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F. De Marinis
Moderator of
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SC27 - P53 and KRAS Mutations in NSCLC (ID 351)
- Event: WCLC 2016
- Type: Science Session
- Track: Biology/Pathology
- Presentations: 4
- Moderators:F. De Marinis, H. Kunitoh
- Coordinates: 12/07/2016, 11:00 - 12:30, Strauss 3
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SC27.01 - The Role of p53 in Lung Cancer (ID 6713)
11:00 - 11:20 | Author(s): P. Hainaut
- Abstract
- Presentation
Abstract not provided
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SC27.02 - Biology of KRAS Mutations (ID 6714)
11:20 - 11:40 | Author(s): J. Tímár
- Abstract
- Presentation
Abstract:
Molecular classification of lung cancer revealed that the most frequently mutated oncogene in lung cancer is the KRAS due to smoking and this molecular subclass is exclusively occur in the adenocarcinoma histologic variant and rarely in large cell variant. It also can be detected in the mixed histological variants like the adenosquamous subtype. The incidence of KRAS mutation in lung adenocarcinoma is 30% based on exon2 testing. (1) However, it is expected that similar to colorectal cancer, a complex RAS panel mutational analysis involving rare KRAS exon3 and 4 and NRAS exon2-4 could increase this figure significantly (probaly by 5-10%). Since RAS mutations are exclusive and do not occur together with other oncogenic driver mutations the complett RAS panel mutation determination could help to clearly define a large set of adenocarcinoma patents where further molecular analysis is not necessary. Analysis of two large patient cohort of lung adenocarcinoma and colorectal cancer (500 pt each) revealed that the alleic variations are highly similar in mutant KRAS exon2 in this two cancer types. The TGT (G-C) transversion in codon 12 was proved to be lung cancer specific while the GAC (G-D) codon 13 alteration was colorectal cancer specific. Since the RAS mutation in lung cancer is considered to be smoking-related, this highly similar allelic profile in colorectal cancer can be the molecular signature of smoking in this cancer type. Analysis of KRAS exon 2 aminoacid conversions by smoking status revealed that in non-smokers mutation is rare and if it occurs it is most frequently G12V unlike in smokers where G12C is the predominant. G12V-type patients may respond better to conventional chemoterapy (2). RAS mutant lung cancer patients are resistant to EGFR TKI inhibitors (1). EGFR protein expression is highly similar in KRAS mutant and wt lung adenocarcinoma but interestingly phosphorylated-EGFR is overexpressed in KRAS mutant tumors even overcoming EGFR mutated ones suggesting an aberrant RAS-driven signaling. (3) KRAS mutation in lung cancer is a poor prognostic factor. Analysis of the organ metastatic pattern of KRAS mutant lung adenocarcinoma revealed that brain and bone metastatic potential of these tumors are similar to KRASwt ones while these tumors tend to prefer pleural dissemination and liver. On the other hand, KRAS mutant lung adenocarcinoma is less likely give rise adrenal- or lung metastasis, a clearly indication a different biology as compared to KRASwt cancers. It is an important issue today the maintenance of the molecular profiles in metastases as compared to the primary tumor. This issue may be less sensitive in case of patients where surgical removal of the primary is impossible (a significant proportion of lung cancers) while can be more significant where only metastases are present in the patients. Analysis of the literature data indicates that the discrepancy rate of RAS mutation status in lymphatic metastases is low (below 10%), in case of visceral metastases increases to 14-24% range while is was reported to be the highest in bone metastasis (1). Lung cancer is reported to be a clonally heterogenous cancer and these alterations are most probably due to clonal variations during metastatic dissemination. With the advent of liquid biopsy technology monitorization of this process is now feasible using circulating DNA. A major issue clinically today is the development of resistance to target therapies. Both lung adenocarcinoma and colorectal cancer is treated by EGFR-targeted therapies where the molecular mechnisms of acquired resistance are now reported. It is interesting that in colorectal cancer patients the main cause of resistance to anti-EGFR antibody therapy is the emergence of RAS mutated clones in progressing tumors which were in minority in the primary. Although RAS mutation is equally frequent in lung adenocarcinoma, EGFR-TKI resistance is most frequently due to EGFR T790M mutation or HER2 amplification but no report on the emergence of RAS mutated clones.(4) In case of ALK mutated lung adenocarcinoma resistance to ALK inhibitors is mainly due to novel mutations in ALK. In a small proportion of cases KRAS amplification or NRAS mutation can be detected which suggest that in ALK-translocated lung cancer no minor RAS mutant clones are present in the tumors. (5) Check point inhibitor therapy is a new modality of lung cancer management targeting CTLA4, PD1 or PDL1 as targets on immune cells or cancer cells (PDL1). Although two drugs are registered in NSCLC, the significance of RAS mutations in this new modality is not known yet. In case of Nivolumab it is known that smokers are responding better to anti-PD1 therapy than nonsmokers suggesting that KRAS mutant tumors might be a better target but direct subgroup analysis is lacking. In case of Pembrolizumab even such an indirect data are missing therefore the question cannot be answered yet. The fact that EGFR mutant tumors are tend to respond less to anti-PD1 therapy suggest that beside PDL1 status molecular classification can also be a predictive factor for selecting patients for immunotherapy. (6) References 1.Tímár J: The clinical relevance of KRAS gene mutation in non-small-cell lung cancer. Curr Opin Oncol 26: 138-144, 2014 2. Cserepes M, Ostoros Gy, Lohinai Z, Rásó E, Barbai T, Tímár J, Rozsás A, Moldvay J, Kovalszky I, Fabián K, Gyulai M, Ghanim B, László V, Klikovits T, Hoda MA, Grusch M, Berger W, Klepetko W, Hegedűs B, Döme B: Subtype-specific KRAS mutations in advanced lung adenocarcinoma: A retrospective study of patients treated with platinum-based chemotherapy. Eur J Cancer 50: 1819-1828, 2014 3.Moldvay J, Barbai T, Bogos K, Piurko V, Fillinger J, Popper HH, Tímár J: EGFR autophosphorylation but not protein score correlates with histologic and molecular subtypes in lung adenocarcinoma. Diagn Mol Pathol 22: 204-209, 2013 4. Belchis DA, Tseng LH, Gmiadek T et. al. Heterogeneity of resistance mutations detectable by next-generation sequencing in TKI-treated lung adenocarcinoma. Oncotarget 2016 (in ress) 5. Dagogo-Jack I, Show AT. Crizotinib resistance: implications for therapeutic strategies. Ann Oncol 273:iii42-iii50,2016 6. El-Osta H, Shahid K, Mills GM, Peddi P. Immune checkpoint inhibitors: the new frontier in non-small-cell lung cancer. Oncotarget 9:5101-5016,2016
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SC27.03 - Transforming KRAS into a Clinically Relevant Biomarker (ID 6715)
11:40 - 12:00 | Author(s): K. O’byrne
- Abstract
- Presentation
Abstract:
TP53 mutations represent the commonest mutation seen in NSCLC. Over 50% of NSCLC tumours harbour a TP53 mutations. TP53 mutations in tobacco smokers are predominantly G-to-T transversions and deletions. In non-smokers, however, these alterations are rare. p53 is a stress response protein/transcription factor and is involved in cellular response to DNA damage induced by oxidative stress and external factors such as sunlight and radiation. Expression of p53 protein is largely controlled through degradation of the protein by the mouse double minute 2 (MDM2) E3 ligase and MDM4. Post-translational modification by various kinases/phosphatases and acetylases/deacetylases also regulates p53 activity. Amongst the various type of TP53 mutation that can occur, conformational TP53 mutations may contribute to the emergence of new functions leading to genomic instability, inhibition of apoptosis, cell migration, and drug resistance. These mutations may result in the binding and inactivation of p53-related proteins such as p63 and p73, or with other transcriptional factors resulting in modification of their activity and, hence, altered gene expression. Apart from the loss of tumour-suppressor functions, TP53 mutations may result in gain of function favouring cellular proliferation, inhibition of apoptosis, and genomic instability. As a result not all P53 mutations are the same with some more likely to affect the pathogenesis of NSCLC than others. Broadly speaking TP53 mutations may be divided into disruptive and non-disruptive cohorts. Many non-disruptive p53 mutations result in gain of function. In a recent series of 318 patients that included 125 with EGFR-mutations, non-disruptive TP53 mutations were associated with a poor prognosis. A recent study using an ELISA demonstrated p53 antibodies in 20.4% of lung cancer patients. A significant correlation between serum p53 antibodies and high levels of p53 expression in the corresponding tumour samples was seen. In NSCLC, the presence of p53 antibodies were significantly associated with poorly differentiated. High levels of p53 antibodies were also associated with high grade tumours, with squamous cell histology and with a poor prognosis in squamous cell carcinoma. Oncogenic KRAS mutations have been reported in up to 40% of adenocarcinomas and 5% of squamous cell carcinomas of the lung. These mutations are found largely in lung adenocarcinomas with solid growth patterns. While KRAS mutations are classically associated with a significant smoking history, they are also identified in a substantial proportion of never-smokers. KRAS mutations are relatively mutually exclusive from EGFR, BRAF and ALK mutations/rearrangements but have considerable overlap with both P53 and PIK3CA mutations. The commonest mutation is in codon 12 but mutations in codon 13 and 61 are also been described. Substitutions in these residues result in constitutively elevated levels of Ras-GTP due to reduced intrinsic GTP hydrolysis and resistance to GTPase-activating proteins and hence activation of the Raf and phosphatidylinositol 3-kinase. Although controversy on the prognostic and predictive value of the presence of a KRAS mutation in a tumour exists, recent studies indicate that patients with KRAS mutations are resistant re chemotherapy and radiotherapy, with a lower objective response rate and worse progression free and overall survival rates. A number of recent studies have allowed us to gain novel insights into the role of KRAS in the pathogenesis of lung cancer, in particular adenocarcinoma of the lung. Increasing evidence indicates a role for chronic inflammation in the pathogenesis of lung cancer, an observation being exploited clinically through the use of immune checkpoint inhibitors such as pembrolizumab. A proportion of KRAS mutation positive tumours have been found to have a high tumour mutation burden that may indicate sensitivity to such agents. KRAS mutations have also been associated with tumour-infiltrating lymphocytes. Recent work has demonstrated that KRAS mutation in lung epithelial cells preferentially leads to recruitment of Th17 positive immune cells that produce IL-17, a cytokine that promotes inflammation. IL-17 induces tumorigenesis by recruiting GR1C CD11bC immune cells. Recent work has demonstrated that miRs may play a role in the regulation of KRAS. For example miR-31 has recently been reported to be over-expressed in lung adenocarcinoma and to correlate with worse survival. Using a transgenic mouse model that allows for lung-specific expression, induction of miR-31 results in lung hyperplasia, followed by adenoma formation and later the development of adenocarcinoma. Induced expression of miR-31 acts with mutant KRAS to accelerate lung tumourigenesis by down-regulating a number of negative regulators of RAS/MAPK signaling. The expression of mesothelin, a cell surface glycoprotein that may have a role in cell adhesion and metastases, is seen in several epithelial cancers and has recently been assessed in adenocarcinoma of the lung using immunohistochemistry. The intensity of staining and the percentage of cells expressing mesothelin in the report was blinded for molecular data and outcome. Mutations of EGFR, KRAS, BRAF, AKT1, PIK3CA and HER2 were assessed by pyrosequencing; HER2 amplification and ALK translocation were assessed by fluorescence in situ hybridization. Of the advanced lung adenocarcinomas, 53% expressed mesothelin to some degree. High mesothelin expression, defined as mesothelin positivity in more than 25% of cells, was found in 24% of patients. High mesothelin expression was associated with a worse survival (median 18.2 months vs. 32.9 months; P = 0.014) and with wild-type EGFR, and was strongly associated with mutant KRAS. The increased understanding of the tumour promoting activities of KRAS mutations, and the association with biomarkers, provides novel insights that will facilitate targeting of these tumours with novel agents in the future.
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SC27.04 - KRAS-Directed Drug Therapy in Advanced NSCLC (ID 6716)
12:00 - 12:20 | Author(s): P. Jänne
- Abstract
- Presentation
Abstract not provided
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Author of
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MA16 - Novel Strategies in Targeted Therapy (ID 407)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:G. Purkalne, J. Von Pawel
- Coordinates: 12/07/2016, 14:20 - 15:50, Strauss 2
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MA16.11 - CNS Response to Osimertinib in Patients with T790M-Positive Advanced NSCLC: Pooled Data from Two Phase II Trials (ID 4920)
15:26 - 15:32 | Author(s): F. De Marinis
- Abstract
- Presentation
Background:
Brain metastases develop in 25–40% of patients with NSCLC. Osimertinib is an oral, potent, irreversible EGFR-TKI, selective for both sensitising (EGFRm) and T790M resistance mutations. Preclinical and early clinical evidence support central nervous system (CNS) penetration and activity of osimertinib. Two Phase II studies (AURA extension [NCT01802632] and AURA2 [NCT02094261]) evaluating the efficacy and safety of osimertinib are ongoing. We present a pre planned subgroup analysis assessing pooled CNS response from these two studies; data cut-off (DCO) was 1 November 2015. An earlier pooled analysis from these two studies (1 May 2015 DCO) showed the objective response rate (ORR) in patients with CNS metastases was consistent with ORR in the overall patient population.
Methods:
Patients with advanced NSCLC who progressed following prior EGFR-TKI therapy with centrally-confirmed T790M positive status (cobas® EGFR Mutation Test) received osimertinib 80 mg once daily (n=411). Patients with stable, asymptomatic CNS metastases were eligible for enrolment. CNS efficacy was assessed in an evaluable for CNS response analysis set, which included patients with at least one measurable CNS lesion on baseline brain scan (RECIST v1.1) by blinded independent central neuroradiology review (BICR). Effect of prior radiotherapy on CNS response was assessed.
Results:
As of 1 November 2015, 50/192 patients with baseline brain scans had at least one measurable CNS lesion identified by BICR. Baseline demographics were broadly consistent with the overall patient population. Confirmed CNS ORR was 54% (27/50; 95% CI: 39%, 68%), with 12% complete CNS response (6/50 patients). The median CNS duration of response (22% maturity) was not reached (95% CI: not calculable [NC], NC). The estimated percentage of patients remaining in response at 9 months was 75% (95% CI: 53, 88). CNS disease control rate (DCR) was 92% (46/50; 95% CI: 81%, 98%). Median time to first response was 5.7 weeks (range: 5.6–6.6). Median best percentage change from baseline in CNS target lesion size was 53% (range: -100% – +80%). Median follow up for CNS progression-free survival (PFS) was 11 months; the median CNS PFS was not reached (95% CI: 7, NC). At 12 months, 56% (95% CI: 40%, 70%) of patients were estimated to remain on study, alive and CNS progression-free. CNS response was observed regardless of prior radiotherapy to the brain.
Conclusion:
Osimertinib demonstrates durable efficacy in patients with T790M NSCLC and measurable CNS metastases, with a CNS response rate of 54% and a DCR of 92%.
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P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.02-064 - MET-Dependent Activation of STAT3 as Mediator of Resistance to MEK Inhibitors in KRAS-Mutant Lung Cancer (ID 4240)
14:30 - 14:30 | Author(s): F. De Marinis
- Abstract
Background:
Targeting the MAPK pathway by MEK inhibition results in limited activity in patients with KRAS-mutant non-small cell lung cancer (NSCLC). The lack of effectiveness may be associated with activation of other effectors including STAT3, as well as MEK inhibition relief from negative feedback loops. Indeed, in KRAS-mutant colorectal cancer, MEK inhibition decreases the activity of the metalloprotease ADAM17, which normally inhibits MET signaling and STAT3 activation by promoting shedding of MET endogenous antagonist, soluble "decoy" MET. Herein, we explore the MET-dependent activation of STAT3 as a mediator of resistance to MEK inhibitors, and whether MET or STAT3 inhibitors can synergistically increase MEK-inhibitor-induced growth inhibition in KRAS-mutant NSCLC cells in vitro.
Methods:
Cell viability was assessed by MTT (thiazolyl blue) assay after treatment with the allosteric MEK inhibitor, selumetinib, the small-molecule dual inhibitor of the MET and ALK receptor tyrosine kinases, crizotinib, and evodiamine, an alkaloid isolated from the dried, unripe Evodia rutaecarpa (Juss.) Benth fruit, that exerts an anticancer effect by inhibiting STAT3. RNA was isolated from four KRAS cell lines and the STAT3 and MET mRNA expression analysis was performed by TaqMan based qRT-PCR. Western blotting was used to assess the effect of selumetinb on ERK, AKT and STAT3 phosphorylation.
Results:
We first evaluated the efficacy of the MEK inhibitor selumetinib in our KRAS-mutant NSCLC cell line panel using an MTT cell proliferation assay. H460 cells were relatively insensitive to selumetinib. Following 48-hour treatment with selumetinib, ERK1/2 and AKT phosphorylation were suppressed but a rebound activation of STAT3 occurred in H460 cells. We next investigated whether MET expression was related to the feedback activation of STAT3 signaling following MEK inhibitor treatment. We compared gene expression profiles of the H460 cell line before and after treatment with selumetinib. Interestingly, we found significant upregulation of MET and STAT3 mRNA expression after seven days of selumetinib treatment. To further interrogate the relationship between MEK inhibition and MET-mediated STAT3 reactivation, H460 cells were treated with the combination of selumetinib and crizotinib or selumetinib and evodiamine. A 72-hour exposure to both combinations resulted in a clear cell synergism, as measured by the combination index (CI) analysis, with a CI of 0.79 and 0.78 respectively.
Conclusion:
Collectively our results showed that the feedback STAT3 activation induced by MET, mitigates the effect of MEK inhibition, and provides rationale for further assessment of combined MEK and MET or STAT3 inhibition in KRAS-mutant NSCLC.
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P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.01-044 - Baseline Peripheral Blood Cell Subsets Associated with Survival Outcomes in Advanced NSCLC Treated with Nivolumab in Second-Line Setting (ID 4103)
14:30 - 14:30 | Author(s): F. De Marinis
- Abstract
Background:
Nivolumab is the first checkpoint inhibitor approved for the treatment of Squamous (Sq) and non-Squamous (non-Sq) metastatic NSCLC in second-line setting, showing a survival benefit in randomized phase III trials. The aim of this study is to investigate the potential role of baseline peripheral blood cells in relation to clinical outcomes following nivolumab treatment.
Methods:
From November 2015 to to June 2016, we evaluated 45 patients with Sq (n = 10) and non-Sq (n = 35) NSCLC, previously treated with first-line platinum-based chemotherapy, that received nivolumab 3 mg/kg IV on day 1 of each 2 week treatment cycle. Clinical characteristics (T-Stage, lymph nodes involvement, M-Stage) were assessed. Total numbers of leukocytes, myeloid-derived suppressor cells (MDSCs), including both monocytic (Mo-MDSC) and granulocytic (Gr-MDSC) type, regulatory T cells (T-regs), and serum lactate dehydrogenase (LDH) were assessed. Endpoints were correlation with objective response (OR), progression-free survival (PFS, categorized as ≤ 3 or > 3 months) and overall survival (OS). Tumor response was assessed using RECIST criteria, version 1.1, at week 9 and every 6 weeks thereafter until disease progression. Statistical methods were based on univariate analyses (Wilcoxon rank test).
Results:
The median PFS of the overall study population was 3 months. Data about Gr-MDSCs (identified by flow cytometry as Lin-CD15+CD14-CD11b+HLA-DR[low/-]), Mo-MDSCs (Lin-CD14-CD11b+HLA-DR[low/-]) and absolute eosinophil counts (AEC) were available in 37/45 patients (82%) of treated patients. Baseline absolute numbers of Gr-MDSCs, Mo-MDSCs and AEC were greater in patients with good prognosis (PFS > 3 months) and better outcomes. In particular among patients with shorter PFS, the median numbers of Gr-MDSCs, Mo-MDSCs and AEC were significantly lower than those detected in patients with longer PFS (4 vs 13 cell/µl, p=0.01; 4 vs 21 cell/µl, p=0.06; 55 vs 155 cell/µl; p=0.02, respectively). No correlation was observed between T-regs, LDH, absolute neutrophil, monocyte, lymphocyte counts and clinical outcomes.
Conclusion:
A baseline blood signature characterized by low levels of Gr-MDSCs, Mo-MDSCs and AEC is associated with poor outcome (median PFS ≤ of 3 months) in 67.6% of patients treated with nivolumab. In contrast, patients (32.4%) with high levels of these three biomarkers showed a median PFS significant longer than 3 months. Overall survival analysis is ongoing.
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-047 - Co-Activation of STAT3 and YAP1 Signaling Pathways Limits EGFR Inhibitor Response in Lung Cancer (ID 4168)
14:30 - 14:30 | Author(s): F. De Marinis
- Abstract
Background:
EGFR tyrosine kinase inhibitors (TKIs) induce early activation of several signaling pathways. Interleukin-6 (IL-6) and signal transducer and activator of transcription 3 (STAT3) hyper-activation occur following EGFR TKI therapy in EGFR-mutant NSCLC cells. We explored the relevance of co-targeting EGFR, STAT3 and Src-YES-associated protein 1 (YAP1) signaling in EGFR-mutant NSCLC.
Methods:
We combined in vitro and in vivo approaches to explore whether concomitant activation of STAT3 and Src-YAP1 can limit the effectiveness of EGFR TKIs in EGFR-mutant NSCLC cells and xenograft models. In two cohorts of EGFR-mutant NSCLC patients, we examined messenger RNA (mRNA) gene expression within signaling pathways, leading to EGFR TKI resistance.
Results:
Gefitinib suppressed EGFR, ERK1/2 and AKT phosphorylation but increased STAT3 phosphorylation (pSTAT3-Tyr705). In EGFR mutant cells, gefitinib plus TPCA-1 (STAT3 inhibitor) abolished pSTAT3-Tyr705 but not the YAP1 phosphorylation on tyrosine 357 by Src family kinases (SFKs). The triple combination of gefitinib, TPCA-1 and AZD0530 (SFK inhibitor) ablated both STAT3 and YAP1 phosphorylation and was highly synergistic, according to the combination index. In two EGFR mutant xenograft mouse models, the triple combination of gefitinib, TPCA-1 and AZD0530 markedly and safely suppressed tumor growth. High levels of STAT3 or YAP1 mRNA expression were associated with worse outcome to EGFR TKI in 64 EGFR-mutant NSCLC patients. Median progression-free survival (PFS) was 9.6 (95%CI, 5.9-14.1) and 18.4 months (95%CI, 8.8-30.2) for patients with high and low STAT3 mRNA, respectively (p<0.001), (HR for disease progression, 3.02; 95% CI, 1.54-5.93; p=0.0013). Median PFS was 9.6 (95%CI, 7.7-15.2) and 23.4 months (95%CI, 13.0-28.1) for patients with high and low YAP1 mRNA, respectively (p=0.005), (HR for disease progression, 2.57; 95%CI, 1.30-5.09; p=0.0067). The results were similar in the validation cohort of 55 EGFR-mutant NSCLC patients treated with first-line EGFR TKI in the Department of Oncology of Shanghai Pulmonary Hospital.
Conclusion:
Our study reveals that STAT3 and Src-YAP1 signaling activation occurs following single EGFR TKI in EGFR-mutant NSCLC. STAT3 and YAP1 mRNA levels were significantly predictive of progression-free survival in the original as well as in the validation cohort of EGFR-mutant NSCLC patients. Co-targeting STAT3 and Src in combination with EGFR TKI could substantially improve survival.
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 4
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-042 - IMpower110: Phase III Trial Comparing 1L Atezolizumab with Chemotherapy in PD-L1–Selected Chemotherapy-Naive NSCLC Patients (ID 5094)
14:30 - 14:30 | Author(s): F. De Marinis
- Abstract
Background:
For patients with advanced NSCLC without genetic driver alterations, cisplatin/carboplatin+pemetrexed is a standard-of-care first-line (1L) treatment for non-squamous histology; and cisplatin/carboplatin+gemcitabine for squamous histology. Although immunotherapies targeting PD-L1/PD-1 are currently available for 2L+ NSCLC, chemotherapy remains the main 1L option despite poor survival and toxicities. Atezolizumab, an anti–PDL1 mAb, prevents PD-L1 from interacting with its receptors PD-1 and B7.1, restoring tumor-specific T-cell immunity. Clinical efficacy was demonstrated with atezolizumab in non-squamous and squamous NSCLC, with Phase I and II studies exhibiting durable responses and survival benefit that increases with higher PD-L1 expression on tumor cells (TC) and/or tumor-infiltrating immune cells (IC). IMpower110, a global Phase III randomized, multicenter, open-label trial, will evaluate efficacy and safety of atezolizumab vs cisplatin/carboplatin+pemetrexed or gemcitabine as 1L therapy for PD-L1–selected chemotherapy-naive patients with advanced non-squamous or squamous NSCLC, respectively.
Methods:
Eligibility criteria include stage IV non-squamous or squamous NSCLC, measurable disease (RECIST v1.1), ECOG PS 0-1, no prior chemotherapy for advanced NSCLC and centrally-assessed PD-L1 expression ≥1% on TC or IC (TC1/2/3 or IC1/2/3 with VENTANA SP142 IHC assay; expected prevalence, ≈65%). Exclusion criteria include active or untreated CNS metastases, prior immune checkpoint blockade therapy or autoimmune disease. Patients will be randomized 1:1 to receive atezolizumab or cisplatin/carboplatin+pemetrexed (non-squamous)/gemcitabine (squamous) for 4 or 6 21-day cycles. Patients in comparator arms can receive pemetrexed (non-squamous)/best supportive care (squamous) until RECIST v1.1 disease progression. Patients receiving atezolizumab may continue until loss of clinical benefit. Co-primary endpoints are PFS and OS. Key secondary efficacy endpoints include ORR, DOR, IRF-assessed PFS (RECIST v1.1) and TTD. Safety and PK will also be evaluated. Tumor biopsies at RECIST v1.1 progression will be assessed for immunologic biomarkers associated with responses to atezolizumab and to differentiate non-conventional responses from radiographic progression.Planned enrollment, N 570 Histology Non-squamous Squamous Experimental arm Atezolizumab (1200 mg q3w) Comparator arm Cisplatin (75 mg/m[2] IV q3w) + pemetrexed (500 mg/m[2] IV q3w) or Carboplatin (AUC 6 mg/mL/min IV q3w) + pemetrexed (500 mg/m[2] IV q3w) Cisplatin (75 mg/m[2] IV q3w) + gemcitabine (1200 mg/m[2] IV days 1, 8) or Carboplatin (AUC 5 mg/mL/min IV q3w) + gemcitabine (1000 mg/m[2] IV days 1, 8) Stratification factors Sex ECOG Histology (non-squamous vs squamous) PD-L1 expression by IHC ClinicalTrials.gov identifier NCT02409342
Results:
Section not applicable
Conclusion:
Section not applicable
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P3.02c-092 - Nivolumab in Multi-Treated Patients with Advanced Sq-NSCLC: Data from the Italian Cohort of Expanded Access Programme (EAP) (ID 4792)
14:30 - 14:30 | Author(s): F. De Marinis
- Abstract
Background:
The prognosis of patients with advanced Sq-NSCLC worsens with the increase of the number of treatment linesand no effective therapeutic options were available for those refractory patients so far.Nivolumab demonstrated significant benefits against the SoC docetaxel in 2[nd] line treatment of advanced sq-NSCLC. In the real life experience of the EAP we could assess the clinical activity and tolerability of nivolumab not only in patients treated in 2[nd] line but also in patients who had received at least 2 lines of therapy prior than nivolumab.
Methods:
Nivolumab was provided upon physician request for patients aged ≥18 years who had relapsed after a minimum of 1 prior systemic treatment for stage IIIB/stage IV Sq-NSCLC. Nivolumab 3 mg/kg was administered intravenously every 2 weeks for <24 months. Pts included in the analysis had received ≥1 dose of nivolumab and were monitored for adverse events (AEs) using Common Terminology Criteria for Adverse Events (version 4.03).
Results:
210 patients, corresponding to 56.4% of the entire Italian cohort (n=372), received nivolumab after at least 2 prior lines of chemotherapy in the EAP: 120 (57.1%), 69 (32.9%) and 21 (10%) had received 2, 3 and > 3 prior lines of therapy, respectively. Response was evaluable in 204 patients: with a median number of 8 doses (range, 1–24) and a median follow-up of 5.1 months, the disease control rate was 47%, with 3 patients (1%) in complete response, 30 patients (14%) in partial response and 66 patients (32%) in stable disease. 36 patients (17%) were treated beyond RECIST-defined progression, with 11 of them achieving disease control. As of April 2016, median progression-free survival and median overall survival were respectively 3.8 and 11.2 months. 117/210 patients (55.7%) discontinued treatment for any reason except toxicity; 11 out of 210 (5.2%) discontinued due to AEs.
Conclusion:
These findings showed that nivolumab provided clinical activity with a manageable safety profile in patients with advanced, refractory Sq-NSCLC. These data suggest that nivolumab can be a treatment option for patients failing more than one line of chemotherapy.
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P3.02c-095 - Italian Nivolumab Expanded Access Programme: Efficacy and Safety Data in Squamous Non Small Cell Lung Cancer Patients (ID 5159)
14:30 - 14:30 | Author(s): F. De Marinis
- Abstract
Background:
Nivolumab monotherapy has shown survival benefit in patients (pts) with melanoma, lung cancer, renal cell carcinoma and head and neck cancer. The experience of pts and physicians in routine clinical practice is often different from those in a controlled clinical trial setting. Here, we report efficacy and safety of nivolumab monotherapy in pts with squamous non small cell lung cancer (Sq-NCSLC) treated in the nivolumab Expanded Access Programme in Italy.
Methods:
Nivolumab was available upon physician request for pts aged ≥18 years who had relapsed after a minimum of one prior systemic treatment for stage IIIB/stage IV Sq-NSCLC. Nivolumab 3 mg/kg wass administered intravenously every 2 weeks to a maximum of 24 months. Pts included in the analysis had received at least 1 dose of nivolumab and were monitored for adverse events (AE) using Common Terminology Criteria for Adverse Events.
Results:
In total, 371 Italian pts participated in the EAP across 96 centres and 363 patients were evaluable for response. With a median follow-up of 5.2 months (range 0-12.9) and a median of 7 doses, the best overall response rate (BORR) was 18%, with 3 complete responses (CR) and 62 partial responses (PR), and the disease control rate (DCR) was 47%. DCR was comparable among pts regardless previous lines of therapy, brain metastasis, age and smoking habits. A non-conventional benefit was observed in 23 (17 SD and 6 PR) out of 66 pts treated beyond RECIST defined progression. As of April 2016, median progression-free survival and median overall survival were 3.9 (95% CI: 3.2-4.6) and 9.1 (95% CI: 6.7-11.5) months, respectively. Regarding the safety profile, 267 out of 371 pts (72%) had at least one AE of any grade, considered to be drug-related in 106 pts (29%). Grade 3/4 AE were reported in 66 pts and considered to be drug-related in 20 pts (5%). AE were generally manageable following the specific guidelines.
Conclusion:
To date, this is the largest clinical experience with nivolumab in a real-world setting. These preliminary EAP data seems to confirm the efficacy and safety data of nivolumab from registrational trials, supporting its use in current clinical practice for pre-treated pts with Sq-NCSLC.
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P3.02c-096 - Use of Nivolumab in Elderly Patients with Advanced Squamous NSCLC: Results from the Italian Expanded Access Programme (EAP) (ID 5706)
14:30 - 14:30 | Author(s): F. De Marinis
- Abstract
Background:
The efficacy and safety of nivolumab in patients with squamous NSCLC (sq-NSCLC) have been demonstrated in several trials including the phase 3, randomized, controlled CheckMate 017 study whose results led to the approval of the product for this indication. However, data on the use of nivolumab in the real world setting is still limited and collecting it is paramount. The Italian nivolumab EAP for sq-NSCLC represents an important source of information in that respect. The current analysis describes results of the use of nivolumab in the group of EAP patients aged >75 years.
Methods:
Nivolumab was provided upon physicians’ request for patients aged ≥18 years who had relapsed after a minimum of one prior systemic treatment for stage IIIB/stage IV Sq-NSCLC. Nivolumab 3 mg/kg was administered intravenously every 2 weeks for <24 months. Patients included in the analysis received ≥1 dose of nivolumab and were monitored for adverse events (AEs) using Common Terminology Criteria for Adverse Events.
Results:
70 out of 372 (18.8%) patients with advanced Sq-NSCLC participating in the EAP in Italy were ≥75 years old and 68 of them were evaluable for response. With a median number of doses of 7 (range, 1–20) and a median follow-up of 4.7 months, the disease control rate was 42.9%, including 13 patients with a partial response and 17 with stable disease. 16 pts were treated beyond RECIST-defined progression and 5 of them achieved disease control. As of April 2016, the median progression-free survival and median overall survival among those elderly patients were 3.2 and 7.6 months, respectively. Among 70 pts, 41 pts (58.6%) discontinued treatment for any reason except toxicity; 8 out of 70 discontinued due to AE (11.4%).
Conclusion:
This analysis, conducted on elderly patients with sq-NSCLC in a real life setting, suggests that nivolumab is an effective and well tolerated treatment for this special population.
