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S.J. Antonia
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MA09 - Immunotherapy Combinations (ID 390)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:M. Sebastian, E.B. Garon
- Coordinates: 12/06/2016, 14:20 - 15:50, Strauss 2
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MA09.05 - Nivolumab Alone or with Ipilimumab in Recurrent Small Cell Lung Cancer (SCLC): 2-Year Survival and Updated Analyses from the Checkmate 032 Trial (ID 4397)
14:50 - 14:56 | Author(s): S.J. Antonia
- Abstract
- Presentation
Background:
Patients with SCLC and disease progression during/after first-line platinum-based chemotherapy have poor prognoses and limited treatment options. Nivolumab alone and in combination with ipilimumab has shown survival benefit and durable responses in multiple tumor types. Here we present updated results for the SCLC cohort of the phase 1/2 CheckMate 032 trial (NCT01928394), which was designed to evaluate nivolumab or nivolumab/ipilimumab in advanced solid tumors.
Methods:
Patients with advanced SCLC that progressed following ≥1 platinum-based chemotherapy regimens were assigned to receive nivolumab monotherapy (nivolumab-3 Q2W) or nivolumab/ipilimumab combination therapy (nivolumab-1/ipilimumab-3 or nivolumab-3/ipilimumab-1 Q3W for 4 cycles, then nivolumab-3 Q2W). Patients were eligible regardless of platinum sensitivity or tumor programmed death ligand 1 (PD-L1) expression. The primary endpoint was ORR. Additional endpoints were duration of response (DOR), OS, PFS, safety, and correlation of tumor PD-L1 expression with activity.
Results:
214 patients have been enrolled to date (nivolumab-3, n=98; nivolumab-1/ipilimumab-3, n=61; nivolumab-3/ipilimumab-1, n=55), including 96 and 118 patients treated with 1 or ≥2 prior regimens, respectively. Efficacy and safety data are shown (table). In the nivolumab-1/ipilimumab-3 cohort, ORR was 23% and 1-year OS was 43%. The proportion of patients with PD-L1–expressing tumors was substantially lower in previously treated SCLC in this study than that previously observed with pretreated NSCLC (16% vs 53%–54% with ≥1% PD-L1 expression). In SCLC, responses were observed regardless of PD-L1 expression. ORR and median OS were similar in patients treated with 1 or ≥2 prior regimens. Rate of discontinuation due to treatment-related AEs ranged from 5% to 11%; there were 3 treatment-related deaths. Figure 1
Conclusion:
Durable objective responses were observed with nivolumab and nivolumab/ipilimumab in patients with previously treated SCLC, and safety profiles were consistent with other tumor types. Updated efficacy (including 2-year OS and DOR), safety, and additional subgroup analyses will be presented from the August 2016 DBL.
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OA03 - Immunotherapy Checkpoint Inhibitors in Advanced NSCLC (ID 367)
- Event: WCLC 2016
- Type: Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
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OA03.01 - First-Line Nivolumab Monotherapy and Nivolumab plus Ipilimumab in Patients with Advanced NSCLC: Long-Term Outcomes from CheckMate 012 (Abstract under Embargo until December 5, 7:00 CET) (ID 5364)
11:00 - 11:10 | Author(s): S.J. Antonia
- Abstract
- Presentation
Background:
Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor antibody, has demonstrated improved efficacy and tolerability vs docetaxel in patients with advanced NSCLC that progressed on or after platinum-based chemotherapy and is approved in >50 countries in this patient population. We report efficacy and safety data from a phase 1 study (CheckMate 012; NCT01454102) evaluating first-line nivolumab in patients with advanced NSCLC.
Methods:
Patients (N=52) with advanced, chemotherapy-naive NSCLC (any histology) were treated with nivolumab monotherapy at 3 mg/kg IV Q2W until disease progression or unacceptable toxicity. Safety and tolerability was the primary study objective. Efficacy, as measured by objective response rate (ORR) and 24-week progression-free survival (PFS) rate per RECIST v1.1, was the secondary objective. Overall survival (OS) was an exploratory endpoint.
Results:
Treatment-related adverse events (TRAEs) were reported in 71% (any grade) and 19% (grade 3‒4) of patients. The most frequent select TRAEs (those with potential immunologic causes) by category were skin, endocrine, and gastrointestinal (Table). With a median follow-up of 14.3 months (range, 0.2 to 30.1), the confirmed ORR was 23% (12/52) and 8% (4/52) of patients had complete responses. Of the 12 responses, 8 (67%) were ongoing at the time of database lock; median duration of response was not reached. Median OS was 19.4 months (range, 0.2‒35.8+). The 24-week PFS rate was 41% (95% CI: 27‒54); 18-month OS rate was 57% (95% CI: 42‒70). Updated long-term data will be presented, including 2-year OS and will represent the longest follow-up to date for a PD-1/PD-L1 inhibitor for first-line advanced NSCLC. Updated data from patients treated with nivolumab plus ipilimumab (N = 77) will also be presented.Nivolumab monotherapy (N=52) Safety Any grade / grade 3‒4 TRAEs,[a] n (%) 37 (71) / 10 (19) Any grade / grade 3‒4 select TRAEs,[a,b] by category (≥10% of patients), n (%) Skin 13 (25) / 2 (4) Endocrine 7 (14) / 0 (0) Gastrointestinal 6 (12) / 1 (2) Any grade / grade 3‒4 TRAEs leading to discontinuation, n (%) 6 (12) / 6 (12) Efficacy Confirmed ORR,[c] n (%) [95% CI] 12 (23) [13‒37] CR 4 (8) PR 8 (15) SD 14 (27) PD 20 (38) Unable to determine[d] 6 (12) Median DOR, mo (range) NR (4.2‒25.8+) Ongoing responders, n/N (%) 8/12 (67) Median PFS, mo (range) 3.6 (<0.1+‒28.0+) 24-week PFS, % (95% CI) 41 (27‒54) Median OS, mo (range) 19.4 (0.2‒35.8+) 1-year OS, % (95% CI) 73 (59‒83) 18-month OS, % (95% CI) 57 (42‒70) Efficacy and safety analyses, except for OS, were based on a March 2015 database lock; OS analyses were based on an August 2015 database lock.[a]No grade 5 events were reported.[b]AEs with a potential immunologic cause.[c]Includes patients with initial observations of CR and PR that were subsequently confirmed by repeat scans performed no earlier than 4 weeks after the original observation.[d]Includes patients who discontinued therapy because of disease progression before first assessment or patients only with assessments suggestive of, but that did not satisfy, the required minimum duration for SD. CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; DOR = duration of response; NR = not reached.
Conclusion:
First-line nivolumab monotherapy in patients with advanced NSCLC had a similar safety profile as previously reported in second-line NSCLC and other tumors, was well tolerated, and demonstrated durable efficacy.
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P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.01-072 - Clinical Associations of MUC1 Expression in Human Lung Cancer and Precancerous Lesions (ID 4473)
14:30 - 14:30 | Author(s): S.J. Antonia
- Abstract
Background:
Mucin 1 (MUC1) is a cell membrane glycoprotein overexpressed in many human cancers, including nonsmall cell lung cancer (NSCLC). Its role has been implicated in carcinogenesis of premalignant lung lesions in animal models and in clinical association with prognosis in NSCLC. Thus, MUC1 has been a target of interest for vaccine strategies as an mmunomodulatory approach to lung cancer treatment and prevention.
Methods:
Tumor samples from 38 patients with biopsy-proven NSCLC were assessed for MUC1 expression as determined by immunohistochemistry, expressed on a 0 to 3 scale. Levels of MUC1 expression in areas of dysplasia, metaplasia, bronchoalveolar carcinoma (BAC) and carcinoma present within the same tissue sample were characterized independently and compared using the paired ttest. Clinical data including patient characteristics, staging, treatment and survival were also assessed for correlation with MUC1 expression.
Results:
16 patients with squamous and 19 patients with glandular lesions had tumor samples that were satisfactory for analyses. Among squamous lesions, there was a significant increase in MUC1 expression score in dysplastic compared with metaplastic areas (mean difference = 0.83, 95% CI, 0.21 to infinity; p = 0.021). We also observed an increase in squamous cell carcinoma compared with dysplastic areas (mean difference = 0.44, 95% CI, 0.006 to infinity; p = 0.052). Among glandular lesions, there was a nonsignificant increase in MUC1 expression in adenocarcinoma compared with BAC (mean difference = 0.20, 95% CI, 0.055 to infinity; p = 0.094). According to the Spearman correlation test (p = 0.020 for carcinoma score; p = 0.008 for dysplasia score), a significant positive correlation was observed between MUC1 expression and survival in patients with squamous lesions; however, no significant correlation was observed between MUC1 expression and survival in patients with adenocarcinoma.
Conclusion:
MUC1 overexpression appears to be increased with the progression of premalignant lung lesions to invasive carcinoma in patients with NSCLC. This supports the rationale for MUC1 as a therapeutic target in tumor vaccines that could be ultimately used to prevent or reverse precancerous lesions and treat lung cancer.
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-024 - Dynamics of EGFR Mutational Load in Urine and Plasma Correlates with Treatment Response in Advanced NSCLC (ID 5529)
14:30 - 14:30 | Author(s): S.J. Antonia
- Abstract
Background:
NSCLC is a heterogeneous and dynamic disease where testing for key mutations is essential. With the emergence of clonal resistance, obtaining serial biopsies to assist in the real-time treatment decision-making has proven challenging. Molecular assessments of circulating tumor (ct)DNA has been previously shown feasible utilizing blood specimens. Here we additionally investigated the utility of serial urine ctDNA analysis in NSCLC.
Methods:
This is a prospective observational study of patients with non-squamous, tissue-confirmed EGFR, KRAS or ALK mutant NSCLC preparing to receive a systemic treatment regimen. Urine and blood specimens were collected at baseline, on treatment and at progression for ctDNA analyses. The primary endpoints were correlation between ctDNA and tumor-based molecular results, and measurable change in ctDNA with response by RECIST v1.1. Blood and urine samples were sent to Trovagene for DNA extraction and mutation enrichment NGS.
Results:
Of the 34 patients enrolled thus far, interim blinded analysis of EGFR activating mutations (L858R, exon 19 deletions) was conducted in 20 patients with EGFR-positive tumors. Of 20 patients, 17 (85%) had detectable concordant EGFR mutation in pre-treatment urine and/or plasma. Of 11 patients with matched serial ctDNA samples, detectable EGFR mutation signal was observed in pre-treatment urine and/or plasma of 9 patients. These 9 patients received first to sixth line treatment with single EGFR TKI (n=3), combination TKIs (n=3), chemotherapy (n=1), immune checkpoint inhibitors alone (n=1) or in combination with TKI (n=1). In 9 of 9 patients, changes in ctDNA levels from baseline to cycle 2 day 1 on therapy correlated with best response to treatment: a 100% decrease in urine and plasma EGFR mutation levels was observed in 6 of 6 patients with partial response (PR, n=3) or stable disease (SD, n=3), while less than a 90% decrease or an increase in urine and plasma EGFR levels was observed in patients with progressive disease (PD, n=3).
Conclusion:
Mutation enrichment NGS testing by urine and plasma ctDNA correctly identified EGFR activating mutations in 85% of patients. Monitoring EGFR levels in urine/plasma enabled accurate assessment of response in advance of radiographic evaluation and regardless of therapy type in 100% of patients, with cut-point of a 90% decrease in EGFR load discriminating between patients with disease control (PR or SD) and patients with progressive disease. With continued enrollment, our study aims to further investigate clinical utility of urine and plasma ctDNA for early detection of resistance and discontinuation of inefficient therapy.
