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Marina Chiara Garassino



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    EX04 - Mini Oral Abstract Session - MA08.06, MA18.02, MA19.02, MA20.11 (ID 1006)

    • Event: WCLC 2018
    • Type: Exhibit Showcase
    • Track: Advanced NSCLC
    • Presentations: 1
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      EX04.03 - Prior Therapy and Increased Expression of PD-L1 in NSCLC Tumor Samples (ID 11881)

      10:05 - 10:10  |  Author(s): Marina Chiara Garassino

      • Abstract
      • Slides

      Background

      Tumor PD-L1 expression has been shown to enrich for response to immunotherapy in several indications, including advanced NSCLC. However, the stability of PD-L1 expression over time and its relationship with non-immunotherapy cancer treatment is currently uncertain. We hypothesized that prior chemotherapy or radiotherapy would increase PD-L1 expression.

      Method

      In the Phase 2, open-label, single-arm durvalumab ATLANTIC study (NCT02087423), patients who had received ≥2 prior systemic regimens in the treatment of Stage IIIB or IV NSCLC were screened for tumor PD-L1 expression by immunohistochemistry using the VENTANA PD-L1 (SP263) Assay (25% tumor cell [TC] cutoff). PD-L1 expression was assessed using either a recent (<3 months) or archival sample; a subset of patients provided both. The relationship between non-immunotherapy cancer treatment and prevalence of tumor PD-L1 expression ≥25% (TC≥25%) was assessed in patients who received therapy prior to sample acquisition versus those who did not. Pearson’s chi-squared test was used to examine the differences between patient subgroups.

      Result

      Of the patients screened for participation in ATLANTIC, 1590 were successfully assessed for PD-L1 expression. PD-L1 TC≥25% prevalence was higher in patients who had received prior radiotherapy or chemotherapy before sample acquisition, with prevalence noticeably higher in those who had received ≥2 lines of prior chemotherapy. Prior EGFR inhibitor treatment did not have any noticeable relationship to TC≥25% prevalence (Table). In the subset of patients with paired recent and archival samples, TC≥25% prevalence remained the same in 74% of cases, increased over time in 19.5%, and decreased in 6.5%.

      Treatment regimen

      Subgroup (n)

      PD-L1 TC≥25% prevalence (%)

      P-value

      Prior tyrosine kinase inhibitor (TKI)

      No prior TKI (607)

      39.9

      0.947

      Prior TKI (411)

      39.7

      Prior EGFR inhibitor (379)

      38.5

      0.154

      Prior ALK inhibitor (15)

      60.0

      Prior chemotherapy

      No prior chemotherapy (145)

      29.0

      0.004

      Prior chemotherapy (873)

      41.6

      Number of lines of prior chemotherapy

      0 (155)

      29.0

      0.031

      1 (10)

      30.0

      2 (138)

      42.8

      >2 (725)

      41.5

      Prior radiotherapy

      No prior radiotherapy (599)

      37.1

      0.034

      Prior radiotherapy (419)

      43.7

      Conclusion

      PD-L1 expression may increase in response to chemotherapy or radiotherapy and is unlikely to decrease over time. Re-biopsy may provide a more accurate assessment of current tumor PD-L1 expression status when a low/negative result is seen in an archival sample, particularly if the patient has received multiple lines of intervening radiotherapy or chemotherapy.

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    MA04 - Novel Approaches with IO (ID 900)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Immunooncology
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 107
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      MA04.06 - PD-1 Blockade Promotes Hyperprogressive Disease in NSCLC Through Macrophages Activation via Antibody-Fc/FcR Interaction (Now Available) (ID 12334)

      14:05 - 14:10  |  Author(s): Marina Chiara Garassino

      • Abstract
      • Presentation
      • Slides

      Background

      In a subset of patients, named hyperprogressors (HPs), immunotherapy seems to paradoxically boost tumor growth. However, neither pathological and clinical features nor the underlying biological mechanism have been identified. We dissected the role of tumor-myeloid cells crosstalk as possible players.

      Method

      HPs were defined on the basis of clinical and radiological features. Baseline histological samples from patients treated with immune checkpoints inhibitors (ICI) were evaluated by immunohistochemistry for myeloid and lymphoid markers. We tested the effect on tumor growth of murine and human ICI in T-cell deficient mice injected with human lung cancer cell lines and PDXs bearing different genotypes (EGFR+, KRAS+, STK11+ and wt). Innate immune microenvironment was evaluated by FACS analysis and immunohistochemistry. In vitro studies of ICI binding functional modulation were performed in human myeloid cells from patients and healthy donors.

      Result

      In a clinical series of 187 patients treated with ICI, hyperprogression was observed in 40 (26.3%) cases. All available HP pre-treatment tissue samples (11 cases) showed CD163+CD33+PD-L1+Arginase-A1+ clustered epithelioid macrophages infiltrating the tumor foci also expressing FcRs including CD32b. No differences in T cell compartment were observed. Murine and human PD1 blocking mAbs induced a boost of tumor growth in H460 xenografs in imunocompromised mice. A similar effect was observed in EGFR+ but not in KRAS+ and wt PDXs treated with human anti-PD1. Notably, no hyperprogression was observed after treatment with murine and human anti PD-1 F(ab)2. Hyperprogressive tumors were enriched in arginase+ myeloid-macrophage cells and fibrotic features. ICI bind in vitro to human macrophages and monocytes via Fc/FcR interactions, likely involving CD32b (FcgRIIb) and triggering functional polarization.

      Conclusion

      Our results provide evidence that FcR triggering on macrophages by ICI delivers a signaling cascade promoting a functional reprogramming of these cells toward a more aggressive pro-tumorigenic behavior eventually inducing hyperprogression in a subset of patients with distinctive immune and genetic profile. A validation prospective study in ongoing.

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      MA04.07 - MicroRNA-Based Liquid Biopsy Combines with PD-L1 Tumor Expression to Predict Response to Immunotherapy in Advance NSCLC Patients (Now Available) (ID 12566)

      14:10 - 14:15  |  Author(s): Marina Chiara Garassino

      • Abstract
      • Presentation
      • Slides

      Background

      The advent of the new immune checkpoint inhibitors (ICIs) targeting the PD-1/L1 axis drastically improves survival of advance non-small-cell lung cancer (NSCLC) patients. However, only a limited subset of patients actually benefits of ICIs treatment and PD-L1 as predictive biomarker has a limited efficacy. We have previously identified a plasma microRNA-signature classifier (MSC) reflecting a circulating tumor-host interaction with diagnostic and prognostic value in low-dose computed tomography (LDCT) lung cancer screening trials.

      Method

      The tumor immune contexture of 40 LDCT-screening detected lung tumors was characterized by the “cell-type identification by estimating relative subsets of RNA transcripts” (CIBERSORT) software. In a consecutive series of 84 advanced lung cancer patients treated with ICIs, both plasma and tissue samples were collected and prospectively analyzed. Both 2-years progression free (PFS) and overall survival (OS) in strata of plasma MSC risk level alone or combined with tumor PD-L1 expression were evaluated in univariate and multivariate analysis by log-rank test and Cox proportional hazards models.

      Result

      A pro-tumorigenic immune contexture was identified in tumors of MSC high risk patients. Lower levels of cytotoxic CD8+ and CD4+ T cells and increased levels of Tregs, γδ T Cells, M2 macrophages characterized these tumors. In addition, genes differentially expressed according to MSC risk level (high vs. intermediate and low) were associated with 5-years OS in the screening series (p-values=0.02), as well as in additional 1000 cases from The Cancer Genome Atlas database (p-values<0.01). In the 84 advanced NSCLC patients treated with ICIs, the PFS hazard ratio ranged from 0.44 (95%CI: 0.25-0.75) of PD-L1 (adjusted p-value=0.005) and 0.38 (95%CI:0.2-0.73) of MSC (adjusted p-value=0.004) alone, to 0.25 (95%CI: 0.14-0.45) if combined (adjusted p-value<0.0001). In the subgroup of 45 patients with both plasma and tumor tissue available, the combination of MSC and PD-L1 stratified patients in three groups with 2-years PFS ranging from 25%to 10% and 0% (p-value=0.01) according to the presence of 2, 1 or 0 favorable markers, respectively. Similar results were obtained when considering OS, where the median survival time for patients with no favorable markers was 5.6 months (p-value<0.0001).

      Conclusion

      Overall, these findings suggest that a circulating microRNA-based risk level, reflecting an altered tumor immune contexture, could implement PD-L1 tumor tissue expression as predictive biomarkers of response to immunotherapy.

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    MA10 - Considerations in Immunotherapy / Real World (ID 911)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 105
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      MA10.02 - Impact of Antibiotics on Outcome of Metastatic Non Small Cell Lung Cancer Patients Treated with Immunotherapy (Now Available) (ID 14021)

      10:35 - 10:40  |  Author(s): Marina Chiara Garassino

      • Abstract
      • Presentation
      • Slides

      Background

      Immunotherapy (IO) is effective against metastatic non small cell lung cancer (mNSCLC). Gut microbioma has a strong impact on immune functions and its imbalance due to antibiotics (atbs) may impair the efficacy of IO. Recent works on other malignancies supported this evidence, but data are still lacking. We studied this topic in a case series of mNSCLC patients (pts) treated with IO.

      Method

      Data about all consecutive pts with mNSCLC treated with IO at Istituto Nazionale dei Tumori, Milan, Italy, between 04/2013 and 01/2018 were retrospectively collected. Pts were stratified according to atb use between 1 month (mo) before and 3 mos after the beginning of IO, and to atb exposure (AEx) defined as the ratio “days under atb/days under IO”. Survival was estimated with Kaplan-Meier method. Log-rank test was used to compare curves. Multivariate analysis was performed with Cox proportional model.

      Result

      One hundred fifty-seven pts were analyzed, for a median follow-up of 28.6 mos. IO consisted in an anti-PD1 agent in 62.4% of cases, in an anti-PDL1 agent in 32.5% of cases, in a combination anti-PDL1+anti-CTLA4 in 5.1% of cases. First-line IO was administered in 25 cases, second-line IO in 66 cases, third- or more advanced-line IO in 66 cases. Twenty-seven pts received atbs. The 3 most commonly used atbs were levofloxacin (55.6%), amoxicillin/clavulanate (25.9%), and ceftriaxone (14.8%). No differences in either response rate, progression free survival (PFS) and overall survival (OS) were observed between the subgroups defined by atb use (p .14, .18 and .24, respectively). Median AEx of the treated pts was 5%. The pts with an AEx longer than the median one had significantly worse PFS (2.2 vs 7.7 mos, p<.0001) and OS (4.9 vs 16.3 mos, p .0004) than the others. This result maintained significance after correction for IO line (p .0003) and performance status (p .0002), which were the only other variables influencing PFS and OS.

      Conclusion

      Though no differences in outcome could be observed in our population according to simple atb use, a significant disadvantage in PFS and OS became evident for pts with a higher AEx. If confirmed, these data may suggest to carefully weigh the prescription of atbs to mNSCLC pts treated with IO.

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      MA10.05 - Effect of Early Steroids use in Advanced NSCLC Patients Treated with Immunotherapy (Now Available) (ID 14163)

      11:00 - 11:05  |  Author(s): Marina Chiara Garassino

      • Abstract
      • Presentation
      • Slides

      Background

      Immunotherapy (IO) radically improved patients (pts) outcomes in advanced non-small cell lung cancer (NSCLC). Because of their immunosuppressive activity, the use of steroids as supportive care medications or for mild adverse events, even if at anti-inflammatory dosage, is debatable. In this study we assessed the effect of early steroids use on clinical outcomes of pts with advanced NSCLC treated with IO.

      Method

      We retrospectively collected demographics, clinical and pathological data of pts with advanced NSCLC treated with IO at our institution with at least one instrumental response assessment. Early use of steroids was defined as the use of a daily prednisone-equivalent dose 10 mg for at least 1 day within 28 days from the start of IO. Chi-square test or Fisher's exact test were used to analyze the association of early use of steroids with pts’ characteristics. The Kaplan-Meier method and the Cox proportional-hazards model were used for survival analyses while the reverse Kaplan-Meier method was used for follow-up quantification.

      Result

      We included 151 pts, 35 (23 %) of whom recurred to an early use of steroids. Six pts (4%) received combinatorial PD-L1+CTLA-4 blockade while 145 (96%) received single agent anti PD-1/PD-L1. Early use of steroids was positively associated with ≥2 metastatic sites (OR 3,08, 95% CI 1.33-7.89; P = .01) and ECOG PS 2 (OR 4.57; 95% CI 1.10-20.37; P = .03) and negatively associated with disease control (OR 0,32; 95% CI 0.14-0.71, P = .006). With a median follow-up of 28.61 months, early use of steroids characterized a poorer median OS (4.86 vs 15.14 months; HR 2.60; 95% CI 1.70-4.10; P < .0001). In the multivariable model including the only other covariate significantly associated with survival (ECOG PS), the early use of steroids was confirmed to independently worsen OS (HR 2.38; 95% CI 1.49-3.81; P = .0003). Early use of steroids was also associated with a poorer median progression-free survival (PFS) (1.98 vs 3.94 months; HR 1.80; 95% CI 1.20-2.80; P = .003).

      Conclusion

      In our analysis, the early use of steroids significantly affected disease control, PFS and OS in advanced NSCLC patients treated with IO. If our findings will be further prospectively confirmed, early use of steroids should be avoided in this setting.

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    MS23 - What's New in Targeted Therapy? (ID 801)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 106
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      MS23.03 - Management of CNS Mets in the Era of CNS-Penetrant TKIs (Med Onc and Rad Onco Perspectives) (Now Available) (ID 11498)

      11:00 - 11:15  |  Presenting Author(s): Marina Chiara Garassino

      • Abstract
      • Presentation
      • Slides

      Abstract

      Central nervous system metastases (CNSMs) are common in non small cell lung cancer (NSCLC). Their incidence is particularly high in presence of driver mutations (25-30% of EGFR mutated NSCLCs, 30-40% of ALK rearranged NSCLCs). CNSMs are associated with short survival and dismal quality of life [1].

      The treatment of CNSMs has traditionally been a challenge for medical oncologists. In fact, most of cytotoxic drugs do not cross the blood-brain barrier (BBB), rendering it difficult to control disease with medical therapy. An integration with radiotherapy (RT) is usually needed, either stereotactic, in presence of a limited number of small lesions, or whole brain (WBRT), in case of disseminated or large metastases. Surgery is generally considered only for single symptomatic lesions [2].

      The introduction of immune checkpoint inhibitors (ICIs) has not radically changed the therapeutic approach to CNSMs, as most of ICIs have a limited intra-cranial activity due to high molecular weight. Potential synergy between ICIs and RT, based on BBB permealization and antigen unmasking, is object of debate [3].

      The major advances have been observed in the field of NSCLC with “druggable” genetic alterations. Recent years have seen the development of many tyrosine kinase inhibitors (TKIs) against EGFR mutations and ALK rearrangements, which are active against a wider range of molecular alterations and often show a significant intra-cranial activity.

      Clinical trials with first and second generation EGFR TKIs (gefitinib, erlotinib, afatinib) showed that their intra-cranial concentration is negligible. As a consequence, brain is the most common site of treatment failure [4].

      Third generation EGFR TKI osimertinib completely changed the perspective. A pooled analyses of patients with CNSMs enrolled in phase II trials showed an intra-cranial objective response rate (IC-ORR) of 54% and a disease control rate (IC-DCR) of 92%, irrespective of RT. Median time to brain progression (B-TTP) was not reached. Brain response was rapid, being evidenced at first evaluation in 80% of patients. A phase I trial investigated the activity and safety of osimertinib 160 mg qd (instead of 80 mg qd) in patients with brain and/or leptomeningeal disease, showing promising activity and manageable toxicity [5].

      First generation ALK TKI crizotinib proved some intra-cranial activity in regulatory trials. However, brain disease control was better in case of previous RT (IC-ORR 33% vs 18%; IC-DCR 62% vs 56%; TTP 13 vs 7 months) [6]

      Ceritinib, the oldest second generation ALK TKI, showed a superior activity on CNSMs (IC-ORR 63% and IC-DCR 63% in ALK-inhibitor-naïve patients). Most of the cases had previously received RT and that the outcome of the remaining patients has not been separately analyzed. However, this result is consistent with the preclinical evidence that ceritinib is transported across the BBB by specific carriers. The ongoing trial ASCEND-7 is addressing the efficacy of ceritinib in a population of patients with brain and/or leptomeningeal disease [7].

      Alectinib, another second generation ALK TKI, has an even higher BBB penetration, with a linear correlation between plasma and brain concentrations. After encouraging data from phase I and II trials, the phase III study ALEX demonstrated a higher IC-ORR for alectinib than for crizotinib in first line (59% vs 26%), with an evident benefit in terms of complete responses (45% vs 9%). About 2/3 of the patients had received RT, but the proportion was balanced between treatment arms [8].

      A higher intra-cranial activity has emerged for brigatinib, one of the newest ALK TKIs. A pooled analyses from 2 clinical trials in both crizotinib-treated and -naïve patients showed an IC-ORR of 46% with 90 mg qd and 67% with 180 mg qd. Median B-TTP was 18.4 months in this last cohort. Interestingly, IC-DCR with brigatinib did not differ according to RT [9].

      Lorlatinib, the last ALK inhibitor, has a broader spectrum of activity on ALK alterations. In a phase I trial on heavily pre-treated patients, IC-ORR was 42%, with 17% of complete responses. Spinal punctures showed that drug concentration in cerebrospinal fluid is 75% of the plasmatic one [10].

      In conclusion, new TKIs have deeply changed the management of CNSMs from NSCLC with driver mutations. Thanks to their intra-cranial activity, rapid and durable brain responses can be seen without RT. The omission of RT allows patients to be spared by the cognitive impairment associated to radiations. Indeed, the optimal tolerability of these molecules favours their upfront administration to patients with CNSMs.

      [1] Rangachari D, et al. Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Can 2015; 88(1):108-111.

      [2] Tsao MN, et al. Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): an American Society for Radiation Oncology evidence-based guideline. Pract Rad Oncol 2012; 2:210-215.

      [3] Chajona E, et al. The synergistic effect of radiotherapy and immunotherapy: a promising but not simple partnership. Crit Rev Oncol Hematol 2017; 111:124-132.

      [4] Park SJ, et al. Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation. Lung Cancer 2012; 77:556–560.

      [5] Goss G, et al. CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials. Ann Oncol 2018; 29:687–693.

      [6] Lei YY, et al. Clinical efficacy of crizotinib in Chinese patients with ALK-positive non-small-cell lung cancer with brain metastases. J Thor Disease 2015; 7(7):1181-1188.

      [7] Landi L, Cappuzzo F. Ceritinib for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer. Exp Rev Pharm Oncol 2016; 9(2):203-214.

      [8] Gadgeel SM, et al. Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study. Lancet Oncol 2014; 15(10):1119–1128.

      [9] Camidge DR, et al. Exploratory analysis of brigatinib activity in patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer and brain metastases in two clinical trials. J Clin Oncol 2018; DOI: 10.1200/JCO.2017.77.5841.

      [10] Shaw AT, et al. Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol 2017; 18:1590-99.

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    OA05 - Clinical Trials in IO (ID 899)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 106
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      OA05.05 - Avelumab vs Docetaxel for Previously Treated Advanced NSCLC: Primary Analysis of the Phase 3 JAVELIN Lung 200 Trial (Now Available) (ID 12930)

      14:15 - 14:25  |  Author(s): Marina Chiara Garassino

      • Abstract
      • Presentation
      • Slides

      Background

      Avelumab is a human anti–PD-L1 IgG1 monoclonal antibody that is an approved treatment for metastatic Merkel cell carcinoma (various regions) and platinum-treated advanced urothelial carcinoma (US). We report findings from a global, open-label, phase 3 trial of avelumab vs docetaxel in patients with advanced NSCLC after platinum failure (NCT02395172).

      Method

      Patients with stage IIIB/IV or recurrent NSCLC with disease progression after platinum doublet therapy were randomized 1:1 to avelumab 10 mg/kg Q2W or docetaxel 75 mg/m2 Q3W, stratified by PD-L1 status (PD-L1+/PD-L1−) and histology (squamous/nonsquamous). The primary endpoint was overall survival (OS) in the PD-L1+ population (expression on ≥1% of tumor cells, assessed using the PD-L1 IHC 73-10 assay).

      Result

      Between April 2015 and February 2017, 792 patients were randomized to receive avelumab or docetaxel, including 264 and 265 with PD-L1+ tumors, respectively; 0.8% vs 7.5% did not receive study treatment. Median follow-up in the avelumab and docetaxel arms was 18.9 and 17.8 months; 15.5% vs 1.5% remained on treatment at data cutoff (November 22, 2017). In the avelumab and docetaxel arms, 39.8% vs 47.5% received subsequent anticancer therapy after discontinuation, including checkpoint inhibitors in 5.7% vs 26.4%, respectively. In the PD-L1+ population, median OS in the avelumab and docetaxel arms was 11.4 vs 10.3 months (hazard ratio [HR], 0.90 [96% CI, 0.72-1.12]; P=0.1627, 1-sided). Pre-planned exploratory analyses based on higher PD-L1 cutoffs showed increased OS with avelumab vs docetaxel, including PD-L1-high (≥80% cutoff, 29% of patients; 17.1 vs 9.3 months; HR, 0.59 [95% CI, 0.42-0.83]; P=.0022, 2-sided) and PD-L1-medium/high (≥50% cutoff, 40% of patients; 13.6 vs 9.2 months; HR, 0.67 [95% CI, 0.51-0.89]; P=0.0052, 2-sided) subgroups. In the PD-L1+ population (≥1% cutoff), ORR was 18.9% vs 11.7% (odds ratio, 1.76 [95% CI, 1.08-2.86]; P=0.0105, 1-sided); median duration of response was not reached with avelumab (95% CI, 9.9-not estimable [NE]) vs 6.9 months with docetaxel (95% CI, 3.5-NE). Overall rates of treatment-related adverse events (AEs) were lower with avelumab than docetaxel, including all grades (63.9% vs 85.8%) and grade ≥3 (9.9% vs 49.3%). Immune-related AEs occurred in 16.5% of avelumab-treated patients (grade ≥3 in 2.8%).

      Conclusion

      Avelumab showed increasing clinical activity in patients who had platinum-treated NSCLC with higher tumor PD-L1 expression; however, the trial did not meet its primary objective of improving OS vs docetaxel in PD-L1+ tumors (≥1% cutoff). OS findings may have been confounded by subsequent checkpoint inhibitor therapy in the docetaxel arm.

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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.01-21 - Safety of Durvalumab Retreatment in Advanced NSCLC Patients Who Progressed Following Initial Disease Control In ATLANTIC (ID 12386)

      16:45 - 18:00  |  Presenting Author(s): Marina Chiara Garassino

      • Abstract
      • Slides

      Background

      In ATLANTIC, patients who completed a year of durvalumab (anti-PD-L1) treatment but later progressed off therapy were eligible for retreatment. We evaluated safety in these patients compared with the overall study population.

      Method

      ATLANTIC (NCT02087423) was a Phase 2, open-label, single-arm trial in patients with Stage IIIB–IV NSCLC who had received ≥2 prior systemic treatment regimens, including one platinum-based. The study included three independent cohorts. In C1 (EGFR+/ALK+) and C2 (EGFR−/ALK−), enrollment was enriched for patients with ≥25% of tumor cells (TC) expressing PD-L1, while patients in C3 (EGFR−/ALK−) only had PD-L1 TC ≥90%. Patients received durvalumab 10 mg/kg q2w for ≤12 months. Patients who achieved and maintained disease control but then progressed after completing the initial 12-month treatment period were offered retreatment for a maximum of 12 months of further treatment. Safety and tolerability was a secondary outcome.

      Result

      As of November 7, 2017, of 442 patients in the ATLANTIC full analysis set, 102 (23.1%) had completed 12 months of initial treatment and 95 (21.5%) had disease control at the end of initial treatment. A total of 40 patients started retreatment. The median actual duration of exposure to durvalumab was 16.0 weeks (range 1–62; 40.1% of patients on treatment for ≥24 weeks) during initial treatment and 18.1 weeks (range 2–52; 37.5% of patients on retreatment for ≥24 weeks) during retreatment. The table shows safety during initial treatment and retreatment.

      Initial treatment (n=444)

      Retreatment phase (n=40)

      Cohort,* n (%)

      C1 (EGFR+/ALK+)

      111 (25.0)

      7 (17.5)

      C2 (EGFR−/ALK−)

      265 (59.7)

      26 (65.0)

      C3 (EGFR−/ALK−; TC ≥90%)

      68 (15.3)

      7 (17.5)

      Any TRAE, n (%)

      256 (57.7)

      19 (47.5)

      Grade ≥3 TRAEs

      42 (9.5)

      6 (15.0)

      TRAEs leading to death

      0

      2 (5.0)

      Serious TRAEs

      28 (6.3)

      4 (10.0)

      TRAEs leading to discontinuation

      10 (2.3)

      4 (10.0)

      Safety analysis set. *A more detailed analysis of exposure and safety by cohort will be presented. Causes of death were: pneumonitis and respiratory failure; cardiac arrest. TRAE=treatment-related adverse event.

      Conclusion

      A large proportion of patients (37.5%) maintained retreatment for ≥24 weeks, suggesting that patients who originally completed 12 months of treatment can tolerate sustained retreatment. The tolerability profile of durvalumab upon retreatment was similar to that seen during initial treatment, although there were two treatment-related deaths during the retreatment phase. Retreatment with anti-PD-L1 may be feasible for selected patients with NSCLC who demonstrate original benefit and progress off therapy.

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      P1.01-22 - Effect of Basal Lymphopenia on Outcome of Non Small Cell Lung Cancer Patients Treated with Immunotherapy (Now Available) (ID 14003)

      16:45 - 18:00  |  Author(s): Marina Chiara Garassino

      • Abstract
      • Slides

      Background

      The advent of immunotherapy (IO) induced profound change in treatment paradigm of metastatic non small cell lung cancer (mNSCLC). Different agents proved efficacy against the disease, leading to an improvement in patients’ (pts) survival. Nonetheless, only a minority of treated pts actually derives a benefit from IO. Some predictive factors, such as PD-L1 and tumor mutation burden, have been identified. Contradictory evidences have shown a potential negative predictive role of basal lymphopenia (BL). We investigated this topic in a retrospective cohort of mNSCLC pts.

      Method

      Data about all consecutive mNSCLC pts treated with IO at Istituto Nazionale dei Tumori, Milan, Italy, between 04/2013 and 01/2018 were retrospectively collected. Pts were stratified according to lymphocyte (Lp) count at the first IO administration. BL was considered as a categorical variable, using the Institutional cutoff of 900 Lps/mL. Survival was estimated with Kaplan-Meier method. Log-rank test was used to compare curves. Multivariate analysis was performed with Cox proportional model.

      Result

      One hundred fifty pts were analyzed, for a median follow-up of 28.6 mos. IO consisted in an anti-PD1 agent in 64.0% of cases, in an anti-PDL1 agent in 31.3% of cases, in a combination anti-PDL1+anti-CTLA4 in 4.7% of cases. First-line IO was administered in 23 cases, second-line IO in 66 cases, third- or more advanced-line IO in 61 cases. Median progression free survival (PFS) and overall survival (OS) of the global population were 3.2 and 11.2 months (mos), respectively. Thirty pts (20.0%) had any grade BL. These group had a significantly worse PFS (1.9 vs 3.0 mos, p.0010) and OS (4.5 vs 13.5 mos, p<.0001) than the control one. Also disease control rate (DCR) showed a significant difference in favor of non-BL pts (58.3% vs 30.0%, p.0074); response rate had a similar trend (25.0% vs 10.0%), without reaching significance (p.0881). The impact of BL on outcome remained significant after correction for the effects of performance status (p. 0045), which was the only other variable influencing OS. No factors other than BL had an influence on PFS at univariate analyses.

      Conclusion

      BL had a detrimental impact on DCR, PFS and OS in our population. Given the limitations of this retrospective analysis, such results deserves confirmation in larger cases series. However, if BL was confirmed as a negative predictive factor for response to IO, it may become part of a multivariable tool to indentify the best treatment option for each pt with mNSCLC.

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