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Julie R Brahmer
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MA 09 - The Current Status of Radiation Oncology (ID 666)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:Tomoki Kimura, Yong Chan Ahn
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 316
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MA 09.08 - Receipt of Chest Radiation and Immune-Related Pneumonitis in Patients with NSCLC Treated with Anti-PD-1/PD-L1 (ID 10075)
11:00 - 12:30 | Author(s): Julie R Brahmer
- Abstract
- Presentation
Background:
Immune-related pneumonitis (IR-pneumonitis) is a potentially fatal toxicity of anti-PD-1/PD-L1. This study investigates the role of chest radiotherapy (RT) and the development of IR-pneumonitis in NSCLC patients treated with anti-PD-1/PD-L1.
Method:
Between January 2011 and April 2017, NSCLC patients treated with anti-PD-1/PD-L1 either as part of a clinical trial or as standard-of-care at a tertiary academic cancer center, were identified. Patient demographics, treatment, adverse event and RT data including type of RT (SBRT, 2D/3D conformal RT, IMRT, multiple), timing of RT (pre or post PD-1/PD-L1), location of RT (chest/non-chest), and number of courses of chest-RT, were collected in an IRB-approved institutional database. IR-pneumonitis was diagnosed clinically by the treating investigator; patients with confirmed RT pneumonitis, progressive NSCLC, or active infection were excluded. Associations between patient, treatment and RT parameters, and development of any grade IR-pneumonitis were evaluated using Student’s t-test and Fisher’s exact tests.
Result:
Of 184 NCSLC patients identified: median age was 67 years (range: 39-88); 57% (n=105) were male, 75% (n=137) were former/current smokers, 64% (n=118) had adenocarcinoma histology, and 59% (n=109) had advanced NSCLC at diagnosis. Anti-PD-1/PD-L1 monotherapy was received in 74% (n=136, nivolumab: 107, pembrolizumab: 14, durvalumab: 7, other: 8) and combination therapy in 26% of patients (n=48, PD-1/CTLA-4: 13, PD-L1/CTLA-4: 5, PD-1/chemotherapy: 4, PD-1/other: 25, PD-L1/other; 1). Any RT was received by 129 patients (70%), and 96 patients received chest-RT (52%). Thirty-eight (21%) patients developed IR-pneumonitis of any grade. IR-pneumonitis incidence was numerically higher in patients receiving combination therapy compared with monotherapy (29%, n=14/48 vs. 18%, n=24/136, p=0.1). Former/current smokers had a higher incidence of pneumonitis compared with never smokers (25% vs. 12%, p=0.03). IR-pneumonitis incidence was numerically higher in patients receiving chest-RT compared with non-chest/no RT (25%, n=24/96 vs. 16%, n=14/88, p=0.15). Of 129 patients who received any RT, there was a trend towards increased IR-pneumonitis in patients who received chest RT compared with those who received non-chest RT (25%,n=24/96 vs 9%, n=3/33; p=0.08). Overall, there were no significant associations between chest-RT type, chest-RT timing, nor receipt of more than one chest-RT course, and development of IR-pneumonitis (p>0.05).
Conclusion:
IR-pneumonitis incidence is 21% and may be higher than reported in clinical trials. Smoking status is associated with the development of IR-pneumonitis. Receipt of chest-RT was numerically higher, but not statistically associated with, development of IR-pneumonitis after receipt of anti-PD-1/PD-L1 in patients with advanced NSCLC. Radiation parameters did not associate with the development of IR-pneumonitis.
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MS 18 - Biomarker for Anti-PD-L1 Therapy (ID 540)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yuichi Ishikawa, Sanja Dacic
- Coordinates: 10/17/2017, 15:45 - 17:30, Main Hall
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MS 18.06 - Future Perspectives of Biomarkers for Anti PD-1/PD-L1 Therapy (ID 8124)
15:45 - 17:30 | Presenting Author(s): Julie R Brahmer
- Abstract
- Presentation
Abstract not provided
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OA 12 - Emerging Genomic Targets (ID 679)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:H. Akita, Maurice Pérol
- Coordinates: 10/18/2017, 11:00 - 12:30, F203 + F204 (Annex Hall)
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OA 12.01 - The Preclinical and Clinical Activity of Poziotinib, a Potent, Selective Inhibitor of EGFR Exon 20 Mutant NSCLC (ID 10369)
11:00 - 12:30 | Author(s): Julie R Brahmer
- Abstract
- Presentation
Background:
Approximately 10% of EGFR mutant NSCLCs have an insertion/mutation in exon 20 of EGFR resulting in primary resistance to currently available tyrosine kinase inhibitors (TKIs). We previously reported that the structural features of poziotinib could potentially enable it to circumvent the steric hindrance induced by exon 20 mutations. Here we further characterize the preclinical activity of poziotinib and report on initial clinical activity of poziotinib in patients with EGFR exon 20 mutations from an ongoing phase II study.
Method:
We evaluated poziotinib activity in vitro using human NSCLC cell lines and the BAF3 model as well as several patient-derived xenograft (PDX) models and genetically engineered mouse models (GEMMs) of exon 20 insertion. We launched a phase 2 investigator-initiated trial of poziotinib in patients with metastatic NSCLC with EGFR exon 20 insertions (NCT03066206).
Result:
In vitro poziotinib was approximately 100x more potent than osimertinib and 40x more potent than afatinib against a common panel of EGFR exon 20 insertions. Furthermore, it had ~65-fold greater potency against common exon 20 insertions compared with EGFR T790M mutations; 3[rd] generation inhibitors osimertinib, EGF816, and rociletinib were all significantly less potent for exon 20 mutations/insertions compared with T790M. in vivo poziotinib led to >85% reduction in tumor burden in GEM models of EGFR exon 20 insertion (D770insNPG) NSCLC and the PDX model LU0387 (H773insNPH). To date, 8 platinum-refractory patients with EGFR exon 20 insertion mutation metastatic NSCLC have been enrolled in the clinical trial and treated with poziotinib at a dose of 16 mg PO daily. Two patients have reached the first interval-imaging time point (at 8 weeks of therapy per protocol). Both patients exhibited dramatic partial response, with one patient reporting improvement in dyspnea and cough at one week of therapy. In this early stage of the study, one case of grade 3 paronchycia was observed. One additional platinum- and erlotinib-refractory patient with EGFR exon 20 insertion was treated with poziotinib on compassionate basis. The patient achieved partial response after three weeks of treatment.
Conclusion:
Poziotinib has selective activity against EGFR exon 20 mutations and potent activity in cell lines, PDX, and GEM models. Three platinum-refractory patients with EGFR exon 20 mutations have been treated thus far and are evaluable for response; all three had partial responses at the time of the initial scan. Updated data from the ongoing phase 2 clinical trial of poziotinib will be presented at the meeting.
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OA 17 - Immunotherapy II (ID 683)
- Event: WCLC 2017
- Type: Oral
- Track: Immunology and Immunotherapy
- Presentations: 2
- Moderators:Yuichiro Ohe, Anne Tsao
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 301 + 302
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OA 17.03 - First-Line Nivolumab plus Platinum-Based Doublet Chemotherapy for Advanced NSCLC: CheckMate 012 3-Year Update (ID 9043)
14:30 - 16:15 | Author(s): Julie R Brahmer
- Abstract
- Presentation
Background:
Platinum-based doublet chemotherapy is the standard-of-care first-line treatment for most patients with advanced NSCLC, but responses are not durable (~4.5–6 mo). Chemotherapy may sensitize NSCLC tumors to immune checkpoint inhibitors. Nivolumab, a fully human programmed death (PD)-1 antibody, demonstrated long-term survival benefit in patients with previously treated advanced NSCLC. Here we report the 3-year update of safety and efficacy of first-line nivolumab combined with chemotherapy in the phase 1 CheckMate 012 study (NCT01454102).
Method:
Chemotherapy-naïve patients with stage IIIB/IV NSCLC were randomly assigned based on histology in 3 cohorts combining nivolumab Q3W with 3 platinum-based doublet chemotherapy regimens: nivolumab 10 mg/kg + gemcitabine-cisplatin (all squamous histology), nivolumab 10 mg/kg + pemetrexed-cisplatin (all non-squamous), and nivolumab 10 mg/kg or 5 mg/kg + paclitaxel-carboplatin (any histology). After 4 cycles of nivolumab plus chemotherapy, patients received nivolumab monotherapy until progression or unacceptable toxicity. The primary objective was safety. ORR, PFS, and OS were secondary/exploratory endpoints.
Result:
56 patients were treated. Median age was 63.5 years, 46% were male, and 14% were never-smokers; 29% of tumors had squamous histology. At database lock (September 19, 2016) the minimum follow-up was 45.5 mo. Median duration of chemotherapy treatment was ~12 weeks (4 cycles; range: 3–18 weeks) and median duration of nivolumab treatment was 17–22 weeks across cohorts (range: 3–204). No new safety signals were observed in patients receiving nivolumab maintenance compared with the September 2014 database lock. ORR was 46%. Median duration of response was 10.4 mo (95% CI: 5.1, 26.3). Median PFS was 6.0 mo (95% CI: 4.8, 8.3). Median OS was 19.2 mo (95% CI: 14.1, 23.8), and the 3-year OS rate was 25%. ORR and OS were similar in patients with tumor PD-L1 expression <1% (n=23) vs ≥1% (n=23): ORR 48% vs 52%; median OS 19.2 mo (95% CI: 12.2, 23.8) vs 20.2 mo (95% CI: 10.9, 27.2). The 3-year OS rate was 22% in both PD-L1 expression subgroups.
Conclusion:
Nivolumab plus chemotherapy resulted in prolonged survival in a subset of patients, with a 3-year OS rate of 25%. In all patients, ORR and OS were similar irrespective of tumor PD-L1 expression. These results support further evaluation of nivolumab-chemotherapy combinations as first-line treatment for advanced NSCLC, which are being explored in CheckMate 227 (NCT02477826).
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OA 17.06 - Updated Analysis of KEYNOTE-024: Pembrolizumab vs Platinum-Based Chemotherapy for Advanced NSCLC With PD-L1 TPS ≥50% (ID 9582)
14:30 - 16:15 | Presenting Author(s): Julie R Brahmer
- Abstract
- Presentation
Background:
KEYNOTE-024 (ClinicalTrials.gov, NCT02142738) is a multicenter, international, phase 3, randomized, open-label, controlled trial of treatment with the anti‒PD-1 antibody pembrolizumab vs platinum-based chemotherapy as first-line therapy for patients with advanced NSCLC of any histology with PD-L1 tumor proportion score (TPS) ≥50% and without EGFR mutations or ALK translocations. Results from the primary analysis of KEYNOTE-024 demonstrated that after a median follow-up of 11.2 months, pembrolizumab significantly improved PFS (HR=0.50; P<0.001) and OS (HR=0.60; P=0.005) and was associated with a lower rate of treatment-related AEs compared with chemotherapy.
Method:
Patients were randomly assigned to receive either 35 cycles of pembrolizumab 200 mg every 3 weeks or 4–6 cycles of investigator's choice of carboplatin/cisplatin + gemcitabine, carboplatin + paclitaxel, or carboplatin/cisplatin + pemetrexed with optional pemetrexed maintenance (for those with non-squamous histology). Randomization was stratified by ECOG performance status (0 vs 1), histology (squamous vs nonsquamous), and geographic region (East Asia vs non–East Asia). Treatment continued until disease progression per RECIST version 1.1, intolerable toxicity, or withdrawal of consent. Patients in the chemotherapy arm who experienced disease progression could cross over to receive pembrolizumab monotherapy. Response was assessed every 9 weeks by blinded independent central review per RECIST version 1.1. The primary endpoint was PFS; secondary endpoints were OS, ORR, and safety.
Result:
305 patients were enrolled (pembrolizumab, n=154; chemotherapy, n=151). At the time of data cutoff (July 10, 2017) after a median follow-up of 25.2 months, 73 patients (47.4%) in the pembrolizumab arm and 96 patients (63.6%) in the chemotherapy arm had died. The hazard ratio for OS was 0.63 (95% CI, 0.47–0.86; nominal P=0.002). Median (95% CI) OS was 30.0 (18.3–not reached) months in the pembrolizumab arm and 14.2 (9.8–19.0) months in the chemotherapy arm. The Kaplan-Meier estimate of OS at 12 months was 70.3% (95% CI, 62.3%–76.9%) for the pembrolizumab group and 54.8% (95% CI, 46.4%–62.4%) for the chemotherapy group. 82 patients allocated to the chemotherapy arm crossed over to receive pembrolizumab upon meeting eligibility criteria. Treatment-related adverse events were less frequent in the pembrolizumab arm than in the chemotherapy arm (76.6% versus 90.0%, respectively) as were treatment-related grade 3-5 adverse events (31.2% versus 53.3%).
Conclusion:
With more than half of patients having OS events and prolonged follow‒up, first-line pembrolizumab monotherapy remains superior to platinum-based chemotherapy despite the crossover from the control arm to an anti-PD1 inhibitor as subsequent therapy.
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P2.07 - Immunology and Immunotherapy (ID 708)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.07-058 - First-In-Human Study of JNJ-64041757, a Live Attenuated Listeria Monocytogenes Immunotherapy, for Non-Small Cell Lung Cancer (ID 9480)
09:30 - 16:00 | Presenting Author(s): Julie R Brahmer
- Abstract
Background:
JNJ-64041757 (JNJ-757) is a live attenuated, double-deleted (LADD) Listeria monocytogenes (Lm)-based immunotherapy engineered to induce adaptive immune responses against the tumor-associated antigen mesothelin. The goals of Part 1 of this first-in-human (FIH) study were to establish the recommended phase 2 dose (RP2D), characterize the safety profile, and evaluate the immunological activity of JNJ-757 in patients with adenocarcinoma of the lung.
Method:
This is an ongoing FIH trial in patients with advanced adenocarcinoma non-small cell lung cancer (Stage IIIb or IV) who have progressed after standard therapy (ClinicalTrials.gov: NCT02592967). Patients were treated at 1 of 2 dose levels (10[8] CFU or 10[9] CFU), infused over 1 hour every 3 weeks until disease progression or unacceptable toxicity. Dose limiting toxicities (DLTs) were evaluated during the first cycle. Disease response was assessed every 3 cycles according to RECIST 1.1. Post-infusion blood, urine, fecal, and saliva samples were evaluated for the presence of JNJ-757. Immunological activity of JNJ-757 was assessed by evaluation of peripheral cytokines and immune cells as well as ELISPOT analysis to defined antigens.
Result:
Nine subjects were enrolled; 6 at 10[8] CFU and 3 at 10[9] CFU. There were no DLTs in either dosing cohort, and 10[9] CFU was identified as the RP2D. Most adverse events (AEs) were of grade 1/2 severity, with fatigue, headache, nausea, and vomiting as the most reported events. One drug-related AE of grade ≥3 severity (hypokalemia, grade 3) was reported in the 10[8] CFU cohort. Best response was stable disease. Four patients had received at least 7 cycles (range, 1 to 14 cycles). JNJ-757 was quickly cleared after infusion, with 7/9 patients showing negative blood cultures at 2 hours; all were negative after 24 hours. Correlative studies demonstrated activation of both innate and adaptive immune responses. Natural killer cell and T cell activation were observed 24 hours after infusion, coinciding with elevated cytokine production (i.e., IFN-γ, TNF-α). Specific T cell responses against Listeria listeriolysin O and mesothelin antigens were documented in a subset of patients, consistent with the mechanism of LADD to prime new immune responses.
Conclusion:
The RP2D of JNJ-757 is 10[9] CFU, with a safety profile consistent with other LADD Lm-based agents such as CRS-207. Both innate and mesothelin-specific adaptive immune responses were demonstrated in multiple patients. Recruitment in the trial continues to further characterize the safety profile and immune response, and a phase 1b/2 trial with JNJ-757 and nivolumab is planned.
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P3.03 - Chemotherapy/Targeted Therapy (ID 719)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.03-007 - LCMC2: Expanded Profiling of Lung Adenocarcinomas Identifies ROS1 and RET Rearrangements and TP53 Mutations as a Negative Prognostic Factor (ID 8338)
09:30 - 16:00 | Author(s): Julie R Brahmer
- Abstract
Background:
The Lung Cancers Mutation Consortium (LCMC) is a multi-institutional effort where 16 sites identify oncogenic drivers and pool data to assess the impact of targeted therapies in patients with lung adenocarcinomas. We now report the results of the second patient cohort (LCMC2) with an expanded multiplex molecular panel to include RET and ROS1 and tumor suppressors.
Method:
904 patients with centrally confirmed stage IV lung adenocarcinomas who were candidates for therapy had at least one of 14 oncogenic drivers assessed in a CLIA-compliant laboratory using genotyping, FISH, massively parallel sequencing (NGS), and immunohistochemistry (IHC) analyses.
Result:
Among 423 patients tested for all 14 targets, we found a driver in 65%. Mutated KRAS was found in 31%, sensitizing EGFR in 14%, MET amplification in 5%, ALK rearrangements in 4%, BRAF V600E in 3%, and HER2 in 3%. Rearrangements in RET and ROS1 were each found in 2% (CI 1 to 3%). Using IHC, PTEN loss was found in 8% (CI 6 to 11%) and MET expression in 58% (CI 55 to 61%). Use of targeted therapies in patients with EGFR, HER2, or BRAF mutations, ALK, ROS1, or RET rearrangements, and MET amplification was associated with a gain in overall survival of 1.5 years relative to those with the same drivers not receiving targeted therapy and a gain of 1 year relative to those without an actionable driver. Current and former cigarette smokers derived a survival benefit from targeted therapies similar to never smokers (p=0.975). Among 154 patients who had all drivers assessed and NGS testing in addition, any TP53 mutation was associated with poorer survival among those with EGFR, ALK, or ROS1 (p=0.014). STK11 was detected in 11%, all in patients with KRAS mutations.
Conclusion:
Using an expanded testing panel, LCMC2 demonstrates the survival benefit of matching targeted treatments to oncogenic drivers in patients with lung adenocarcinomas, identifies additional prognostic factors, and supports the performance of multiplex molecular testing on specimens from all individuals with lung adenocarcinomas irrespective of clinical characteristics. We detected either MET amplifications or HER2 mutations in 7%, together more than the 4% with ALK. A targeted drug is available in the United States for 35% of patients with lung adenocarcinomas. The routine use of massively parallel sequencing (NGS) detects both targetable drivers and tumor suppressor genes that have significance for therapy selection and prognosis. Supported by Free to Breathe
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YI 01 - Young Investigator and First Time Attendee Session (ID 588)
- Event: WCLC 2017
- Type: Young Investigator
- Track: Education/Publication/Career Development
- Presentations: 1
- Moderators:Peter Goldstraw, Giorgio Vittorio Scagliotti
- Coordinates: 10/15/2017, 08:00 - 11:30, F201 + F202 (Annex Hall)
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YI 01.04 - Clinical Trials 101 (ID 7848)
08:00 - 11:30 | Presenting Author(s): Julie R Brahmer
- Abstract
- Presentation
Abstract not provided
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