- Email: [email protected]
MS 05.04 Practical Approach to Combination of Chemotherapy with IO
November 2017
MS 05.02 First-line versus Second-Line Anti-PD-(L)1 Therapy for Patients with Positive PD-L1 Expression F. Barlesi Multidisciplinary Oncology & Therapeutic Innovations, Aix Marseille University, Marseille/FR Lung cancer is the leading cause of cancer-related deaths in other Western countries, with more than 1.8 million new cases and 1.5 million deaths worldwide in 2012 (Globocan, 2012). Recent advances in the management of NSCLC have included use of therapies targeting oncogenes (EGFR, BRAF or HER2 mutations, ALK or ROS1 rearrangements) but molecular alteration is currently detected in only the half of the patients with non-squamous NSCLC (Barlesi et al., 2016). Immune check point inhibitors (ICI), the first of which targeted the lymphocyte cell surface inhibitory receptor PD-1 or its ligand PD-L1, have recently become available and have been shown to provide an overall survival advantage over standard second-line chemotherapy (Borghaei et al., 2015; Brahmer et al., 2015; Herbst R et al, Lancet 2016; Rittmeyer et al, 2016), and more recently over first-line standard chemotherapy in monotherapy for a small subgroup driven by PD-L1 expression (Reck et al., 2016) or in combination regardless of PD-L1 expression (Langer et al, Lancet Oncol 2016), for both squamous and non-squamous NSCLC. Unfortunately, the long-term overall survival benefit is driven by only about 20-25% of the patients. PD-L1 tumor expression has been proposed to guide the patients’ selection but remains controversial (Kerr K, 2016). However, PD-L1 tumor expression of more than 1% and 50% is mandatory for the use of pembrolizumab monotherapy in second and first-line, respectively. Therefore, how to choose the best way to use ICIs for advanced NSCLC patients? Many aspects may be considered and will be discussed during the session including the PD-L1 expression and other potential predictive biomarkers (as tumor mutational burden), the current contra-indications to ICIs, the potential suspected factors predicting a higher risk of rapid progression on ICIs, the potential synergy for the concomitant combination of ICIs with chemotherapy or conversely a sequential use, the side effects for monotherapies and combinations, and the recent data on ICIs combinations versus standard chemotherapy. In summary, the attendees will have the arguments to globally assess the risk/benefit balance in using ICIs first or at resistance to chemotherapy and discuss the chosen strategies with their patients. Keywords: Immune Check points inhibitors, First line treatment, Combination immunotherapy and chemotherapy
MS 05.04 Practical Approach to Combination of Chemotherapy with IO Y. Ohe Thoracic Oncology, National Cancer Center Hospital, Tokyo/JP Combination of chemotherapy with immune-check point inhibitor is considered to be one of the most promising strategy to improve efficacy of immune-check point inhibitors. Several clinical trials of chemotherapy with immune-check point inhibitor are conducted and the results have been reported. KEYNOTE-021 cohort G is a randomized, open-label, phase 2 cohort of a multi-cohort study assessed whether the addition of pembrolizumab to carboplatin and pemetrexed improves efficacy in patients with advanced non-squamous NSCLC. Thirty-three (55%; 95% CI 42e68) of 60 patients in the pembrolizumab plus chemotherapy group achieved an objective response compared with 18 (29%; 18e41) of 63 patients in the chemotherapy alone group (p¼0$0016). Progression-free survival (PFS) was significantly longer with pembrolizumab plus chemotherapy compared with chemotherapy alone (HR 0$53 [95% CI 0$31e0$91]; p¼0$010). Median PFS was 13$0 months for pembrolizumab plus chemotherapy and 8$9 months for chemotherapy alone. The FDA has granted an accelerated approval to
Abstracts
S1677
pembrolizumab for use in combination with pemetrexed plus carboplatin as a frontline treatment for patients with metastatic or advanced non-squamous NSCLC, regardless of PD-L1 expression. Antiangiogenic monoclonal antibodies, bevacizumab and ramucirumab that are currently approved for use in the treatment of NSCLC. Bevacizumab, in addition to platinum-based chemotherapy is widely used for the firstline treatment of advanced, metastatic, or recurrent NSCLC, excluding squamous cell carcinoma. VEGF influences lymphocyte trafficking across endothelia to the tumor by inhibiting lymphocyte adhesion and VEGF has a systemic effect on immune-regulatory cell function through multiple mechanisms, such as Tregulatory cells (Tregs) and myeloidderived suppressor cells (MDSCs); suppression of dendritic cell maturation; and inhibition of T-cell development from hematopoietic progenitor cells. Thus, combination of antiangiogenic monoclonal antibody and immune-check point inhibitor is potentially synergistic. National Cancer Center Hospital conducted a single-center phase Ib study investigated the tolerability, safety, and pharmacokinetics of nivolumab combined with standard chemotherapy in patients with advanced NSCLC. In this trial, nivolumab with gemcitabine/cisplatin, pemetrexed/ cisplatin, paclitaxel/carboplatin/bevacizumab, or docetaxel were evaluated for six patients each arm. Combination of nivolumab and chemotherapy showed an acceptable toxicity profile and encouraging antitumor activity in patients with advanced NSCLC. Although small number of patients, nivolumab with paclitaxel/carboplatin/bevacizumab seems to be most promising with higher response rate and longer PFS. Based on these data, phase III study of paclitaxel/carboplatin/bevacizumab with/without nivolumab for advanced non-squamous NSCLC is ongoing. Keywords: antiangiogenic monoclonal antibody, chemotherapy, immune-check point inhibitor
MS 05.06 Brain Metastasis: Rationale and Efficacy with IO I. Gil-Bazo Oncology, Clinica Universidad de Navarra, Pamplona/ES The development of metastases from a primary tumor is the ultimate cause of death in most of patients with cancer. In a non-small cell lung cancer (NSCLC) series of 236 patients with advanced disease, brain metastasis appeared to be the second leading site of metastasis after bone.1 In fact, 31.8% of the patients presented brain metastasis at onset and a total of 42.8% of all patients included developed brain metastasis at any time point.1 Despite recent advances in the treatment of patients with NSCLC, CNS infiltration remains a frequent complication leading to impaired quality of life and shortened survival among NSCLC patients. In the era of personalized medicine for patients harboring oncogenic driver mutations, CNS infiltration has become an especially relevant clinical issue. In fact, an apparent higher incidence of brain metastasis at onset, among patients with molecular alterations, in particular for ALK + tumors has been reported.2 In addition, a higher cumulative incidence of CNS involvement overtime during treatment with targeted agents has been shown and CNS may be the only site of progression to first or second-line tailored therapies. Unfortunately however, most patients with advanced NSCLC present tumors lacking druggable oncogenic driver aberrations. In 2011, the tumors’ capacity of avoiding immune destruction was recognized as a new emerging hallmark of cancer. More recently, the constellation of interactions between tumor cells and the immune environment around them has definitely emerged as a potential and valuable source of innumerable novel anti-cancer targets. From the clinical perspective, treatment with immune checkpoint inhibitors targeting programmed-cell death 1 (PD-1) and its ligand (PDL-1) represent the best treatment option for many patients with advanced NSCLC in firstline3 and most of them in second-line4-6 due to an improved quality of life and a significant survival benefit. Unfortunately, most phase II randomized/phase III clinical trials assessing the efficacy of monoclonal antibodies against PD-13,4,6 and PDL-15 immune checkpoints in second or first-line settings excluded patients with active or untreated brain
MS 05.02 First-line versus Second-Line Anti-PD-(L)1 Therapy for Patients with Positive PD-L1 Expression F. Barlesi Multidisciplinary Oncology & Therapeutic Innovations, Aix Marseille University, Marseille/FR Lung cancer is the leading cause of cancer-related deaths in other Western countries, with more than 1.8 million new cases and 1.5 million deaths worldwide in 2012 (Globocan, 2012). Recent advances in the management of NSCLC have included use of therapies targeting oncogenes (EGFR, BRAF or HER2 mutations, ALK or ROS1 rearrangements) but molecular alteration is currently detected in only the half of the patients with non-squamous NSCLC (Barlesi et al., 2016). Immune check point inhibitors (ICI), the first of which targeted the lymphocyte cell surface inhibitory receptor PD-1 or its ligand PD-L1, have recently become available and have been shown to provide an overall survival advantage over standard second-line chemotherapy (Borghaei et al., 2015; Brahmer et al., 2015; Herbst R et al, Lancet 2016; Rittmeyer et al, 2016), and more recently over first-line standard chemotherapy in monotherapy for a small subgroup driven by PD-L1 expression (Reck et al., 2016) or in combination regardless of PD-L1 expression (Langer et al, Lancet Oncol 2016), for both squamous and non-squamous NSCLC. Unfortunately, the long-term overall survival benefit is driven by only about 20-25% of the patients. PD-L1 tumor expression has been proposed to guide the patients’ selection but remains controversial (Kerr K, 2016). However, PD-L1 tumor expression of more than 1% and 50% is mandatory for the use of pembrolizumab monotherapy in second and first-line, respectively. Therefore, how to choose the best way to use ICIs for advanced NSCLC patients? Many aspects may be considered and will be discussed during the session including the PD-L1 expression and other potential predictive biomarkers (as tumor mutational burden), the current contra-indications to ICIs, the potential suspected factors predicting a higher risk of rapid progression on ICIs, the potential synergy for the concomitant combination of ICIs with chemotherapy or conversely a sequential use, the side effects for monotherapies and combinations, and the recent data on ICIs combinations versus standard chemotherapy. In summary, the attendees will have the arguments to globally assess the risk/benefit balance in using ICIs first or at resistance to chemotherapy and discuss the chosen strategies with their patients. Keywords: Immune Check points inhibitors, First line treatment, Combination immunotherapy and chemotherapy
MS 05.04 Practical Approach to Combination of Chemotherapy with IO Y. Ohe Thoracic Oncology, National Cancer Center Hospital, Tokyo/JP Combination of chemotherapy with immune-check point inhibitor is considered to be one of the most promising strategy to improve efficacy of immune-check point inhibitors. Several clinical trials of chemotherapy with immune-check point inhibitor are conducted and the results have been reported. KEYNOTE-021 cohort G is a randomized, open-label, phase 2 cohort of a multi-cohort study assessed whether the addition of pembrolizumab to carboplatin and pemetrexed improves efficacy in patients with advanced non-squamous NSCLC. Thirty-three (55%; 95% CI 42e68) of 60 patients in the pembrolizumab plus chemotherapy group achieved an objective response compared with 18 (29%; 18e41) of 63 patients in the chemotherapy alone group (p¼0$0016). Progression-free survival (PFS) was significantly longer with pembrolizumab plus chemotherapy compared with chemotherapy alone (HR 0$53 [95% CI 0$31e0$91]; p¼0$010). Median PFS was 13$0 months for pembrolizumab plus chemotherapy and 8$9 months for chemotherapy alone. The FDA has granted an accelerated approval to
Abstracts
S1677
pembrolizumab for use in combination with pemetrexed plus carboplatin as a frontline treatment for patients with metastatic or advanced non-squamous NSCLC, regardless of PD-L1 expression. Antiangiogenic monoclonal antibodies, bevacizumab and ramucirumab that are currently approved for use in the treatment of NSCLC. Bevacizumab, in addition to platinum-based chemotherapy is widely used for the firstline treatment of advanced, metastatic, or recurrent NSCLC, excluding squamous cell carcinoma. VEGF influences lymphocyte trafficking across endothelia to the tumor by inhibiting lymphocyte adhesion and VEGF has a systemic effect on immune-regulatory cell function through multiple mechanisms, such as Tregulatory cells (Tregs) and myeloidderived suppressor cells (MDSCs); suppression of dendritic cell maturation; and inhibition of T-cell development from hematopoietic progenitor cells. Thus, combination of antiangiogenic monoclonal antibody and immune-check point inhibitor is potentially synergistic. National Cancer Center Hospital conducted a single-center phase Ib study investigated the tolerability, safety, and pharmacokinetics of nivolumab combined with standard chemotherapy in patients with advanced NSCLC. In this trial, nivolumab with gemcitabine/cisplatin, pemetrexed/ cisplatin, paclitaxel/carboplatin/bevacizumab, or docetaxel were evaluated for six patients each arm. Combination of nivolumab and chemotherapy showed an acceptable toxicity profile and encouraging antitumor activity in patients with advanced NSCLC. Although small number of patients, nivolumab with paclitaxel/carboplatin/bevacizumab seems to be most promising with higher response rate and longer PFS. Based on these data, phase III study of paclitaxel/carboplatin/bevacizumab with/without nivolumab for advanced non-squamous NSCLC is ongoing. Keywords: antiangiogenic monoclonal antibody, chemotherapy, immune-check point inhibitor
MS 05.06 Brain Metastasis: Rationale and Efficacy with IO I. Gil-Bazo Oncology, Clinica Universidad de Navarra, Pamplona/ES The development of metastases from a primary tumor is the ultimate cause of death in most of patients with cancer. In a non-small cell lung cancer (NSCLC) series of 236 patients with advanced disease, brain metastasis appeared to be the second leading site of metastasis after bone.1 In fact, 31.8% of the patients presented brain metastasis at onset and a total of 42.8% of all patients included developed brain metastasis at any time point.1 Despite recent advances in the treatment of patients with NSCLC, CNS infiltration remains a frequent complication leading to impaired quality of life and shortened survival among NSCLC patients. In the era of personalized medicine for patients harboring oncogenic driver mutations, CNS infiltration has become an especially relevant clinical issue. In fact, an apparent higher incidence of brain metastasis at onset, among patients with molecular alterations, in particular for ALK + tumors has been reported.2 In addition, a higher cumulative incidence of CNS involvement overtime during treatment with targeted agents has been shown and CNS may be the only site of progression to first or second-line tailored therapies. Unfortunately however, most patients with advanced NSCLC present tumors lacking druggable oncogenic driver aberrations. In 2011, the tumors’ capacity of avoiding immune destruction was recognized as a new emerging hallmark of cancer. More recently, the constellation of interactions between tumor cells and the immune environment around them has definitely emerged as a potential and valuable source of innumerable novel anti-cancer targets. From the clinical perspective, treatment with immune checkpoint inhibitors targeting programmed-cell death 1 (PD-1) and its ligand (PDL-1) represent the best treatment option for many patients with advanced NSCLC in firstline3 and most of them in second-line4-6 due to an improved quality of life and a significant survival benefit. Unfortunately, most phase II randomized/phase III clinical trials assessing the efficacy of monoclonal antibodies against PD-13,4,6 and PDL-15 immune checkpoints in second or first-line settings excluded patients with active or untreated brain