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Nuria Viñolas
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MS01 - Immunotherapy Resistance (ID 64)
- Event: WCLC 2019
- Type: Mini Symposium
- Track: Immuno-oncology
- Presentations: 4
- Now Available
- Moderators:Ignacio Gil-Bazo, Nuria Viñolas
- Coordinates: 9/08/2019, 10:30 - 12:00, San Francisco (2009)
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MS01.01 - Biological Mechanisms of Resistance (Now Available) (ID 3439)
10:30 - 12:00 | Presenting Author(s): Justin F. Gainor
- Abstract
- Presentation
Abstract
Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1) axis have transformed the management of non-small cell lung cancer (NSCLC). Despite the dramatic and sometimes durable activity of these agents, a majority of patients will progress on therapy.1 Patients who experience a de novo lack of response to initial therapy are deemed as having primary (intrinsic) resistance. By contrast, acquired resistance refers to patients who initially achieve an objective response to therapy but eventually progress over time.
The mechanistic basis for primary versus acquired resistance to immune checkpoint inhibitors is still poorly defined. To date, studies into the biological mechanisms of resistance to immunotherapies have centered around preclinical studies and analyses of repeat biopsies obtained from patients at the time of disease progression.2 These efforts have been complemented by similar studies in other immuno-oncology settings (e.g., melanoma),3,4 since there is potential for shared biology underlying immunotherapy resistance across malignancies.
Both tumor cell-intrinsic and tumor cell-extrinsic factors have been implicated in mediating resistance to immunotherapies.2 In the setting of primary resistance, disease progression is commonly driven by a lack of neoantigens sufficient to illicit an initial immune response, commonly due to a low tumor mutation burden.5 Alternatively, tumors may actually harbor antigens capable of generating an immune response, but defects in antigen processing may ultimately limit the presentation of these antigens on the cell surface via MHC. Defective antigen presentation may be due to loss of beta-2 microglobulin (B2M), elimination of transporters associated with antigen processing (TAP) proteins, or downregulation of HLA.2,3 In addition, intrinsic resistance to immune checkpoint inhibitors may be due to altered oncogenic cell signaling (e.g., WNT/B-catenin pathway) and/or tumor de-differentiation with impaired antigen expression.
Molecular mechanisms of acquired resistance to checkpoint blockade likely include many of the same processes as those implicated in intrinsice resistance. Indeed, homozygous loss of B2M, which is required for stabilization of HLA on the cell surface, has been described in NSCLC at the time of acquired resistance to PD-1 pathway blockade.6 Additionally, neoantigen loss through elimination of specific tumor subclones (i.e., immunoediting), genetic alterations in interferon gamma (IFN) signaling, and upregulation of alternative checkpoints (e.g., TIM3) have also been purported to confer acquired resistance to checkpoint inhibitors.4,7,8 At present, the relative frequencies of these processes and the interplay among them within NSCLC and other malignancies remains to be defined.
Moving forward, it will be critical to pursue more in-depth preclinical and clinical studies of resistance to PD-1 pathway blockade in NSCLC. Just as insights into the molecular mechanisms of resistance to targeted therapy have transformed the therapeutic landscape for oncogene-driven tumors, it will be imperative for immuno-oncology to develop a framework for understanding resistance to checkpoint inhibitors and apply this framework to clinical development of next-generation immuno-onclogy agents. This is especially critical due to the sheer number of immuno-oncology combinations currently in clinical testing. Ultimately, knowledge of the mechanisms of resistance to immune checkpoint inhibitors may help better inform the rationale design of trials evaluating PD-1 inhibitor combinations.
References:
1. Garon EB, et al. J Clin Oncol 2019 Jun 2 [Epub ahead of print]. 2. Sharma P, et al. Cell 2017;168(4):707-23. 3. Sade-Feldman M, et al. Nat Commun 2017;8(1):1136. 4. Zaretsky JM, et al. NEJM 2016;375:819-29. 5. Rizvi NA, et al. Science 2015;348(6230):124-128. 6. Gettinger S, et al. Cancer Discov 2017:7:1420-35. 7. Anagnostou V, et al. Cancer Discov 2017;7(3):264-76. 8. Koyama S, et al. Nat Commun 2016;7:10501.
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MS01.02 - Treatment Determining Markers - What Have We Achieved so Far? (Now Available) (ID 3440)
10:30 - 12:00 | Presenting Author(s): Naiyer A Rizvi
- Abstract
- Presentation
Abstract
Progress has been made selecting patients for immune checkpoint blockade employing expression of PD-L1 however limitations exist with this approach. Increasing use of genetic markers has been incorporated into clinical trials and clinical practice. Beyond MSI testing, tumor mutation burden has gained increasing traction and prospective trials employing TMB are under way and will be reviewed. Additional unique sensitivity and resistance mutations are emerging and may be incorporated into our genetic analysis paradigm. Additionally genetic studies are now being performed with success on plasma ctDNA and emerging ctDNA analyses will be discussed.
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MS01.03 - Overcoming Resistance - Clinical Results? (Now Available) (ID 3441)
10:30 - 12:00 | Presenting Author(s): Ross Soo
- Abstract
- Presentation
Abstract
Overcoming resistance- clinical results.
The management of oncogene negative advancednon-small cell lunghas been transformed with the use of immune checkpoint inhibitors targeting programmed death receptor-1 (PD-1) and programmed death receptor ligand-1 (PD-L1). However, in a significant number of patients, either primary or acquired resistance has been observed. Primary resistance, usually defined as disease progression upon the first radiologic evaluation, represents an important clinical problem and has been reported in up to 20% of patients. Acquired resistance, defined as tumors with initial response following treatment but eventually develop disease progression, has been reported in approximately 20-40% of patients.
The mechanisms of primary and acquired resistance to immunotherapy are complex and are interdependent, involving alterations in immune cells, cytokines, metabolic and oncogene signaling pathways in the tumor cell and the tumor microenvironment. The usual treatment following progression on first line immune checkpoint inhibitor with or without a platinum doublet is single agent docetaxel or a platinum doublet +/- bevacizumab.
With an improvement in the understanding of the mechanisms of resistance to immune checkpoint inhibitors, to improve patients’ outcomes following resistance, strategies have been devised to tailor subsequent therapy according to the mechanism of resistance, including the use of therapies to increase antigenicity, enhance immune cell function, and modulate the tumor microenvironment.
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MS01.04 - Smoking and Immunotherapy (Now Available) (ID 3442)
10:30 - 12:00 | Presenting Author(s): Nise Yamaguchi
- Abstract
- Presentation
Abstract
Smoking disrupts the homeostasis of the innate and the adaptive immune system. Carcinogenic and pro-inflammation compounds of tobacco leaves and other chemicals present in cigarette interfere with the regulation of immunity in two opposing ways. Some compounds trigger chronic inflammation inducing cell damage and transformation; others inhibit apoptosis, a protective strategy against transformed cell proliferation. Smoking attenuates response by dendritic cells (DC), natural killer cells (NK), macrophages against transformed cells1. Smoking affects as well the adaptive immune cells, B lymphocytes, T helper cells, CD4+ / CD25+ regulatory T cells, and CD8+ T cells.[1]
Patients with NSCLC had low levels of serum bilirubin correlated with tumor progression and poor response to platinum-based chemotherapy[2]. Studies found that high normal levels of serum bilirubin indicated favorable prognosis in NSCLC and colorectal tumor.[3], [4] Bilirubin has anti-inflammatory, anti-oxidative, and anti-proliferative effects[5] and smoking decreased bilirubin in a cohort study using metabolomics profiling.[6] Zhang et al. reported that pretreatment with bilirubin correlated with overall survival (OS) in NSCLC patients with EGFR mutations.[7]
Epithelial to mesenchymal transition (EMT) is an important process of cell-transformation that facilitates metastases and smoking induced hypoxia, inflammation, and oxidative stress, culminating in malignancy and EMT.[8],[9] The effect of smoking on EMT also occurs in other cancer histologies. A study showed that the HDAC inhibitor MS-275 restores E-cadherin expression, reversing EMT, metastases, and invasion induced by smoking.[10], [11], 8
Smoking impairs lung cancer chemotherapy, requiring increased doses for patients who smoke. The polycyclic aromatic hydrocarbons (PAH) of smoke increases the synthesis of enzymes that metabolize many antineoplastic drugs. PAH increase clearance, requiring dose adjustments to reach toxicity levels of efficacy.[12] Smokers receiving irinotecan had increased clearance and lower exposure to therapeutic metabolites; and treatments with paclitaxel, docetaxel, irinotecan, and gemcitabine showed lesser neutropenia in smokers than in nonsmokers.12 Nicotine-derived nitrosamine ketones antagonizes cisplatin and carboplatin regimens by blocking apoptosis.[13],[14],[15]
Erlotinib blocks the receptor for tyrosine-inhibiting epidermal growth activation (EGFR) and is metabolized by CYP3A4 and, by CYP1A2 and CYP1A1.[16] Smoking accelerates drug catabolism, decreasing erlotinib plasma concentrations and survival rates in NSCLC. Retrospective analysis of 88 patients NSCLC receiving erlotinib or pemetrexed showed better progression-free survival (PFS) with erlotinib in never smokers than in former smokers (3.5 versus 2.7 months, p = 0.005)[17] and smokers with squamous histology receiving erlotinib lived longer than former smokers.[18] A study on the efficacy of second-line docetaxel and erlotinib in NSCLC patients with smoking history versus never smokers shoed decreased overall survival (hazard ration [HR] 3.61 [1.77–7.4], p = 0.0005) in the erlotinib arm.[19]
Nicotine affected EGFR/AKT/ERK pathways, preventing/decreasing erlotinib action in NSCLC, promoting tumor growth in the PC9 xenograft model. [20]
[1] Qiu F. et al. (2016) Impacts of cigarette smoking on immune responsiveness: up and down or upside down? Oncotarget, 2017, Vol. 8, (No. 1), pp: 268-284.
[2] Song Y-J. et al. (2018) Direct bilirubin levels are prognostic in non-small cell lung cancer. Oncotarget, 2018, Vol. 9, (No. 1), pp: 892-900.
[3] Li N, et al. Elevated serum bilirubin levels are associated with improved survival in patients with curatively resected non-small-cell lung cancer. Cancer Epidemiol. 2015; 39:763–8. https://doi.org/10.1016/j.canep.2015.06.007.
[4] Zhang Q, et al. Nomograms incorporated serum direct bilirubin level for predicting prognosis in stages II and III colorectal cancer after radical resection. Oncotarget. 2017; 8:71138–46. https://doi.org/10.18632/oncotarget.11424
[5] Marnett LJ. Oxyradicals and DNA damage. Carcinogenesis. 2000; 21:361–70.
[6] Wen CP et al. (2015) The ability of bilirubin in identifying smokers with higher risk of lung cancer: a
large cohort study in conjunction with global metabolomics profiling. Clin Cancer Res. 2015; 21:193–200. https://doi.org/10.1158/1078-0432.CCR-14-0748.
[7] Zhang Y, et al. Pretreatment direct bilirubin and total cholesterol are significant predictors of overall survival in advanced non-small-cell lung cancer patients with EGFR mutations. Int J Cancer. 2017; 140:1645–52. https://doi.org/10.1002/ijc.30581.
[8] Milara, J.; Peiró, T.; Serrano, A.; Cortijo, J. Epithelial to mesenchymal transition is increased in patients with
COPD and induced by cigarette smoke. Thorax 2013, 68, 410.
[9] Dasgupta, P.; Rizwani,W.; Pillai, S.; Kinkade, R.; Kovacs, M.; Rastogi, S.; Banerjee, S.; Carless, M.; Kim, E.;
Coppola, D.; et al. Nicotine induces cell proliferation, invasion and epithelial to mesenchymal transition in a
variety of human cancer cell lines. Int. J. Cancer 2009, 124, 36–45.
[10] Sohal, S.S.; Walters, E.H. Role of epithelial mesenchymal transition (EMT) in chronic obstructive pulmonary disease (COPD). Respir. Res. 2013, 14, 120.
[11] Ibidem 10.
[12] O’Malley et al. Effects of Cigarette Smoking on Metabolism and Effectiveness of Systemic Therapy for Lung Cancer. J Thorac Oncol. 2014;9: 917–926.
[13] Xu J, Huang H, Pan C, Zhang B, Liu X, Zhang L. Nicotine inhibits apoptosis induced by cisplatin in human oral cancer cells. Int J Oral Maxillofac Surg 2007;36:739–744.
[14] Zeng F, Li YC, Chen G, et al. Nicotine inhibits cisplatin-induced apoptosis in NCI-H446 cells. Med Oncol 2012;29:364–373.
[15] Zhang J, Kamdar O, Le W, et al. Nicotine induces resistance to chemotherapy by modulating mitochondrial signaling in lung cancer. Am J Respir Cell Mol Biol 2009;40:135–146.
[16] Ling J, Johnson KA, Miao Z, et al. Metabolism and excretion of erlotinib, a small molecule inhibitor of epidermal growth factor receptor tyrosine kinase, in healthy male volunteers. Drug Metab Dispos 2006;34:420–426.
[17] Zugazagoitia J, Puente J, González-Larriba JL, et al. Erlotinib versus pemetrexed for pretreated non-squamous non-small cell lung cancer patients in clinical practice. Oncology 2013;84:255–264.
[18] Chiang CL, Tsai CM, Chou TY, et al. Erlotinib in patients with advanced lung squamous cell carcinoma. Cancer Chemother Pharmacol 2013;71:203–208.
[19] Krawczyk P, Kowalski DM, Wojas-Krawczyk K, et al. The qualification of docetaxel or erlotinib for second-line therapy should be based on clinical and molecular predictive factors. Chemotherapy 2012;58:60–69.
[20] Li H, Wang S, Takayama K, et al. Nicotine induces resistance to erlotinib via cross-talk between 1nAChR and EGFR in the non-small cell lung cancer xenograft model. Lung Cancer 88 (2015) 1–8.
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Author of
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EP1.01 - Advanced NSCLC (ID 150)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.01-41 - Feasibility of EBUS-TBNA Cytologies for an Extensive Assessment of Predictive Biomarkers in Lung Cancer (Now Available) (ID 1640)
08:00 - 18:00 | Author(s): Nuria Viñolas
- Abstract
Background
Clinical guidelines support the determination of several driver genes as well as PD-L1 to drive treatment decisions in non-small cell lung cancer (NSCLC). Endobronchial-ultrasound transbronchial needle aspiration (EBUS-TBNA) cytology specimens are useful for the initial diagnosis of NSCLC, although its capacity to provide enough material for a complete genotyping remains controversial. The aim of this study is to determine the yield of EBUS for a comprehensive multiplex genotyping in patients (pts) with suspected NSCLC.
Method
In this single-center, ongoing, prospective study, samples from mediastinal lymph nodes were obtained from pts undergoing EBUS-TBNA for lung cancer diagnosis/staging. Following malignant confirmation and appropriate cell content by rapid on-site evaluation, the study sample was obtained and formalin-fixed paraffin-embedded (FFPE). Three analytes were evaluated (DNA/RNA/protein). DNA and RNA were extracted and analyzed by Oncomine Solid Tumour panel (22 genes) and a customized nCounter panel (ALK, ROS; RET, NTRK, METDe14). Tumor Proportion Score (TPS) for PD-L1 protein expression was evaluated by an expert pathologist and scored into <1% (negative), 1-49% (weakly positive) and 50% (high).
Result
Twenty-five pts with NSCLC have been included and cytology samples of 20 of them molecularly characterized (5 still in progress). Overall, cytological analysis of EBUS-TBNA yield a complete characterization for the three analytes (DNA/RNA/protein) in 15 pts (75%). EBUS-TBNA sampling was sufficient for both, Nanostring and Oncomine evaluation, in a total of 18 pts (90%): 15 patients (83%) had any alteration detected by oncomine (TP53 61% [11/18],KRAS 44% [8/18], EGFRe 195.5% [1/18], BRAF V600E 5,5% [1/18], DDR2 5.5% [1/18], STK11 11% [2/18]) and 1 pt (5.5 %) by nanostring (METDex14). A total of 19 samples were sufficient for PD-L1 expression scoring (95%). TPS for PD-L1 expression was negative in 8 pts (42%), week in 4 (21%) and high in 7 pts (37%). Overall, half of the pts evaluated (10/20) would be potential candidates for an upfront personalized treatment strategy using targeted agents or immunotherapy.
Conclusion
EBUS-TBNA is a promising alternative source of material for NSCLC genotyping and allows the identification of pts candidates for personalized therapies.
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EP1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 206)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Treatment in the Real World - Support, Survivorship, Systems Research
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.16-01 - A Spanish Initiative to Know the Unmet Needs of Women with Lung Cancer: "Circulos Program" (Now Available) (ID 1847)
08:00 - 18:00 | Author(s): Nuria Viñolas
- Abstract
Background
The personal and family impact of an oncological disease can only be adequately understood and managed from a biopsychosocial perspective. Lung cancer experience has a profound impact on the well-being of both patient and family caregiver and is largely influenced by communication within the family environment. Lung cancer impact can be especially significant when women are affected.
Method
The objective of this study was to develop an informative program for women with lung cancer, implementing the development of strategies in order to get a deepening knowledge of their perceived needs. Additionally, we aimed to define and design new useful resources that may help other women with lung cancer. A qualitative research allowed to collect data on the experiences in the circle of women and their families, and the identification of the needs and the coping resources used of the participants. The collection of these data was what led to the development of the tools used to develop the support strategies.
Result
A total of 10 women with lung cancer from Galicia (Spain) participated in 7 sessions. At the personal and psychological level in the women circle, needs were related to improve medical information they get from their physicians, share information and experiences with women in the same situation, more holistic-human care, and the need for more supporting groups. About the social and labor environment, they expressed concern about the social stigma associated with lung cancer, and the culpability for having smoked as well as the concern related to the interruption of working life. The family environment also expressed the need for emotional support and preparation for families and caregivers to be able to support the patient, the need to provide them with strategies to improve the situation, and the need to overcome initial isolation through working groups. Regarding resources, women´s circle was mainly focused on occupying time with new activities, humor and not stigmatizing the disease and the professionals who assist them.
Conclusion
“Círculos program”, even being a pilot program, show the benefits of a more humane approach to the treatment of lung cancer in women, with a better understanding of patients and families needs. More similar programs should be done in order to improve the quality of life of these patients and their transit through this disease.
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MA03 - Clinomics and Genomics (ID 119)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:Heather A Wakelee, Wilfried Ernst Erich Eberhardt
- Coordinates: 9/08/2019, 10:30 - 12:00, Colorado Springs (1994)
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MA03.06 - Efficacy Results of Selective AXL Inhibitor Bemcentinib with Pembrolizumab Following Chemotherapy in Patients with NSCLC (Now Available) (ID 2271)
10:30 - 12:00 | Author(s): Nuria Viñolas
- Abstract
- Presentation
Background
The RTK AXL is implicated in epithelial-to-mesenchymal transition, negative regulation of anti-tumour immunity and resistance to multiple therapies including immune checkpoint inhibitors.
Bemcentinib (BGB324) is a first-in-class, oral, highly selective and potent AXL inhibitor which has been demonstrated to enhance anti-PD1 therapy.
Method
This phase II trial (Cohort A, NCT03184571) enrolled 48 advanced lung adenocarcinoma patients with progression on or after no more than one prior line of platinum-based chemotherapy. Patients with EGFR/ALK mutations were included in this study and must have progressed on or after at least one standard targeted therapy. The primary endpoint was ORR according to RECIST v1.1. Additional endpoints included efficacy according to biomarker expression, DCR, PFS, OS, and safety. Tumour biopsies were analysed for PD-L1 expression (22C3 pharmDx), AXL by IHC, and infiltrating immune cells.
Result
As of April 2019, the trial was fully recruited: median age 65 (range 39-82) yrs, 61% male, 76% smokers or ex-smokers.
At time of writing, a total of 210 treatment cycles had been completed by all patients. 17 patients were ongoing.
17 of 32 biomarker-evaluable patients (53%) were PD-L1 negative, 13 (41%) had TPS 1-49%, and 2 (6%) had TPS >50%. Of 28 biomarker-evaluable patients, 14 (50%) expressed AXL on their tumours.
Among patients who had at least 1 evaluable on-treatment scan: 5 responses were observed in 13 AXL positive patients (38%), and 7 in 30 patients with TPS 0-49% (23%). There were 10 responses observed among 34 evaluable patients overall (29%).
In Stage 1, two of the 4 AXL positive responses are ongoing; mDoR is not mature in the AXL positive patients. mPFS was 5.9 mo in AXL positive patients (n=10, 3.0-NR) and 4.0 mo (95% CI 1.9-NR) overall (n=24). mOS was not mature.
The most common TRAEs (occurring in >10% of patient in both stages) were transaminase increases (34%), asthenia/fatigue (30%), diarrhoea (26%), nausea (13%), anaemia (11%), decreased appetite (11%), and pruritus (11%). All cases of transaminase increase were reversible and resolved with concomitant administration of systemic corticosteroids and interruption of study treatments.
Conclusion
Patients had predominantly low or no PD-L1 expression; approximately half were AXL positive. The combination of bemcentinib and pembrolizumab was well tolerated and showed promising efficacy in previously treated IO-naïve NSCLC patients, particularly in those with AXL positive disease, including PD-L1 negative patients. Mature ORR for both stages, as well as 12-month OS for stage 1 will be presented at the meeting.
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MA22 - Partnering with Patients to Understand Stigma, Disparities and Values Leading to Improved Lung Cancer Care (ID 154)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Advocacy
- Presentations: 1
- Now Available
- Moderators:Diego Villalón, Christina Sit
- Coordinates: 9/09/2019, 15:45 - 17:15, Amsterdam (2011)
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MA22.05 - Assessment of Gender Differences in the Psychosocial and Economic Impact on Patients with Stage IV Non-Small Cell Lung Cancer (Now Available) (ID 718)
15:45 - 17:15 | Author(s): Nuria Viñolas
- Abstract
- Presentation
Background
Incidence of lung cancer in women is rising overtime reporting evident gender-based differences in epidemiology, biology, and treatment outcome. However, little is known about gender-differences regarding psychological, economic and social aspects. The objectives of this prospective study are to evaluate the psychosocial and economic impact of metastatic non-small cell lung cancer (NSCLC), according to gender. Additionally, to assess the emotional burden and the economic impact of the disease on the primary caregiver from a gender perspective
Method
Multicenter, prospective, observational, study of two cohorts of patients with metastatic NSCLC (male and female) in Oncology departments of 20 Spanish hospitals. The following measurement tools were used: the APGAR questionnaire (family functionality: adaptability, partnership, growth, affection, and resolve), the Relationship impact scale, the DUKE-UNC scale (perceived socio-affective support), the patient and the caregiver economic impact scale and the Zarit scale (caregiver burden). All questionnaires were performed at the first visit, repeated 4 months later and following the first and second disease progression.
Result
Of the 333 pts included, 104 were females and 229 male, of whom 63% and 97%, respectively, were smokers/ex-smokers (p=0.0001). More women than men (85% vs 70%) had adenocarcinomas . The median overall survival was longer in women but did not reach statistical significance [17.1 vs 11.0 months, HR 0.732 (95% CI 0.534 to 1.005), p=0.0524]. Most families considered themselves functional (high score in APGAR questionnaire) with no changes in their partner relationship and social support was evaluated as optimal for majority of patients. Around a quarter of interviewed patients said their economic situation was a little worse after the lung cancer diagnosis, without remarkable differences by gender. Statistically significant differences were found between both groups regarding the caregiver´s relationship to the patient (more parents were the caregiver in females than in males) (p <0.0001) and the caregiver’s employment situation (more employed caregivers in females) (p<0.0001). Most caregivers of both sexes considered that taking care of their relative did not pose a significant burden. No remarkable differences by gender were found between the different variables across the study.
Conclusion
This study provides a preliminary insight into gender-related characteristics in the management of advanced NSCLC and its impact on the emotional, social and economic burden of patients and their caregivers, and recall the high priority of researching in cancer from a gender perspective
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OA13 - Ideal Approach to Lung Resection and Novel Perioperative Therapy (ID 146)
- Event: WCLC 2019
- Type: Oral Session
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Now Available
- Moderators:Tomasz Grodzki, Kenji Suzuki
- Coordinates: 9/10/2019, 11:30 - 13:00, Toronto (1985)
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OA13.05 - NADIM Study: Updated Clinical Research and Outcomes (Now Available) (ID 1670)
11:30 - 13:00 | Author(s): Nuria Viñolas
- Abstract
- Presentation
Background
Patients with stage IIIA (N2 or T4N0) are potentially curable but median overall survival is only around 15 months
Method
A Phase II, single-arm, open-label multicenter study of resectable stage IIIA N2-NSCLC in adult patients with CT plus IO as neoadjuvant treatment: 3 cycles of nivolumab (NV) 360 mg IV Q3W + paclitaxel 200 mg/m2 + carboplatin AUC 6 IV Q3W followed by adjuvant NV treatment for 1 year. After completing neoadjuvant therapy, all patients underwent tumor assessment prior to surgery. Surgery was performed during the 3rd or 4th week after day 21 of the 3rd neoadjuvant treatment cycle. The study aimed to recruit 46 patients. The primary endpoint was Progression-Free Survival (PFS) at 24 months. Efficacy was explored using objective pathologic response criteria. Here we present the final data on all study patients that underwent surgical assessment.
Result
At the time of submission, the 46 patients had been included. None of the patients were withdrawn from the study preoperatively due to progression or toxicity. 41 patients had undergone surgery and all tumors were deemed resectable with R0 resection in all cases. Intention to treat analysis shows 35 patients (85%; 95% CI, 71; 94%) achieved major pathologic response (MPR) of which 25 (71%; 95% CI, 54; 85%) were complete pathologic responses (CPR). Downstaging was seen in 38 (93%; 95% CI, 80; 98%) of cases. The median follow-up was 13.8 months (P25; P75: 11.7; 16.6 months) for both the whole series and resected patients, and 12 month PFS was 95.7% (95% CI, 84; 99%).
Conclusion
This is the first multicentric study to test CT-IO in the neoadjuvant setting in stage IIIA. Neoadjuvant CT-IO with nivolumab in resectable IIIA NSCLC yields a complete pathologic response rate that is higher than ever seen previously, together with a promising PFS which may translate into increased overall survival. EudraCT Number: 2016-003732-20. Clinical trial information: NCT 03081689.
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 3
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-43 - Programmed-Death Ligand 1 Spectrum in a Large Cohort of Genetically Characterized Non-Small Cell Lung Cancer Patients (ID 1760)
09:45 - 18:00 | Author(s): Nuria Viñolas
- Abstract
Background
Programmed-death ligand 1 (PD-L1) expression, assessed by immunohistochemistry (IHC), is used to select patients (pts) for checkpoint inhibitors. However, the pattern of PD-L1 expression across rare oncogenic alterations remains poorly characterized. We aimed to evaluate PD-L1 expression in a large dataset of pts with activating molecular alterations to define the potential responsiveness to immunotherapy.
Method
From 2016 to 2018, we prospectively characterized advanced NSCLC pts from a single institution. Tumor Proportion Score (TPS) for PD-L1 protein expression was evaluated by IHC (22C3 clone) using formalin-fixed paraffin-embedded tumor samples and scored into <1% (negative), 1-49% (weakly positive) and >=50% (high). DNA and RNA were extracted and analysed by Oncomine Solid Tumour panel (22 genes) and a customized nCounter-based panel (ALK, ROS1, RET, NTRK1, MET∆14). Associations between PD-L1 expression and the most prevalent driver alterations were assessed. Smoking habit and its possible relationship with PD-L1 expression was also appraised. Statistical analyses were performed using Kruskal-Wallis and Mann-Whitney tests.
Result
TPS for PD-L1 expression was available for a total of 140 patients (pts) fully genotyped. The cohort included: 36% women; 89% adenocarcinoma; 87% smokers. TPS for PD-L1 expression was negative (<1%), weak (1-49%) and high (>=50%) in 40%, 35% and 25% of pts, respectively. Actionable drivers were found in 84 pts (60%) being KRAS (n=43.31%) the most commonly detected, followed by EGFR (n=22.16%), BRAF (n=7.5%), MET∆14 (n=8.6%), ALK (n=3.2%) and ERBB2 (n=1, 1%). Thirty (21.4%) [ME1] pts harboured TP53 co-mutations. By comparing all genotyped cohorts, MET∆14 alteration was associated with higher PD-L1 expression levels compared with other subgroups (median TPS 58.62 vs 25.26, p=0.017[ME2] ). In addition, PD-L1 expression was also higher in pts harbouring any TP53 co-mutation than those with any alteration but TP53-WT (median TPS 41.53 vs 21.45, p=0.035). When KRAS-mut, BRAF-mut and EGFR-mut were evaluated separately, PD-L1 expression was higher in TP53 mutated tumors compared to TP53 WT only in BRAF-mut (p=0.028). Finally, no significant differences were found regarding patients’ smoking status (p=0.527).
Conclusion
Our results suggest differential expression of PD-L1 based on the presence of MET alterations and TP53 mutations and highlight the need of further characterizing PD-L1 expression across oncogenic alterations.
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P1.01-72 - A Phase II Study of Selective AXL Inhibitor Bemcentinib and Pembrolizumab in Patients with NSCLC Refractory to Anti-PD(L)1 (ID 1632)
09:45 - 18:00 | Author(s): Nuria Viñolas
- Abstract
Background
The RTK AXL is implicated in epithelial-to-mesenchymal transition, negative regulation of anti-tumour immunity and resistance to multiple therapies including immune checkpoint inhibitors.
Bemcentinib (BGB324) is a first-in-class, oral, highly selective and potent AXL inhibitor which has been demonstrated to enhance anti-PD1 therapy.
The combination of bemcentinib and pembrolizumab was well tolerated and showed promising efficacy in previously treated IO-naïve NSCLC patients (Cohort A, NCT03184571), particularly in those with AXL positive disease, including PD-L1 negative patients.
The novel combination is now being assessed in patients refractory to anti-PD-(L)1 therapy, considering the emerging need in this population and AXL’s role as a mediator of resistance.
Method
This is an open-label, single-arm, 2-stage phase II study (Cohort B, NCT03184571) to evaluate the safety and efficacy of bemcentinib (200mg/d) in combination with pembrolizumab (200mg/q3wk) in patients post anti-PD-(L)1 therapy. The primary endpoint is overall response rate (ORR), and additional endpoints include efficacy by biomarker expression, duration of response (DoR), disease control rate (DCR), progression free survival (PFS), overall survival (OS), and safety. Clinical efficacy endpoints are based on tumour imaging evaluable by RECIST v1.1.
Eligible patients received a maximum of 2 prior lines of therapy, with the most recent course having included a PD-(L)1 inhibitor. To be eligible, patients must have exhibited disease control (CR/PR/SD) for at least 6 months on prior PD-(L)1 inhibitor therapy with disease progression occurring within 12 weeks since last dose.
Bemcentinib will be administered as a loading dose of 400mg on days 1, 2 and 3 followed by a dose of 200mg once daily. A fixed dose of 200 mg pembrolizumab will be given by intravenous infusion over 30 minutes every 3 weeks. Bemcentinib and pembrolizumab will be given until disease progression, unacceptable dose toxicity, or for a maximum of 35 cycles.
Tumour specimens will be analysed for PD-L1 expression (22C3 pharmDx), AXL by IHC, and infiltrating immune cells.
The pre-specified efficacy threshold for continuation into the second stage is 1 objective response among the first 13 patients, at which point up to a further 16 patients may be evaluated, for a total of 29 patients.
Result
Section not applicable
Conclusion
Section not applicable
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P1.01-93 - Metastases Sites as a Prognostic Factor in a Real-World Multicenter Cohort Study of Spanish ALK-Positive NSCLC Patients (p) (ID 1377)
09:45 - 18:00 | Author(s): Nuria Viñolas
- Abstract
Background
ALK gene rearrangements are detected in 3-7% of Non-Small-Cell-Lung-Cancer (NSCLC) p. EML4-ALK translocation was first identified as an oncogene in NSCLC p in 2007. To date, published real-world data on the prognostic factors of patients with ALK-positive advanced NSCLC in Spain are limited. We aim to evaluate the effect of number of metastases (M1) organs on overall survival (OS) in a multicenter cohort of Spanish ALK-positive NSCLC p diagnosed between 2008 and 2017.
Method
We included p with stage IV at diagnosis since 2011 to April 2018. OS (months [m]) was estimated with the Kaplan-Meier method. Survival curves were compared between groups of p using the log-rank test. Hazard risk (HR) to death was estimated with multivariable Cox model, adjusted by site of metastases, gender, age and first line type of treatment.
Result
Out of the 163 p in the cohort a total of 98 p were included, with a median follow-up of 28.6 m and 45 deaths reported. Characteristics at diagnosis were median age 58 years, female 46.9%, never-smokers 59.2%, 50% with comorbidities, PS by ECOG 0-1 93%, 58.2% lung M1, 45.9% central nervous system M1, 42.9% bone M1, 22.4% liver M1 and 29.6% pleural M1.
54.3% p and 89.4% p were treated with ALK inhibitors as first line and second line respectively. The median OS was 34.4 months, being 46.9 months in p treated with ALK inhibitors and 38.8 months in p treated with chemotherapy as first line (p= 0.9).
There were 72 p who presented M1 in more than one organ and 26 p in a single organ. The risk of death increased with greater number of organs involved at diagnosis (HR= 3.0, p=.016), and presenting liver M1 at diagnosis (HR=2.2, p=.046, with OS of 19.1 m), compared to p single site involvement (OS: 45.4 m).
Conclusion
OS was worse with increased metastatic sites involved at diagnosis in p with ALK positive NSCLC, being liver M1 associated with the highest risk of mortality. Brain metastases at diagnosis were not a prognostic factor for OS in our series.
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P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 3
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.04-10 - Biomarkers of Pathological Response on Neo-Adjuvant Chemo-Immunotherapy Treatment for Resectable Stage IIIA NSCLC Patients (ID 1466)
10:15 - 18:15 | Author(s): Nuria Viñolas
- Abstract
Background
PD1/PDL1 treatments have become the main therapy in advanced stages of NSCLC due to its significant increase in overall survival (OS), but recently, combination with chemotherapy in locally advanced stages is showing promising results. Many studies have described peripheral blood immune cells parameters as biomarkers of response to immunotherapy. In our study, we described the effect of neo-adjuvant chemo-immunotherapy treatment in Complete Blood Count (CBC) and Peripheral Blood Mononuclear Cells (PBMCs) phenotype, as well as, the association of these parameters with the degree of pathological response.
Method
Immune cell populations of 46 resectable stage IIIA NSCLC patients treated with neo-adjuvant chemo-immunotherapy from NADIM clinical trial were analysed. Samples were extracted before initiating the neo-adjuvant treatment with nivolumab plus carboplatin and at the third cycle before patients underwent surgery. We classified patients in 3 subgroups of pathological response assessed in the resection specimen: complete response (pCR), major response (<10% viable tumour) and incomplete response (>10% viable tumour, pIR). Wilcoxon and Mann-Whitney U statistic test were used to evaluate differences between pre and post treatment and between pathological responses groups respectively.
Result
From 46 patients, 5 patients did not undergo surgery, so they were excluded from the analysis. Absolute numbers of Leucocytes, Eosinophil, Monocytes, Neutrophils, Haemoglobin and Platelets from hemograms were significantly reduced after neo-adjuvant treatment. However, no changes were observed for Lymphocytes, Basophils, LDH levels or the Lung Immune Prognostic Index (LIPI). Additionally, post-treatment Neutrophil-to-Lymphocyte (NLR), Myeloid-to-Lymphoid lineage (M:L) and Platelets-to-Lymphocytes (PLR) ratios were decreased. Remarkably, from all the CBC absolute numbers and ratios, only PLR variation showed differences between pCR and pIR.
On the other hand, percentages of PBMCs (T cells, B cells, NK cells and macrophages) did not vary after neo-adjuvant treatment, however activation of CD4 T cells and NK cells as well as PD-1 receptor expression on immune cells were downregulated after neo-adjuvant chemo-immunotherapy. Interestingly, these variations correlate with pCR.
Conclusion
In our study, PLR, PD-1 expression, CD4 T cells and NK cells activation are predictive biomarkers of response to treatment. Thus, a higher decrease on PLR post neo-adjuvant treatment is associated to pCR. Moreover, a decrease of PD-1 expression in CD4, CD8 and NK cells, as well as, a reduction of CD4 T cells and NK cells activation after neo-adjuvant treatment, are associated to pCR.
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P2.04-22 - Programmed Death 1-mRNA Expression Predicts Benefit to Anti-PD1 Monotherapy in a Prospective Cohort of Advanced NSCLC (ID 1092)
10:15 - 18:15 | Author(s): Nuria Viñolas
- Abstract
Background
Immunotherapy (IO) targeting PD1 or PD-L1 represents a new treatment option for patients (pts) with advanced non-small cell lung cancer (NSCLC). Besides PD-L1 IHC, other predictive biomarkers are being explored as potential predictors of outcomes. Our group has recently described an association between PD1-mRNA expression and response to IO in a retrospective multi-tumor dataset (Annals Oncol 2018). We aimed to corroborate these results in a prospective cohort of advanced NSCLC.
Method
We prospectively evaluated the expression of 7 immune-related genes (CD4, CD8, PD1, PDL1, IFNG, GZMM andFOXP3) and 5 housekeeping genes in formalin-fixed paraffin-embedded tumor samples obtained before anti-PD1 therapy using the nCounter platform (Nanostring Technologies). The study cohort included consecutive pts with advanced NSCLC, ECOG/PS 0-1, no targetable oncogenes, treated in the first or second-line setting with anti-PD1 monotherapy from June 2017 to January 2019. Associations between the expression of PD1 mRNA (as a continuous variable and using a previously defined pre-specified cutpoint) and response (complete and partial response) were assessed using logistic regression analysis. Kaplan-Meier method was used for survival analysis. PD-L1 IHC tumor cell expression was assessed using the 22C3 clone. Pearson correlation between PD-L1 IHC and PD1 mRNA was explored.
Result
A total of 43 pts were included (men 79%; adenocarcinoma 53%; nivolumab 55%; pembrolizumab 45%; first-line 30%; second-line 70%). Response occurred in 23% of pts and was significantly associated with PD1 (p=0.029) and FOXP3 (p=0.035) expression. Using the pre-established PD1 cutoff (Annals Oncol 2018), 37% and 63% samples were PD1-high and PD1-low, respectively. PD1-high was significantly associated with increased overall response rate (ORR) (43% vs 11%, OR=6.22 [CI=1.31-29.44], p=0.021) and progression-free survival (HR 0.36 [CI= 0.14-0.90], p=0.028) but not with overall survival (p=0.117). PD-L1 IHC expression was available in 35 cases, of which 46% had high (>=50%) expression levels. A moderate concordance (0.49) was observed between PD-L1 IHC and PD1-mRNA. In this subset analysis, high PD-L1 IHC was significantly associated with response (50% vs 11%, OR=8.50 [CI= 1.45-49.53], p=0.043). Importantly, when combining predefined high/low-sets for both biomarkers (PD-L1 IHC/PD1-mRNA), response was significantly increased in PD-L1-high/PD1-high compared to PD-L1-low/PD1-low (ORR 58% vs 0%, p=0.019).
Conclusion
PD1-mRNA expression is associated with response to anti-PD1 monotherapy and can increase the predictive ability of PD-L1 IHC. Further validation of these findings in pivotal clinical trials evaluating IO in advanced NSCLC pts seems warranted.
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P2.04-61 - Preliminary Report of a Multidisciplinary Task Group for the Study of Immune-Mediated Pulmonary Toxicity (ID 1647)
10:15 - 18:15 | Author(s): Nuria Viñolas
- Abstract
Background
Immunotherapy (IO) is now the standard of care for many tumor types. However, it is not free of risks, being pulmonary toxicity one of the most relevant immune-related adverse event due to its severity. Differential diagnosis with other pulmonary complications such as infections or tumor dissemination further complicates its management.
Method
In order to raise awareness, gather information, and to discuss early management strategies in patients (pts) with immune-related interstitial lung disease (irILD), in 2017 we created a multidisciplinary task group comprised of pneumologists, pathologists, oncologists and radiologists. We herein report the main features of the first series of pts treated with IO who subsequently developed ILD, prospectively identified from a tertiary University Hospital over a period of two years (2017-2019), focusing on clinical presentation, radiological patterns, outcomes and therapeutic intervention.
Result
We identified a total of 23 pts with suspicion of irILD. Patients mainly received programmed cell death-1 (PD-L1) inhibitors (61%). Main characteristics are summarized in Table 1. ILD occurred more often in males, and former or current smokers (91%), with a median age of 62 years. The most common radiological pattern was the presence of ground-glass opacities (87%), followed by consolidations (61%). Forty-eight percent of the cases had grade 3 severity according to the Common Terminology Criteria for Adverse Events (CTCAE). Thirteen of the patients (57%) underwent a fibrobronchoscopy during the diagnostic period and a specific microorganism was isolated from BAL in three cases (13%) (Aspergillus fumigatus, cytomegalovirus and herpes type 1 virus). Ten pts (43%) underwent transbronchial biopsies being focal organizing pneumonia and desquamative changes the most common pathological patterns observed. Twenty patients (87%) received prednisone (1mg/kg/day) and thirteen of them (57%) also received antibiotic treatment.
ConclusionPatients (%)
Mean age (years)
61.63 ± 12.35
Gender
Male
19 (83%)
Female
4 (17%)
Smoking history
Current
2 (9%)
Never
7 (30%)
Former
14 (61%)
Type of cancer
Lung
8 (35%)
Kidney
5 (22%)
Skin
4 (17%)
Others*
6 (26%)
* Others: haemathologic, bladder, liver, sigma, urothelial, timic.
Immunotherapy
Nivolumab
8 (35%)
Pembrolizumab
6 (26%)
Durvalumab
2 (9%)
Others*
7 (30%)
* Others: Atezolizumab, Nivolumab+Ipilimumab, Atezolizumab+Daratumumab, Atezolumab+Bevacizumab, CX-072, Nivolumab/Nivolumab+Ipilipumab, Avelumab.
Immuno-mediated pulmonary toxicity is a rare but severe complication that carries a significant mortality. Due to their complexity, multidisciplinary approach is required to provide an adequate treatment and to guarantee early intervention.
