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M.M. Awad
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MA 05 - Immuno-Oncology: Novel Biomarker Candidates (ID 658)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yoichi Nakanishi, P. Mitchell
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 303 + 304
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MA 05.02 - STK11/LKB1 Loss of Function Genomic Alterations Predict Primary Resistance to PD-1/PD-L1 Axis Blockade in KRAS-Mutant NSCLC (ID 10367)
15:45 - 17:30 | Author(s): M.M. Awad
- Abstract
- Presentation
Background:
The genomic landscape of primary resistance to PD-1 blockade in lung adenocarcinoma (LUAD) is largely unknown. We previously reported that co-mutations in STK11/LKB1 (KL) or TP53 (KP) define subgroups of KRAS-mutant LUAD with distinct therapeutic vulnerabilities and immune profiles. Here, we present updated data on the clinical efficacy of PD-1/PD-L1 inhibitors in co-mutation defined KRAS mutant and wild-type LUAD patients and examine the relationship between genetic alterations in individual genes, tumor cell PD-L1 expression and tumor mutational burden (TMB) using cohorts form the SU2C/ACS Lung Cancer Dream Team and Foundation Medicine (FM).
Method:
The cohorts included 924 LUAD with NGS (FM cohort) and 188 patients with KRAS non-squamous NSCLC (SU2C cohort) who received at least one cycle of PD-1/PD-L1 inhibitor therapy and had available molecular profiling. Tumor cell PD-L1 expression was tested using E1L3N IHC (SU2C) and the VENTANA PD-L1 (SP142) assay (FM). TMB was defined as previously described and was classified as high (TMB-H), intermediate (TMB-I) or low (TMB-L).
Result:
188 immunotherapy-treated (83.5% nivolumab, 11.7% pembrolizumab, 4.8% anti-PD1/PD-L1 plus anti-CTLA-4) pts with KRAS-mutant NSCLC were included in the efficacy analysis. The ORR differed significantly between the KL (8.8%), KP (35.9%) and K-only sub-groups (27.3%) (P=0.0011, Fisher’s exact test). KL LUAC exhibited significantly shorter PFS (mPFS 1.8m vs 2.7m, HR=0.53, 95% CI 0.34-0.84, P<0.001, log-rank test) and OS (mOS 6.8m vs 15.6m, HR 0.53, 95% CI 0.34 to 0.84, P=0.0072, log rank test) compared to KRAS-mutant NSCLC with wild-type STK11. Loss-of function (LOF) genetic alterations in STK11 were the only significantly enriched event in PD-L1 negative, TMB-I/H compared to PD-L1 high positive (TPS≥50%), TMB-I/H tumors in the overall FMI cohort (Bonferroni adjusted P=2.38x10[-4], Fisher’s exact test) and among KRAS-mutant tumors (adjusted P=0.05, Fisher’s exact test) . Notably, PD-1 blockade demonstrated activity among 10 PD-L1-negative KP tumors, with 3 PRs and 4SDs recorded. In syngeneic isogenic murine models PD-1 blockade significantly inhibited the growth of Kras mutant tumors with wild-type LKB1 (K), but not those with LKB1 loss (KL), providing evidence that LKB1 loss can play a causative role in promoting PD-1 inhibitor resistance.
Conclusion:
Loss of function genomic alterations in STK11 represent a dominant driver of de novo resistance to PD-1/PD-L1 blockade in KRAS-mutant NSCLC. In addition to tumor PD-L1 status and tumor mutational burden precision immunotherapy approaches should take into consideration the STK11 status of individual tumors.
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OA 07 - Biomarker for Lung Cancer (ID 659)
- Event: WCLC 2017
- Type: Oral
- Track: Biology/Pathology
- Presentations: 1
- Moderators:Philip Christopher Mack, Shinichi Toyooka
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 503
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OA 07.03a - Impact of Tumor Mutation Burden on the Efficacy of Nivolumab or Nivolumab + Ipilimumab in Small Cell Lung Cancer: An Exploratory Analysis of CheckMate 032 (ID 11063)
15:45 - 17:30 | Author(s): M.M. Awad
- Abstract
- Presentation
Background:
CheckMate 032 is a phase 1/2 clinical trial evaluating nivolumab ± ipilimumab in solid tumors, including small cell lung cancer (SCLC). Initial results have shown durable responses and encouraging survival, with benefit seen regardless of PD-L1 status. There is a need for improved biomarkers in SCLC. SCLC is nearly universally found in smokers and is characterized by high tumor mutation burden (TMB). The association of high TMB and clinical benefit from nivolumab ± ipilimumab in patients with SCLC was evaluated in an exploratory analysis of CheckMate 032.
Method:
CheckMate 032 evaluated nivolumab ± ipilimumab in non-randomized and randomized cohorts, which were pooled for this analysis. Whole exome sequencing (WES) was conducted on tumor and matched blood samples. TMB was defined as the total number of nonsynonymous somatic mutations. For the exploratory analyses, patients were equally divided into TMB tertiles (defined as low, medium, and high). Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan-Meier methods.
Result:
Among 401 patients in the intent-to-treat (ITT) population, 211 (53%) had an evaluable TMB result for these analyses (86% of the 246 patients with tissue available to attempt WES). Baseline characteristics and outcomes were similar between the ITT and TMB-evaluable populations. In TMB-evaluable patients treated with nivolumab (n=133), objective response rate (ORR), PFS, and OS were improved in the high TMB cohort vs the medium and low TMB cohorts (ORR: 21.3% vs 6.8% and 4.8%; 1-year PFS: 21.2% vs 3.1% and not calculable; 1-year OS: 35.2% vs 26.0% and 22.1%). Similar benefits were seen in TMB-evaluable patients treated with nivolumab + ipilimumab (n=78) in the high vs medium and low TMB cohorts (ORR: 46.2% vs 16.0% and 22.2%; 1-year PFS: 30.0% vs 8.0% and 6.2%; 1-year OS 62.4% vs 19.6% and 23.4%).
Conclusion:
In patients with SCLC, efficacy with nivolumab ± ipilimumab was enhanced in those with high TMB. Among patients with high TMB, ORR and 1-year OS rates were approximately double with nivolumab + ipilimumab compared with nivolumab monotherapy. TMB has a potential role as a biomarker in lung cancer. Optimization of TMB cutoff and prospective investigation are warranted.Acknowledgements: All authors contributed to and approved the abstract; writing and editorial assistance was provided by Beth Burke, PhD, CMPP, of Evidence Scientific Solutions, funded by Bristol-Myers Squibb.Trial Registration: clinicaltrials.gov, NCT01928394
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OA 17 - Immunotherapy II (ID 683)
- Event: WCLC 2017
- Type: Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yuichiro Ohe, Anne Tsao
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 301 + 302
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OA 17.01 - Pemetrexed-Carboplatin Plus Pembrolizumab as First-Line Therapy for Advanced Nonsquamous NSCLC: KEYNOTE-021 Cohort G Update (ID 9059)
14:30 - 16:15 | Author(s): M.M. Awad
- Abstract
- Presentation
Background:
Cohort G of the multicenter, open-label, phase 1/2 KEYNOTE-021 study (ClinicalTrials.gov, NCT02039674) evaluated efficacy and safety of pembrolizumab + pemetrexed and carboplatin (PC) compared with PC alone as first-line therapy for patients with advanced nonsquamous NSCLC. At the primary analysis of cohort G (minimum follow up, 6 months; median, 10.6 months), pembrolizumab significantly improved ORR (estimated treatment difference, 26%; P=0.0016) and PFS (hazard ratio [HR], 0.53; P=0.010). The HR for OS was 0.90 (95% CI, 0.42‒1.91). In a subsequent analysis (median follow-up, 14.5 months), the HR for OS was 0.69 (95% CI, 0.36‒1.31). We present results from the May 31, 2017 data cutoff.
Method:
Patients with stage IIIB/IV nonsquamous NSCLC, no prior systemic therapy, and no EGFR mutation or ALK translocation were randomized 1:1 (stratified by PD-L1 TPS ≥1% versus <1%) to receive 4 cycles of carboplatin AUC 5 + pemetrexed 500 mg/m[2] Q3W with or without pembrolizumab 200 mg Q3W. Pembrolizumab treatment continued for up to 2 years; maintenance pemetrexed was permitted in both arms. Eligible patients in the PC arm with radiologic progression could cross over to pembrolizumab monotherapy. Response was assessed by blinded, independent central review per RECIST v1.1. All P values are nominal (one-sided P<0.025).
Result:
123 patients were randomized. Median follow-up was 18.7 months (range, 0.8‒29.0 months). 40 of 53 (75%) patients in the PC arm who discontinued received subsequent anti-PD-1/anti-PD-L1 therapy (including 25 who received pembrolizumab in the on-study cross over). ORR was 57% with pembrolizumab + PC versus 32% with PC (estimated difference, 25%; 95% CI, 7%‒41%; P=0.0029). PFS was significantly improved with pembrolizumab + PC versus PC (HR, 0.54; 95% CI, 0.33‒0.88; P=0.0067) with median (95% CI) PFS of 19.0 (8.5‒NR) months versus 8.9 (6.2‒11.8) months. The HR for OS was 0.59 (95% CI, 0.34‒1.05; P=0.0344). Median (95% CI) OS was not reached (22.8‒NR) months for pembrolizumab + PC and 20.9 (14.9‒NR) months for PC alone; 18-month OS rates were 70% and 56%, respectively. Grade 3–5 treatment-related AEs occurred in 41% of patients in the pembrolizumab + PC arm versus 29% in the PC arm.
Conclusion:
Over the course of the 3 analyses, the HR for OS continues to improve for pembrolizumab + PC versus PC (HR: 0.90 to 0.69 to 0.59). The significant improvements in PFS and ORR with pembrolizumab + PC versus PC first observed in the primary analysis have been maintained with longer follow-up (median, 18.7 months).
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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-055 - Spectrum of Early Progression in Advanced NSCLC Patients Treated with PD-1 Inhibitors: Identifying Markers for Poor Outcome (ID 8275)
09:30 - 16:00 | Author(s): M.M. Awad
- Abstract
Background:
While marked responses have been observed in patients with non-small-cell lung cancer (NSCLC) treated with PD-1 pathway inhibitors, anecdotal evidence indicates that rapid progression with dramatic tumor burden increase early in the course of therapy may be noted in a few patients. The study characterized the spectrum of early progression of advanced NSCLC treated with PD-1 inhibitors, and investigated quantitative imaging markers for poorer outcome.
Method:
The study included 134 patients (53 men, 81 women; median age: 66) with advanced NSCLC treated with commercially prescribed single-agent nivolumab or pembrolizumab, who had follow-up CT scans at 8 +/- 2 weeks of therapy. Tumor burden measurements were performed using RECIST1.1 on baseline and 8-week scans to characterize the spectrum of early progression during PD-1 therapy. Tumor burden changes at 8 weeks were studied for association with overall survival (OS), which was measured from the 8-week scan date.
Result:
The tumor burden changes at 8 weeks comparing to baseline ranged from -72.7% to +138.7% (median: +4.3%; the 90[th] percentile: +50.07%). OS of 15 patients with ≥50% increase of tumor burden at 8 weeks was significantly shorter compared to 119 patients with <50% increase at 8 weeks (median OS: 4.5 months [95%CI: 1.3-4.9] vs. 12.7 months [95%CI: 8.5-14.7]; log-rank p=0.0003). Among 42 patients who experienced tumor burden increase ≥20% (RECIST progression threshold) at 8 weeks, 15 patients with ≥50% increase had shorter OS than 27 patients with ≥20% but <50% increase (median OS: 4.5 months [95%CI: 1.3-4.9] vs. 6.8 months [95%CI: 5.4-20.1]; log-rank p=0.08), indicating that ≥50% increase threshold may identify a distinct group of early progressors with poorer prognosis. Never smokers were more likely to experience ≥50% increase at 8 weeks than former or current smokers (Fisher p=0.03).
Conclusion:
Tumor burden increase of ≥50% at 8 weeks of therapy was associated with significantly shorter OS in advanced NSCLC patients treated with commercial PD-1 inhibitors, indicating that it can serve as an imaging marker to identify a distinct subset of patients with poorer outcome of PD-1 inhibitor therapy, and may thus help guide treatment decisions.
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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: 2
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.07-002 - Drug-Related Pneumonitis in Advanced Non-Small-Cell Lung Cancer (NSCLC) Patients Treated with Commercial PD-1 Inhibitors (ID 7559)
09:30 - 16:00 | Author(s): M.M. Awad
- Abstract
Background:
PD-1 inhibitor-related pneumonitis is recognized as a serious immune-related adverse event especially among NSCLC patients. The study investigated the radiographic patterns, clinical course, and risk factors of pneumonitis in advanced NSCLC patients treated with commercial PD-1 inhibitors.
Method:
The study included 210 patients (93 men, 117 women; median age: 65) with advanced NSCLC treated with commercially prescribed single-agent nivolumab or pembrolizumab. Chest CT scans during therapy were reviewed for abnormalities suspicious for pneumonitis by an independent review of two radiologists. Radiographic patterns of pneumonitis were classified using the ATS/ERS classification of interstitial pneumonia.
Result:
Pneumonitis was radiographically detected in 20 patients (20/210; 9.5%). Median time from the initiation of therapy to pneumonitis was 7.8 weeks. The radiographic pattern of pneumonitis was a cryptogenic organizing pneumonia (COP) pattern in 18, a non-specific interstitial pneumonia (NSIP) pattern in one, and a hypersensitivity pneumonitis (HP) pattern in one patient. Fifteen patients (75%) were symptomatic and 5 patients (25%) were asymptomatic with radiographic abnormalities alone. PD-1 inhibitors were held in 17 patients (85%), and corticosteroids were given in 12 patients (60%). Seven patients were hospitalized for treatment of pneumonitis. Three patients were re-treated with PD-1 inhibitors and two developed recurrent pneumonitis. There were no significant differences in clinical characteristics between patients with and without pneumonitis (p>0.34). Figure 1
Conclusion:
PD-1 inhibitor-related pneumonitis was noted in 9.5% of the advanced NSCLC patients treated with commercially prescribed PD-1 inhibitors. Radiographic pattern of pneumonitis was most commonly a COP pattern. Recurrent pneumonitis was common among those who were re-treated with PD-1 inhibitors. Further studies are necessary to identify risk factors for pneumonitis.
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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 | Author(s): M.M. Awad
- 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.
