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David R Spigel

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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: 12
    • Now Available
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      MA07.01 - Circulating Immature Neutrophils, Tumor-Associated Neutrophils and dNLR for Identification of Fast Progressors to Immunotherapy in NSCLC (Now Available) (ID 1618)

      13:30 - 15:00  |  Presenting Author(s): Laura Mezquita  |  Author(s): Patricia Martin-Romano, Edouard Auclin, Boris Duchemann, Lydie Cassard, David Planchard, Marie Naigeon, Ithar Gataa, Melinda Charrier, Roberto Ferrara, Lisa Boselli, Jonathan Grivel, Maud Ngocamus, Julien Adam, Nathalie Chaput, Benjamin Besse

      • Abstract
      • Presentation
      • Slides

      Background

      Neutrophils are active regulators of the antitumor immune response, with pro- and antitumor- properties, but generally are associated with progression (PD) and poor outcomes. We reported that pretreatment dNLR ((neutrophils/[leucocytes-neutrophils]; high>3) correlated with immune checkpoint inhibitor (ICI) outcomes in advanced (a) NSCLC pts. Although neutrophil population is heterogeneous, the immature neutrophils (i.e. CD15+CD244-CD16low, among others) seem to be a key subpopulation linked to PD. Tumor-associated neutrophils (TAN) can be also modulator on the microenvironment. We aimed to assess the role of pretreatment circulating immature-neutrophils and tissue-TAN, combined with dNLR, on ICI outcomes in aNSCLC pts.

      Method

      aNSCLC pts treated with ICI at our institution between 11/2012 and 08/2018 were eligible. Pretreatment immunophenotyping of monocytes, monocytic MDSC (mMDSC) and granulocytes (CD15, CD11b, CD33, CD244, CD16, CD14, CD32, CD64, HLA-DR) was prospectively performed by flow cytometry in fresh whole blood in 58 pts; we defined immature-neutrophils as CD15+CD244-CD16low. TAN in the stroma were assessed using H&E staining from archival specimen, available from 80 pts. dNLR was retrospectively collected; available from 343 pts. Correlation between baseline circulating neutrophils phenotype, TAN and dNLR was evaluated as well as their impact on outcomes: progression-free survival (PFS), overall (OS), including death before 12 weeks (12wk-death) (fast-PD)

      Result

      366 pts included; 320 (90%) smokers, median age 63; 280 (77%) nonsquamous, 117 (64%) ≥1%PDL1 and 183 missing. Median PFS (mPFS) was 1.93 months (m) [95%CI, 1.8-2.3] and mOS 8.8m [6.5-11.6]. Overall, 12wk-death rate was 31% [25.9-35.6].

      Pretreatment high-dNLR (143/343; 42%) was correlated with poor PFS (P=0.002), OS P=0.0003) and a 12wk-death rate of 43% [34.5-50.9]. Pretreatment high immature-neutrophils (30/58; 53%), defined by logrank maximization method (>0.22%), were also associated with poor PFS (P=0.04), OS (P=0.0007) and a 12wk-death rate of 48.7% [26.7-64.1]. TAN (9/80; 11%) were not correlated with outcomes. There was not a correlation between immature-neutrophils, tissue-TAN and dNLR.

      When evaluating pretreatment immature-neutrophils and dNLR together, we identified a fast-PD phenotype (high immature-neutrophils/high-dNLR, 10/58; 17%), with a mOS of 1.3m [0.73- not reached (NR)] and 12wk-death rate of 60% [14.5-81.3] compared to a responder-phenotype (low immature-neutrophils/low-dNLR, 12/58; 21%), associated with good outcomes: mOS NR [18.23-NR] (P=0.002).

      Conclusion

      Pretreatment high circulating immature-neutrophils (CD15+CD244-CD16low) correlate with early failure to ICI and fast-PD phenotype. The combination of circulating immature-neutrophils and dNLR could improve the identification of this population. The impact of immature-neutrophils on ICI should be more deeply explored.

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      • Abstract
      • Presentation
      • Slides

      Background

      The [neutrophils/[leucocytes-neutrophils] ratio (dNLR) correlates with immune checkpoint inhibitors (ICI) outcomes in advanced non-small cell lung cancer (aNSCLC) patients. Significance of early dNLR change after the first course of ICI is unknown.

      Method

      Patients with NSCLC treated with ICI (PD(L)1+/-CTLA4) between Nov. 2012 and Jun. 2018 at 16 EU/US centers were included. A control group treated with chemotherapy (CT) only was also evaluated (NCT02105168). dNLR was collected at baseline (B) and at cycle 2 (C2). Patients were categorized as low vs high dNLR at each timepoint (defined as < vs > 3, as previously done), and the change between B and C2 (good = low at both timepoints, poor = high at both timepoints, mixed = different at each timepoint).

      Result

      1485 patients treated with ICI were analyzed. PDL1 was negative in 162 (11%), 1-49% in 178 (12%), ≥50% in 201 (14%), and missing in 944 (64%). dNLR at B and C2 did not associate with PD-L1 status.

      At baseline, dNLR was high in 509 (34%) patients and associated with worse PFS compared to those patients with low dNLR at baseline (HR 1.56, P<0.0001) and OS (HR 2.02, P<0.0001). At C2, dNLR was high in 484 (34%) and similarly associated with worse outcomes compared to patients with low dNLR at C2 (PFS HR 1.64, P<0.0001; OS HR 2.13, P<0.0001).

      Between B and C2, dNLR remained low in 804 (56%, « good ») or high in 327 (23%, « poor ») or changed in 310 pts (22%, « intermediate »). Those with a good dNLR demonstrated mPFS 5.3, mOS 18.6 mo), followed by those intermediate with mixed dNLR (mPFS 3, mOS 9.2 mo), and finally poor dNLR (mPFS 2, mOS 5mo). Outcomes were independant of PD-L1 expression (adjusted HR for PFS 1.94 for intermediate and 3.16 for poor groups, compared to good dNLR group, P<.001; adjusted HR for OS was 2.08 for intermediate and 3.67 for poor groups, P<0.001).A bootstrap tested the stability of OS/PFS prediction (P<0.001).

      In the chemo-cohort (n=173), high C1-dNLR (n=81, 47%) was not associated with OS (P=0.84).

      Conclusion

      dNLR at baseline, at cycle 2, and the change between these two timepoints associated with outcomes in patients treated with immunotherapy independent of PD-L1, but not in patients treated with chemotherapy alone. dNLR is specifically prognostic in the context of immunotherapy.

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      MA07.03 - A Circulating MicroRNAs-Based Test as Biomarker of Primary and Secondary Resistance in PD-L1 ≥50% NSCLC Treated with Immunotherapy (Now Available) (ID 2495)

      13:30 - 15:00  |  Presenting Author(s): Claudia Proto  |  Author(s): Arsela Prelaj, Carla Verri, Diego Signorelli, Giuseppe Lo Russo, Roberto Ferrara, Giulia Galli, Benedetta Trevisan, Mavis Mensah, Filippo Guglielmo Maria De Braud, Marina Chiara Garassino, Gabriella Sozzi, Mattia Boeri

      • Abstract
      • Presentation
      • Slides

      Background

      PD-L1 represents the only clinically approved biomarker to select patients for immunotherapy. However, about 20-25% of PD-L1≥50% NSCLC patients do not benefit of ICIs treatment. We showed that a plasma microRNA signature classifier (MSC), reflecting the switch towards an immunosuppressive profile of immune cells, identifies NSCLC patients with worse prognosis after ICIs, irrespective from PD-L1 expression. Aim of this trial is to prospectively define the MSC role as biomarker of primary or secondary resistance in PD-L1≥50% NSCLC treated with ICIs.

      Method

      Fifty consecutive advanced NSCLC patients with PD-L1≥50% treated with ICI as first (n=32) or further line were enrolled. Plasma samples, as well as demographics information, smoking history and ECOG PS were collected before starting ICI treatment. The MSC test identified patients at high (H) risk vs intermediate/low (I/L) risk levels. According to RECIST 1.1 criteria, patients were classified as responders (R), patients with stable disease (SD), and progressors (P). Objective Response Rate (ORR), Progression Free Survival (PFS) and Overall Survival (OS) in MSC risk level strata at the baseline were considered as endpoints. For 26 R or SD patients with extended follow-up, additive, not mandatory plasma samples were collected and analyzed at the time of revaluations. To determine changes in the risk level during follow-up, we evaluated changes in the probability of having progressive disease after two consecutive MSC tests, considering all possible combinations.

      Result

      Overall 17 (34%) R, 17 (34%) patients with SD, 11 (22%) P and 5 (10%) not evaluable patients were identified. Considering the baseline blood samples 11 (22%) NSCLC patients were MSC H. ORR was 0% in MSC H vs 45% for other patients (p=0.0090). Median PFS was 2.3 months for MSC H vs 10.9 months for other patients (HR=0.38; 95%CI=0.17-0.84; p=0.0174). Median OS was 2.9 months for MSC H vs 22.0 months for other patients (HR=0.18; 95%CI=0.07-0.47; p=0.0004). Data remained significant adjusting for age, sex, pack-years and ECOG performance status: PFS HR=0.31 (95%CI=0.13-0.73; p=0.0072) and OS HR=0.13 (95%CI=0.04-0.39; p=0.0003). Among the 26 patients with longitudinal evaluation of MSC risk level, all the 12 patients reaching progression during treatment showed an increase in the risk level (Sign-test p-value=0.0039). Conversely, when considering the 14 NSCLC patients still maintaining SD or responding to ICIs at the time of the analysis, the risk level decreased for 9 (64%) of them (Sign-test p-value=0.1655).

      Conclusion

      These preliminary results suggest that MSC risk level at the baseline and during treatment could help to identify primary or secondary resistance in PD-L1≥50% NSCLC patients treated with ICIs. Ongoing clinical trials are validating these results.

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      MA07.04 - Discussant - MA07.01, MA07.02, MA07.03 (Now Available) (ID 3739)

      13:30 - 15:00  |  Presenting Author(s): Sara Pilotto

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      • Abstract
      • Presentation
      • Slides

      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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      MA07.06 - Immunotherapy Re-Challenge After Nivolumab Treatment in Advanced Non-Small Cell Lung Cancer in French Real-World Setting (Now Available) (ID 1281)

      13:30 - 15:00  |  Presenting Author(s): Matteo Giaj Levra  |  Author(s): François-Emery Cotté, Romain Corre, Christophe Calvet, Baptiste Jouaneton, Ronan Jolivel, Anne-Françoise Gaudin, Valentine Grumberg, Jean-Baptiste Assié, Christos Chouaid

      • Abstract
      • Presentation
      • Slides

      Background

      Real‐world evidence of nivolumab as treatment for advanced non-small cell lung cancer (aNSCLC) can complement evidence from clinical trials to optimize routine usage and personalization of care. Further, little is known about treatment options and outcomes after discontinuation of nivolumab.

      Method

      Based on the National hospitals database (PMSI), we built a retrospective cohort of all NSCLC patients (ICD code: C34*) starting nivolumab in 2015-2016 and followed them until Dec 2017. Information on patients’ baseline characteristics (demographics, comorbidities, treatment history) was retrieved. Nivolumab treatment was considered discontinued if ≥3 infusions were missed. Time to treatment discontinuation (TTD) and overall survival (OS) were estimated with Kaplan-Meier methodology. Re-challenged patients were analyzed according to their first nivolumab treatment duration i.e. <3; 3-6; ≥6 months.

      Result

      We identified 10,452 NSCLC patients initiating nivolumab during the inclusion period (male: 71%; mean age; 63.8±9.6 years; squamous histology: 44%; cerebral metastasis: 17.4%; median aNSCLC history: 12.5 months; previous curative surgery: 15.6%; median time since first chemotherapy: 10.5 months; mean dose of nivolumab: 213±54mg). Median TTD and OS were 2.8 months and 11.6 months. One-year and 2-year OS rates were 48.8% and 27.4%. Overall, 5118 (53.4%) patients received subsequent systemic therapy after nivolumab discontinuation. Among them, 1517 patients (29.6%) were re-treated with anti-PD1 agents (nivolumab: 98.8%) either after a therapeutic break (‘immunotherapy resumption group’: n=1127; mTTD: 4.1 months; mOS: 14.9 months from second initiation) or after chemotherapy (‘immunotherapy re-challenge group’: n=390; mTTD: 3.0 months; mOS: 18.2 months from second initiation). The Figure presents OS curves of the ‘re-challenge group’ according to first nivolumab treatment duration.

      graph os re-challenge according to ttd 1st nivo.jpg

      Conclusion

      After nivolumab discontinuation, around 30% of patients received immunotherapy again, either as a resumption or as a re-challenge following non-immunotherapy treatment. The influence of the first nivolumab treatment duration on re-challenged patients' OS should be further investigated.

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      MA07.07 - Discussant - MA07.05, MA07.06 (Now Available) (ID 3740)

      13:30 - 15:00  |  Presenting Author(s): Helena Linardou

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA07.08 - The Role of a Cachexia Grading System in Patients with NSCLC Treated with Immunotherapy: Implications for Response and Survival (Now Available) (ID 2046)

      13:30 - 15:00  |  Presenting Author(s): Jenny Georgina Turcott  |  Author(s): Andrés Felipe Cardona, Laura Alejandra Ramírez-Tirado, Zyanya Lucia Zatarain Barrón, Feliciano Barrón, Luis Corrales, Claudio Martin, Pablo Alan Barragán Castillo, Diana Flores-Estrada, Alejandro Ruiz-Patiño, Oscar Gerardo Arrieta

      • Abstract
      • Presentation
      • Slides

      Background

      The association between cancer-induced weight-loss (CIWL) and poor clinical outcomes is well established. However, many of these studies were performed in the chemotherapy era. Meanwhile, current standard of care for NSCLC patients has shifted towards the more efficacious immunotherapy agents (IO). IO has improved survival outcomes, nonetheless clinicians face the challenge of identifying who will derive substantial clinical benefit from these more costly agents. Response to IO is influenced by several patient-related factors, including microbiome, medications, and nutritional status.

      Method

      In this study we sought to evaluate the effect of cachexia in survival of NSCLC patients undergoing treatment with IO. Included patients had advanced NSCLC (IIIB, IV), who received IO agents in any line of therapy, and had a good performance status. All the patients were evaluated by the nutritionist specialist and were graded according to a previously documented cachexia scale which takes into consideration body mass index (BMI) and weight loss in order to stratify patients into 5 risk categories (0 [pre-cachexia] - 4 [refractory cachexia]). Primary endpoint was overall survival (OS), secondary endpoints included objective response rate (ORR) and progression-free survival.

      Result

      A total of 181 patients met the inclusion criteria and were included in the analysis. Among these 82 (45%) were classified in the first category (risk grade 0-1 [low risk]), 83 (46%) were classified in the second category (risk grade 2-3[intermediate risk]) and 9% were in the third category (risk grade 4 [high risk]). Patients classified as low-risk had a significantly longer OS compared to those with intermediate or high risk (22.4 months [95%CI: 18.7-26.1] vs. 15.7 [95%CI: 10.8-20.7] vs. 3.9 [0.0-7.8]; p<0.001; Hazard ratio: 1.81 [1.29-2.53]; p<0.001). In the multivariate analysis ORR, hemoglobin and risk category were independent factors associated with OS. Grade of cachexia was also significantly associated with ORR, with low-risk patients having a significantly higher ORR compared to intermediate and high-risk patients (36.6% vs. 17.3% vs. 25%; p=0.021). PFS was also influenced by risk category, with low risk patients having a longer PFS compared with intermediate and high-risk patients. diapositiva1.jpg

      Conclusion

      Cachexia is independently associated with worse OS in NSCLC patients who receive IO, while better nutritional status is related to higher ORR, highlighting a potential role for nutritional assessment in the selection of patients who are candidates for IO. Early assessment of nutritional status in these patients is imperative in order to timely diagnose and treat anorexia-cachexia and improve outcomes.

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      MA07.09 - Impact of Body Mass Index on Clinical Outcomes of Immune Checkpoint Blockers in Advanced Non-Small Cell Lung Cancer (Now Available) (ID 653)

      13:30 - 15:00  |  Presenting Author(s): Amit Arun Kulkarni  |  Author(s): Shijia Zhang, Todd De For, Manish Patel

      • Abstract
      • Presentation
      • Slides

      Background

      Studies have suggested that obesity may have a paradoxical effect on the efficacy of immune check-point blockers (ICB). Higher Body Mass Index (BMI) has been associated with favorable outcomes with ICB. There is limited data on the impact of BMI on ICB efficacy in real-world patients with advanced non-small-cell lung cancer (NSCLC). We evaluated whether BMI is associated with survival outcomes in metastatic NSCLC patients treated with ICB.

      Method

      We identified advanced NSCLC patients treated with anti-PD1/PD-L1 at our institution between 5/2015 to 1/2019. Data regarding BMI at the beginning of ICB treatment were collected. Patients with BMI > 25 (overweight and obese) were assigned to high-BMI group and patients with BMI < 25 were assigned to low-BMI group. The primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Cox proportional hazards model were used for statistical analysis.

      Result

      148 patients with NSCLC were eligible for inclusion. The median follow-up time was 12 months. Median age was 66 years. Majority of patients were female (52.1%), Caucasian (93%), had adenocarcinoma histology (66%), current or previous smokers (88%) and received Nivolumab (88%) in the 2nd or later line setting. The median number of treatment doses were 7. Median BMI of the patient population was 25.4 kg/m2. 64/148 (43%) of patients were in the low-BMI group (BMI < 25) and 84/148 (57%) patients were included in the high-BMI group (BMI > 25). Patients in high-BMI group had superior OS (HR=0.64, 95% CI 0.45-0.90; p=0.01) that was statistically significant. 1-year OS was 46.4% and 39.0% in the high-BMI and low-BMI group respectively. PFS was also greater in high-BMI group with a trend towards statistical significance (HR=0.73, 95% CI 0.51-1.03; p=0.07). 1-year PFS was 25.0% and 15.6% in the high-BMI and low-BMI group respectively. In multivariate analysis, OS benefit remained statistically significant after adjustment for clinical covariates (age, sex, performance status, number of previous lines of therapy, smoking status and brain metastasis).

      Conclusion

      Our study provides independent validation of previously published results demonstrating an association of BMI with survival outcomes in NSCLC patients treated with ICB. The OS benefit in the high-BMI group is independent of classical prognostic factors. While the reasons underlying this relationship remains unknown, prospective studies are needed to confirm this association. Future clinical trials with ICB should consider stratification of patients based on BMI.figure 1.png

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      MA07.10 - The Influence of Sex on Immunotherapy Efficacy in Non-Small Cell Lung Cancer (Now Available) (ID 712)

      13:30 - 15:00  |  Presenting Author(s): Stephanie Tuminello  |  Author(s): Rajwanth Veluswamy, Naomi Alpert, John Lazar, Raja Flores, Maaike Van Gerwen

      • Abstract
      • Presentation
      • Slides

      Background

      Patient’s sex impacts clinical outcomes for multiple cancers, including non-small cell lung cancer (NSCLC). A recent meta-analysis demonstrated sex may also impact response to novel immunotherapeutic agents, where men appear to derive greater benefit than women. However, the role of important clinical confounders of immunotherapy response that differ according to sex was not accounted for. The aim of this project was to investigate the effect of sex on immunotherapy benefit for NSCLC patients using a large, nationally representative database while adjusting for important clinical confounders.

      Method

      Advanced metastatic NSCLC patients diagnosed between 2013-2015 were identified in the National Cancer Database (NCDB). A Cox Proportional Hazards model was used to assess the interaction between sex and immunotherapy treatment for overall survival. This model was also adjusted for histology, stage, age, race, tumor size, comorbidities and other treatment (i.e. chemotherapy, radiation).

      Result

      Of 103,525 advanced NSCLC patients, 69,120 (67%) had adequate follow-up information for survival analysis. Of these, 37,423 (54.1%) were males and 31,697 (45.9%) females; 4,012 patients received immunotherapy as first-course treatment. In the adjusted model, both males (Hazard Ratio [HR]adj: 0.77, 95% Confidence Interval [CI] 0.73-0.81) and females (HRadj: 0.80, 95% CI 0.76-0.85) receiving immunotherapy had improved survival compared to those not receiving immunotherapy. The interaction between sex and immunotherapy was not significant (p=0.2539) after adjusting for clinical variables. Among the covariates, younger age, adenocarcinoma histology, Black race, smaller tumor size, lower comorbidity score and additional cancer treatment (either chemotherapy or radiation) were independently associated with better survival (p<0.0001 for all comparisons).

      Conclusion

      Patient sex does not appear to affect the benefit of immunotherapy in advanced NSCLC patients after adjusting for potential clinical confounders. Other clinical factors may play a role in immunotherapy response and should be explored in future research.

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      MA07.11 - Survival Outcomes Based on Gender of Advanced Nonsmall Cell Lung Cancer Patients Treated with Pembrolizumab or Nivolumab in Everyday Clinical Practice (Now Available) (ID 841)

      13:30 - 15:00  |  Presenting Author(s): Doran Ksienski  |  Author(s): Elaine S Wai, Nicole Croteau, Ashley T. Freeman, Leathia Fiorino, Angela Chan, Dave Fenton, Georgia Geller, Edward Brooks, Zia Poonja, Sarah Irons, Mary Lesperance

      • Abstract
      • Presentation
      • Slides

      Background

      Women are underrepresented in clinical trials of PD1 Ab. We investigated the relationship between gender and overall survival (OS) in aNSCLC patients (pts) treated with PD1 Ab in a large Canadian provincial cohort.

      Method

      All aNSCLC pts treated with nivolumab (NIV) or pembrolizumab (PEM) between 06/2015 and 11/2018 at BC Cancer were identified. Demographic, tumor, treatment details, and survival status were collected from chart review. Kaplan-Meier (KM) curves of OS from initiation of PD1 Ab were generated and compared by the log-rank test.

      Result

      Of 527 pts analyzed (58.9% NIV, 36.1% PEM), 50.5% were female. Women were more likely to have Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0/1 at PD1 Ab initiation (72.9% vs. 64.8%, p=0.05), lower median Charlson Comorbidity Index score (CCI, 2.0 vs. 3.0, p=0.006), and tumors with non-squamous histology (83.5% vs. 69.7%, p<0.001) or Epidermal Growth Factor Receptor (EGFR) mutation (9.8% vs. 3.4%, p=0.006). No significant gender variation in age at diagnosis, smoking status, and programmed death ligand 1 tumor proportion score (PD-L1 TPS) was observed. In addition, there were no differences in type of PD1 Ab, line of treatment, duration of treatment, or treatment discontinuation due to immune related adverse events. With a median follow-up of 16.3 months by reverse KM method, 65% of pts had died. In the entire cohort, women had a longer median OS than men (10.2 vs. 8.1 months, p=0.029). In the subgroup of ECOG PS 2/3 pts, men had worse OS (3.9 vs. 6.5 months, p=0.034). Women ≥60 years of age at initiation of PD1 Ab demonstrated superior median OS to men (12.2 vs. 6.1 months, p=0.006). On multivariable analysis of NIV pts, male gender (HR=1.3, 95% CI 1.0-1.7, p=0.02), baseline ECOG PS 2/3 (HR=2.5, 95% CI=1.9-3.2 p<0.001), CCI score≥3 (HR=1.6, 95% CI=1.3-2.1, p<0.001), and EGFR/ALK aberration (HR=2.3, 95% CI 1.4-3.9, p<0.001) predicted for worse survival; for PEM pts, only ECOG PS 2/3 (HR=2.5, 95% CI 1.6-3.9, p<0.001) was associated with OS.

      Conclusion

      In this large series with a significant proportion of women, females treated with PD1 Ab for aNSCLC lived longer than men (especially if ECOG PS 2/3 or age≥ 60 years.) Despite similarities in smoking status and PD-L1 TPS, gender divergence in outcome could be attributed to more favorable histology and baseline ECOG PS in females. Increased enrollment of women in PD1 Ab trials would facilitate evaluation of gender as a predictive variable.

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      MA07.12 - Discussant - MA07.08, MA07.09, MA07.10, MA07.11 (Now Available) (ID 3741)

      13:30 - 15:00  |  Presenting Author(s): Sonja Loges

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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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
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      ES01.05 - Future of Dual Anti-CTLA4 and PD1/PDL1 Blockade (Now Available) (ID 3153)

      10:30 - 12:00  |  Presenting Author(s): David R Spigel

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA13 - Going Back to the Roots! (ID 139)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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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

      • Abstract
      • Presentation
      • Slides

      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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    OA03 - Systemic Therapies for SCLC: Novel Targets and Patients' Selection (ID 121)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Now Available
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      OA03.03 - Initial Efficacy and Safety Results of Irinotecan Liposome Injection (nal-IRI) in Patients with Small Cell Lung Cancer (Now Available) (ID 1985)

      13:30 - 15:00  |  Author(s): David R Spigel

      • Abstract
      • Presentation
      • Slides

      Background

      SCLC accounts for ~15% of lung cancers, with 5-year survival <10%. 50-90% of patients with extensive disease respond to initial treatment; many rapidly relapse due to acquired resistance to front-line platinum-based chemotherapy. Limited treatment options are available for second-line patients. nal-IRI is a liposomal formulation of irinotecan (topoisomerase-1 inhibitor), utilizing intraliposomal stabilization technology to enable high drug load and in-vivo stability.

      Method

      RESILIENT (NCT03088813) is a two-part Phase 2/3 study assessing the safety, tolerability, and efficacy of monotherapy nal-IRI in SCLC patients who progressed on/after a front-line platinum regimen: Part 1 includes dose-finding then dose-expansion. Key eligibility criteria included ECOG PS 0-1 and adequate organ function, with prior exposure to immunotherapy allowed. Eligible patients received nal-IRI 70mg/m2 or 85mg/m2 (free-base equivalent) q2w. Primary endpoints were safety and tolerability. Efficacy assessments included objective response rate (ORR), best overall response (BOR), progression-free survival (PFS), and overall survival (OS).

      Result

      30 patients were treated for >12 weeks in Part 1 (male, 43%; median age, 60.4y; platinum-resistant, 40%) with tumor assessments q6w. During dose-finding, 5 patients received nal-IRI 85mg/m2 (deemed not tolerable: dose-limiting toxicity) and 12 patients received nal-IRI 70mg/m2 (deemed tolerable: selected for dose expansion). At data cut-off** (median follow-up, 4.4mo), 25 patients had received nal-IRI 70mg/m2. Diarrhea was the most common gastrointestinal adverse events (AEs) (Gr3, 20%). Hematologic AEs included neutropenia (Gr3, 8%; Gr4, 8%), anemia (Gr3, 8%), febrile neutropenia (Gr3, 4%), thrombocytopenia (Gr3, 4%; Gr4, 4%). Preliminary efficacy identified 11 patients with partial responses (ORR 44%), BOR (PR+SD) of 72%, and 12-week disease control rate (DCR12wks PR+SD) of 48%. PFS and OS are not yet mature.

      Conclusion

      Part 1 demonstrated encouraging anti-tumor activity for nal-IRI 70mg/m2 in patients with SCLC (ORR: 44%, BOR: 72%). nal-IRI 70mg/m2 was generally well tolerated. Future research is warranted to assess nal-IRI in second-line SCLC.

      Table 1. Baseline Demographic, Patient Disposition, Safety & Tolerability, and Clinical Efficacy for Part 1 of the RESILIENT study

      Dose-Finding /
      Dose-Exploration Phase
      Irinotecan
      Liposome
      Injection
      85mg/m2
      (N=5)
      Irinotecan
      Liposome
      Injection
      70mg/m2
      (N=25)
      Baseline Characteristics
      Gender, Male, n (%) 3 (60.0) 10 (40.0)
      Age (Years, median) 62.0 59.0
      Baseline ECOG
      0 1 (20.0) 3 (12.0)
      1 4 (80.0) 22 (88.0)
      Time Since Most Recent Progression (Weeks, median) 3.4 3.2
      Disease Location, n (%)
      Locally Advanced 0 2 (8.0)
      Metastatic 5 (100.0) 23 (92.0)
      Disposition, n (%)
      Patient Completed Study 4 (80.0) 12 (48.0)
      Patient Currently Ongoing* 7 (28.0)
      Deaths 2 (40.0) 6 (24.0)
      Disease Related 1 3
      Adverse Event Not Related to Study Drug 1 1
      Cardiac Arrest 1 -
      Hepatic Failure - 1
      Adverse Event Related to Study Drug 0 2
      Abdominal Sepsis - 2
      Patient Discontinued Treatment 5 (100.0) 18 (72.0)
      Safety & Tolerability, n (%)
      Any Treatment-Emergent Adverse Event (TEAE) 5 (100.0) 25 (100.0)
      Grade 3 or Higher TEAE (≥ 2 patients) 5 (100.0) 15 (60.0)
      Neutropenia 1 (20.0) 4 (16.0)
      Anemia 2 (8.0)
      Thrombocytopenia 2 (8.0)
      Diarrhea 3 (60.0) 5 (20.0)
      Asthenia 2 (8.0)
      General Physical Health Deterioration 2 (8.0)
      Pneumonia 2 (40.0) 1 (4.0)
      Abdominal Sepsis 2 (8.0)
      Hypokalemia 1 (20.0) 2 (8.0)
      Renal Failure 2 (8.0)
      Best Overall Response
      Complete Response (CR)
      Partial Response (PR) 2 (40.0) 11 (44.0)
      Stable Disease 1 (20.0) 7 (28.0)
      Progressive Disease 1 (20.0) 5 (20.0)
      Non-evaluable 1 (20.0) 2 (8.0)
      Objective Response Rate
      CR + PR 2 (40.0) 11 (44.0)
      Non-responder 3 (60.0) 14 (56.0)
      ** Data Cut-off: May 8, 2019.
      * Per RECIST v1.1 or RANO criteria.

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    OA14 - Update of Phase 3 Trials and the Role of HPD (ID 148)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
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      OA14.04 - Five-Year Outcomes From the Randomized, Phase 3 Trials CheckMate 017/057: Nivolumab vs Docetaxel in Previously Treated NSCLC (ID 894)

      11:30 - 13:00  |  Author(s): David R Spigel

      • Abstract
      • Slides

      Background

      Historically, outcomes for advanced non-small cell lung cancer (NSCLC) have been poor, with 5-year survival rates < 5% with conventional chemotherapy. Nivolumab, a programmed death-1 (PD-1) inhibitor, was approved in 2015 for patients with previously treated advanced NSCLC based on two randomized phase 3 trials, CheckMate 017 (NCT01642004; squamous) and CheckMate 057 (NCT01673867; non-squamous), which demonstrated improved overall survival (OS) vs docetaxel. We report 5-year pooled efficacy and safety from these trials, representing the longest survival follow-up for randomized phase 3 trials of an immune checkpoint inhibitor in advanced NSCLC.

      Method

      Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG performance status (PS) ≤ 1, and progression during or after first-line platinum-based chemotherapy, were randomized 1:1 to nivolumab 3 mg/kg Q2W or docetaxel 75 mg/m2 Q3W until progression or unacceptable toxicity. After completion of the primary analyses, patients in the docetaxel arm no longer receiving benefit could cross over to receive nivolumab. OS was the primary endpoint for both studies.

      Result

      At 5-year follow-up, 50 nivolumab patients and 9 docetaxel patients were alive. Baseline characteristics of 5-year survivors in both arms were similar to the overall population and patients who survived < 1 year, except for a higher percentage of patients with ECOG PS 0 or tumor programmed death ligand-1 (PD-L1) expression ≥ 1% on nivolumab and ECOG PS 0 and Stage IIIB NSCLC on docetaxel. Nivolumab continued to show long-term OS and progression-free survival (PFS) benefit vs docetaxel with 5-year OS rates 13% vs 3% (HR, 0.68 [95% CI, 0.59–0.78]) and PFS rates 8% vs 0% (0.79 [0.68–0.92]). OS benefit with nivolumab vs docetaxel was observed across subgroups including patients with tumor PD-L1 expression < 1%, baseline liver and adrenal metastases, neutrophil-to-lymphocyte ratio < median, lactate dehydrogenase ≥ upper limit of normal or no baseline proton-pump inhibitor use. Among patients with an objective response to nivolumab (20%) or docetaxel (11%), 32% remained in response at 5 years vs none on docetaxel, with a median duration of response of 19.9 vs 5.6 months, respectively. Of the 5-year nivolumab vs docetaxel survivors, 36% vs 0% were on study drug, 20% vs 67% received subsequent immunotherapy (on or off study), and 10% vs 0% were off study drug, progression free, with no subsequent therapy. No new safety signals were observed with longer follow-up. Between 3 and 5 years’ follow-up, 8 of the 31 (26%) nivolumab-treated patients reported a treatment-related adverse event, 1 (3%) grade 3–4. The most common select adverse events (events with a potential immunological cause) were related to skin, in 4 (13%) patients, none of which were grade 3–4.

      Conclusion

      CheckMate 017 and 057 are the first phase 3 trials to report 5-year outcomes for a PD-1 inhibitor in previously treated advanced NSCLC, demonstrating a greater than 4-fold increase in 5-year OS rates with nivolumab (13%) over docetaxel (3%). Nivolumab remained well tolerated with no new safety signals.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-110 - Novel Regimens Versus Standard-of-Care in NSCLC: A Phase II, Randomized, Open-Label, Platform Trial Using a Master Protocol (Now Available) (ID 2288)

      09:45 - 18:00  |  Presenting Author(s): David R Spigel

      • Abstract
      • Slides

      Background

      Although non-small cell lung carcinoma (NSCLC) is intrinsically resistant to immunotherapy agents, a subset of tumors are susceptible to T cell-mediated antitumor effects. Treatment regimens combining agents that target different processes within the cancer immunity cycle have the potential to enhance response in relapsed or refractory NSCLC. GSK3359609 is a humanized IgG4 antibody with potent agonist activity against Inducible T cell Costimulator (ICOS) and no or low depleting effect on antibody-dependent cell-mediated cytotoxicity.

      Method

      This is a randomized, phase II, open-label, platform trial utilizing a master protocol in patients with advanced NSCLC who have progressed on initial PD1/PDL1-based immunotherapy and platinum-based chemotherapy. The trial will consist of several sub-studies, with each sub-study comparing novel combinations vs. current standard-of-care (SOC). No treatment crossover is allowed. Additional sub-studies may be added over time following protocol amendments. In the first sub-study, patients are centrally randomized by internet to SOC (docetaxel) or novel ICOS drug combination (NIDC) (GSK3359609 + docetaxel) in a 1:2 ratio, stratified by squamous versus non-squamous NSCLC and line of PD1/PDL1; randomization to SOC is minimized thereafter. Primary endpoint is overall survival (OS). Secondary endpoints are survival rate at 12 and 18 months; tumor response according to RECIST 1.1 and iRECIST criteria; pharmacokinetic parameters of the novel immunotherapy; and safety. Exploratory endpoints include tumor and blood-based biomarker evaluations such as tumor mutational burden and gene expression. Interim analysis of OS will be done after approximately 45 deaths in both study groups, with ≥18 deaths in the combination immunotherapy group; final analysis will be done after 85 deaths (35 in combination immunotherapy group). The study will employ a Bayesian decision-making framework based on predictive probability of observing a significant improvement in OS in a future phase III trial. A sample size of ≤70 participants in each combination immunotherapy group and ≥35 participants in the SOC group will provide ≥81% power with a type 1 error of ≤2.3% for each pairwise comparison.

      Sub-study 1 will compare the efficacy of GSK3359609 plus docetaxel versus docetaxel alone. At least 105 patients are expected to enroll. GSK3359609/docetaxel will be administered for ≤2 years or 35 visits, or until disease progression, death or unacceptable toxicity. Both drugs are given as an IV infusion (docetaxel 75mg/m2; GSK3359609 80 mg).

      Result

      Study enrollment has begun and the primary endpoint results of sub-study 1 are expected mid-2020.

      Conclusion

      The study will provide information on the efficacy of novel immunotherapies used in combination.

      GlaxoSmithKline (NCT03739710).

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-02 - CANOPY-A: A Phase 3 Study of Canakinumab as Adjuvant Therapy in Patients with Surgically Resected NSCLC (ID 1569)

      10:15 - 18:15  |  Author(s): David R Spigel

      • Abstract

      Background

      Overexpression of interleukin (IL)-1β has been described in solid tumors, including lung. IL-1β can promote angiogenesis, tumor invasiveness, and induces tumor-associated immunosuppression through myeloid-derived suppressor cell (MDSC) accumulation in tumors. Pre-clinical data has shown that IL-1β inhibition reduced tumor growth, by limiting pro-tumorigenic inflammation and polarization of MDSCs into M1 phenotype. Canakinumab is a human monoclonal antibody with high affinity and specificity for IL-1β. Recently, it was found that canakinumab was associated with a significant and dose-dependent reduction in incidence and mortality from lung cancer based on CANTOS study.

      Method

      CANOPY-A (NCT03447769) is a phase III, randomized, double-blind, placebo-controlled study designed to evaluate efficacy and safety of adjuvant canakinumab versus placebo in patients with surgically resected NSCLC. This trial will enroll adult patients, with completely resected (R0) AJCC/UICC v.8 stages II-IIIA and IIIB (T >5 cm and N2) NSCLC, who have completed standard-of-care adjuvant treatments, including cisplatin-based chemotherapy and mediastinal radiation therapy (if applicable). Prior treatment with neoadjuvant chemotherapy or neoadjuvant radiotherapy is not permitted. Approximately 1500 patients will be randomized 1:1 to receive canakinumab (200 mg Q3W, s.c) or placebo (Q3W, s.c.) for 18 cycles or until disease recurrence, unacceptable toxicity, treatment discontinuation at the discretion of the investigator or patient, death, or loss to follow-up. Randomization will be stratified by AJCC/UICC v.8 stage, tumor histology, and region. The primary objective is disease-free survival, per investigator assessment. Secondary objectives include overall survival (key secondary objective), lung cancer-specific survival, safety, pharmacokinetics and immunogenicity of canakinumab, and patient-reported outcomes. Enrollment is ongoing.CANOPY-A (NCT03447769) is a phase III, randomized, double-blind, placebo-controlled study designed to evaluate efficacy and safety of adjuvant canakinumab versus placebo in patients with surgically resected NSCLC. This trial will enroll adult patients, with completely resected (R0) AJCC/UICC v.8 stages II-IIIA and IIIB (T >5 cm and N2) NSCLC, who have completed standard-of-care adjuvant treatments, including cisplatin-based chemotherapy and mediastinal radiation therapy (if applicable). Prior treatment with neoadjuvant chemotherapy or neoadjuvant radiotherapy is not permitted. Approximately 1500 patients will be randomized 1:1 to receive canakinumab (200 mg Q3W, s.c) or placebo (Q3W, s.c.) for 18 cycles or until disease recurrence, unacceptable toxicity, treatment discontinuation at the discretion of the investigator or patient, death, or loss to follow-up. Randomization will be stratified by AJCC/UICC v.8 stage, tumor histology, and region. The primary objective is disease-free survival, per investigator assessment. Secondary objectives include overall survival (key secondary objective), lung cancer-specific survival, safety, pharmacokinetics and immunogenicity of canakinumab, and patient-reported outcomes. Enrollment is ongoing.

      Result

      Section not applicable

      Conclusion

      Section not applicable