Pretreated Non-small Cell Lung Cancer Research Articles

PS01.07 Registrational Phase 2 Trial of Sotorasib in KRAS p.G12C Mutant NSCLC: First Disclosure of the Codebreak 100 Primary Analysis

Outcome in patients with advanced non-small cell lung cancer (NSCLC) on second- or third-line therapies is poor, with a response rate of <20% and median progression-free survival (PFS) of <4 months. Approximately 13% of patients with lung adenocarcinomas harbor KRAS p.G12C mutation. Sotorasib is a first-in-class small molecule that specifically and irreversibly inhibits KRASG12C. In the phase 1 cohort of the CodeBreaK 100 trial (NCT03600883), sotorasib was well tolerated and demonstrated a confirmed response rate of 32.2%, a median duration of response (DoR) of 10.9 months, and a median PFS of 6.3 months in patients with heavily pretreated NSCLC. Here, we present for the first time the primary analysis from the registrational phase 2 portion of the trial. This international, single-arm, phase 2 study evaluated the efficacy and safety of sotorasib, administered orally once daily at 960 mg, in the cohort of patients with locally advanced or metastatic KRAS p.G12C mutant NSCLC. Key inclusion criteria: centrally confirmed KRAS p.G12C; progression on anti-PD-1/PD-L1 immunotherapy and/or platinum-based combination chemotherapy, and targeted therapy if EGFR, ALK, and ROS1 alterations were identified; and ≤3 prior lines of therapy. Patients with untreated active brain metastases were excluded. Primary endpoint was confirmed objective response rate (ORR), assessed by blinded independent central review per RECIST 1.1. Key secondary endpoints included disease control rate (DCR), PFS, DoR, and safety. Data cutoff was September 1, 2020. A total of 126 patients were enrolled and received at least 1 dose of sotorasib. Median follow-up time on study was 9.3 months (range: 1.1+ to 12.2). Median age was 63.5 years (range: 37 to 80), and 117 (92.9%) were former or current smokers. 72 (57.1%) patients received 2 or 3 prior lines of anticancer therapy. 91.3% received anti-PD-1/PD-L1 immunotherapy, and 81.0% received both platinum-based chemotherapy and anti-PD-1/PD-L1 immunotherapy. Per central review, 123 patients had at least 1 measurable lesion at baseline and were evaluated for efficacy. 46 patients experienced a confirmed response (2 complete responses and 44 partial responses), resulting in an ORR of 37.4% (95% Cl: 28.8–46.6). At a median follow-up of 6.9 months for DoR, 52.2% of responders remained on treatment without progression. DCR was 80.5% (95% Cl: 72.4–87.1). Median PFS was 6.7 months (95% Cl: 4.9–8.1). Treatment-related adverse events (TRAEs) of any grade occurred in 88 (69.8%) patients and led to discontinuation in 9 (7.1%) patients. Grade ≥3 TRAEs were reported in 26 (20.6%) patients; those that occurred in >3% of patients were alanine aminotransferase increase (8/126, 6.3%), aspartate aminotransferase increase (7/126, 5.6%), and diarrhea (5/126, 4.0%). No fatal TRAEs were reported. In the phase 2 CodeBreaK 100 trial, sotorasib provided deep responses and durable clinical benefit with a favorable safety profile in patients with pretreated NSCLC harboring KRAS p.G12C, validating the previous phase 1 results. After four decades of scientific effort, sotorasib may have the potential to be the first targeted treatment option for this patient population with a high unmet need. Updated data including DoR, PFS, and biomarkers will be presented.

P78.08 Prediction of Pembrolizumab Efficacy in Non-Small-Cell Lung Cancer (NSCLC) Based on Experience From Expanded Access Program in Poland

Efficacy of pembrolizumab in advanced pretreated NSCLC was documented in prospective trials. We aimed to confirm the benefits of pembrolizumab in daily practice. This study was a retrospective analysis of patients (pts) treated in the Expanded Access Program in Poland. Median of progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Analyses were performed with R 3.6.0 software. A total of 34 pts were qualified to pembrolizumab in second or third line of NSCLC treatment. Poor performance status (ECOG 2) was found in 14.7% of pts, brain and liver metastases were diagnosed in 8.8% and 17.6%, respectively. 38% of pts ended the treatment before radiological assessment mainly due to clinical deterioration. In the landmark of 12 and 24 months 35% and 17.6% pts remained alive. Median PFS and OS were 4.4 months (95% confidence interval [CI]: 3.4–9.0) and 8.2 months (95% CI: 4.1–16.1). Immune related adverse events (irAE) were reported in 23% of pts. No treatment-related deaths were reported. In an univariate analysis an ECOG PS 2 (p < 0.001), tumor diameter of >100 mm (p = 0.019), PD during previous chemotherapy (p = 0.037), platelet count (PLT) >409 109/L (p = 0.011), a neutrophil-to-lymphocyte ratio (NLR) ≥3.1 (p = 0.0001) and platelet-to-lymphocyte ratio (PLR) of >183 (p = 0.018) had a negative impact on PFS. The age, sex, histology, location of metastases, PD-L1 expression, level of tumor-infiltrating lymphocytes and comorbidities had no impact. In terms of OS, an ECOG 2 (p < 0.001), PD during chemotherapy (p = 0.037), lack of irAE (p = 0.026), NLR of ≥3.1 (p < 0.001), PLT of ≥409 109 /L (p = 0.011), and PLR of ≥183 (p = 0.018) were negative prognostic factors. ECOG 2 (hazard ratio [HR] 72.63, 95% CI 6.64–794.4; p <0.001), PD during chemotherapy (HR 8.18, 95% CI 1.32–50.4; p = 0.024), and a PLT >409 109 /L (HR 6.18, 95% CI 1.35–28.32; p = 0.019) were independent prognostic factors for OS in multivariate analysis. Pembrolizumab produces durable benefit in 20% of pts with pretreated NSCLC. Clinical and laboratory factors may help to indicate subgroups likely to benefit. Poor PS and lack of response to previous chemotherapy are major determinants of worse prognosis.

Clinical implications of germline BCL2L11 deletion polymorphism in pretreated advanced NSCLC patients with osimertinib therapy

IntroductionB-cell lymphoma 2-like 11 (BCL-2-like 11, BCL2L11, also known as BIM) deletion polymorphism (BIM-del) has been associated with resistance to first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), and is a poor prognostic factor for EGFR-mutant non-small-cell lung cancer (NSCLC) patients. Nevertheless, the impact of BIM-del in advanced NSCLC patients treated with the third-generation EGFR-TKI osimertinib remains undetermined. This study aims to evaluate the relationship between BIM-del and therapeutic efficacy of osimertinib in pretreated NSCLC patients. MethodsPatients subjected to EGFR T790 M detection and prior osimertinib treatment between December 2015 and December 2019 in our hospital were enrolled in this study. Peripheral blood samples from these patients were collected to detect BIM-del by polymerase chain reaction. Cox proportional hazards models were used to analyze the clinical outcomes of patients with and without BIM-del. ResultsIn total, 152 Chinese Han NSCLC patients—including 143 T790M-positive and nine T790M-negative patients—were enrolled. BIM-del was detected in only 17.5 % of T790M-positive patients (25/143). The majority of patients were aged <65 years (81.8 %, 117/143), were female (58.7 %, 84/143), were non-smokers (82.5 %, 118/143), had Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–1 (88.8 %, 129/143), and exhibited metastases in the central nervous system (CNS) (54.5 %, 78/143). There were no associations between the BIM-del and clinical characteristics (including age, sex, histology, smoking status, stage, ECOG PS score, and CNS metastases). Patients with BIM-del had a poorer objective response rate than those without (28.0 % versus 52.5 %, p = 0.026). Besides, BIM-del was associated with a significantly shorter progression-free survival (PFS) and a moderately shorter overall survival (OS) (8.3 versus 10.5 months, p = 0.031 and 15.9 versus 25.2 months, p = 0.1, respectively). Multivariate analysis indicated that BIM-del was an independent prognostic factor for PFS but not for OS in EGFR T790 M NSCLC patients. ConclusionsBIM-del is associated with poor clinical responses and outcomes, and might be a negative predictive and prognostic biomarker in EGFR T790 M NSCLC patients with osimertinib treatment.

381MO Durability of clinical benefit and biomarkers in patients (pts) with advanced non-small cell lung cancer (NSCLC) treated with AMG 510 (sotorasib)

The phase I trial of sotorasib, a KRASG12C inhibitor, demonstrated a favorable safety profile and preliminary antitumor activity in pts with advanced solid tumors harboring KRAS p.G12C. Here, we present durability of clinical benefit and biomarker data in pts with NSCLC. Key eligibility criteria include KRAS p.G12C mutation and prior systemic anticancer treatment (tx). Primary endpoint is safety; key secondary endpoints include objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and progression-free survival (PFS). KRAS p.G12C mutant allele frequency (MAF) and PD-L1 level were examined. As of July 17, 2019, 40 pts with NSCLC (22 female [55.0%], median age: 68.0 years [range: 49-77]) were enrolled. Data cutoff date was March 25, 2020. 31 (77.5%) and 19 pts (47.5%) received ≥ 2 and 3 prior lines of therapy, respectively. Median follow-up was 10.2 (range: 8.3–19.0) months (mos). 3 pts (7.5%) had adverse events leading to discontinuation. There were no dose-limiting toxicities or fatal tx-related adverse events. Median PFS for all pts was 6.9 (range: 1.2–13.9) mos. ORR was 30% (95% Cl, 16.56–46.53). DOR ranged from 1.6 (+) to 12.7 mos, with 7 of 12 responders still in response at data cutoff. DCR was 92.5% (95% Cl, 79.61–98.43). 18 pts (45.0%) had progressive disease. At data cutoff, 10 pts (25.0%) were on study without disease progression, and 9 pts (22.5%) died. 18 pts (45.0%) (5 partial response (PR), 12 stable disease (SD), 1 progressive disease (PD)) had KRAS p.G12C MAF data available. There was no significant association between KRAS p.G12C MAF and response (Wilcoxon P = 0.80 for PR vs SD). 11 pts (27.5%) had PD-L1 data available. The median PD-L1 tumor proportion score [TPS] was 3% (range: 1–5) in 2 pts with PR, 0% (range: 0–0) in 8 pts with SD, and 75% (range: 75–75) in the pt with PD (Wilcoxon P = 0.044 for PR vs. SD). In pts with heavily pretreated NSCLC, durable responses to sotorasib were seen, with the majority of pts achieving disease control leading to a median PFS of 6.9 months. The current limited dataset suggests that neither KRAS p.G12C MAF nor PD-L1 expression level predicts response to sotorasib.

Abstract CT267: A phase 1b/2, open-label study of bintrafusp alfa with chemotherapy in patients with stage IV non-small cell lung cancer

Abstract Background: The combinations of pembrolizumab plus chemotherapy (CT) and atezolizumab plus bevacizumab and CT have been approved for first-line therapy in patients with advanced non-small cell lung cancer (NSCLC) regardless of PD-L1 expression; however, there is still a significant unmet need for this patient population who may not respond to immune checkpoint treatment. Bintrafusp alfa (M7824) is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor designed to function as a TGF-β “trap” fused to a human IgG1 mAb blocking PD-L1. Promising antitumor activity and a manageable safety profile were observed with bintrafusp alfa in multiple cohorts of a phase 1 study (NCT02517398) that enrolled patients with advanced, pretreated NSCLC who experienced disease progression either after platinum-based CT or anti-PD-(L)1 monotherapy. This study is evaluating the safety and efficacy of bintrafusp alfa in combination with CT in patients with stage IV NSCLC. Trial Design: This is a phase 1b/2, open-label, 4-cohort study (NCT03840915) evaluating bintrafusp alfa in combination with CT in patients with stage IV NSCLC. All patients will receive bintrafusp alfa 2400 mg Q3W intravenously and either cisplatin or carboplatin + pemetrexed (cohort A), carboplatin + nab-paclitaxel or paclitaxel (cohort B), cisplatin or carboplatin + gemcitabine (cohort C), or docetaxel (cohort D) Q3W for 4 cycles, followed by bintrafusp alfa maintenance (monotherapy or combination with pemetrexed [cohort A]) for up to 31 cycles or until disease progression, unacceptable toxicity, or death. Patients must be adults with histologically confirmed diagnosis of stage IV nonsquamous or squamous NSCLC (nonsquamous for cohort A), adequate organ function, ECOG PS ≤1, life expectancy ≥3 months, and measurable disease based on RECIST 1.1. Patients in cohorts A-C must not have received prior systemic therapy, and patients in cohort D must have disease progression on previous anti-PD-(L)1 therapy. Patients with tumors with actionable mutations (for which targeted therapy is locally approved), mixed SCLC and NSCLC, active CNS metastases, active autoimmune disease, known severe hypersensitivity, or interstitial lung disease are not eligible. The primary endpoint of this study is to assess the safety of bintrafusp alfa in combination with CT. Planned enrollment is 64 patients (32 patients among the 4 cohorts during the safety phase, and an additional 32 patients in cohort A for expansion phase). Citation Format: Fabrice Barlesi, Sandrine Hiret, Christian Rolfo, Italia Grenga, Andre Köenig, Yulia Vugmeyster, Leora Horn. A phase 1b/2, open-label study of bintrafusp alfa with chemotherapy in patients with stage IV non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT267.

Post-Progression Survival in Secondary EGFR T790M-Mutated Non-Small-Cell Lung Cancer Patients With and Without Osimertinib After Failure of a Previous EGFR TKI.

Osimertinib is effective in non-small-cell lung cancer (NSCLC) with an acquired epidermal growth factor receptor (EGFR) T790M mutation, the most common resistance mechanism to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs). We aimed to evaluate survival outcome of patients with EGFR-mutant NSCLC who have progressed on previous EGFR TKI therapy. Advanced NSCLC patients with EGFR mutation after acquired resistance to first- or second-generation EGFR TKI who received tumor rebiopsy after EGFR TKI failure from 1 January 2012 to 31 December 2017 were reviewed. Patient clinical characteristics, T790M mutation status, and post-progression survival (PPS) were recorded by chart review. We included 240 patients and the percentage of secondary T790M mutations in first time tissue rebiopsy was 52.9%. 38 of the initial T790M-negative patients received second rebiopsies and 14 (36.8%) of these were T790M positive. The duration between first and second rebiopsy tended to be longer in patients who had T790M mutation in the second biopsy (11.5 vs. 6.9months, p = 0.043). After EGFR TKI failure, the median PPS of patients who had the T790M mutation and history of osimertinib use was 42.6months (95% CI 34.6-50.5), compared to 18.0 (95% CI 9.6-26.4) months in T790M-positive patients without a history of osimertinib use, and 18.8 (95% CI 9.3-28.4) months in patients with no T790M mutation (p < 0.0001). Multivariate analysis showed that history of osimertinib use was correlated with improved survival. These data further emphasize that osimertinib should be a standard of care in patients with pretreated EGFR T790M-positive NSCLC.

Phase I expansion study of XMT-1536, a novel NaPi2b-targeting antibody-drug conjugate (ADC): Preliminary efficacy, safety, and biomarker results in patients with previously treated metastatic ovarian cancer (OC) or non-small cell lung cancer (NSCLC).

3549 Background: XMT-1536 is a first-in-class ADC targeting the sodium-dependent phosphate transport protein NaPi2b, broadly expressed in NSCLC and ovarian cancer. XMT-1536 utilizes the Dolaflexin platform to deliver 10-12 DolaLock auristatin payload molecules per antibody. In the dose-escalation portion of the Phase I study (NCT03319628), XMT-1536 showed clinical activity at doses &gt;20mg/m2 with confirmed responses and prolonged stable disease in heavily pretreated OC and NSCLC patients, without preselection for NaPi2b expression. XMT-1536 was generally well-tolerated without the severe toxicities observed with other ADC platforms such as neutropenia, peripheral neuropathy, or ocular toxicity (Tolcher et al., ASCO 2019; Richardson et al., SGO 2020). Here, we report on the expansion (EXP) cohort, which included patients with fewer prior lines of therapy, in the ongoing Phase I study. Methods: Doses administered intravenously every 4 weeks (q4w) of 36 and 43 mg/m2 were evaluated in two cohorts (1) high grade serous ovarian, fallopian tube, or primary peritoneal cancer (OC) with up to 4 prior lines of therapy and (2) NSCLC adenocarcinoma; prior treatment with a platinum-based therapy, immune checkpoint inhibitor, and TKI, if indicated. Archival tumor tissue and tissue from a new tumor biopsy were required for retrospective evaluation of NaPi2b expression. Results: As of 10 February 2020, 23 patients (19 OC and 4 NSCLC) were enrolled in the EXP cohort: 16 dosed at 36 mg/m2 and 7 dosed at 43 mg/m2. Adverse events were generally similar to those previously reported, including transient AST elevation, fatigue, nausea, and pyrexia. Clinical responses and stable diseases have been observed. Efficacy data (objective response rate) and initial correlation of NaPi2b score with clinical response will be reported. Available data from all patients with data cutoff in May 2020 will be included. Conclusions: Overall, XMT-1536 treatment demonstrated clinical activity in high grade serous ovarian cancer and NSCLC adenocarcinoma and was generally well-tolerated with no new safety signal trends identified in the EXP. Clinical efficacy and the relevance of NaPi2b expression for treatment with XMT-1536 will be presented. Clinical trial information: NCT03319628 .

Safety and preliminary clinical activity of the MET antibody mixture, Sym015 in advanced non-small cell lung cancer (NSCLC) patients with MET amplification/exon 14 deletion (METAmp/Ex14∆).

9510 Background: Sym015, a mixture of 2 humanized antibodies, triggers MET degradation by a unique mechanism with superior specificity compared to tyrosine kinase inhibitors (TKIs). The Sym015-01 phase (P)1a trial met, the primary objective of identifying the recommended P2 dose (RP2D) as 18 mg/kg on cycle 1 day 1 followed by 12 mg/kg Q2W. The P2a was expanded to enroll METAmp/Ex14∆ NSCLC patients (pts) based on preliminary efficacy findings. Here we present interim safety (n = 45) and efficacy (NSCLC cohort, n = 20) results from P2a. Methods: The expansion NSCLC Cohort enrolled pts with METEx14Δ (n = 12) or METAmp (n = 8 defined as &gt; 5 MET copies by NGS or MET/CEP7 ratio &gt; 2.2 updated to ≥3.0 by in situ hybridization; including 1 with METAmp+Ex14Δ). Tumor MET status was confirmed centrally and longitudinal ctDNA was analyzed by Guardant360. Results: By January 2020, 45 pts (median age 61.7 years) have been treated in P2a. Median duration of exposure (DoE) was 3.8 months (m) (n = 45; range 0.4+ to 22 m). Treatment emergent adverse events occurred in 93%, treatment related AEs (TRAE) in 42.2% and TRAE ≥G3 in 13.3% pts. No pts discontinued or died due to TRAE. The most common TRAE in ≥10% pts were fatigue (13.3%) and peripheral edema (11.1%). Of 20 NSCLC pts, 5 had confirmed PR (ORR 25%; 2/8 METAmp and 3/12 METEx14Δ); 11 had SD (DCR 80%; 6/8 METAmp and 5/12 METEx14Δ); 2 had PD (2/12 METEx14Δ); and 2 were not evaluable. 10 NSCLC pts were MET TKI naive (7 METAmp and 3 METEx14Δ) and had 50% ORR and 100% DCR (5 PR and 5 SD; DoR range 1 to 18.3 m; DoE 1.5 to 22 m); 10 NSCLC pts were prior MET TKI treated (9 METEx14Δ and 1 METAmp+Ex14Δ) with DCR 60%, (6 SD; DoE 0.4-9.6 m). Median PFS was 5.5 m overall (95% CI 3.5-9.7 m). Median PFS for MET TKI naive and MET TKI pre-treated NSCLC pts was 6.5 m (95% CI 3.4-21.9 m) and 5.4 m (95% CI 1.2-9.7 m) respectively. Median OS was not reached for overall or for prior MET TKI subgroups. 89% METEx14∆ tumor tissue to blood concordance (8/9 NSCLC pts) was observed. Conclusions: Sym015 was well-tolerated at the RP2D with a response rate similar to MET TKI in MET-treatment naïve METAmp/Ex14Δ NSCLC and seems to delay disease progression in MET TKI pretreated NSCLC pts. Combination with MET TKI to delay or prevent resistance should be further explored. Clinical trial information: NCT02648724 .

Real-World Experience of Nivolumab in Non-small Cell Lung Cancer in Korea.

PurposeThe introduction of immune checkpoint inhibitors represents a major advance in the treatment of lung cancer, allowing sustained recovery in a significant proportion of patients. Nivolumab is a monoclonal anti–programmed death cell protein 1 antibody licensed for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior chemotherapy. In this study, we describe the demographic and clinical outcomes of patients with advanced NSCLC treated with nivolumab in the Korean expanded access program.Materials and MethodsPreviously treated patients with advanced non-squamous and squamous NSCLC patients received nivolumab at 3 mg/kg every 2 weeks up to 36 months. Efficacy data including investigator-assessed tumor response, progression data, survival, and safety data were collected.ResultsTwo hundred ninety-nine patients were treated across 36 Korean centers. The objective response rate and disease control rate were 18% and 49%, respectively; the median progression-free survival was 2.1 months (95% confidence interval [CI], 1.87 to 3.45), and the overall survival (OS) was 13.2 months (95% CI, 10.6 to 18.9). Patients with smoking history and patients who experienced immune-related adverse events showed a prolonged OS. Cox regression analysis identified smoking history, presence of immune-related adverse events as positive factors associated with OS, while liver metastasis was a negative factor associated with OS. The safety profile was generally comparable to previously reported data.ConclusionThis real-world analysis supports the use of nivolumab for pretreated NSCLC patients, including those with an older age.

Apatinib Monotherapy or Combination Therapy for Non-Small Cell Lung Cancer Patients With Brain Metastases.

Apatinib, an oral small molecular receptor tyrosine kinase inhibitor (TKI) developed first in China, exerts antiangiogenic and antineoplastic function through selectively binding and inhibiting vascular endothelial growth factor receptor 2 (VEGFR-2). In this study, we aimed to explore the efficacy and safety profile of apatinib monotherapy, or combined with chemotherapy or endothelial growth factor receptor (EGFR)-TKI in heavily pretreated non-small cell lung cancer (NSCLC) patients with brain metastases. We performed a retrospective analysis for relapsed NSCLC patients with brain metastases from our institute, who received apatinib (250 mg or 500 mg p.o. qd) monotherapy, or combination with EGFR-TKI or chemotherapy as second or more line systemic therapy until disease progression or unacceptable toxicity occurred. The objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), median overall survival (mOS), and safety were analyzed. A total of 26 eligible patients were included: 24 patients diagnosed with adenocarcinoma, 2 with squamous carcinoma, and 14 patients harboring EGFR sensitizing mutations. The mPFS and mOS were 4.93 (range, 0.27–32.91; 95% CI 3.64–6.22) and 14.70 (range, 0.27–32.91; 95% CI 0.27–43.60) months for the whole group. The ORR and DCR were 7.7% (2/26) and 69.2% (18/26) for the entire lesions, and 7.7% (2/26) and 79.6% (20/26) for brain metastases, respectively. Compared with patients who received apatinib monotherapy, patients who received apatinib combination treatment had more favorable mPFS (11.77 vs. 2.27 months, p < 0.05) and mOS (24.03 vs. 6.07 months, p < 0.05). Treatment-related toxicities were tolerable including grade 1/2 hypertension, hand-and-foot syndrome, fatigue, nausea, liver dysfunction, myelosuppression, skin rash, and palpitation. In conclusion, apatinib exhibited high activity and good tolerance for NSCLC patients with brain metastasis, and it might become a potential choice for metastatic brain tumors in NSCLC patients.

Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), and Outcomes with Nivolumab in Pretreated Non-Small Cell Lung Cancer (NSCLC): A Large Retrospective Multicenter Study.

Immune checkpoint inhibitors have provided substantial benefit in non-small cell lung cancer (NSCLC) with unprecedented results in terms of survival. However, the identification of reliable predictive biomarkers to these agents is lacking and multiple clinicopathological factors have been evaluated. The aim of this study was to analyze the potential role of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lactate dehydrogenase (LDH) levels in patients with pretreated NSCLC receiving nivolumab. This was a retrospective multicenter study involving 14 Italian centers, evaluating the role of some laboratory results in patients with NSCLC treated with nivolumab in the second or later lines of therapy for at least four doses and with a disease re-staging. A total of 187 patients with available pretreatment laboratory results were included. NLR levels below 5 were associated with an improvement in terms of both progression-free survival (PFS) (p = 0.028) and overall survival (OS) (p = 0.001), but not in terms of overall response rate (ORR) or disease control rate (DCR). Moreover, PLR levels below 200 were associated with longer PFS (p = 0.0267) and OS (p = 0.05), as well as higher ORR (p = 0.04) and DCR (p = 0.001). In contrast, LDH levels above the upper normal limit (UNL) were not associated with significant impact on patient outcomes. Patients with pretreated NSCLC and high pretreatment levels of NLR and PLR may experience inferior outcomes with nivolumab. Therefore, in this subgroup of patients with poor prognosis the use of alternative therapeutic strategies may be a valuable option, especially in programmed cell death ligand 1 (PD-L1)-negative patients and/or in the presence of other additional poor prognostic factors.

Sarcopenia and Visceral Adiposity Did Not Affect Efficacy of Immune-Checkpoint Inhibitor Monotherapy for Pretreated Patients With Advanced Non-Small Cell Lung Cancer

BackgroundThis study aimed to investigate the association of computed tomography (CT)-assessed sarcopenia and visceral adiposity with efficacy and prognosis of immune-checkpoint inhibitor (ICI) therapy for pretreated non-small cell lung cancer (NSCLC).MethodsWe retrospectively collected 74 patients with pretreated NSCLC who had initiated programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitor monotherapy between December 2015 and November 2018 at our hospital. As CT-assessed pretreatment markers, we used psoas muscle index (PMI), intramuscular adipose tissue content (IMAC), visceral-to-subcutaneous ratio (VSR) and visceral fat area (VFA) at lumbar vertebra L3 level. We divided 74 patients into high and low groups according to each Japanese sex-specific cut-off value. Using Kaplan-Meier curves and log-rank tests, we compared overall survival (OS) and progression-free survival (PFS). Adjusted by serum albumin, neutrophil-to-lymphocyte ratio, performance status and driver mutations, multivariate Cox proportional hazard analyses evaluated various variables as independent prognostic factors of OS and PFS.ResultsWe could not find significant difference in response rate (RR) and disease control rate (DCR) between low and high groups according to any factors. The OS of patients with body mass index (BMI) < 18.5 was significantly shorter than that of patients with BMI ≥ 18.5 (median 3.3 vs. 15.8 months, P < 0.01), while there was no significant difference in OS and PFS according to PMI, IMAC, VSR and VFA. Multivariate analyses detected no significant prognostic factor in OS and PFS, except for low IMAC (hazard ratio 0.43, 95% confidence interval 0.18 - 0.998, P = 0.0496) as a favorable prognostic factor of longer OS.ConclusionsNeither PMI nor VSR, VFA might be a significant prognostic factor of PFS and OS of ICI monotherapy for pretreated NSCLC. According to our multivariate analyses, IMAC was a significant prognostic factor of OS, but not of PFS. Thus, neither sarcopenia nor visceral adiposity may be associated with the efficacy of ICI therapy.

Efficacy and safety of programmed cell-death-protein-1 and its ligand inhibitors in pretreated patients with epidermal growth-factor receptor-mutated or anaplastic lymphoma kinase-translocated lung adenocarcinoma.

Immune-checkpoint inhibitor (ICI) efficacy in patients with non-small cell lung cancer (NSCLC) harboring molecular alterations remains poorly elucidated. This study was undertaken to determine ICI efficacy against epidermal growth-factor receptor (EGFR)/anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1)-mutated NSCLC patients in the real-world setting.In this retrospective, multicenter study on adults with ICI-treated EGFR-mutated or ALK- or ROS1-translated NSCLCs, we analyzed clinical characteristics and outcomes: ICI-treatment duration, and progression-free survival (PFS), objective response rate, duration of response, and overall survival (OS) from immunotherapy initiation.Fifty-one NSCLC patients (mean age, 58.0 years) were included from 20 French centers: 61% were never-smokers and 59% were women. Among them, 82% had EGFR-activating mutations, 16% ALK translocations, or 2% ROS1 translocations. Before ICI therapy, patients had received a median of 3 treatment lines (including tyrosine-kinase inhibitor). The median PFS was 2.1 (95% confidence interval [CI], 1.5–3.2) months for the entire cohort, 2.2 (95% CI, 1.4–3.2) for EGFR-mutated patients, and 2.4 (95% CI, 2.1–not reached) months for ALK-translocated patients. The median OS was 14.7 (95% CI, 12.1–19.2) months for the entire population and 13.9 (95% CI, 8.8–20.0) and 19.2 (95% CI, 13.1–not reached) months for EGFR-mutated and ALK-translocated patients, respectively. Seven (13.7%) patients were treated with ICI for >9 months. Toxicities were reported in 22% (11/51), including 8% (4/51) grade ≥3.In this real-world setting, analysis of ICI PFS against EGFR-mutated or ALK-translocated NSCLC patients appeared close to that observed in pretreated unselected NSCLC patients. The more promising OS probably linked to post-ICI treatments. Large prospective studies on these patient subsets are needed.

Abstract C027: A Phase I, dose finding study of BI 754111, an anti-LAG-3 antibody, in combination with BI 754091, an anti-PD-1 antibody, in patients with advanced solid tumors: preliminary results from the microsatellite stable (MSS) metastatic colorectal cancer (mCRC) cohort

Abstract Background: Inhibition of the PD-1 pathway is an effective immunotherapeutic approach in a subset of patients with various solid tumors and hematologic malignancies. Blockade of the PD-1 pathway leads to overexpression of other checkpoint receptors, including LAG3, potentially providing an escape pathway for tumor cells. LAG-3 signaling contributes to immune cell exhaustion, preventing T-cell proliferation. Dual blockade of PD-1 and LAG-3 has the potential to synergistically restore T-cell functionality and therefore enhance antitumor immune responses. This Phase I trial is evaluating the combination of BI 754111, an anti-LAG-3 monoclonal antibody (mAb), and BI 754091, an anti-PD-1 mAb, in patients with advanced solid tumors. Methods: This open-label, Phase I study is being conducted in two parts. Part 1 (dose-escalation) enrolled patients with advanced solid tumors; no dose limiting toxicities were reported and BI 754111 600 mg intravenous (iv) every 3 weeks (q3w) in combination with BI 754091 (240 mg iv q3w) was selected for further assessment in part 2 (dose expansion). In part 2, patients are being enrolled in 4 cohorts: 1) anti-PD-(L)1 pretreated non-small cell lung cancer (NSCLC) that progressed after having achieved benefit on previous PD-(L)1; 2) previously treated (anti-PD-[L]1 naïve) MSS mCRC; 3) anti-PD-(L)1 pretreated TMB &amp;gt;10 and/or MSI-h and/or dMMR solid tumors; 4) treatment-naive NSCLC with EGFR and ALK wild type tumors. Primary endpoint for the expansion cohorts is objective response. Safety and pharmacokinetics of the combination were secondary endpoints. The mCRC cohort is fully recruited; other cohorts are open to recruitment. This abstract presents data from the MSS CRC cohort. Results. 40 patients with MSS mCRC were enrolled (27 male [67.5%]; median age 56.5 years [range 25–85]; median of 3.0 prior regimens [range 1–10]) and received BI 754111 600 mg q3w in combination with BI 754091 240 mg q3w. Treatment-related AEs (TRAEs) were reported in 18 patients (45%); most commonly infusion-related reactions (10.0%), myalgia (10.0%), hypothyroidism (7.5%), diarrhea (7.5%) and arthralgia (7.5%). Grade 3/4 TRAEs occurred in 4 patients (grade 3 colitis, grade 3 maculo-papular rash, grade 4 diabetic ketoacidosis [n=2]). Treatment-emergent immune-related AEs occurred in 9 patients; of these, 4 had grade 3/4 events (colitis and maculo-papular rash [grade 3] and diabetic ketoacidosis [grade 4; n=2]). To date, 2 (5%) patients achieved a partial response, and 12 (30%) achieved stable disease. Updates will be presented. Conclusion. BI 754111 + BI 754091 was well-tolerated and showed preliminary activity in patients with previously treated MSS mCRC. Assessment of the combination in other cohorts is ongoing. Citation Format: Johanna Bendell, Susanna V Ulahannan, Quincy Chu, Manish Patel, Ben George, Renee Landsberg, Mabrouk Elgadi, Christine Duffy, Ralph Graeser, Wenbo Tang, Michael Merger, Miaomiao Ge, Melissa Johnson. A Phase I, dose finding study of BI 754111, an anti-LAG-3 antibody, in combination with BI 754091, an anti-PD-1 antibody, in patients with advanced solid tumors: preliminary results from the microsatellite stable (MSS) metastatic colorectal cancer (mCRC) cohort [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C027. doi:10.1158/1535-7163.TARG-19-C027

520P - A phase II study to evaluate abscopal effect by palliative radiation therapy in nivolumab treatment for pretreated non-small cell lung cancer (HANSHIN 0116)

BackgroundWhile immune checkpoint inhibitors (ICIs) have been shown to be effective for non-small cell lung cancer (NSCLC), their monotherapeutic response rate (RR) is roughly 20%. It has been noted that local radiation therapy (RT) might potentially activate off-target antitumor effect, which is so called “abscopal effect” induced by immune-mediated mechanism. We evaluated whether palliative-RT induced abscopal effect, resulting in improvement of Nivolumab (Nivo) effectiveness. MethodsPretreated advanced NSCLC patients (pts) who were indicated for Nivo and scheduled for palliative-RT were started on RT within 10 days of administration of Nivo 3 mg/kg q2 weeks until attached document was revised to 240 mg/body q2 weeks. The primary endpoint was RR of non-irradiated tumor lesions. ResultsTwenty-eight pts were enrolled from May 2016 to January 2019. The study was terminated before completion of targeted initial sample size (n = 35), because of poor accrual. The median age was 67 years (range: 53-89). 15 pts were male. 21 pts had adenocarcinoma histology, 2 pts squamous histology, and 6 pts driver oncogene alterations. 25 pts were PS0/1, and 3 pts PS2. 14 pts were treated as 2nd-line, 2 pts as 3rd-line, and 12 pts as 4th-line or later. The median number of treatment cycles was 4 (range: 1-6). Median radiation dose was 30 Gy (range: 25-40), and 16 pts were irradiated on the bone, 5 pts on the adrenal grand, and 2 pts on the primary lesion. The objective RR of non-irradiated tumor lesions was 14.3% (95% CI: 1.3–27.2). Partial response (PR) was observed in 3 pts treated as 2nd-line (3/14, 21.4%), and 1 pt as 3rd-line (1/2, 50%). No PR was observed in pts treated as 4th-line or later (0/12, 0%). The median PFS was 2.7 months (95% CI: 1.0–3.5). No severe and specific adverse events (AEs) of Nivo in combination with RT were observed compared to historical data of Nivo monotherapy. ConclusionsAlthough the sample size was small, cleared abscopal effect by palliative-RT was not observed in Nivo treatment. However, some pts well responded to Nivo with palliative-RT during early-lines of treatment (2nd/3rd-line). Further investigations in the early-lines are warranted to evaluate a substantial synergistic effect of RT with ICIs. Clinical trial identificationUMIN000023646. Legal entity responsible for the studyHANSHIN Oncology Group. FundingONO Pharmaceutical Company. DisclosureA. Hata: Speaker Bureau / Expert testimony, Research grant / Funding (institution): Boehringer Ingelheim; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eli Lilly; Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Speaker Bureau / Expert testimony: Chugai; Research grant / Funding (institution): MSD. M. Satouchi: Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Boehringer Ingelheim; Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Chugai; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eli Lilly; Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Speaker Bureau / Expert testimony, Research grant / Funding (institution): ONO; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Takeda; Speaker Bureau / Expert testimony: Taiho. D. Harada: Honoraria (self): ONO; Honoraria (self): BMS. All other authors have declared no conflicts of interest.

Real-life results from the overall population and key subgroups within the Italian cohort of nivolumab expanded access program in non-squamous non–small cell lung cancer

BackgroundNivolumab was the first immune checkpoint inhibitor approved for previously treated advanced non–small cell lung cancer (NSCLC). Before its introduction in the market, nivolumab was made available to NSCLC patients through an expanded access program (EAP). Here we present the Italian cohort of patients with non-squamous NSCLC enrolled in a worldwide nivolumab EAP, with subgroup analyses involving elderly patients, patients with central nervous system (CNS) metastases and patients receiving nivolumab beyond progression. MethodsPretreated patients with advanced non-squamous NSCLC received nivolumab at 3 mg/kg every 2 weeks up to 24 months. Efficacy data (investigator-assessed tumour response, progression date and survival) and safety data were collected. Findings1588 patients were treated across 153 Italian centres. Overall response rate and disease control rate were 18% and 44%, respectively; median overall survival (OS) was 11.3 months (95% CI: 10.2–12.4). Elderly patients (≥70 n = 522; ≥75 n = 232) achieved outcomes similar to the global study population; patients with CNS metastases (n = 409) had an OS of 8.6 months (95% CI: 6.4–10.8), and a 1-year OS rate of 43%. Nivolumab was administered beyond progression to 276 patients (26%), 57 of whom achieved subsequent disease control; the median OS of patients receiving nivolumab beyond progression was 16.2 months (95% CI: 14.0–18.4), while 1-year OS rate was 62%. InterpretationTo date, this is the largest clinical experience with nivolumab in a real-world setting. Our data support its use in clinical practice for pretreated non-squamous NSCLC, including patients with older age or CNS metastases.

Real-World Data Of Osimertinib In Patients With Pretreated Non-Small Cell Lung Cancer: A Retrospective Study.

PurposeOsimertinib is an oral, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeted for both EGFR sensitizing mutations and T790M resistance mutation in patients with non-small-cell lung cancer (NSCLC). We assessed efficacy and safety of osimertinib in patients with pretreated NSCLC in a real-world setting.Patients and methodsNinety-four patients with advanced NSCLC who received osimertinib after progression of prior EGFR-TKIs or chemotherapy treatments were retrospectively collected.ResultsIn patients evaluable for response analysis (n = 91), overall objective response rate (ORR) was 47.3%, and disease control rate (DCR) was 90.1%. Median duration of response (DoR) in responding patients was 12.5 months (95% confidence interval [CI], 10.7 to 14.3). Median progression-free survival (PFS) was 8.5 months (95% CI, 7.4 to 9.6) in 2nd line group, 9.1 months (95% CI, 6.6 to 11.6) in ≥3rd line group, and 8.6 months (95% CI, 7.2 to 10.0) in overall population. For subgroup analysis, DCR and median PFS were 91.9% and 8.6 months (95% CI, 7.2 to 10.0) in patients with detectable T790M mutation, respectively, while 80.0% and 3.2 months (95% CI, 0.5 to 5.9) for those without. Median PFS was significantly longer for T790M-positive patients co-occurring with exon19del than with L858R (17.9 months vs 7.3 months; P<0.001). Among 45 patients with metastases to the central nervous system (CNS), median systemic PFS was 8.8 months (95% CI, 6.9 to 10.7), while intracranial time to progression (iTTP) was not reached. Safety profile was acceptable, no adverse events (AEs) related deaths was observed.ConclusionOsimertinib was highly active in patients with pretreated advanced NSCLC who harbored EGFR T790M mutation, with manageable side-effects.

1584P - Exploring resistance to nivolumab [NIV] applying an Immune Genomic Signature (IGS) in advanced pretreated NSCLC [PRINCiPe study

BackgroundSpecific genomic abnormalities in immune-escape/editing-related genes have been demonstrated to be associated with immunotherapy resistance. In the light of this hypothesis, with the final aim to identify a potential predictive signature for immunotherapy, we designed the PRINCiPe (Predictors of Resistance to Immunotherapy with NIV) study in advanced pretreated non-small cell lung cancer (APNSCLC). MethodsFFPE-tumor blocks of APNSCLC pts undergone NIV were retrospectively sequenced for Somatic Mutations/Copy Number Variations (SM/CNV) (Ampliseq 17-genes customized panel: APLNR, B2M, IFNAR1, IFNAR2, IFNGR1, IFNGR2, IRF9, JAK1, JAK2, JAK3, PIAS4, PTPN2, SOCS1, STAT1, STAT2, STAT3, TYK2). Endpoints of the PRINCiPe study were overall-, progression-free-survival (OS/PFS) and objective response rate (ORR). ResultsOverall, 44 APNSCLC pts were collected and analysed. Main patients characteristics: median age 69.5 yrs, median number of previous lines 3 (2-5), 2nd line NIV (75.0%), male/female 77.3/22.7%, squamous/non-squamous 31.8/68.2%, EGFR mutant 5 (11.4%), median follow-up 6.8 months (range 1-23), deaths 24 (54.5%). JAK3/JAK2 (7/3 pts, 15.9/6.8%) CNV and IFNAR2 SM (4 pts, 9.1%) were the most frequent (>1 pts) abnormalities. Those pts (n=15) harboring JAK3, PIAS4, PTPN2, STAT3, IFNAR2 SM and/or JAK2/3 CNV (IGS+) had a significantly lower PFS than those without (IGS-) (median PFS 2.8 vs. 6.6 months; p=0.006), while a trend towards significance was observed in terms of OS (median OS 5.1 vs. 13.0 months for IGS+ and IGS-, respectively; p=0.06 log-rank, p=0.05 Tarone-Ware). At multivariate analysis, IGS+ was independently associated with a shorter PFS (HR 2.64, 95% CI 1.3-5.4, p=0.008). IGS+ pts were significantly more probable to be affected by liver metastases than those without (p=0.01). ConclusionsThe identified IGS was able to select APNSCLC pts with a significant lower chance to benefit from NIV, supporting the existence of an intrinsic genomic-detectable resistance. Further analyses are ongoing, including a comprehensive transcriptome analysis. Legal entity responsible for the studyEmilio Bria. FundingUniversity of Verona. DisclosureS. Pilotto: Honoraria (self): AstraZeneca, BMS, Roche, MSD, Boeringher Ingelheim; Research grant / Funding (self): AIRC ; Travel / Accommodation / Expenses: BMS, Roche, AstraZeneca, Boeringher Ingelheim. M. Milella: Honoraria (self): Pfizer, EUSA Pharma, AstraZeneca. E. Bria: Honoraria (self): MSD, AstraZeneca, Celgene, Pfizer, Helsinn, Eli Lilly, BMS, Novartis, and Roche; Research grant / Funding (self): AIRC. All other authors have declared no conflicts of interest.

Associations between baseline serum biomarker levels and cachexia/precachexia in pretreated non-small cell lung cancer (NSCLC) patients.

3054 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. Methods: 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. Results: High baseline values of BMI and low baseline NLR were associated with both OS and PFS (each p &lt; 0.05), though weight failed to reach significance. PFS and OS were similarly associated with percent changes (relative to baseline) in weight (p &lt; 0.01), BMI (p &lt; 0.01), and NLR (p &lt; 0.001). Thirteen biomarkers were found to be associated (p &lt; 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 &lt; 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 &lt; 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 &lt; 0.05) with percent change in NLR. Conclusions: 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.

Single-arm, phase II study of pyrotinib in advanced non-small cell lung cancer (NSCLC) patients with HER2 exon 20 mutation.

9089 Background: HER2 exon 20 mutation is a well-known oncogenic driver in non-small cell lung cancer (NSCLC) and its testing is recommended by NCCN guidelines for NSCLC patients. However, up to now, there has been no approved targeted therapy for this patient population. Pyrotinib is an oral, irreversible pan-Her tyrosine kinase inhibitor (TKI) against HER1, HER2 and HER4, which, combined with chemotherapy, has recently been approved in China for HER2 positive advanced breast cancer. Methods: Stage IIIB or IV NSCLC patients with HER2 exon 20 mutation (confirmed in a central lab) and previously treated with at least one platinum-based chemotherapy were enrolled in this open-label, multi-center, single-arm phase II study. Patients with active brain metastases or prior use of HER2 TKI agents were excluded. Eligible patients received pyrotinib 400 mg once daily until disease progression, intolerable toxicity or withdrawal of consent. The primary endpoint was objective response rate (ORR) according to RECIST 1.1. Secondary endpoints included safety, progression-free survival (PFS), time to disease progression (TTP), duration of response (DOR) and overall survival (OS). This trial is registered on ClinicalTrials.gov (NCT02834936). Results: Between October 20, 2016 and December 10, 2018, 60 patients (33 female, 27 male) were enrolled. The median age was 57 years (range: 40, 72). A majority were stage IV patients (95%). Over 58% of patients have been treated with two or more prior chemotherapy regimens. As of Jan 21, 2019, the ORR as evaluated by investigators was 31.7% (95% CI 20.3%, 45.0%). Median DOR was 7.0 months (95% CI 5.5, 11.0) and median PFS was 6.8 months (95% CI 4.1, 8.3). 26.7% patients reported treatment-related grade 3 AEs. Diarrhea (20.0%) was the only treatment-related grade 3 AE that occurred in ≥ 2 patients. Treatment-related grade 4 AE was reported in 1 subject (elevated gamma-glutamyl transferase). The anti-tumor activities of pyrotinib was shown in various mutation types. Conclusions: Pyrotinib as a single agent demonstrated promising anti-tumor activity and acceptable safety profile in heavily pretreated HER2 mutant NSCLC patients. Clinical trial information: NCT02834936.