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J. Brahmer
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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: 2
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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 - 12:30 | Author(s): J. Brahmer
- 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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OA03.05 - Analysis of Early Survival in Patients with Advanced Non-Squamous NSCLC Treated with Nivolumab vs Docetaxel in CheckMate 057 (Abstract under Embargo until December 5, 7:00 CET) (ID 4392)
11:00 - 12:30 | Author(s): J. Brahmer
- Abstract
- Presentation
Background:
Nivolumab significantly improved OS versus docetaxel in patients with previously treated advanced non-squamous NSCLC (CheckMate 057; NCT01673867). Kaplan−Meier OS curves for nivolumab and docetaxel crossed at ~7 months, suggesting non-proportional hazards between arms.
Methods:
Post-hoc analyses were conducted to explore relationships between baseline patient/disease characteristics, including PD-L1 expression, and death within the first 3 months of treatment (3motx). Additionally, the association between PD-L1 expression level and magnitude of clinical benefit was explored.
Results:
During the first 3motx, risk of death (rDt) was numerically higher with nivolumab versus docetaxel (59 versus 44 deaths among 292 and 290 patients, respectively). Early deaths were most commonly attributed to disease progression (no treatment-related deaths occurred). At 3motx, 80% of nivolumab-treated patients (233/292) and 85% of docetaxel-treated patients (246/290) were alive. After 3motx, the rDt was consistently higher in the docetaxel arm. In univariate analyses, no single baseline factor, including PD-L1 expression, EGFR mutation, ECOG PS, or smoking status, reliably characterized the rDt within the first 3motx with nivolumab. Among patients alive >3 months, the OS HR (95% CI) favored nivolumab in the overall population (0.59 [0.47−0.74]) and PD-L1 non-expressors (PD-L1 expression <1%; 0.66 [0.45−0.97]). In a multivariate analysis, factors associated with higher rDt within the first 3motx on nivolumab versus docetaxel were ECOG PS=1, time since last treatment <3 months, and/or progressive disease as best response to prior treatment combined with lower or no PD-L1 expression. However, the majority of nivolumab-treated patients with these attributes (including PD-L1 non-expressors), did not die within the first 3motx and experienced subsequent benefit. PD-L1 expression was a continuum, ranging from 1 to 100%, with increasing expression associated with enhanced ORR/OS benefit from nivolumab.
Conclusion:
In CheckMate 057, the benefit−risk profile of nivolumab versus docetaxel was favorable across the overall patient population. During the first 3motx, a small difference in the number of deaths (n=15) was observed; thereafter the OS rate consistently favored nivolumab (2-year OS was >2-fold higher with nivolumab versus docetaxel). Patients with poorer prognostic factors and/or more aggressive disease combined with lower or no PD-L1 expression appeared to be at higher rDt within the first 3motx on nivolumab versus docetaxel. With the exception of PD-L1 status, these are recognized prognostic factors. While PD-L1 expression may help inform individual treatment decisions, PD-L1 status alone is not considered an appropriate biomarker for nivolumab treatment selection in pre-treated advanced NSCLC, but rather should be considered in the context of other patient/disease characteristics.
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OA20 - Immunotherapy and Markers (ID 401)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:M. Früh, C.S. Baldotto
- Coordinates: 12/07/2016, 11:00 - 12:30, Stolz 2
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OA20.02 - Neoantigen Targeting in NSCLC Patients with Complete Response to Anti-PD-1 Immunotherapy (ID 4352)
11:00 - 12:30 | Author(s): J. Brahmer
- Abstract
- Presentation
Background:
Anti-PD-1 immunotherapy has resulted in durable clinical responses in heavily pretreated patients with non-small cell lung cancer (NSCLC). While NSCLC is typically seen as non-immunogenic, there is a 15-20% objective response rate and a median duration of response of 17 months in patients treated with the PD-1 inhibitor, nivolumab. This duration of response has not been reported with other systemic therapies in advanced NSCLC. While tumor PD-L1 expression may be a biomarker of sensitivity to anti-PD-1 therapy, and the number of somatic mutations may play a role in PD-1 upregulation on T cells, the mechanisms underlying response vs. progressive disease have yet to be fully elucidated.
Methods:
Whole exome sequencing and mutation-associated neoantigen (MANA) prediction was performed on tumor sections from two advanced NSCLC patients with complete response to nivolumab. Peptides representing MANAs were synthesized and tested against PBMC in a 10-day cultured IFNg ELISpot assay. Reactive MANAs were assessed in binding and stability assays. TCR sequencing was performed on reactive cell cultures and on DNA obtained from tumor resections to match MANA-reactive TCR clones with clones that were infiltrating the tumor.
Results:
The mean mutational burden in NSCLC as reported previously is 360 sequence alterations. In our study, patient 1 had 30 sequence alterations and patient 2 had 314. Despite the difference in mutational load, MANA reactivity was detected in peripheral blood of both patients >1 year after being declared cancer-free. TCR clones of MANA-reactive peripheral T cells were detected in tumor resections and were expanded in MANA-stimulated T cell cultures. Binding and stability assays confirmed that these MANAs bind to their cognate HLA with high affinity and stability.
Conclusion:
These findings show that NSCLC tumors with differential mutational burden can show regression following checkpoint blockade and suggest that the quality of mutations may be more influential in immunogenicity than the overall quantity of mutations. Our data also show that MANA reactivity may be the underlying mechanism by which T cells eliminate tumor following anti-PD-1 immunotherapy. Additional studies should evaluate mechanisms of enhancing MANA reactivity in patients who do not respond to checkpoint blockade and should further validate the link between MANA reactivity and clinical response to anti-PD-1.
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