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Maurice Perol
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MA13 - Going Back to the Roots! (ID 139)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 12
- Now Available
- Moderators:Maurice Perol, Kaoru Kubota
- Coordinates: 9/09/2019, 14:00 - 15:30, Vancouver (2003)
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MA13.01 - Associations Between Baseline Serum Biomarker Levels and Cachexia/Pre-Cachexia in Pretreated Non-Small Cell Lung Cancer (NSCLC) Patients (Now Available) (ID 2991)
14:00 - 15:30 | Presenting Author(s): Jeffrey Allen Borgia | Author(s): Gabriela C Lobato, Mary Jo Fidler, Jared D Fialkoff, Maneet Multani, Conner Wakefield, Sanjib Basu, Marta Batus, Philip Bonomi
- Abstract
- Presentation
Background
We previously reported associations of pretreatment serum biomarkers with clinical outcomes in a cohort of advanced NSCLC patients that progressed on front-line therapy. This study aims to elucidate mechanisms underlying cancer cachexia/ pre-cachexia by evaluating relationships between baseline serum biomarker values and sequential changes in body weight, body mass index (BMI), and neutrophil/lymphocyte ratio (NLR) in NSCLC patients.
Method
We used Luminex immunobead assays to survey 101 protein biomarkers in sera from advanced NSCLC (n=138) collected prior to their salvage regimen. Serial parameters associated with cancer cachexia included body weight, BMI, and NLR. Outcome variables (progression-free survival (PFS) and overall survival (OS)) were extracted with full IRB-approval. Biomarkers were evaluated as continuous variables with the cachexia surrogates using Pearson correlations, whereas associations of PFS and OS were accomplished with the Cox PH test.
Result
High baseline values of BMI and low baseline NLR were associated with both OS and PFS (each p<0.05), though weight failed to reach significance. PFS and OS were similarly associated with percent changes (relative to baseline) in weight (p<0.01), BMI (p<0.01), and NLR (p<0.001). Thirteen biomarkers were found to be associated (p<0.05) with baseline BMI values, including positive correlations with leptin, sol.VEGFR2, and c-peptide and inverse correlations with adiponectin, ferritin, ghrelin, IGFBP-1 and IL-8; fifteen biomarkers were associated with baseline NLR (all p<0.05), including positive correlations with visfatin, insulin, and serum amyloid A and inverse correlations with IGF-II. Fifteen biomarkers were found to be associated (p<0.05) in common with percent weight and BMI changes, including positive correlations with IGFBP-3 and inverse correlations with insulin, FGF-2, TNF-alpha, and resistin. Only prolactin and placental growth factor were found to be associated (p<0.05) with percent change in NLR.
Conclusion
A series of circulating protein biomarkers primarily connected with metabolic regulation and systemic inflammation/ acute phase response were found to be associated with cachexia/ pre-cachexia in NSCLC patients. Additional cohorts are currently being tested to verify these findings.
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MA13.02 - Incidence of Venous Thromboembolism at the Time of Lung Cancer Diagnosis: A Multicenter, Prospective Observational Trial (Rising-VTE/NEJ037) (Now Available) (ID 1195)
14:00 - 15:30 | Presenting Author(s): Kosuke Hamai | Author(s): Yukari Tsubata, Naoki Furuya, Tae Hata, Ryota Saito, Takeshi Masuda, Takamasa Hotta, Megumi Hamaguchi, Shoichi Kuyama, Ryoichi Honda, Kikuo Nakano, Masamoto Nakanishi, Kunihiko Funaishi, Masahiro Yamasaki, Nobuhisa Ishikawa, Kazunori Fujitaka, Tetsuya Kubota, Kunihiko Kobayashi, Takeshi Isobe
- Abstract
- Presentation
Background
Venous thromboembolism (VTE) is a most well-known kind of cancer associated thrombosis, and a common complication of malignancy. However, little is known about the incidence of VTE at the time of lung cancer diagnosis. This information is important for clinicians and patients to inform their decision-making about cancer treatment.
Method
The Rising-VTE/NEJ037 study was a multicenter, prospective, observational study with 40 participating Japanese institutions. It included 1,021 patients diagnosed with lung cancer unsuitable for radical resection or radiation between June 2016 and August 2018. The incidence of VTE and characteristics of patients diagnosed with VTE based on contrast-enhanced computed tomography or ultrasonography of the leg are described. Diagnosis of VTE was confirmed via central review by two radiologists.
Result
Baseline data was available for 1,013 patients. The median age was 71 years (range 30-94). Eighty-six percent of patients had non-small cell lung cancer and 13.5% had small cell lung cancer. Histological types included adenocarcinoma (N=645, 63.7%), squamous cell carcinoma (N=180, 17.8%), small-cell lung cancer (N=137, 13.5%) and others (N=42, 4.1%). There were 59 patients (5.8%) diagnosed with VTE, of whom 53.9% had deep vein thrombosis (DVT), 28.7% had pulmonary embolism (PE) and 24.6% had both DVT and PE. Most patients with VTE had adenocarcinomas (89.1%).
Conclusion
The incidence of VTE in this study seems to be higher than in the clinical setting, suggesting that screening may be desirable. Adenocarcinoma of the lung seems to be a risk factor for VTE that we should consider more carefully. The primary endpoint of this trial is the rate of symptomatic or asymptomatic recurrence or newly diagnosed VTE during 2 years after registration. Follow-up is ongoing, with a report of final findings planned for 2021. Clinical trial information: UMIN000020194. Funding: Daiichi Sankyo Company.
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MA13.03 - Retrospective Study of Intrathecal Therapy for Non-Small Cell Lung Cancer (NSCLC) Patients with Leptomeningeal Carcinomatosis (Now Available) (ID 2086)
14:00 - 15:30 | Presenting Author(s): Noelia Vilariño | Author(s): Juan Antonio Marín, Marta Simó, Roser Velasco, Montserrat Alemany, Maria Jove, Jose Carlos Ruffinelli, Isabel Brao, Monica Arellano, Ramon Palmero Sánchez, Jordi Bruna, Ernest Nadal
- Abstract
- Presentation
Background
Leptomeningeal carcinomatosis (LMC) is a devastating cancer-related neurological complication with poor prognosis. In EGFR-mutant (mut) NSCLC patients (pts), osimertinib achieves high penetration into cerebral-spinal fluid (CSF) and promising efficacy. However, for EGFR-mut T790M-negative pts treated with prior 1st- and 2nd-generation tyrosine kinase inhibitors (TKI) and for driver negative NSCLC pts, a combination of intrathecal therapy (IT) and systemic therapy (ST) seems to be an appropriate approach. Our purpose is to explore the clinical outcome of IT combined with ST among NSCLC with LMC depending on EGFR status.
Method
NSCLC pts with LMC treated with IT in our institution between 2010 and 2018 were retrospectively studied. After LMC diagnosis, intrathecal methotrexate (scheduled: 12mg twice weekly for 4 weeks, then 12mg weekly for 4 weeks) was given in combination with ST. A Kaplan-Meier survival analysis was performed for overall survival (OS) and progression free survival (PFS).
Result
A total of 39 pts were included. Patient’s clinical characteristics are summarized in table 1. EGFR status was 17 mut (del19: 11pts); 11 wild-type (wt) and 11 unknown (unk). LMC and NSCLC diagnosis were more likely to be synchronous in EGFR wt compared with EGFR mut. The median follow-up from LCM diagnosis was 10.2 months. At the time of this analysis, only 6 pts were alive. Thirty-two pts received ST in combination with IT, 18 (46%) pts chemotherapy (6wt/ 3mut/ 9unk), while 14 (36%) pts an EGFR TKI (1wt/ 13mut). Clinical response (improvement of neurological symptoms and/or KPS) was seen in 11 (65%) EGFR mut pts vs 2 (18%) wt pts (p=0.033). Median OS and PFS for the whole cohort were 23 weeks (95%CI, 8.1 to 37.9) and 10 weeks (95%CI, 7.1 to 12.8) respectively. Median OS was higher for EGFR mut pts compared to wt pts, 38 weeks (95%IC 13.6-62.4) and 19 weeks (95%IC, 4.06-33.9) respectively, however this difference was not statistically significant (p=0.36) probably due to lack of statistical power.
Conclusion
Methotrexate-based IT given concurrently with systemic TKI may confer a higher clinical benefit and a trend toward OS benefit in NSCLC patients with LCM and EGFR activating mutations.
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MA13.04 - Discussant - MA13.01, MA13.02, MA13.03 (Now Available) (ID 3776)
14:00 - 15:30 | Presenting Author(s): Ramaswamy Govindan
- Abstract
- Presentation
Abstract not provided
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MA13.05 - Nab-Paclitaxel Maintenance in Squamous Non-Small Cell Lung Cancer (NSCLC): Updated Results of the Phase III ABOUND.sqm Study (Now Available) (ID 294)
14:00 - 15:30 | Presenting Author(s): David R Spigel | Author(s): Robert M Jotte, Santiago Ponce Aix, Laurent Gressot, Daniel Morgensztern, Michael McCleod, Mark A Socinski, Davey Daniel, Oscar Juan, Kathryn F Mileham, HOWARD WEST, Ray Page, Niels Reinmuth, Jeanna Knoble, Olivia Yu Tian, Rafia Bhore, Marianne Wolfsteiner, Teng Jin Ong, Cesare Gridelli, Michael Thomas
- Abstract
- Presentation
Background
Background: nab-Paclitaxel maintenance therapy after nab-paclitaxel/carboplatin induction in patients with advanced squamous NSCLC was evaluated in the phase III, randomized, controlled, open-label, multicenter ABOUND.sqm trial. At the 12-month follow-up, there was no statistically significant difference in progression-free survival (PFS) between patients randomized to maintenance nab-paclitaxel + best supportive care (BSC) vs BSC alone. However, a trend of an overall survival (OS) advantage was observed with nab-paclitaxel + BSC vs BSC alone. Here we report the 18-month follow-up of OS.
Method
Methods: Patients (aged ≥ 18 years) with histologically or cytologically confirmed stage IIIB/IV squamous NSCLC and no prior chemotherapy were eligible. Patients received four 21-day cycles of nab-paclitaxel 100 mg/m2 (days 1, 8, and 15) plus carboplatin AUC 6 (day 1) as induction. Patients with radiologically assessed complete or partial response or stable disease without clinical progression after 4 cycles were randomized 2:1 to maintenance nab-paclitaxel 100 mg/m2 (days 1 and 8 of each 21-day cycle) plus BSC or BSC alone until disease progression. The primary efficacy analysis was performed on the ITT population. PFS from randomization into the maintenance part of the study was the primary endpoint. Secondary endpoints included safety, OS (from randomization), and response.
Result
Results: 420 patients received induction therapy; 202 were randomized to maintenance nab-paclitaxel + BSC (n = 136) or BSC alone (n = 66). The median PFS in patients in the nab-paclitaxel + BSC arm vs those in the BSC-alone arm was 3.1 vs 2.6 months (HR, 0.85; P = 0.349), respectively; the median OS was 17.8 vs 12.2 months (HR, 0.71; P = 0.058), respectively. The overall response rate was 69.1% vs 57.6% (RRR, 1.20; P = 0.087). Following the maintenance part, 73.5% (nab-paclitaxel + BSC) and 68.2% (BSC alone) of patients received subsequent anti-cancer treatment. Over the entire study, the most frequent grade 3/4 TEAEs were neutropenia (53.1% vs 50.0%) and anemia (33.1% vs 32.3%); only peripheral neuropathy occurred in ≥ 5% of patients during maintenance (13.1% in the nab-paclitaxel + BSC arm).
Conclusion
Conclusion: Although PFS and OS differences were not statistically significant in the ITT population, the 18-month follow-up of OS demonstrated the feasibility of nab-paclitaxel maintenance therapy for patients with anced squamous NSCLC.
ClinicalTrials.gov identifier: NCT02027428
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MA13.06 - Ph3 Study of Maintenance Therapy with S-1 vs BSC After Induction Therapy with Carboplatin + S-1 for Advanced Squamous Cell Lung Cancer (WJOG7512L) (Now Available) (ID 563)
14:00 - 15:30 | Presenting Author(s): Kaoru Tanaka | Author(s): Satoshi Morita, Masahiko Ando, Takuma Yokoyama, Atsushi Nakamura, Hiroshige Yoshioka, Takashi Ishiguro, Satoru Miura, Ryo Toyozawa, Tetsuya Oguri, Haruko Daga, Ryo Ko, Akihiro Bessho, Motoko Tachihara, Yasuo Iwamoto, Katsuya Hirano, Yoichi Nakanishi, Kazuhiko Nakagawa, Nobuyuki Yamamoto, Isamu Okamoto
- Abstract
- Presentation
Background
Our previous phase 3 study established carboplatin plus the oral fluorinated pyrimidine formulation S-1 as a standard option for first-line treatment of advanced non–small cell lung cancer (NSCLC) (J Clin Oncol 2010; 28:5240). The importance of maintenance therapy for patients with advanced squamous NSCLC has been unknown, however.
Method
WJOG7512L was designed as a randomized phase 3 study to evaluate whether maintenance therapy with S-1 improves clinical outcome after induction therapy with carboplatin plus S-1 in such patients. Before randomization, patients received carboplatin (AUC of 5 on day 1 every 3 weeks) plus S-1 (40 mg/m2 twice per day on days 1 to 14 every 3 weeks) as induction therapy. Those who did not progress after four cycles of induction therapy were randomized to receive either S-1 plus best supportive care (BSC) or BSC alone. The primary objective was to confirm the superiority of S-1 plus BSC with regard to progression-free survival.
Result
Of the 365 patients enrolled, 347 participated in the induction phase and 131 of these individuals were randomized to receive S-1 plus BSC (n = 67) or BSC alone (n = 64). Baseline demographics and clinical characteristics of the subjects, including the response to induction therapy, were well balanced. Patients receiving S-1 plus BSC showed a significantly reduced risk of disease progression compared with those receiving BSC alone (hazard ratio [HR], 0.548; 95% confidence interval [CI], 0.374–0.802; P = 0.0019). Median overall survival from randomization did not differ significantly between the two arms: 17.8 months for BSC alone and 16.7 months for S-1 plus BSC (HR, 0.890; 95% CI, 0.583–1.357). Time to deterioration in quality of life also showed no significant difference (P = 0.8754 for FACT-TOI, P = 0.9016 for FACT-LCS). The incidence of adverse events during maintenance therapy was low, with neutropenia, anemia, and thrombocytopenia of grade 3 or 4 each occurring in ~1% to 4% of patients.
Conclusion
Maintenance with S-1 plus BSC is an effective and well-tolerated treatment option for patients with advanced squamous NSCLC.
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MA13.07 - Phase I/II Study of Carboplatin Plus Weekly Nab-Paclitaxel in Aged ≥75 Patients with Squamous-Cell Lung Cancer: TORG1322 (Now Available) (ID 1369)
14:00 - 15:30 | Presenting Author(s): Yoshitaka Zenke | Author(s): Seiji Niho, Shigeki Umemura, Masashi Ishihara, Ryosuke Ochiai, Naoyuki Nogami, Yukio Hosomi, Tsuneo Shimokawa, Takaaki Tokito, Yasushi Goto, Yosuke Miura, Haruhiro Saito, Naoya Hida, Satoshi Ikeda, Hiroshi Tanaka, Naoki Furuya, Toshihiro Misumi, Yuichiro Ohe, Hiroaki Okamoto
- Abstract
- Presentation
Background
Combination chemotherapy of carboplatin (CBDCA) plus weekly nab-paclitaxel (nab-PTX) showed a favorable efficacy for elderly (70 year or older) patients with squamous non-small cell lung cancer (Sq-NSCLC) in a subgroup analysis of the CA031 study. We conducted a phase I/II study of CBDCA plus nab-PTX in chemo-naïve elderly patients with advanced Sq-NSCLC.
Method
Patients aged ≥75 years with untreated, measurable lesion, advanced Sq-NSCLC, performance status (PS) 0-1, and adequate organ function were eligible. In a phase I study, doses of carboplatin at an area under the curve (AUC) of 5 or 6 mg/mL min on day 1 (levels 1 and 2, respectively) were administered along with weekly nab-PTX (100 mg/m2) on days 1, 8, and 15 every 4 weeks up to 6 cycles using a modified 3 + 3 design. The primary endpoint for the phase II study was the 6-month progression-free survival (6m PFS) rate and hypothesis required 36 patients to be enrolled with expecting and threshold values for the primary endpoints of 40% and 25% (one-sided alpha = 0.05; beta = 0.2).
Result
A total of 46 patients were enrolled in this study. The median age was 78 (range 75-85 years); male (n = 41); PS 0/1, (n = 15/31). Ten patients were enrolled in the phase I part. At dose level 1, 2/7 patients showed dose-limiting toxicities (DLTs) of grade 3 diarrhea and febrile neutropenia, and at dose level 2, 1/3 patient showed DLT of grade 3 anorexia. The recommended dose was determined to be level 2. Additional 36 patients were enrolled, and a total of 39 patients were evaluated in the phase II study. The median number of cycles was 4 (range 1-6), and the median follow-up time was 17.5 months (range 5.6-28.9). The 6m PFS rate was 59% (90% CI, 44.8-71.4), and the primary endpoint was met. The median overall survival time was 23.5 months (95% CI, 11.6-35.4), and the median PFS was 6.8 months (95% CI, 5.4-9.1). The response rate was 54% and disease control rate was 92%. Nineteen patients (49%) received post-study treatment and 14 out of 19 patients (74%) received immunotherapy. Common toxicities of grade 3 or 4 were neutropenia (61.5%), anemia (46.2%), thrombocytopenia (17.9%), and febrile neutropenia (15.4%). There was no treatment-related death.
Conclusion
Combination chemotherapy of CBDCA plus weekly nab-PTX had a promising efficacy and acceptable toxicities in elderly (aged ≥75) patients with advanced Sq-NSCLC. Clinical trial information: UMIN000011216.
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MA13.08 - Discussant - MA13.05, MA13.06, MA13.07 (Now Available) (ID 3775)
14:00 - 15:30 | Presenting Author(s): Karen L Reckamp
- Abstract
- Presentation
Abstract not provided
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MA13.09 - Cisplatin Sustains Lung Cancer Metastasis Through the Systemic Activation of SDF-1/CXCR4 Axis (Now Available) (ID 2821)
14:00 - 15:30 | Presenting Author(s): Giulia Bertolini | Author(s): Valeria Cancila, Claudio Tripodo, Gabriella Sozzi, Giuseppe Lo Russo, Orazio Fortunato, Massimo Milione, Giovanni Centonze, Monica Tortoreto, Stefania Scala, Luca Roz
- Abstract
- Presentation
Background
Standard chemotherapy regimens have limited long-term efficacy in lung cancer patients due to chemoresistance and inefficacy in controlling metastatic disease. In pre-clinical models we have shown that cisplatin treatment enriches for the chemoresistant fraction of CD133+CXCR4+ lung cancer metastasis initiating cells (MICs), increasing distant metastasis development that can be prevented by CXCR4 blockade. Therefore, we hypothesize that the SDF-1/CXCR4 axis, implied in MICs maintenance/migration and in immune and stromal cells trafficking, could play a critical role in cisplatin-induced pro-metastatic effects.
Method
To study the effects of cisplatin in promoting a pre-metastatic niche, naïve SCID mice were treated with cisplatin plus/minus peptide R (5mg/kg), a novel inhibitor of CXCR4 and after 72h injected intravenously with metastatic H460 cell line. To assess the effect of the combination treatment in pre-clinical model, H460 subcutaneous xenografts were treated with cisplatin alone or with peptide R for three weeks. Content of MICs in xenografts, number and phenotype of lung metastasis and immune cells modulationt were evaluated by FACS and IHC
Result
We showed that cisplatin treatment of naïf SCID mice resulted in a rapid BM expansion of the subset of CCR2+CXCR4+Ly6Chigh inflammatory monocytes (IM), concomitantly with their recruitment to murine lungs guided by increased level of SFD-1 released by PDGFRβ+ stromal cells in response to cisplatin. Peptide R partially prevented these effects.
Tail-vein injection of H460 human lung cancer cells 72h after cisplatin administration resulted in augmented number of lung metastases (p=0.003), that showed a 3.5-fold enrichment in CD133+CXCR4+ MICs (p=0.005) and increase of IM and derived macrophages. Pre-treatment with peptide R abolished these effects. We verified that the abundance of CXCR4+CCR2+IM together with increased endothelial permeability caused by cisplatin may favor tumor cells extravasations and expansion of MICs through SDF-1/CXCR4 axis activation which determined metastasis overgrowth.
SDF-1 was also increased in cisplatin-treated subcutaneous H460 xenografts that expanded the subset of chemoresistant CD133+CXCR4+ MICs and recruited CXCR4+tumor associated macrophages which may allow MICs to escape primary tumor. At the metastatic site cisplatin treatment of H460 xenografts caused an increase in stromal SDF-1 and recruitment of both CXCR4+ inflammatory monocytes/macrophages (1.6-fold change p=0.01) and MICs subset (1.8-fold change p=0,04), overall resulting in a boost in micrometastases. CXCR4 inhibition prevented the co-recruitment and cross-talk of MICs and IM at distant site, counteracting the pro-metastatic effects of cisplatin.
Matched case series of stage III chemo-naive NSCLC patients and cisplatin-based neo-adjuvant treated patients demonstrated a significant increased in SDF-1 after chemotherapy (p=0,0001). An high expression of tumoral SDF-1 ( Score: staining intensity x % positive tumor cells >6) induced by cisplatin neo-adjuvant treatment was associated with a shorter DFS (p=0,0056) and poor OS (p=0,029).
Conclusion
Conclusions: Our data reveal a paradoxical pro-metastatic effect of cisplatin that fosters MIC-IM recruitment and cross-talk via SDF-1/CXCR4 axis activation. A new combination strategy based on CXCR4 inhibition may disrupt these interactions, providing more effective and long-lasting results for lung cancer treatment
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MA13.10 - A Phase II Study of Carboplatin and Nab-Paclitaxel for Advanced Non-Small Cell Lung Cancer with Interstitial Lung Disease (HOT1302) (Now Available) (ID 990)
14:00 - 15:30 | Presenting Author(s): Hiroshi Yokouchi | Author(s): Hajime Asahina, Satoshi Oizumi, Kei Takamura, Toshiyuki Harada, Masao Harada, Kenya Kanazawa, Yuka Fujita, Tetsuya Kojima, Fumiko Sugaya, Hisashi Tanaka, Ryoichi Honda, Takahiro Ogi, Eiki Kikuchi, Tomoo Ikari, Hirotoshi Dosaka-Akita, Hiroshi Isobe, Masaharu Nishimura
- Abstract
- Presentation
Background
Because of the high risk of exacerbation of pre-existing interstitial lung disease (ILD), patients with concomitant advanced non-small cell lung cancer (NSCLC) and ILD have been excluded from most clinical trials of chemotherapy, despite the high prevalence (around 10%) of all NSCLC cases. This study prospectively evaluated the efficacy and safety of albumin-bound paclitaxel (nab-paclitaxel) in combination with carboplatin in advanced NSCLC patients with pre-existing ILD.
Method
Enrolled patients had treatment-naïve, advanced NSCLC with pre-existing ILD. Patients received 100 mg/m2nab-paclitaxel weekly and carboplatin at area under the concentration-time curve (AUC) 6 once every 3 weeks for 4-6 cycles. The primary endpoint was overall response rate (ORR); secondary endpoints included toxicity, progression-free survival (PFS) and overall survival (OS). The interactions between histology [Squamous (Sq) vs. Non-Squamous (Non-Sq)] and treatment outcomes were also investegated.
Result
Thirty-six patients were enrolled between April 2014 and September 2017. Sixteen patients (44.4%) had an adenocarcinoma, followed by 15 (41.7%) squamous cell carcinoma, and 5 (13.9%) non-small cell carcinoma. The median number of cycles administered were 4 (range: 1-6). The ORR, the primary endpoint, was 55.6% (95% confidence interval [CI]: 39.6-70.5%). The median PFS and OS were 5.3 months (95% CI: 3.9-8.2 months) and 15.4 months (95% CI: 9.4-18.7 months), respectively. There was no significant difference between two groups, however, numerically better treatment outcomes were observed in the Sq group: the ORR was 66.7% (95% CI: 41.7–84.8%) in the Sq group compared with 47.6 % (95% CI: 28.3–67.6%) in the Non-Sq group (P =0.254); median PFS was 8.2 months (95% CI: 4.0–10.2 months) in the Sq group vs. 4.1 months (95% CI: 3.3-5.4 months) in the Non-Sq group (HR, 0.60 [95% CI, 0.30–1.20]; p=0.15); median OS was 16.8 months (95% CI: 9.8 months–not reached) in the Sq group vs. 11.9 months (95% CI: 7.3-17.4 months) in the Non-Sq group (HR, 0.56 [95% CI, 0.24–1.28]; p=0.17). Two patients (5.6%) experienced grade ≥2 pneumonitis and one patient (2.8%) died.
Conclusion
This is the first prospective phase 2 study of weekly nab-paclitaxel in combination with carboplatin in advanced NSCLC patients with pre-existing ILD. This treatment showed favorable efficacy and was well tolerated.
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MA13.11 - A Randomized Phase III Study of Cisplatin-Polymeric Micelle Paclitaxel vs Cisplatin-Solvent-Based Paclitaxel in 1st Line Advanced NSCLC (Now Available) (ID 696)
14:00 - 15:30 | Presenting Author(s): Yi-Long Wu | Author(s): Baohui Han, Meiqi Shi, Haiyan Tu, Aiqin Gu, Cheng Huang, Huijuan Wang, Zhuang Yu, Xiuwen Wang, Lejie Cao, Yongqian Shu, Huaqing Wang, Runxiang Yang, Xingya Li, Jianhua Chang, Yanping Hu, Peng Shen, Yi Hu, Zhongliang Guo, Min Tao, Yiping Zhang, Xunyan Liu, Qian Sun, Xin Zhang, Zuguang Jiang, Junhui Zhao, Feng Chen, Jing Sun, Duan Li, Jinsong Zhou
- Abstract
- Presentation
Background
Cisplatin-sb-Pac is the one of current standard of chemotherapy in aNSCLC, It produced 15% to 32% objective response rate (ORR) and 7.9 to 10.6 months of median overall survival (OS). Alternative nab-paclitaxel to sb-Pac only increased ORR but not improved progression-free survival (PFS) and OS. Thus the unmet medical need for new chemo regimen remains.
Method
From May 2015 to Jan 2018 448 untreated patients (pts) with stage IIIB to IV NSCLC from 24 sites were randomly assigned 2:1 to receive 230 mg/m2 pm-Pac and cisplatin 70 mg/m2 on day 1 of a 3-week cycle, and then dose escalation of pm-Pac to 300 mg/m2 from the second cycle if no prespecified toxic effects observed or 175 mg/m2 sb-Pac plus cisplatin 70 mg/m2 once every 3 weeks. Pts were stratified by stage and histology. The primary end point was ORR by Independent review committee (IRC) and Investigator (INV) in the intent-to-treat population. The second endpoints included PFS, OS and safety. Data cutoff was Jan 26, 2019.
Result
300 pts were assigned to pm-Pac and 148 to sb-Pac. Baseline characteristic were balance in both arms. Nonsquamous carcinoma (non-squ) and stage IV were 57.3% and 81.0% in pm-Pac and 58.1% and 81.8% in sb-Pac respectively. 73.2% pts in pm-Pac arm escalated their dose to 300mg/m2, 0.7% down to 184mg/m2. ORR and PFS in pm-Pac were significant better than that in sb-Pac (table 1). OS was immature. For histology subgroup the ORR was 58.6% v 37.1% (P=0.0054) in squamous carcinoma (Squ) and 44.2% v 18.6% (P<0.0001) in non-squ. Grade ≥3 AEs was 80.0% for pm-Pac and 79.7% for sb-Pac. No new safety issues were identified.
Conclusion
The phase 3 trial met its primary endpoint. pm-Pac significantly improved ORR and PFS than sb-Pac, and pm-Pac regimen should be a new standard chemo for aNSCLC. (NCT 02667743).
Tab. Efficacies comparison between pm-Pac and sb-Pac
pm-Pac
sb-Pac
P value
ORR % (95% CI)
IRC
INV
50.3 (44.5-56.1)
52.0 (46.2-57.8)
26.4 (19.5-34.2)
28.4 (21.3-36.4)
<0.0001
<0.0001
PFS (months)
6.4 (6.2-6.9)
5.3 (4.6-6.0)
HR 0.66 (0.52-0.84), P=0.0006
OS at 12 months
67.3%
61.8%
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MA13.12 - Discussant - MA13.09, MA13.10, MA13.11 (Now Available) (ID 3774)
14:00 - 15:30 | Presenting Author(s): Lyudmila Bazhenova
- Abstract
- Presentation
Abstract not provided
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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: 1
- Now Available
- Moderators:Oscar Gerardo Arrieta, Reyes Bernabe
- Coordinates: 9/08/2019, 10:30 - 12:00, Hilton Head (1978)
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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.
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MA07 - Clinical Questions and Potential Blood Markers for Immunotherapy (ID 125)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:David R Spigel, Roberto Ferrara
- Coordinates: 9/08/2019, 13:30 - 15:00, Vancouver (2003)
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MA07.05 - Immune Checkpoint Inhibitor (ICPi) Re-Challenge: Outcomes Analysis in a French National Cohort of Non-Small-Cell Lung Cancer (NSCLC) Patients (Now Available) (ID 1903)
13:30 - 15:00 | Author(s): Maurice Perol
- Abstract
- Presentation
Background
Anti-PD1/PDL1 deeply changed the NSCLC therapeutic algorithm in the past few years. Unfortunately, a majority of patients experiences disease progression. ICPis re-challenge could be an attractive option but no data supporting this strategy are available. Here we report outcomes of a large cohort of NSCLC patients treated with anti-PD1/PDL1 re-challenge.
Method
We retrospectively collected data about 144 advanced NSCLC patients (diagnosis between 2010 and 2018) from 26 French centers. Patients were re-challenged with ICPis after at least 12 weeks of discontinuation for toxicity, disease progression or clinical decision. Progression Free Survival (PFS) and Overall Survival (OS) were calculated from the start of first or second ICPi to disease progression (PFS1;PFSR) and death or last follow-up (OS1;OS2) respectively.
Result
Median age was 63 year [39 –83], most of patients were male (67%), smokers (87%), adenocarcinomas (62%) and stage IV at diagnosis (66%). Most of patients received the first ICPi round in first or second line (66%) and the second ICPi round in third line or later (79%). In both settings patients received preferentially an anti-PD1 (87%) and no differences were detected regarding brain metastasis or ECOG PS (P = 1.10-1 and P = 1.10-1 respectively). The Best Response during the re-challenge was not associated to that one achieved to the first ICPi (P = 1.10-1). The median PFS1 and PFSR were 13 months [95% CI 10-16.5] and 4.4 months [95% CI 3-6.5] respectively. PFSR was longer in patients discontinued because of clinical decision (6.5 months [95% CI 2.5-11.9]) or toxicity (5.8 months [95%CI 3.5-18]) compared to disease progression (2.9 months [95% CI 2.0-4.4]) (P = 2.10-2) and in those not receiving chemotherapy between the two ICPis (5.8 months [95%CI 4.1-10.5]) compared to those who did (3.0 months [95% CI 2.0-4.4])(P = 2.10-3). Median OS1 was 3.3 years [95% CI 2.9-3.9] without differences according to the discontinuation reason (P =2.10-1). Median OS2 was 1.5 y [95%CI 1.0-2.1] and was longer in patients discontinuing the first ICPi due to toxicity (2.1y [95%CI 1.4-NR]) compared to disease progression (1.0y [95%CI 0.4-1.5]) or clinical decision (1.5y [95%CI 0.4-NR]) (P = 3.10-2). Neither OS1 nor OS2 were affected by treatments received between the two ICPis (P = 3.10-1 and P = 1.10-1 respectively).
Conclusion
ICPis re-challenge might be a useful option mainly in patients discontinuing the first ICPi because of toxicity or clinical decision and in those able to keep a treatment-free period between the two ICPis.
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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
- Moderators:Benjamin Besse, Michael Thomas
- Coordinates: 9/10/2019, 14:30 - 16:00, Vienna (2016)
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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): Maurice Perol
- Abstract
- Presentation
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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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-116 - Early Immune-Related Adverse Events Under PD-1/PD-L1 Inhibitors Predict Better Progression-Free Survival in NSCLC (ID 1932)
09:45 - 18:00 | Author(s): Maurice Perol
- Abstract
Background
Immune checkpoint blockers (ICB) targeting the PD-1/PD-L1 axis improve survival in patients with advanced non-small-cell lung cancer (NSCLC) without oncogenic addiction; however, they are also responsible for immune-related adverse events (irAE) sometimes leading to treatment discontinuation. Despite a clear association with response to ICB in melanoma, the predictive significance of a better outcome for irAE in NSCLC is unclear.
Method
We retrospectively collected clinical and basic biological data from 160 stage IV NSCLC patients who received nivolumab, pembrolizumab or atezolizumab as second-line single agent in two cancer centers in France between January 2015 and December 2017. All irAE were collected using the Common Terminology Criteria for Adverse Events v5.0 ; general symptoms (e.g. fatigue) and cancer-related symptoms were discarded. We used two different statistical approaches to evaluate whether early irAE (≤ 12 weeks) were correlated to a better progression-free survival: i- a 12-week landmark method, including a multivariate Cox proportional hazards model (with ECOG PS and PD-L1 as covariates), ii- a propensity score matching (PSM) method, using PD-L1 level as the matching variable, followed by a Cox proportional hazards model. Finally, we investigated whether grade and number of early irAE were associated with improved PFS.
Result
Most patients were male (n=107; 66.3%), smokers (n=146; 91.3%) and ECOG PS 0-1 (n=121; 75.7%) and received ICB as second (n=96; 60%), third line (n=38; 23.8%) or more (n=22; 13.8%). Nivolumab was the most used ICB (n=145; 90.6%). Within the first 12 weeks of treatment, 46 irAE occurred in 30 patients (18.8%), including 3 grade 3 irAE (1 pneumonitis, 1 myocarditis, 1 renal failure). Musculoskeletal (8.8%) and skin toxicity (5%) were the most frequent irAE. Clinical baseline characteristics were comparable between patients displaying early irAE (irAE+) and those who did not (irAE-), except for ECOG status (71.5% of PS 0-1 patients in irAE- group versus 93.3% in irAE+, p = 0.023) and PD-L1 level (PD-L1 ≥ 50% in 13.1% of patients in irAE- group versus 30.0% of patients in the irAE+ group, p = 0.016). The 12-week landmark analysis included 80 patients; 23/80 (28.8%) of them experienced at least 1 early irAE. PFS was improved in the irAE+ group in both univariate (HR = 0.24 [0.11-0.53], p < 0.001), and multivariate Cox models (HR = 0.33 [0.14-0.76] p = 0.009). After matching irAE+ and irAE- patients on PD-L1 level, early irAE were still associated with prolonged PFS (HR = 0.29 [0.15-0.57], p = 0.001). In the 12-week landmark population, grade ≥2 irAE were associated with even longer PFS (HR = 0.43 [0.26-0.71], p = 0.0009), and so were multiple co-occurring early irAE (HR = 0.30 [0.15-0.60], p = 0.0007).
Conclusion
Early occurrence of irAE before 12 weeks appears to be associated with prolonged response to ICBs, independently of PD-L1 baseline expression in advanced NSCLC.
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P1.01-124 - Health-Related Quality of Life (HRQoL) Data in a Phase 3 Study of First-Line Brigatinib vs Crizotinib in NSCLC (ALTA-1L) (ID 507)
09:45 - 18:00 | Author(s): Maurice Perol
- Abstract
Background
Results from ALTA-1L (NCT02737501) showed that brigatinib vs crizotinib as first-line ALK therapy significantly improves progression-free survival (PFS; HR: 0.49, 95% CI, 0.33, 0.74) in advanced ALK+ NSCLC. HRQoL was evaluated as a secondary objective.
Method
ALK+ NSCLC patients were randomized 1:1 to brigatinib or crizotinib as first-line ALK therapy. HRQoL was assessed with the EORTC QLQ-C30 and LC13. Change from baseline, duration of improvement, and time to worsening were analyzed in the ITT-PRO population (n=131 for both groups).
Result
HRQoL compliance was >90% for both groups. Brigatinib substantially improved overall HRQoL vs crizotinib, as demonstrated by the estimated mean difference on change from baseline (4.1, P<0.05; Figure 1) and duration of improvement for GHS/QoL (HR=0.16, P<0.001; Figure 2), which was also supported by improvement in several functional domains and symptoms (Figure 1). No domains significantly favored crizotinib. Similar results were also observed in patients with baseline CNS metastases.
Conclusion
Consistent with the prolongation of PFS seen in first-line treatment of advanced ALK+ NSCLC, brigatinib improved HRQoL and prolonged the duration of improvement in GHS/QoL, and the majority of functional and symptom domains vs crizotinib.
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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): Maurice Perol
- 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
