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Julien Mazieres

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    PC02 - Combining with Chemo: Old School Is New Again (ID 84)

    • Event: WCLC 2019
    • Type: Pro-Con Session
    • Track: Advanced NSCLC
    • Presentations: 4
    • Now Available
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      PC02.01 - TKIs Should Be Given as Single Agent (Now Available) (ID 3561)

      14:00 - 15:30  |  Presenting Author(s): Tony Mok

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      PC02.02 - TKIs Should Be Given with Chemo (Now Available) (ID 3562)

      14:00 - 15:30  |  Presenting Author(s): Rafael Rosell

      • Abstract
      • Presentation
      • Slides

      Abstract

      TKIs Should Be Given with Chemotherapy. This is an open question, with some pros and cons, mainly due to the complexities of chemotherapy activity regarding genetic alterations. However, there are several promising hints that the combination could be useful, but not all chemotherapeutic drugs prove beneficial. This information will be provided in the presentation.

      Resistance to erlotinib and, in general, to any generation of EGFR TKIs, is heterogeneous and requires the comprehensive dynamic molecular profiling of the tumor with either tissue, liquid biopsies, or both. Before the development of the third-generation EGFR TKIs, at the time of progression to erlotinib or gefitinib, patients were successfully treated with chemotherapy [Sequist et al Sci Trans Med 2011]. The alternation of chemotherapy and EGFR TKIs merits revisiting. The intercalation of erlotinib with chemotherapy has shown a median PFS of 16.8 months in EGFR-mutant NSCLC patients [Wu et al Lanect Oncol 2013]. The most salient biological concept to re-address the contribution of chemotherapy in EGFR-mutant NSCLC is the fact that nuclear cyclic GMP-AMP (cGAMP) synthase (cGAS) expression suppresses DNA repair and, therefore, can enhance the activity of EGFR TKIs. Preclinical data strongly favors this model, showing that etoposide or other chemotherapeutic drugs can promote the translocation of cGAS to the nucleus by phosphorylation of cGAS on the tyrosine residue 215. In the nucleus, cGAS is recruited to double stranded breaks, interacting with PARP1. The cGAS-PARP1 interaction jeopardizes the generation of the PARP1-Timeless complex and suppresses homologous recombination [Liu et al Nature 2018]. The fact that cGAS transcripts are increased in NSCLC is of clinical interest, indicating that cGAS could be a new biomarker involved in the response to immune checkpoint inhibitors [Gui et al Nature 2019].

      Multilayer research sheds light on potential safe and active combinatory therapies in EGFR-mutant NSCLC and many therapeutic approaches converge in the complex signaling pathway crosstalk. Perhaps tumor heterogeneity is not the major difficulty and the mechanisms of resistance are more dependent on the capacity of tumor cells to re-wire and re-program the signaling pathways that they use to grow and migrate [Karachaliou et al EBioMedicine 2018]. Epi-transcriptomics are also involved in resistance to EGFR TKIs (Figure) [Zanconato et al Nat Med 2018]. Several chromatin regulators have emerged as druggable targets, including bromodomain-containing protein 4 (BRD4). BRD4 interacts with YAP1, and Bromodomain and Extra-Terminal motif (BET) inhibitors impair the expression of YAP1 direct target genes, including AXL, FST1 and aurora A [Zanconato et al Nat Med 2018]. We have recently reported that the combination of EGFR TKIs with barasertib, an aurora kinase B inhibitor, illustrates a strong antiproliferative activity in a broad panel of EGFR-mutant resistant cell lines [Bertran-Alamillo Nat Comm 2019].

      DNA repair modulators may be associated with resistance to EGFR TKIs. In our original study of erlotinib in EGFR-mutant NSCLC [Rosell et al NEJM 2009], we explored the role of DNA repair genes on the treatment outcome. Among several transcripts examined, breast cancer type 1 susceptibility (BRCA1) gene mRNA surfaced as relevant in the repair of erlotinib-induced DNA damage through an H2A histone family member X (H2AX)-independent pathway [Rosell et al Clin Cancer Res 2011]. Normally, DNA damage repair involves a homologous recommendation, through H2AX [Wang et al Science 2007]. Patients with low BRCA1 mRNA expression had significantly longer PFS than patients with high BRCA1 mRNA levels, and BRCA1 levels were an independent predictor of PFS in the Cox-multivariate regression analysis.

      Finally, turning off the DNA damage checkpoint after DNA repair involves the removal of phosphorylated H2AX from the chromatin, followed by its replacement with canonical H2A. This exchange of phosphorylated H2AX for H2A is mediated by facilitates of chromatin transcription (FACT) (Figure). The ability of FACT to remove phosphorylated H2AX from the chromatin is inhibited by PARP1 [Rosell et al Clin Cancer Res 2011]. A novel class of drugs, curaxins, act as a chromatin trapping of the FACT, suppressing simultaneously NF-ĸB signaling and promoting activation of p53 [Gasparian et al Sci Trans Med 2011]. The combination of erlotinib with curaxins, or FACT inhibitors, like CBL0137 [Lindner et al Cancer Res 2018], may be a significant advance in the field of EGFR-mutant NSCLC therapy.figure.jpg

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      PC02.03 - IO Should Be Given as a Single Agent (Now Available) (ID 3563)

      14:00 - 15:30  |  Presenting Author(s): Julie R Brahmer

      • Abstract
      • Presentation
      • Slides

      Abstract

      Programmed cell death 1 (PD-1) checkpoint pathway inhibitors have greatly changed the treatment paradigm for advanced stage non-small cell lung cancer (NSCLC). Durvalumab is approved for use as a single agent after chemotherapy combined with radiation for stage 3 NSCLC.(1) Pembrolizumab is approved for use in the first line treatment setting for advanced NSCLC not amenable to radiation for patients whose tumor has a tumor proportion score (TPS) of 1% or greater in the United States.(2) For patients whose tumor has a TPS of > 50%, it is approved for use in the first-line treatment setting in multiple countries throughout the world.(3) However, PD-1 checkpoint blockade combinations, either anti-PD1 or anti-PD-L1 antibodies, with chemotherapy regardless of PD-L1 status have shown benefit as well. (4,5,6)

      Single agent immunotherapy (IO) has several advantages. Cost of combination therapy is an issue. While these PD-1 pathway blocking antibodies are expensive as single agents, combining them with chemotherapy adds to the cost, time in infusion, and adds chemotherapy related side effects. So, if patients can, single agent immunotherapy is still preferred, particularly in a population i.e. TPS > 50% who is more likely to benefit compared to chemotherapy. Some would say the same is true for patients with TPS > 1, but here the data for single agent IO compared to combinations with chemotherapy is mixed. While trials comparing this scenario, i.e. comparing single agent PD-1 antibody compared to chemotherapy plus IO, head to head have not yet been done, it is hard not to do cross trial comparisons as seen in table 1. Clearly though, chemotherapy and IO combinations have increased objective response rates regardless of PD-L1 TPS status where response rates range from 57.9%-62.1%.(4,5,6,7,10)

      While combinations with chemotherapy show increased response rate regardless of PD-L1 TPS, chemotherapy can have deleterious effects on the immune system. (8) Chemotherapy can alter immune function by causing lymphopenia. Steroids, added to chemotherapy regimens to prevent allergic reactions and control nausea, can suppress pro-inflammatory cytokines and impair Natural Killer (NK) cell function and dendritic cell differentiation or activation. Taxanes specifically can cause inhibition of T-cell and NK-cell activation. Thus, these combinations may prevent immune activation and suppress immune memory. Duration of response in single agent IO in the first line treatment setting is 16.8-20.2+ month.(9,2,3) The duration of response in the IO plus chemotherapy patient population is 7.7-11.2 months.(4,5,6) The data from the chemotherapy IO combinations is too immature to know what the potential five-year survival is compared to the impressive 23.2% 5 year survival rate of the initial trial of pembrolizumab in the treatment-naïve setting(Keynote 001).(9)

      Immunotherapy, particularly PD-1 pathway checkpoint antibodies, have drastically changed the treatment landscape for advanced stage lung cancer patients. Single agent pembrolizumab particularly in patients with TPS > 50% lung cancer results in an impressive long term survival that is not seen with chemotherapy alone. Combining immunotherapy agents with chemotherapy increases disease response but long term survival outcome data and duration of response is immature.

      Table 1 – Overview of Results in NSCLC PD-L1 TPS > 50% patient population

      KeyNote 0243

      KeyNote 0422

      KeyNote 1894,10

      KeyNote 4076

      ORR

      44.8%

      39.5%

      62.1%

      60.3%

      DOR (mo)

      NR (1.9-14.5+)

      20.2

      15.1

      Not reported

      mPFS (mo)

      10.3

      HR 0.5 (0.37-0.68), p<0.001

      7.1

      HR 0.81 (0.67-0.99), p=0.017

      11.1

      HR 0.36 (0.26-0.51)

      8

      HR 0.37 (0.24-0.58)

      mOS (mo)

      30

      HR 0.63 (0.47-0.86), p=0.002

      20

      HR 0.69 (0.56-0.85), p=0.0003

      NR

      HR 0.59 (0.39-0.88)

      NR

      HR 0.64 (0.37-1.10)

      2 year OS

      51.5%

      44.7%

      51.9%

      Not reported

      NR=not reached, ORR=overall response rate, DOR=duration of response, mPFS=median progression free survival, mo=months, mOS=median overall survival, OS=overall survival

      1-Antonia SJ, Villegas A, Daniel D et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med. 2018 Dec 13;379(24):2342-2350.

      2-Mok TSK, Wu YL, Kubaba I et al. Pembrolizumab versus Chemotherapy for Previously Untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomized, open-label, controlled, phase 3 trial. Lancet 2019 May 4:383(10183):1819-1830.

      3-Reck M, Rodriquez-Abreu D, Robinson AG et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833.

      4-Gandhi L, Rodriquez-Abreu D, Gadgeel S et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2018 May 31;378(22):2078-2092.

      5-Socinski MA, Jotte RM, Cappuzzo F et al. Atezolizumab for First-Line treatment of Metastatic Nonsqumaous NSCLC. N Engl J Med 2018 Jun 14;378(24):2288-2301.

      6-Paz-Ares L, Alexander L, Vicente D et al. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med 2018;379:2040-2051.

      7-Reck M, Rodriquez-Abreu D, Robinson AG et al. Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer with PD-L1 Tumor Proportion Score of 50% or Greater. J Clin Oncol 2019 Mar 1;37(7):537-546.

      8-Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological Aspects of Cancer Chemotherapy, Nature Reviews Immunology 2008 (8), 59-73.

      9-Garon, E, Hellmqann M, Carcereny Costa E et al. Five-year long-term overall survival for patients with advanced NSCLC treated with pembrolizumab: Results from KEYNOTE-001. J Clin Oncol 37, 2019(suppl; abstr LBA9015).

      10-Gadgeel S, Garassino M, Esteban E et al. KEYNOTE-189: Updated Overall Survival and Progression After the Next Line of therapy with Pembrolizumab plus Chemotherapy with Pemetrexe3d and Platinum vs Placebo Plus Chemotherapy for Metastatic Nonsquamous NSCLC. J Clin Oncol 37, 2019 (Suppl; abstr LBA9013).

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      PC02.04 - IO Should Be Given with Chemo (Now Available) (ID 3564)

      14:00 - 15:30  |  Presenting Author(s): Luis Paz-Ares

      • Abstract
      • Presentation
      • Slides

      Abstract

      Lung cancer is the leading cause of cancer death worldwide. Non-small-cell lung cancer (NSCLC) accounts for almost 85% of all cases. The prognosis of NSCLC patients remains quite unsatisfactory due to the frequent advanced disease stage at diagnosis and the relatively low efficacy of the available systemic treatments. Of note, over the las few years significant progress as inhibitors of programmed death-1 (PD-1) and its ligand PD-L1 have proven to be effective therapies in metastatic NSCLC lacking sensitizing EGFR or ALK mutations, initially in pretreated patients. Subsequently, in metastatic NSCLC patients with PD-L1 expression of at least 50% on tumor cells, upfront pembrolizumab improved median progression-free survival (PFS) and overall survival (OS) compared to standard platinum-based chemotherapy. However, patients with a tumor proportion score (TPS) of 50% or greater represent only some 30% of those with NSCLC, and progression during the first three months is frequent in one third of the cases. To enhance the immune response through PD-1 inhibition, several studies have combined the potential immunogenic effects of cytotoxic chemotherapy with immune checkpoint inhibitors (ICPI), particularly of some chemotherapy regimens such as those pemetrexed-based. The first study that gave some important information regarding the efficacy of combining IO and chemotherapy was Keynote 021, randomized phase II trial of carboplatin plus pemetrexed with and without pembrolizumab. It showed significantly better response rates (RR) and longer PFS with the addition of pembrolizumab to chemotherapy. Over the last two years at least 6 other phase III clinical trials with pembrolizumab (KN 189 and KN 407) have showed the benefits of combined chemotherapy plus IO therapy in terms of PFS and OS (HR 0.49-0.64). Consistent data have been achieved on atezolizumab trials, although the magnitude of the OS benefit (HR 0.78-0.93) have been somehow lower. Randomized studies with nivolumab, durvalumab and avelumab are expected to be reported in the near future. Chemo-immunotherapy combinations are associated with the expected toxicities of chemotherapy and IO on their own.

      At present, for patients with tumors with TPS >50%, there are no comparative trials of IO monotherapy (e.g. pembrolizumab) as compared to chemotherapy. Across trial comparisons may support the use of IO monotherapy for most of cases. Chemo-IO regimens may be considered for patients requiring rapid responses (e.g. symptomatic patients) or those with aggressive disease. In patients, whose tumors express PD-L1 in 1-49% of cells, chemo-IO combinations are seen as the best treatment options. Of note, in the IMPOWER 150 trial, patients with EGFR/ALK aberrations also benefitted from the addition of atezolizumab to the paclitaxel/carboplatin/bevacizumab regimen. In patients with tumors with negative expression of PD-L1 the benefits on PFS were more debatable but the pembrolizumab-based combos, and to some extend those with atezolizumab, resulted in prolonged survival. The value of certain genomic aberrations (e.g. Keap or LKB1) or low tumor mutational burden (TMB) as a predictive tool in this setting needs further validation. In addition, the results of several ongoing combination studies (CheckMate-9LA, POSEIDON ) investigating two and four drug regimens of PD-(L)1 plus CTLA-4 inhibition with/without chemotherapy are eagerly awaited and will reveal further knowledge of efficacy and tolerability in this setting.

      References

      Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. . Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. (2015) 373:1627–39.

      Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. (2016) 375:1823–33.

      Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. (2016) 17:1497–508.

      Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. (2018) 378:2078–92.

      Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, et al. KEYNOTE-407 Investigators. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med. 2018; 379: 2040-2051.

      Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, Minenza E, et al. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. N Engl J Med. 2018; 378: 2093-2104.

      Jotte RM, Cappuzzo F, Vynnychenko I, Stroyakovskiy D, Abreu DR, Hussein MA, et al. IMpower131: primary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC. J Clin Oncol. (2018) 36:LBA9000–LBA9000. 10.1200/JCO.2018.36.18_suppl.LBA9000.

      Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, et al.. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. (2018) 378:2288–301.

      Socinski MA, Jotte RM, Cappuzzo F, Orlandi FJ, Stroyakovskiy D, Nogami N, et al. Overall survival (OS) analysis of IMpower150, a randomized Ph 3 study of atezolizumab (atezo) + chemotherapy (chemo) ± bevacizumab (bev) vs chemo + bev in 1L nonsquamous (NSQ) NSCLC. J Clin Oncol. (2018) 36:9002.

      Papadimitrakopoulou V, Cobo M, Bordoni R, Dubray-Longeras P, Szalai Z, Ursol G, et al. IMpower132: PFS and safety results with 1L Atezolizumab + Carboplatin/Cisplatin + Pemetrexed in stage IV non-squamous NSCLC. In: International Association for the Study of Lung Cancer's (IASLC) 2018 World Conference on Lung Cancer (WCLC); 2018 Sept 23-26. Toronto, ON: (2018).

      West H, McCleod M, Hussein M, Morabito A, Rittmeyer A, Conter HJ, et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019; 20: 924-937.

      Borghaei H, Hellmann MD, Paz-Ares LG, Ramalingam SS, Reck M, O'Byrne KJ, et al. Nivolumab (Nivo) + platinum-doublet chemotherapy (Chemo) vs chemo as first-line (1L) treatment (Tx) for advanced non-small cell lung cancer (NSCLC) with < 1% tumor PD-L1 expression: results from CheckMate 227. J Clin Oncol. (2018) 36:9001 10.1200/JCO.2018.36.15_suppl.900.

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Author of

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    MA05 - Update on Clinical Trials and Treatments (ID 123)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
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      MA05.05 - Post-Discontinuation Treatments in IFCT-GFPC-0701 MAPS Trial: Real-World Effectiveness of 2nd-Line (2L) Treatments for Mesothelioma (Now Available) (ID 815)

      13:30 - 15:00  |  Author(s): Julien Mazieres

      • Abstract
      • Presentation
      • Slides

      Background

      MAPS phase 3 trial assessing the addition of bevacizumab to pemetrexed-cisplatin doublet set a new standard of care in malignant pleural mesothelioma (MPM) patients, showing 18.8 months median overall survival (OS) with triplet combo. While both arms were well balanced in terms of 2L treatments, the size of the OS benefit from second-line treatments remains controversial.

      Method

      Long-term survival data were collected in the 342 MAPS patients alive at the end of the first-line (1L) treatments, in both arms. Median OS and 2-year survivals were calculated from the initiation of 2L. Multivariate analysis using Cox model included the stratification variables of the MAPS trial, along with the treatment arm (with or without bevacizumab).

      Result

      342/442(77.4%) patients received 2L treatment for disease progression after MAPS trial, of which 324 received chemotherapy (CT), 18 palliative radiotherapy (RT), while 100/442 (22.6%) remained untreated. 160/342 patients (46.8%) had a platinum-based doublet CT. 163 patients (47.7%) received a single-drug CT. 172/324 (53.1%) received a pemetrexed-containing regimen (alone or with platinum), 84 (25.9%) a gemcitabine-based CT, 16 (4.9%) vinorelbin alone, 48 (14.8%) gemcitabine alone, while in 12 (3.7%) single-agent bevacizumab was resumed. Median age was lower in patients with doublet CT (64.4 years, IQR 60.2-68.9) vs. single-drug CT patients (66.3 years, IQR 61.5-70.3), patients receiving RT (68.5 years, IQR 63.3-70.5) or untreated patients (67.8 years, IQR 63.4-71) (p=0.007). There were more PS=2 patients (10%) in the untreated group, compared with 0.6%, 1.8% and 5.6% in those receiving doublet, monotherapy or radiotherapy, respectively (p<0.001). A lower proportion of patients receiving 2L doublet CT had sarcomatoid/biphasic MPM (11.2%) compared with 21.5%, 38.9% and 25% in those with single-arm agent, RT or untreated, respectively (p=0.002). When compared with those treated with 2L single-agent, patients with 2L doublet had more frequently objective response (11.9 vs. 3.1%, p=0.005) and disease control (60.3 vs. 34.6%, p<0.0001). From the date of 2L therapy initiation, median OS was 3.2 months, 95%CI [1.7-5.0] for RT vs. 7.0 months 95%CI[5.6-7.8] for single-agent CT, or 12.2 months 95%CI [9.5-14.1] for doublet CT. HRs were adjusted for 1L treatment type (bevacizumab-containing or not), PS, smoking, and histology. Adj.HR (single-agent vs. doublet) was 1.21, 95% CI(0.96-1.53), p=0.11. Adj.HR (monotherapy vs. RT) was 0.39, 95%CI[0.24-0.65], p=0.0003. Adj.HR (combination CT vs. RT) was 0.32 95%CI[0.19-0.54], p<0.0001. 1-year OS was 11.8%, 95%CI [0.0-27.1], 48.7%, 95%CI [39.9-57.5], and 32.9%, 95%CI [25.1-40.6], in patients with RT alone, single agent CT or combination CT, while 2-year OS was 0%, 14.2%, and 20.0% respectively.

      Conclusion

      Second-line monotherapy only gave a 7-months median OS in MPM patients, comparing unfavorably to 11.9 and 15.9-months median OS with 2nd/3rd-line nivolumab or nivolumab+ipilimumab respectively, in the IFCT-1501 MAPS-2 randomized phase 2 trial. Conversely, 2L platinum-based chemo, in younger fit patients, still gave a 12.2-months median OS, not statistically different from monotherapy in the multivariate analysis, as a consequence of PS influence, although clinically meaningful. Based on these results, immunotherapy might be preferred for 2L/3L MPM patients, while monotherapy CT shows limited survival benefit.

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    MA12 - New Frontiers from Pathology to Genomics (ID 138)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
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      MA12.01 - Redefining Malignant Pleural Mesothelioma Types as a Continuum Uncovers Immune-Vascular Interactions (Now Available) (ID 1773)

      14:00 - 15:30  |  Author(s): Julien Mazieres

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant Pleural Mesothelioma (MPM) is a deadly disease. The current histopathologycal classification recognises three major types (epithelioid, biphasic, and sarcomatoid) with different prognosis, but showes high interobserver variability. This classification also has a role in the clinical decision-making although, ultimately, MPM becomes refractory to all conventional treatment modalities, and alternative therapeutic options have been evaluated with limited success.

      Method

      We have performed unsupervised analyses of publicly available RNA-seq data of 284 MPM tumours1,2 with no assumption of discreteness. We have performed an orthogonal validation in a subset of 187 samples, and we have replicated the findings in an independent series of 77 MPM from the French MESOBANK.

      Result

      A continuum of molecular profiles appeared to explain the prognosis of this disease better than discrete models based on the histopathological classification or on expression data. We identified the immune and vascular pathways as major sources of molecular variation, with strong differences in the expression of immune checkpoints and pro-angiogenic genes across samples; the extrema of this continuum had very specific molecular profiles: a "hot" bad-prognosis profile (median survival of 7 months), with high lymphocyte infiltration, and high expression of immune checkpoints and pro-angiogenic genes; a "cold" bad-prognosis profile (median survival of 10 months), with low lymphocyte infiltration and high expression of pro-angiogenic genes; and a better-prognosis profile (VEGFR2+/VISTA+, median survival of 36 months), with high expression of the immune checkpoint VISTA and the pro-angiogenic VEGFR2 gene. We selected five genes belonging to the immune and vascular pathways (CD8A, PDL1, VEGFR3, VEGFR2, and VISTA), which expression was enough to capture the three molecular profiles, to validate the expression of these genes at the protein level by immunohistochemistry on a subset of 187 samples from the discovery cohort, and to replicate the molecular profiles as well as their prognostic value in an independent series of 77 MPMs.

      picture copy.jpg

      Conclusion

      In this study we found that the prognosis of MPM is best explained by a continuous model, which extremes show characteristic molecular profiles with specific expression patterns of genes involved in the angiogenesis and immune response3. These data may inform future classifications of MPM and provides insights that may assist the clinical management of this disease.

      1Bueno et al., Nat Genet 2016; 2Hmeljak et al., Cancer Discov 2018; 3Alcala et al., under review in Cancer Res; NA and LM equally contributed to this work; MF, FGS, and LFC jointly supervised this work

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    MA21 - Non EGFR/MET Targeted Therapies (ID 153)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      MA21.07 - Circulating Tumor DNA Analysis Depicts Potential Mechanisms of Resistance to BRAF-Targeted Therapies in BRAF+ Non-Small Cell Lung Cancer (Now Available) (ID 1365)

      14:30 - 16:00  |  Author(s): Julien Mazieres

      • Abstract
      • Presentation
      • Slides

      Background

      Oncogenic BRAF-V600 mutations are observed in 1-2% of non-small cell lung cancer (NSCLC). Targeted therapies including vemurafenib (V), dabrafenib (D) or combination of dabrafenib plus trametinib (D+T) are associated with favorable outcomes in these patients (pts). The mechanisms of resistance to BRAF-targeted therapies (BRAF-TT) in NSCLC are largely unknown.

      Method

      We performed genomic profiling of serial circulating-tumor DNA (ctDNA) in a cohort of 79 metastatic BRAF-mutant NSCLC pts (96% V600E, 4% non-V600). BRAFmutational status was ascertained based on local testing. Plasma samples were collected, from 2014-2018 in 27 Hospitals, from pts treated with V (n=34), D (n=2) or D+T (n=23). We collected 41 plasma samples at baseline to BRAF-TT, 40 at progressive disease (PD) and ~200 samples during treatment follow-up, concomitant to routine radiological evaluation. Inivata InVisionSeq™ assay was used to detect the presence of SNVs, indels and CNAs in 36-cancer related genes.

      Result

      At baseline, 72,5% of BRAF mutations (V600E and non-V600E) were detected in plasma. BRAF-V600E detection in plasma was associated with the presence of liver metastasis, versus BRAF-V600E-negative cases (22% vs. 7%, respectively). Co-occurring molecular alterations at baseline, besides BRAF-V600E, were observed in 18/26 (70%) cases: FGFR2 (1pt), PIK3CA (2pts), ERBB2 (1pt), CTNNB1 (2pts) and IDH1 (2pts). FGFR2, PIK3CA or CTNNB1 alterations were associated with PD as the best response to the subsequent BRAF-TT. TP53 and STK11 mutations were observed in 54% (14/26) and 8% (2/26) of pts, respectively. Complete clearance of BRAF-V600E in plasma at baseline was observed at the first CT-scan evaluation in 42% (3/7) and 82% (9/11) pts treated with V or D+T, respectively. These pts were in complete or partial response, suggesting that monitoring BRAF-V600E levels in plasma on treatment may be a clinically useful marker of tumor response. At PD, a consistent rebound in BRAF-V600E plasma levels was observed in 60% (24/40) pts. Resistance to V was associated with alterations in the MAPK pathway: 1pt (KRAS), 1pt (GNA11), 1pt (NRAS and GNAS) and 1pt (MAP2K1 and NFE2L2). Activating PI3KCA mutations were observed in 4 pts who progressed in <6 months on V treatment. ctDNA analyses at PD under D+T revealed that, similar to what we observed in patients who progressed on V, alterations in KRAS, NRAS, PIK3CA and CTNNB1 are associated with D+T resistance. Prediction of the impact of these alterations, at the protein level, was assessed using in silico structure modeling and will be presented.

      Conclusion

      ctDNA monitoring might be an informative tool for assessing disease response and resistance in NSCLC pts treated with BRAF-TT. MAPK reactivation remains an important resistance mechanism to BRAFi-monotherapy or to BRAFi and MEKi combination therapy.

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    OA02 - A New Vision of Targets and Strategies (ID 120)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      OA02.07 - Phase 3 ALUR Study of Alectinib in Pretreated ALK+ NSCLC: Final Efficacy, Safety and Targeted Genomic Sequencing Analyses (Now Available) (ID 2267)

      10:30 - 12:00  |  Author(s): Julien Mazieres

      • Abstract
      • Presentation
      • Slides

      Background

      The ALUR (NCT02604342) primary analysis (cut-off January 2017) demonstrated improved efficacy and safety with alectinib versus chemotherapy in patients with ALK+ NSCLC previously treated with chemotherapy and crizotinib. These patients can develop crizotinib resistance through ALK secondary mutations, but limited data exist regarding alectinib’s efficacy in patients with different post-crizotinib genetic profiles. We report final data from ALUR including treatment outcomes according to genetic profile.

      Method

      Overall, 119 patients with locally determined ALK+ NSCLC were randomised 2:1 to receive alectinib 600mg bid or chemotherapy (pemetrexed 500mg/m2 or docetaxel 75mg/m2 q3w). The primary endpoint was PFS by investigator. Targeted genomic sequencing (FoundationONE® [tissue; 315 genes] and FoundationACT® [plasma; 62 genes]) was performed retrospectively using tumour tissue (n=33) and baseline plasma (n=59).

      Result

      Final efficacy data confirmed those of the primary analysis (table). Grade ≥3 treatment-emergent adverse events were lower with alectinib (37.7%) than with chemotherapy (43.2%); adverse events causing treatment discontinuation were lower with alectinib (5.2% versus 10.8% chemotherapy), despite alectinib’s longer treatment duration. ALK fusions were confirmed retrospectively in 26/33 (78.8%) tissue and 41/59 (69.5%) plasma (post-crizotinib) samples. ORR in alectinib-treated patients with ALK fusions was 72.2% (13/18, tissue) and 63.0% (17/27, plasma) versus 0% for chemotherapy (tissue [0/8], plasma [0/14]). ALK secondary mutations were detected in 16/59 (27.1%) patients (plasma, both arms). ORR in the alectinib arm (plasma) was similar in patients with ALK fusions with (60.0%, 6/10) or without (64.7%, 11/17) ALK secondary mutations, but lower in patients with gene mutations other than ALK (23.1%, 3/13).

      Conclusion

      Final data from ALUR confirm the primary analysis, demonstrating improved efficacy and safety with alectinib versus chemotherapy in post-crizotinib ALK+ NSCLC. The role of reconfirming ALK status upon sequential ALK inhibitor treatment requires further investigation, due to the limited data and known technical challenges of plasma testing.

      Funding: F. Hoffmann-La Roche Ltd.

      table.jpg

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    OA08 - Advanced Models and "Omics" for Therapeutic Development (ID 133)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Biology
    • Presentations: 1
    • Now Available
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      OA08.05 - Notch Inhibition Overcomes Resistance to Tyrosine Kinase Inhibitors Promoted by Gate-Keeper Mutations in EGFR-Driven Lung Adenocarcinoma  (Now Available) (ID 639)

      11:00 - 12:30  |  Author(s): Julien Mazieres

      • Abstract
      • Presentation
      • Slides

      Background

      EGFR mutated lung adenocarcinoma patients treated with gefitinib and osimertinib showed a therapeutic benefit limited by the appearance of secondary mutations, such as EGFRT790M and EGFRC797S. It has been generally assumed that these secondary mutations render EGFR completely unresponsive to the inhibitors, indicating that the use of single drug to treat efficiently EGFR-driven lung adenocarcinoma might have limited value while a strategy based on combinational drug therapy could be more effective at mitigating the effects of gatekeeper mutations.

      Method

      We have combined the use of EGFR-driven genetic engineered mouse models and patient-derived xenografts, adenocarcinoma cell lines and primary samples from EGFR mutated patients.

      Result

      We uncover here that gefitinib and osimertinib increase STAT3 phosphorylation (pSTAT3) in EGFRT790M and EGFRC797S tumoral cells. Interestingly, we also found that concomitant Notch inhibition with gefitinib or osimertinib treatment induces a pSTAT3-dependent strong reduction in the levels of the transcriptional repressor HES1. Importantly, we show that tyrosine kinase inhibitor resistant tumors, with EGFRT790M and EGFRC797S mutations, are highly responsive to the combined treatment of Notch inhibitors with gefitinib and osimertinib respectively. Finally, in patients with EGFR mutations treated with tyrosine kinase inhibitors, HES1 protein levels increase during relapse and correlate with shorter progression-free survival.

      Conclusion

      Our results show that the Notch pathway plays a major role in the relapse of lung adenocarcinoma patients treated with EGFR TKIs, providing a rationale to treat patients that become resistant to EGFR TKI with a combination of the same TKI and Notch inhibitors.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-108 - PACIFIC-6: A Phase II Study of Durvalumab Following Sequential Chemoradiotherapy in Patients with Stage III, Unresectable NSCLC (ID 2318)

      09:45 - 18:00  |  Author(s): Julien Mazieres

      • Abstract
      • Slides

      Background

      Non-small cell lung cancer (NSCLC) represents 85% of all lung cancers, with ~30% of patients (pts) presenting with Stage III disease. Platinum-based chemoradiotherapy (CRT) has historically been the standard of care (SoC) in this setting, but with poor long-term outcomes. Durvalumab is a selective high-affinity, human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80. The phase III PACIFIC trial assessed durvalumab vs placebo in pts with locally advanced, unresectable, Stage III NSCLC, who did not progress following ≥2 overlapping cycles of platinum-based concurrent CRT (cCRT) (Antonia et al, NEJM 2017; 2018). Significant improvements in progression-free survival (PFS) and overall survival (OS) were observed with durvalumab (HR for PFS, 0.52; 95% CI 0.42–0.65; P<0.001; HR for OS, 0.68; 99.73% CI 0.47–0.997; P=0.0025). This data, along with comparable safety profiles between durvalumab and placebo in PACIFIC, supports the PACIFIC regimen (durvalumab following cCRT) as the new SoC in this setting. However, a proportion of pts are ineligible for cCRT for various reasons, and receive sequential CRT (sCRT) instead. PACIFIC-6 (NCT03693300) will assess the safety, efficacy, and quality of life of durvalumab in NSCLC pts who have not progressed following platinum-based sCRT.

      Method

      PACIFIC-6 is a phase II, open-label, multi-centre study to be conducted in 6 countries across Europe and North America. Pts ≥18 years old, with histologically or cytologically documented Stage III, unresectable NSCLC who have not progressed following platinum-based sCRT, and are ECOG PS ≤2 are eligible for inclusion; enrolment is not restricted to a biomarker-defined population. Approximately 150 pts will receive durvalumab (1500 mg intravenously) every 4 weeks for 24 months or until disease progression. Pts will be divided into 2 cohorts according to PS status. Pts will be assessed every 12 weeks, until death, withdrawal of consent, or the end of the study. The primary objective is to assess the safety and tolerability of durvalumab, as defined by grade 3 and 4 treatment-related adverse events (TRAEs) occurring within 6 months from initiation of durvalumab. Secondary objectives include investigator-assessed efficacy measurements such as PFS, overall response rate, duration of response (according to RECIST v1.1), as well as OS, lung-cancer mortality, and further safety assessments of all AEs and serious AEs. Exploratory objectives include assessment of pt-reported symptoms and quality of life, as well as evaluation of the association of tumour-based biomarkers (including PD-L1 expression and tumour mutational burden) with efficacy. Recruitment is ongoing.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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      P1.01-120 - Immune Checkpoint Inhibitors Versus Second Line Chemotherapy for Patients with Lung Cancer Refractory to First Line Chemotherapy (Now Available) (ID 2662)

      09:45 - 18:00  |  Author(s): Julien Mazieres

      • Abstract
      • Slides

      Background

      Anti Programmed Death-ligand (PD1/PD-L1) directed immune-checkpoint-inhibitors (ICI) are widely used to treat patients with advanced non-small cell lung cancer (NSCLC) who progress after first line chemotherapy. The best strategy after early progression under first line has not been specifically studied

      Method

      We conducted a multicenter, retrospective study including all consecutive NSCLC patients progressing within the first 3 months following introduction of first-line chemotherapy and being treated with second line ICI monotherapy or chemotherapy between March 2010 and November 2017. We analysed the clinicopathological data and outcome under second line chemotherapy vs. second line ICI: progression-free survival (PFS), overall survival (OS), and objective response rate (ORR).

      Result

      We identified 176 patients with refractory disease, 99 who received subsequent immunotherapy and 77 undergoing chemotherapy. The 2 populations were comparable regarding the main prognostic criteria, median age was 60, main histology was adenocarcimoma (68,2%). Compared to chemotherapy, ICI treated patients had a superior OS (logrank test, p=0.03) (Median [95% CI] OS 4.6 [2.8-6.7] versus 4.2 months [3.4-5.9] and a non-significant improvement in ORR (17.2% and 7.9%, respectively, p = 0.072). PFS was not significantly different (1.9 [1.8-2.1] versus 1.6 months [1.4- ; 2.0] (p=0.125). Poor performance status (ECOG PS≥2) and a higher number of metastatic sites (≥3) were associated with poorer prognosis. KRAS-mutated patients did not seem to benefit more from ICI than chemotherapy.

      Table 1 Multivariable analysis of characteristics associated

      n= 175

      OS

      PFS

      Variable

      HR [CI 95%]

      p value

      HR [CI 95%]

      p value

      Treatment

      0.045

      0.040

      Chemotherapy (ref)

      1.00

      1.00

      Immunotherapy

      0.70 [0.49 ; 0.99]

      0.71 [0.51 ; 0.98]

      Number of metastatic location before 2nd line

      0.005

      0.011

      0-1-2 (ref)

      1.00

      1.00

      3 or +

      1.64 [1.16 ; 2.31]

      1.52 [1.10 ; 2.10]

      Performance Status

      0.038

      0 -1

      1.00

      2 - 3 - 4

      1.46 [1.02 ; 2.09]

      Figure 1 : Kaplan Meier curves for Overall Survival for ICI group and CT group

      figure.png

      Conclusion

      ICI appears to be the preferred second-line treatment for patients who are refractory to first line chemotherapy

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-30 - Pioneer Study: Precision Immuno-Oncology for Advanced Non-Small Cell Lung Cancer Patients with PD1/L1 ICI Resistance (ID 1865)

      09:45 - 18:00  |  Author(s): Julien Mazieres

      • Abstract

      Background

      In the management of advanced Non-Small Cell Lung Carcinoma (NSCLC), both PD1/L1 immune checkpoint inhibitors (ICIs) have been shown to increase overall survival (OS) over standard second-line chemotherapy. While this long-term increase in OS is driven by about 20% of patients, others display disease progression during the first weeks (w.). PIONeeR aims to understand, through a strategy based on a comprehensive biomarkers assessment, and overcome, through rescue IO strategies, the resistance to ICIs.

      Method

      Stage IV or recurrent NSCLC patients (n=450), with an archived pre-ICI tumor block, planned for a standard 2nd or 3rd line ICIs monotherapy, will be screened. If eligible, after signing an informed written consent, they will be blood-sampled, every cycle throughout the 18 w. post C1D1, and systematically be re-biopsied (primitive or metastasis tumor) at 6 w. of treatment. Efficacy of ICIs will be assessed by RECIST, after 6, 12 and 18 w. Feces will be self-collected by patients, before and during ICIs, to analyze impact of gut microbiome in resistance to ICIs. Characterization of the specific immune contexture of each patient to potentially predict the efficacy of ICIs will be based on the investigation of tumors and their microenvironment (Immunoscore® IC & Multiplex ImmunoHistoChemistry, Tumor Mutational Burden –T cell clonality- ctDNA investigation), effector immune cells, cytokines and endothelial activation (ELISA-Flow cytometry). Protocol’s legal and ethical authorizations were obtained on February 2018 (NCT03493581), patient inclusions were enhanced on April 2018 with the activation of 3 main centers; 10 satellites centers were opened at Q4 2018, inclusions are expected to be completed at Q4 2020. Patients who will progress between 6 and 18 w. (n=150) will be randomized within a precision immuno-oncology experimental masterprotocol using a Bayesian, adaptive design (4 combinations of PDL1i and NKG2Ai, STAT3i, ATRi or CD73i or a control arm). Legal authorizations were obtained on December 2018 (NCT03833440), the inclusion period is expected to last 24 months, from the beginning of Q2 2019.Descriptive statistics will be used to characterize distributions of marker’s expression and to evaluate their predictive value on treatment response and prognostic value on Progression Free Survival., in both protocols. The primary endpoint of the randomized clinical trial is the 12-week Disease Control Rate, assessed in each arm of treatment.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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    P1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 186)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.16-46 - Genetic Testing Patterns, Treatment Characteristics, and Overall Survival in ALK-Positive Metastatic NSCLC Patients Treated with Ceritinib (ID 1345)

      09:45 - 18:00  |  Presenting Author(s): Julien Mazieres

      • Abstract
      • Slides

      Background

      In patients with ALK-positive metastatic non-small cell lung cancer (mNSCLC), the majority of data on ALK inhibitor (ALKi) use and related survival outcomes are from clinical trials; information from community practice is sparse. This study therefore sought to assess ALK testing patterns, treatment characteristics, and overall survival (OS) in patients with mNSCLC treated with ceritinib in routine practice.

      Method

      In this retrospective cohort study, medical records for patients with ALK-positive mNSCLC (diagnosed during 2008-2016; aged ≥18 years) were selected from sites in Canada and Europe. Patients were treated with ceritinib in any line for mNSCLC and had at least 8 months of follow-up after ceritinib initiation, except for patients who died sooner than 8 months. Baseline patient characteristics, treatment patterns, and timing of ALK testing relative to start of therapy lines were descriptively assessed. OS was assessed using Kaplan-Meier methods.

      Result

      87 patients were selected (median age: 53 years). Nearly 56% of patients had been tested for ALK mutation before initiating the first-line therapy (1L); 72% were tested before 2L and 77% before 3L. The most common regimens were cisplatin/pemetrexed (25%) in 1L, crizotinib (28%) in 2L, and ceritinib (35%) in 3L. Over two-thirds (68%) received treatment with at least 2 ALKis. The most commonly observed ALKi sequences were crizotinib followed by ceritinib (52%), ceritinib only (23%), and crizotinib followed by ceritinib followed by alectinib (12%). Median OS (95% CI) from mNSCLC diagnosis was 39 (33.1-50.1) months. Median OS (95% CI) from treatment initiation was 36 (28.2-48.9) months for 1L, 29 (22.1-42.8) months for 2L, and 23 (14.0-40.5) months for 3L.

      Conclusion

      Only slightly more than half of patients with ALK-positive mNSCLC were tested for ALK mutation before initiating the first-line therapy during the study period. ALKis were the preferred therapies in the second and third lines. Median OS following the first-line therapy initiation was nearly 3 years among the selected study patients.

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