Virtual Library
Start Your Search
Reyes Bernabe
Moderator of
-
+
ES01 - What Is the Role of Chemotherapy in the Era of Immunotherapy in Advanced NSCLC? (ID 4)
- Event: WCLC 2019
- Type: Educational Session
- Track: Advanced NSCLC
- Presentations: 5
- Now Available
- Moderators:Oscar Gerardo Arrieta, Reyes Bernabe
- Coordinates: 9/08/2019, 10:30 - 12:00, Hilton Head (1978)
-
+
ES01.01 - Chemotherapy is Strictly Additive to Immunotherapy (Now Available) (ID 3149)
10:30 - 12:00 | Presenting Author(s): Johan Vansteenkiste | Author(s): Els Wauters
- Abstract
- Presentation
Abstract
Historically, chemotherapy was the only systemic therapy for advanced NSCLC. Over the last decades, effective targeted therapy has been developed. EGFR is the prime target since 20 years now [1], and is followed by an increasing number of targetable rare oncogenic driver mutations. This decade, the phase I trial of nivolumab – including NSCLC patients – started recruitment on July 1, 2011 [2]. Since then, immunotherapy with immune checkpoint inhibition (ICI) has become the third pillar in our therapeutic armentarium, with a very rapid development for relapsed, and thereafter for untreated advanced NSCLC. Most patients with non-oncogene addicted advanced NSCLC will nowadays have both chemotherapy and ICI, either in a concurrent or sequential way. This raises the question whether their interaction is synergistic or additive, favoring the former versus the latter approach. We will look at this from the perspective of adverse events, mechanistic background, and clinical trial outcomes.
There is not much overlap between the typical and common adverse events (AEs) of chemotherapy or ICI. The former are mostly bone marrow inhibition, nausea/vomiting, mucositis, hair loss and neuropathy. ICIs are well tolerated, with no or mild AEs in most patients, but may induce immune related AEs mostly in skin or endocrine organs, liver, lungs or kidneys. Hence, there is little difference in overall adverse event profiles when the chemotherapy+ICI (chemo+ICI) and chemotherapy+placebo (chemo+PL) arms from randomized trials are compared. In the Keynote-189 trial - an example with the anti-PD-1 agent pembrolizumab – overall grade 3 to 5 AEs were present in 67.2% and 65.8% of patients with chemo+ICI and chemo+PL, respectively [3]. Grade 3 to 5 immune-related AEs, as rated by investigators blinded to the assigned therapy, were 8.9% for chemo+ICI, while 4.5% for chemo+PL. AEs leading to discontinuation of all treatment were 13.8% and 7.9%, respectively. Hence, irAEs acted additive to the overall AE profile. The notable exception in this trial was renal toxicity. There was a low frequency of auto-immune nephritis (1.7%), but there was a 5.2% incidence of acute kidney injury in the chemo+ICI arm, compared to 0.5% in the control arm.
In the IMpower-133 trial – an example with the anti-PD-L1 agent atezolizumab – overall grade 3 to 5 AEs were present in 67.2% and 63.8% of patients with chemo+ICI and chemo+PL, respectively [4]. All grade immune-related AEs, as rated by investigators blinded to the assigned therapy, were 39.9% for chemo+ICI, and 24.5% for chemo+PL. So, here again a rather additive pattern in AE profile is put forward.
Chemotherapy has long time been regarded as immunosuppressive and incompatible with immunotherapy. To improve on the rather low response rate with ICI alone, recent trials focused on the combination of chemo+ICI, trying to exploit the immune modulatory (synergistic) effects of chemotherapy both on the tumor cells and immune cells. The details of this interaction are beyond the scope of this abstract, but a central one is immunogenic cell death (ICD) by chemotherapy. In contrast with necrotic/apoptotic cell death, ICD is characterized by immune-promoting features on dendritic cells and macrophages, by means of inducing calreticulin expression on tumor cells, release of adenosine triphosphate in the extracellular space and of high mobility group box 1 protein from the nucleus of the cancer cell. ICD, however, has been associated with only a limited number of chemotherapeutic agents used in clinical practice, such as doxorubicin, mitoxantrone, oxaliplatin and cyclophosphamide [5]. None of these agents is part of the modern chemotherapeutic armentarium for NSCLC.
Recent phase III trials with chemo+ICI versus chemo+PL demonstrated a convincing benefit in response rate, progression-free survival (PFS) and overall survival (OS) with the combination (e.g. [3]). Of note, there are no randomized data comparing the combination of chemo+ICI in a concurrent versus a sequential way. Ideally, such a trial should have several arms: one with the concurrent use of chemo+ICI in all PD-L1 tumors; a sequential one with pembrolizumab followed by chemotherapy in PD-L1 >=50% tumors; and one with the sequential use of a chemotherapy and then ICI in PD-L1 <50% tumors. The primary endpoint preferably should be PFS2 in a intention-to-treat analysis.
In the absence of such data, there is no definitive evidence that one or the other strategy is superior, and we can only make speculations about this question. At the meeting, we will present suggested algorithms based on the comparison of PFS from several recent trials. Especially the PFS2 analysis of the Keynote-024 [6,7] and KN-189 [3,8] trials are helpful in this respect. Even if there are many caveats with this approach, it may be helpful to guide clinical practice between concurrent and sequential treatment strategies.
References
1. Vansteenkiste J, Wauters E. Tyrosine kinase inhibition of EGFR: A successful history of targeted therapy for NSCLC since 20 years. Ann Oncol 2018; 29 Suppl 1: i1-i2.
2. Topalian SL, Hodi FS, Brahmer JR et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366: 2443-54.
3. Gandhi L, Rodriguez-Abreu D, Gadgeel S et al. Pembrolizumab plus chemotherapy in metastatic non-small cell lung cancer. N Engl J Med 2018; 378: 2078-92.
4. Horn L, Mansfield AS, Szczesna A et al. First-line atezolizumab plus chemotherapy in extensive-stage small cell lung cancer. N Engl J Med 2018; 379: 2220-9.
5. Bezu L, Gomes-de-Silva LC, Dewitte H et al. Combinatorial strategies for the induction of immunogenic cell death. Front Immunol 2015; 6: 187.
6. Brahmer JR, Rodriguez-Abreu D, Robinson AG et al. Progression after the next line of therapy (PFS2) and updated OS among patients with advanced NSCLC and PD-L1 TPS >=50% enrolled in KEYNOTE-024. J Clin Oncol 2017;. 35S, abstr 9000.
7. Reck M, Rodriguez-Abreu D, Robinson AG et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small cell lung cancer. N Engl J Med 2016; 375: 1823-33.
8. Gadgeel SM, Garassino MC, Esteban E et al. KEYNOTE-189: Updated OS and progression after the next line of therapy (PFS2) with pembrolizumab (pembro) plus chemo with pemetrexed and platinum vs placebo plus chemo for metastatic non-squamous NSCLC. J Clin Oncol 2019; 37S, abstract 9013.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
ES01.02 - Chemotherapy Enhances the Efficacy of Immunotherapy (Now Available) (ID 3150)
10:30 - 12:00 | Presenting Author(s): Natasha B Leighl
- Abstract
- Presentation
Abstract
Combination chemotherapy with anti-PD-1 therapy has now become standard of care as first-line therapy in patients with advanced NSCLC. Several trials demonstrate the improvement of combination therapy versus chemotherapy alone, but trials comparing immunotherapy +/- chemotherapy are ongoing (e.g. INSIGNA, CCTG BR.34, Checkmate 9LA, Checkmate 227).
Several preclinical studies suggest that adding chemotherapy to immunotherapy is additive. Chemotherapy has been shown to disrupt immunsuppressive cell activity, for example regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC) and tumour associated macrophages (TAM) in preclinical studies (reviewed in Yan et al. Frontiers in Immunology, 2018). Chemotherapy may also promote immune responses via induction of tumor cell death, upregulation of MHC Class 1 expression and dendritic cell maturation. Lara et al recently reported activity both preclinically and clinically when combining gemcitabine with anti-PD1 therapy in mesothelioma, despite lack of activity of either as a single agent (Lara et al. Clin Cancer Res 2018).
A key question in the first-line setting for those eligible for anti-PD1 monotherapy (PDL1 TPS >=50%) is whether the addition of chemotherapy is of benefit. Keynote 024 demonstrates superior survival, progression-free survival and response in this population compared to platinum doublet therapy, with a response rate of 45%. Overall response rates in the Keynote 189 and 407 trials in the subgroup with PDL1 TPS>=50% were 60% and 63% for chemotherapy plus pembrolizumab. Despite consensus that some patients clearly benefit from combination therapy while others likely can receive anti-PD-1 monotherapy, it is unclear how to select patients for each strategy. Ongoing studies are currently examining this question, such as the US cooperative-group-led INSIGNA trial (NCT03793179). In this study, patients with advanced PDL1 TPS>=1% nonsquamous NSCLC will be randomized to receive either (1) pembrolizumab monotherapy followed by pemetrexed/platinum upon progression; (2) pembrolizumab monotherapy and upon progression, the addition of pemetrexed/platinum to pembrolizumab; and (3) pembrolizumab/pemetrexed/platinum followed by maintenance pembrolizumab/pemetrexed with investigator's choice of treatment upon progression. It is hoped that this study will provide answers in how to best select patients for either strategy.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
ES01.03 - Chemotherapy Directly Targets the Immune System to Improve Efficacy (Now Available) (ID 3151)
10:30 - 12:00 | Presenting Author(s): Daniel SW Tan
- Abstract
- Presentation
Abstract
Multiple phase III trials support the use of combination chemotherapy with immune checkpoint inhibitors in the first line setting. Yet the exact mechanism of synergy is poorly understood. In this third instalment of three talks dissecting this topic, the focus will be on the impact of chemotherapy on the immune system, ranging from its effect on recognition of tumor antigens, circulating immune cells and/or cytokines, as well as on immune cells in the tumor microenvironment. Elucidating the mechanism of action can delineate more tailored approaches to first line therapy, including the use of single agent checkpoint inhibitors or alternative/ additional combinations that further enhance the immune response.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
ES01.04 - Immunotherapy, Radiotherapy and Chemotherapy Combination: A Potential New Standard? (Now Available) (ID 3152)
10:30 - 12:00 | Presenting Author(s): Maurice Perol
- Abstract
- Presentation
Abstract
The advent of immunotherapy in lung cancer with immune checkpoints inhibitors (CPIs) has first involved stage IV non-small cell lung cancer (NSCLC), recently in combination with cytotoxic chemotherapy in first-line setting. The rationale to combine chemotherapy with CPIs is theoretically based on the chemotherapy-induced immunogenic cell death triggering an immune response and the modification of the tumor microenvironment (TME) by depletion of immunosuppressive cells. Radiotherapy remains one of the main components of the NSCLC treatment, from early stages with stereotactic ablative radiotherapy (SABR) and locally advanced stage III NSCLC in combination with chemotherapy to stage IV disease for the local palliative treatment of metastatic sites. Radiation therapy (RT) techniques have been considerably improved with image-guidance, and technological developments in linear accelerators, allowing now a very precise delivery of radiation.
Radiation biology has been mainly concentrated on radiation-induced DNA damage with irreparable double strand break, leading to cell cycle inhibition and cell death. There are also a rationale and a preclinical evidence to expect a synergy between RT and CPIs. RT can also cause immunogenic cell death by direct cytotoxic effects, resulting in the release of tumor-associated antigens (TAAs) and danger signals (DAMPs: damage associated molecular pattern) that can be recognized by toll-like receptors, thus facilitating the presentation of TAAs to CD8+ T cells by MHC I. The dendritic cell activation and up-regulation of interferon pathway also enhance TAAs presentation to immune cells and up-regulate MHC-1 expression on tumor cells. Radiotherapy can therefore act as an auto-vaccine, activating the dendritic cells, broadening up the immune repertoire of T cells and increasing the "visibility" of TAAs. Beside this promotion of priming and activation of cytotoxic T cells, RT upregulates PD-L1 expression in the TME. Nevertheless, the modification of TME induced by RT may be equivocal with on one hand an increase in the CD8+ T cells recruitment by up-regulation of adhesion molecules, but on the other hand, the promotion of immune tolerance via the recruitment of MDSCs and Treg cells. Moreover, RT activates the immunosuppressive TGF-β pathway by reactive oxygen species. In addition to the potential synergism in terms of local control, the RT might also mediate an abscopal effect, describing the tumor regression of lesions distant from the irradiated volume, due to circulating of T cells locally activated by RT. This phenomenon has been experimentally demonstrated in preclinical models and occasionally reported in case reports.
In stage IV NSCLC, the impact of RT delivered on a metastatic site or on the primary tumor on CPIs anti-tumor effect has been suggested by the retrospective analysis of the Keynote 001 phase I trial of pembrolizumab showing that patients who received radiotherapy before pembrolizumab had a better overall survival (OS) and progression-free survival (PFS) than those patients who did not receive radiotherapy. Many ongoing trials are exploring the possibility to "boost" the activity of CPIs by the addition of local RT, especially SABR; these trials have to face many challenges in terms of treatment timing, radiation dosing, and minimization of the RT toxicity on local and circulating T-cells. The main advance was brought in stage III NSCLC by the Pacific study which evaluated the impact of a treatment consolidation with durvalumab (anti-PD-L1), administered during 1 year after completion of concurrent chemoradiation therapy. This trial was a double-blinded, 2:1 randomized versus placebo study; randomization was authorized between 1 and 42 days after the end of radiation therapy. PD-L1 status was not required for enrollment. The majority of the 713 included patients were male, smokers and received a dose of radiotherapy between 54 and 66 Gy. The addition of durvalumab after concurrent chemo-RTsignificantly improved both PFS (median 17.2 vs. 5.6 months, HR 0.51 95%CI, 0.41-0.63) and OS at the first interim analysis (median not reached vs. 28.7 months, HR 0.68 99.73%CI, 0.469-0.997). The effect of durvalumab was mainly due to a reduction of metastatic relapses, including brain metastases. Subgroups analysis showed a trend toward a greater magnitude of PFS and OS benefit for patients randomized early after completion of radiotherapy (<14 days). The exploratory analysis of the impact of PD-L1 expression on the magnitude of benefit was planned with a cutoff at 25% for tumor cells. Knowing that 37% patients had no PD-L1 assessment, the analysis showed a PFS benefit in both subgroups of patients and no OS benefit for patients with PD-L1<25%. At the request of EMA, an additional unplanned subgroup analysis at the cutoff of 1% showed no PFS benefit and a trend toward a worse survival with durvalumab for the PD-L1<1% tumors, due to an unexpected very good survival for patients randomized in the placebo group in this small subset of patients. While FDA approval of durvalumab was unrestricted, the European label is limited to the PD-L1≥1% tumors, even if the statistical validity of the subgroup analysis is questionable. The risk of pneumonitis after radiation therapy was slightly increased in the durvalumab arm without significant augmentation of grade ≥3 events.
Pacific was the first study demonstrating the potential for CPIs to obtain a potential synergy with radiation therapy, defining a new standard of care for these patients. However, further already ongoing clinical research will have to address the questions of a similar benefit with sequential chemoradiation therapy and of the optimization of this potential synergy by administering immunotherapy concurrently with thoracic radiotherapy as suggested by preclinical data. Potential long term toxicities must also be carefully assessed. Another area of further development of RT and CPIs combinations actually investigated is the incorporation of immunotherapy after SABR in the treatment of early stage NSCLC.
The combination of RT and immunotherapy has proven effective in preclinical studies and in stage III NSCLC. A lot of challenges still exist to harness the combination of chemotherapy, RT and CPIs, especially in terms of timing, irradiated volume, fractionation, and dose that likely play a major role in the modulation of the RT different effects on the tumor cells, the immune response and the TME.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
ES01.05 - Future of Dual Anti-CTLA4 and PD1/PDL1 Blockade (Now Available) (ID 3153)
10:30 - 12:00 | Presenting Author(s): David R Spigel
- Abstract
- Presentation
Abstract not provided
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
Author of
-
+
OA03 - Systemic Therapies for SCLC: Novel Targets and Patients' Selection (ID 121)
- Event: WCLC 2019
- Type: Oral Session
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Now Available
- Moderators:Christine Lee Hann, Makoto Nishio
- Coordinates: 9/08/2019, 13:30 - 15:00, Hilton Head (1978)
-
+
OA03.03 - Initial Efficacy and Safety Results of Irinotecan Liposome Injection (nal-IRI) in Patients with Small Cell Lung Cancer (Now Available) (ID 1985)
13:30 - 15:00 | Author(s): Reyes Bernabe
- Abstract
- Presentation
Background
SCLC accounts for ~15% of lung cancers, with 5-year survival <10%. 50-90% of patients with extensive disease respond to initial treatment; many rapidly relapse due to acquired resistance to front-line platinum-based chemotherapy. Limited treatment options are available for second-line patients. nal-IRI is a liposomal formulation of irinotecan (topoisomerase-1 inhibitor), utilizing intraliposomal stabilization technology to enable high drug load and in-vivo stability.
Method
RESILIENT (NCT03088813) is a two-part Phase 2/3 study assessing the safety, tolerability, and efficacy of monotherapy nal-IRI in SCLC patients who progressed on/after a front-line platinum regimen: Part 1 includes dose-finding then dose-expansion. Key eligibility criteria included ECOG PS 0-1 and adequate organ function, with prior exposure to immunotherapy allowed. Eligible patients received nal-IRI 70mg/m2 or 85mg/m2 (free-base equivalent) q2w. Primary endpoints were safety and tolerability. Efficacy assessments included objective response rate (ORR), best overall response (BOR), progression-free survival (PFS), and overall survival (OS).
Result
30 patients were treated for >12 weeks in Part 1 (male, 43%; median age, 60.4y; platinum-resistant, 40%) with tumor assessments q6w. During dose-finding, 5 patients received nal-IRI 85mg/m2 (deemed not tolerable: dose-limiting toxicity) and 12 patients received nal-IRI 70mg/m2 (deemed tolerable: selected for dose expansion). At data cut-off** (median follow-up, 4.4mo), 25 patients had received nal-IRI 70mg/m2. Diarrhea was the most common gastrointestinal adverse events (AEs) (Gr3, 20%). Hematologic AEs included neutropenia (Gr3, 8%; Gr4, 8%), anemia (Gr3, 8%), febrile neutropenia (Gr3, 4%), thrombocytopenia (Gr3, 4%; Gr4, 4%). Preliminary efficacy identified 11 patients with partial responses (ORR 44%), BOR (PR+SD) of 72%, and 12-week disease control rate (DCR12wks PR+SD) of 48%. PFS and OS are not yet mature.
Conclusion
Part 1 demonstrated encouraging anti-tumor activity for nal-IRI 70mg/m2 in patients with SCLC (ORR: 44%, BOR: 72%). nal-IRI 70mg/m2 was generally well tolerated. Future research is warranted to assess nal-IRI in second-line SCLC.
Table 1. Baseline Demographic, Patient Disposition, Safety & Tolerability, and Clinical Efficacy for Part 1 of the RESILIENT studyDose-Finding /
Dose-Exploration PhaseIrinotecan
Liposome
Injection
85mg/m2
(N=5)Irinotecan
Liposome
Injection
70mg/m2
(N=25)Baseline Characteristics Gender, Male, n (%) 3 (60.0) 10 (40.0) Age (Years, median) 62.0 59.0 Baseline ECOG 0 1 (20.0) 3 (12.0) 1 4 (80.0) 22 (88.0) Time Since Most Recent Progression (Weeks, median) 3.4 3.2 Disease Location, n (%) Locally Advanced 0 2 (8.0) Metastatic 5 (100.0) 23 (92.0) Disposition, n (%) Patient Completed Study 4 (80.0) 12 (48.0) Patient Currently Ongoing* – 7 (28.0) Deaths 2 (40.0) 6 (24.0) Disease Related 1 3 Adverse Event Not Related to Study Drug 1 1 Cardiac Arrest 1 - Hepatic Failure - 1 Adverse Event Related to Study Drug 0 2 Abdominal Sepsis - 2 Patient Discontinued Treatment 5 (100.0) 18 (72.0) Safety & Tolerability, n (%) Any Treatment-Emergent Adverse Event (TEAE) 5 (100.0) 25 (100.0) Grade 3 or Higher TEAE (≥ 2 patients) 5 (100.0) 15 (60.0) Neutropenia 1 (20.0) 4 (16.0) Anemia – 2 (8.0) Thrombocytopenia – 2 (8.0) Diarrhea 3 (60.0) 5 (20.0) Asthenia – 2 (8.0) General Physical Health Deterioration – 2 (8.0) Pneumonia 2 (40.0) 1 (4.0) Abdominal Sepsis – 2 (8.0) Hypokalemia 1 (20.0) 2 (8.0) Renal Failure – 2 (8.0) Best Overall Response Complete Response (CR) – – Partial Response (PR) 2 (40.0) 11 (44.0) Stable Disease 1 (20.0) 7 (28.0) Progressive Disease 1 (20.0) 5 (20.0) Non-evaluable 1 (20.0) 2 (8.0) Objective Response Rate CR + PR 2 (40.0) 11 (44.0) Non-responder 3 (60.0) 14 (56.0) ** Data Cut-off: May 8, 2019. * Per RECIST v1.1 or RANO criteria. Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
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)
-
+
OA13.05 - NADIM Study: Updated Clinical Research and Outcomes (Now Available) (ID 1670)
11:30 - 13:00 | Author(s): Reyes Bernabe
- 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.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
-
+
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): Reyes Bernabe
- 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.
-
+
P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
-
+
P2.01-10 - Real Clinical Practice Study to Evaluate 2 Line Treatment Based on Comprenhensive Genomic Profiling in NSCLC. LungONE Study (Now Available) (ID 1558)
10:15 - 18:15 | Author(s): Reyes Bernabe
- Abstract
Background
Cancer is a genomic disease and molecular-targeted therapy plays an increasingly important role in the treatment of advanced NSCLC. The current standard of care (SoC) indication for NSCLC is defined by genomic biomarkers to classify the tumor as a carrier of a therapeutic approved target. However, the current standard of practice for molecular testing in NSCLC in Spain is highly heterogeneous, depending on several factors such as hospital size, resources, laboratory equipment and experience. In addition, there are several other markers and/or genomic signatures which are not determined due to the current lack of scientific evidence, i.e. MSI, TMB, KRAS, BRAF, RET, MET, HER2 and NTKR, which could guide physician second line treatment choice, including clinical trial options. The aim of this study is to evaluate the impact on decision making in the 2nd line treatment using a comprehensive genomic profiling (CGP) in advanced/metastatic NSCLC with adenocarcinoma histology.
Method
Section not applicable
Result
Section not applicable
Conclusion
This is a multicenter, prospective, single-cohort study to describe the clinical management of the 2nd line SoC treatment in patients with locally advanced/metastatic NSCLC with adenocarcinoma histology, when a comprehensive genomic profile based on FoundationOne®CDx or FoundationOne® Liquid test, is provided. 12 academic institutions in Spain were selected and 180 patients were planned to be recruited. The principal objective is to evaluate if there is any change in planned 2nd line treatment decisions after receiving the CGP report. Secondary objectives for this study are:1) to identify non-previously detected actionable molecular aberrations by conventional molecular assays; 2) to evaluate the economic impact in terms of use of healthcare resources of the CGP vs. standard diagnostic panels; and 3) to describe each patient’s status 2 years after the inclusion of the last patient in the study. Patients will follow usual clinical pathways for biomarker analysis and a comprehensive genomic profiling in the remaining tissue through FoundationOne® CDx, will be conducted or liquid biopsy with FoundationOne® Liquid, if exhausted. To be enrolled in the study, patients must have an ECOG between 0 and 2 and biomarkers ALK, EGFR, ROS1 must have been assayed (negative or unknown results). Enrolment begun on October 2018 and, to date, a total of 110 patients have been included.
-
+
P2.03 - Biology (ID 162)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
-
+
P2.03-16 - Agreement Between Different Methodologies for Non-Invasive p.T790M and EGFR Sensitizing Mutation Testing (ID 1965)
10:15 - 18:15 | Author(s): Reyes Bernabe
- Abstract
Background
Tyrosine kinase inhibitors (TKIs) are the current standard of care for patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). However, most patients progressed within 1 to 2 years. The EGFR p.T790M mutation is the most common resistance mechanism to first and second generation EGFR TKIs. The identification of p.T790M mutation is of considerable clinical relevance as osimertinib has demonstrated clinical efficacy in this setting. Guidelines recommend testing for the p.T790M mutation in blood at relapse to TKIs, and re-biopsy only in case of a negative result. Several blood based methodologies for detection of EGFR mutations have been developed in the recent years. However, the number of comparison studies between platforms is very limited.
Method
This is a multicenter, cross-sectional study (ClinicalTrials.gov Identifier: NCT03363139) performed by the Spanish Lung Cancer Group. Samples from 75 consecutive EGFR mutant NSCLC patients were collected at disease progression to first line TKI treatment. The presence of EGFR mutations in the cfDNA was evaluated in 39 samples by 7 methodologies, namely: Cobas® EGFR Mutation Test v2 (Roche Diagnostics), Therascreen EGFR Plasma RGQ PCR Kit (Qiagen), QuantStudio® 3D Digital PCR System (Thermofisher), a 5′-nuclease real-time PCR (TaqMan®) assay in presence of PNA, OncoBEAM EGFR (Sysmex Inostics), NGS with two different gene panels: Oncomine® (Thermofisher) and Lung Cancer Panel (Qiagen). The agreement between methodologies was assessed using the kappa coefficient (K) and its corresponding 95% confidence intervals (95% CI). For quantitative variables the concordance correlation coefficient (ccc) was used.
Result
Complete results are available for 39 patients. Overall, the agreement between all methodologies for the detection of p.T790M mutation as well as the original EGFR sensitizing mutation was good (K=0.669; 95CI: 0.504-0.835 and K=0.750 95CI: 0.599-0.899 respectively). Remarkably, the agreement between FDA-approved methodologies for p.T790M detection was almost perfect (K=0.926; 95CI: 0.712-1) and good for the EGFR sensitizing mutations (K=0.657; 95CI: 0.417-0.902). Similarly, the agreement between NGS-based methodologies for the detection of p.T790M and the EGFR activating mutations was very high (K=0.843; 95CI: 0.567-1 and K=0.872 95CI: 0.595-1 respectively). Moreover, concordance between both technologies for p.T790M and EGFR sensitizing mutation mutant allele frequency was excellent (ccc=0.956; 95CI: 0.906-1 and ccc=0.980 95CI: 0.950-1 respectively). The proportion of samples that were positive for p.T790M detection varied from 28% (PCR based technologies) to 37% depending on the methodology.
Conclusion
NGS and PCR-based methodologies show a good to excellent agreement for the detection of EGFR mutations, including the p.T790M. Our results support the use of liquid biopsies for non-invasive testing of clinically relevant mutations (Data from the whole cohort will be presented at the meeting).
-
+
P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
-
+
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): Reyes Bernabe
- 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.
-
+
P2.05 - Interventional Diagnostic/Pulmonology (ID 168)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Interventional Diagnostics/Pulmonology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
-
+
P2.05-12 - Analysis of Biomarkers in Lung Cancer in Spain (ID 854)
10:15 - 18:15 | Author(s): Reyes Bernabe
- Abstract
Background
The analysis of biomarkers in lung cancer (LC) is currently one of the most important care needs, given the importance of their presence in the selection of specific treatments. Our objective was to know the implementation degree of these tests in a large cohort of patients in Spain using the Thoracic Tumor Registry (TTR) of the Grupo Español de Cáncer de Pulmón (Spanish Lung Cancer Group).
Method
The TTR is an observational cohort multicenter study of the LC in Spain. Information on patients (p) enrolled from August 2016 to December 2018. The study is conducted according to the Declaration of Helsinki and approved by the institutional review board of each participating institute. The registry was approved by the Spanish Drug Agency as a non-post-authorization, non-interventional study.
Result
A total of 7,872 patients from 58 Spanish sites were enrolled. Analysis of molecular markers considering all the LC stages: A molecular test, the most frequent being the EGFR test, was performed in 4,456 patients (67.5%). The proportion of biomarker evaluation has varied over time, ranging from 57.9% prior to 2012 up to 73.7% in 2017.
Molecular markers in patients with stage IV. Three thousand four hundred forty-six (3,446) patients (52.2%) had a stage IV on diagnosis. The molecular assessment of some biomarkers reached 81.4% of all the patients, there being differences between Regional Communities in regard to the molecular tests made.
There was performed some biomarker test in 92% of the 2570 patients with stage IV and adenocarcinoma histology. The analysis of ALK was tested in 79% of the patients, this being in 40% only 2 years ago. ROS was studied in 20% of the cases and EGFR in 92%.
Conclusion
Although no national plan exists for molecular biomarker analysis in LC in Spain, the implementation of the biomarkers analysis in all the hospitals that contribute to the TTR is high, as close to the maximum as possible. The increase in the ALK analysis in the last period is relevant. As regional differences exist, it would be of interest to go in depth to study its cause
-
+
P2.10 - Prevention and Tobacco Control (ID 176)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Prevention and Tobacco Control
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
-
+
P2.10-02 - Smoking Habit in Lung Cancer in Spain (ID 732)
10:15 - 18:15 | Author(s): Reyes Bernabe
- Abstract
Background
Tobacco is the leading cause of lung cancer. The fight against the smoking habit is essential and should be continuous, to detect the national situation that makes it possible to design health care policies against this consumption. To do so, the Grupo Español de Cáncer de Pulmón (Spanish Lung Cancer Group) made this analysis within the context of the Thoracic Tumor Registry (TTR).
Method
The TTR is an observational cohort multicenter study in Spain. The study is conducted according to the Declaration of Helsinki and approved by the institutional review board of each participating site. The registry was approved by the Spanish Drug Agency, as a non-post-authorization, non-interventional study.
Result
We collected data from 6,600 patients diagnosed of lung cancer from 58 different Spanish hospital sites.
A total of 3,039 patients were former smokers (46%), 2,611 were active smokers (39%) and only 866 (12%) patients stated to be non-smokers; the status in 2% is unknown. If we make a comparison by gender regarding the presence of this habit, large differences (p-valor < 0.001) are observed, with a greater number of non-smokers in women (37 % vs. 4.5% in males), while the percentage of former smokers is much higher in the males (53.4% vs. 27.9% in women) and a minor difference in active smokers (42.1% vs. 34.4% in women).
Significant differences were observed in the study on the distribution of the smoking habit by gender and year of diagnosis. An increase is also observed in the last two years regarding the percentage of patients who were active smoked, both for the total population as well as for each one of the two genders separately. The increase is greater among the women and, also, the number of women who are active smokers is greater in recent years.
Mean age of onset of the smoking habit is 18.2 years. Significant differences are observed between both genders (p-valor < 0.001), with a mean age of initiation of 17.9 years in the men (95%CI 17.6-18.2 years) and 19.2 years in the women (95%CI 18.5-19.8 years). Significant differences between Regional Communities were also found in the mean age at onset of the habit, with much lower levels in the Valencian Community (16.6 years) or Navarra (16.9 years) regarding other communities, such as the Region of Murcia (22.9 years) or the Balearic Islands (21.6 years)
Conclusion
Lung cancer in Spain is associated to tobacco consumption in 85% of the cases diagnosed. Consumption has shown an increase in both genders in recent years and is especially rapid and worrisome in women. Anti-smoking campaigns should be reactivated and the causes of the regional differences analyzed in depth
