambilla E, Le Teuff G, Marguet S, Lantuejoul S, Dunant A, Graziano S, Pirker R, Douillard JY, Le Chevalier T, Filipits M, Rosell R, Kratzke R, Popper H, Soria JC, Shepherd FA, Seymour L, Tsao MS. Prognostic Effect of Tumor Lymphocytic Infiltration in Resectable Non-
Abstracts
S177
Small-Cell Lung Cancer. J Clin Oncol. 2016;34:1223-30. 9. Soria JC, Marabelle A, Brahmer JR, Gettinger S. Immune checkpoint modulation for non-small cell lung cancer. Clin Cancer Res. 2015;21:2256-62. 10. Kitazono S, Fujiwara Y, Tsuta K, Utsumi H, Kanda S, Horinouchi H, Nokihara H, Yamamoto N, Sasada S, Watanabe S, Asamura H, Tamura T, Ohe Y. Reliability of Small Biopsy Samples Compared With Resected Specimens for the Determination of Programmed Death-Ligand 1 Expression in Non–Small-Cell Lung Cancer. Clin Lung Cancer 2015;16:385-90. Keywords: Lung Cancer, Immunohistochemistry
Immunotherapy,
PD-L1,
MTE26.02 EGFR Targeted Therapies: Lessons Learned Shun Lu,1 Federico Cappuzzo2 1Shanghai Lung Cancer Center, Shanghai Chest Hospital, Jiao Tong University, Shanghai/China, 2Department of Oncology, Ausl Romagna, Ravenna/Italy
Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs) are the standard therapy for
S178
patients with Non-Small-Cell Lung Cancer (NSCLC) harboring activating EGFR mutations. During the last 10 years several trials demonstrated that first and second generation EGFR-TKIs such as erlotinib, gefitinib or afatinib are superior to standard platinum-based chemotherapy in terms of efficacy and tolerability and quality of life. Development of EGFR-TKIs led to a dramatic change in mentality of physicians treating NSCLC. For many years NSCLC has been treated with chemotherapy and platinum-based doublets were offered to all patients irrespective of biological characteristics. Knowledge in the field of molecular biology were limited and even a small cytological sample was sufficient for defining the therapy. Tumor biopsy was recommended only at the time of initial diagnosis and changes in tumor biology as a consequence of therapy exposure were largely unknown. Discovery of EGFR mutations and the impressive activity observed with EGFR-TKIs in EGFR mutated patients led clinicians to understand the relevance of patient selection based on biomarker assessment and therefore the importance of tumor tissue analysis. Since EGFR-TKI approval, EGFR testing entered onto clinical practice and today several biomarkers are routinely tested in NSCLC patients for defining the best therapeutic strategy. In addition to EGFR, other biomarkers such as ALK or ROS1 rearrangements or PD-L1 expression are guiding physician for therapy choice and additional tests are expected to reach the clinic in the next future. As a consequence, tumor biopsy and tissue collection become relevant in clinical practice and also in trial design, since modern studies often claim for tumor tissue. In addition, identification of mechanisms responsible for acquired resistance led to repeat tumor biopsies. Unfortunately, in NSCLC, the amount of tissue obtained at the time of primary diagnosis is often not abundant and tumor rebiopsy if feasible in the minority of patients. Such limitations are leading to development of the so-called “liquid biopsy,” allowing physicians to obtain biomarker information in circulating tumor DNA. In addition, new technologies are implementing the possibility to test for multiple biological events using a single experiment, with a significant reduction in amount of tissue needed, reducing time and costs. Development of EGFR inhibitors also led to a different approach for treating lung cancer. For the first time, physicians faced with oligo-progressing diseases, consisting in disease slowly progressing under EGFR-TKI therapy. Often the disease remains asymptomatic and it is still partially sensitive to the therapy. The possibility to control disease outcome by continuing the targeted agent led to the
Journal of Thoracic Oncology
Vol. 12 No. 1S
concept of “treatment beyond progression,” an approach that is preserving patient quality of life with also a favorable impact on duration of life. Finally, anti EGFR therapies also highlighted the new opportunity for treating brain metastases. Brain metastases (BM) are a frequent complication of NSCLC, with 25e40% of patients developing BM during the course of the disease, often within the first 2 years after the primary tumor diagnosis. A review of 1,127 NSCLC patients found that those with EGFR mutations were more likely to develop BM than those without such mutations. The frequency of BM was thus 31.4% for the mutationpositive patients but only 19.7% for the negative ones. Improvements in neurologic symptoms and performance status have been reported with whole-brain radiation therapy (WBRT) in combination with steroid therapy in these patients. However, due to their poor performance status, many patients with BM are not eligible for surgery or radiosurgery. Furthermore, the role of systemic chemotherapy for the treatment of BM is controversial due to the impenetrable nature of the blood brain barrier (BBB), with reported response rates to chemotherapy ranging from 15e30% (overall survival [OS] 6e8 months). Response rates of brain metastases to EGFR tyrosine kinase inhibitor (TKI) treatment (e.g. gefitinib, erlotinib, afatinib) in patients with NSCLC harboring EGFR mutations reach 60e80%, with a complete response rate as high as 40%. Median OS is 15e20 months, and progression-free survival in the brain reaches 6.6e11.7 months, demonstrating improved clinical outcome (Table I). Nevertheless, first and second generation EGFR-TKI may have limited BBB penetration. New EGFR-TKIs including the thirdgeneration EGFR-TKI osimertinib and AZD3759, an oral reversible inhibitor of EGFR activating mutations, recently showed impressive activity in presence of BM. The possibility to obtain a long lasting brain disease control together with the positive impact on duration of life is also impacting on the strategy of BM treatment, with preference for therapies not or modestly impacting on cognitive functions, such as stereotaxic radiotherapy, and a lower usage of WBRT. References: 1. Porta R, et al. Eur Respir J 37: 624-631, 2011. 2. BPark SJ, et al. Lung Cancer 77: 556-560, 2012. 3. Li Z. J Clin Oncol 29 (Suppl): abstract e18065, 2011. 4. Kim JE, et al. Lung Cancer 65: 351-354, 2009. 5. Welsh JW, et al. J Clin Oncol 31: 895-902, 2013. 6. Iuchi T, et al. Lung Cancer 82: 282-287, 2013. 7. Hoffknecht P, et al. J Thorac Oncol 10: 156-163, 2015. Keywords: EGFR, brain metastases
molecular predictor of effectiveness. As for prognostic evaluations, thresholds of 1%, 5%, 10%, 50% or continuous H score have been used. In addition, in a few trials, PD-L1 expression in TILs was predictive more than PD-L1 on tumor cells but the best cut off was not revealed. Conclusion: PDL1 expression predicts response to immune checkpoint inhibitors. Concordant results showing a better response if PDL1 + in several trials, using drug specific test and for Nivolumab also histology specific. We should evaluate membranous staining in tumor sample with at least 100 tumors cells and immune cells. Perspective for upgrading includes: 1) heterogeneity of the expression of PDL1 within tumor, primitive vs metastases number and size of samples; 2) surgical tissue versus biopsy and 3) archival versus new biopsy and 4) standardize the assays. Published abstracts showed high rates of concordance between primary and metastases (81%). Obtaining multiple biopsies from different areas of the tumor would enhance the validity of the results of IHC evaluation (160 patients¼48% discordance). References: 1. Sholl LM, Aisner DL, Allen TC, Beasley MB, Borczuk AC, Cagle PT, Capelozzi V, Dacic S, Hariri L, Kerr KM, Lantuejoul S, Mino-Kenudson M, Raparia K, Rekhtman N, Roy-Chowdhuri S, Thunnissen E, Tsao MS, Yatabe. Programmed Death Ligand-1 Immunohistochemistry–A New Challenge for Pathologists: A Perspective From Members of the Pulmonary Pathology Society. Arch Pathol Lab Med. 2016;140(4):341-4. 2. Couzin-Frankel J. Breakthrough of the year 2013: cancer immunotherapy. Science 2013;342:1432e1433. 3. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of nonesmall-cell lung cancer. N Engl J Med 2015;372:2018e2028. 4. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373:123e135. 5. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015;373: 1627e1639. 6. Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014;515:563e567. 7. Stewart R, Morrow M, Hammond SA, et al. Identification and characterization of MEDI4736, an antagonistic anti-PD-L1 monoclonal antibody. Cancer Immunol Res 2015;3:1052e1062. 8. Brambilla E, Le Teuff G, Marguet S, Lantuejoul S, Dunant A, Graziano S, Pirker R, Douillard JY, Le Chevalier T, Filipits M, Rosell R, Kratzke R, Popper H, Soria JC, Shepherd FA, Seymour L, Tsao MS. Prognostic Effect of Tumor Lymphocytic Infiltration in Resectable Non-
Abstracts
S177
Small-Cell Lung Cancer. J Clin Oncol. 2016;34:1223-30. 9. Soria JC, Marabelle A, Brahmer JR, Gettinger S. Immune checkpoint modulation for non-small cell lung cancer. Clin Cancer Res. 2015;21:2256-62. 10. Kitazono S, Fujiwara Y, Tsuta K, Utsumi H, Kanda S, Horinouchi H, Nokihara H, Yamamoto N, Sasada S, Watanabe S, Asamura H, Tamura T, Ohe Y. Reliability of Small Biopsy Samples Compared With Resected Specimens for the Determination of Programmed Death-Ligand 1 Expression in Non–Small-Cell Lung Cancer. Clin Lung Cancer 2015;16:385-90. Keywords: Lung Cancer, Immunohistochemistry
Immunotherapy,
PD-L1,
MTE26.02 EGFR Targeted Therapies: Lessons Learned Shun Lu,1 Federico Cappuzzo2 1Shanghai Lung Cancer Center, Shanghai Chest Hospital, Jiao Tong University, Shanghai/China, 2Department of Oncology, Ausl Romagna, Ravenna/Italy
Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs) are the standard therapy for
S178
patients with Non-Small-Cell Lung Cancer (NSCLC) harboring activating EGFR mutations. During the last 10 years several trials demonstrated that first and second generation EGFR-TKIs such as erlotinib, gefitinib or afatinib are superior to standard platinum-based chemotherapy in terms of efficacy and tolerability and quality of life. Development of EGFR-TKIs led to a dramatic change in mentality of physicians treating NSCLC. For many years NSCLC has been treated with chemotherapy and platinum-based doublets were offered to all patients irrespective of biological characteristics. Knowledge in the field of molecular biology were limited and even a small cytological sample was sufficient for defining the therapy. Tumor biopsy was recommended only at the time of initial diagnosis and changes in tumor biology as a consequence of therapy exposure were largely unknown. Discovery of EGFR mutations and the impressive activity observed with EGFR-TKIs in EGFR mutated patients led clinicians to understand the relevance of patient selection based on biomarker assessment and therefore the importance of tumor tissue analysis. Since EGFR-TKI approval, EGFR testing entered onto clinical practice and today several biomarkers are routinely tested in NSCLC patients for defining the best therapeutic strategy. In addition to EGFR, other biomarkers such as ALK or ROS1 rearrangements or PD-L1 expression are guiding physician for therapy choice and additional tests are expected to reach the clinic in the next future. As a consequence, tumor biopsy and tissue collection become relevant in clinical practice and also in trial design, since modern studies often claim for tumor tissue. In addition, identification of mechanisms responsible for acquired resistance led to repeat tumor biopsies. Unfortunately, in NSCLC, the amount of tissue obtained at the time of primary diagnosis is often not abundant and tumor rebiopsy if feasible in the minority of patients. Such limitations are leading to development of the so-called “liquid biopsy,” allowing physicians to obtain biomarker information in circulating tumor DNA. In addition, new technologies are implementing the possibility to test for multiple biological events using a single experiment, with a significant reduction in amount of tissue needed, reducing time and costs. Development of EGFR inhibitors also led to a different approach for treating lung cancer. For the first time, physicians faced with oligo-progressing diseases, consisting in disease slowly progressing under EGFR-TKI therapy. Often the disease remains asymptomatic and it is still partially sensitive to the therapy. The possibility to control disease outcome by continuing the targeted agent led to the
Journal of Thoracic Oncology
Vol. 12 No. 1S
concept of “treatment beyond progression,” an approach that is preserving patient quality of life with also a favorable impact on duration of life. Finally, anti EGFR therapies also highlighted the new opportunity for treating brain metastases. Brain metastases (BM) are a frequent complication of NSCLC, with 25e40% of patients developing BM during the course of the disease, often within the first 2 years after the primary tumor diagnosis. A review of 1,127 NSCLC patients found that those with EGFR mutations were more likely to develop BM than those without such mutations. The frequency of BM was thus 31.4% for the mutationpositive patients but only 19.7% for the negative ones. Improvements in neurologic symptoms and performance status have been reported with whole-brain radiation therapy (WBRT) in combination with steroid therapy in these patients. However, due to their poor performance status, many patients with BM are not eligible for surgery or radiosurgery. Furthermore, the role of systemic chemotherapy for the treatment of BM is controversial due to the impenetrable nature of the blood brain barrier (BBB), with reported response rates to chemotherapy ranging from 15e30% (overall survival [OS] 6e8 months). Response rates of brain metastases to EGFR tyrosine kinase inhibitor (TKI) treatment (e.g. gefitinib, erlotinib, afatinib) in patients with NSCLC harboring EGFR mutations reach 60e80%, with a complete response rate as high as 40%. Median OS is 15e20 months, and progression-free survival in the brain reaches 6.6e11.7 months, demonstrating improved clinical outcome (Table I). Nevertheless, first and second generation EGFR-TKI may have limited BBB penetration. New EGFR-TKIs including the thirdgeneration EGFR-TKI osimertinib and AZD3759, an oral reversible inhibitor of EGFR activating mutations, recently showed impressive activity in presence of BM. The possibility to obtain a long lasting brain disease control together with the positive impact on duration of life is also impacting on the strategy of BM treatment, with preference for therapies not or modestly impacting on cognitive functions, such as stereotaxic radiotherapy, and a lower usage of WBRT. References: 1. Porta R, et al. Eur Respir J 37: 624-631, 2011. 2. BPark SJ, et al. Lung Cancer 77: 556-560, 2012. 3. Li Z. J Clin Oncol 29 (Suppl): abstract e18065, 2011. 4. Kim JE, et al. Lung Cancer 65: 351-354, 2009. 5. Welsh JW, et al. J Clin Oncol 31: 895-902, 2013. 6. Iuchi T, et al. Lung Cancer 82: 282-287, 2013. 7. Hoffknecht P, et al. J Thorac Oncol 10: 156-163, 2015. Keywords: EGFR, brain metastases