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Amy Lauren Cummings
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MA11 - Immunotherapy in Special Populations and Predictive Markers (ID 135)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:Frank Griesinger, Lecia Sequist
- Coordinates: 9/09/2019, 14:00 - 15:30, Hilton Head (1978)
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MA11.11 - STK11/LKB1 Genomic Alterations Are Associated with Inferior Clinical Outcomes with Chemo-Immunotherapy in Non-Squamous NSCLC (Now Available) (ID 2898)
14:00 - 15:30 | Author(s): Amy Lauren Cummings
- Abstract
- Presentation
Background
Addition of pembrolizumab (P) to platinum-doublet chemotherapy [carboplatin (or cisplatin) and pemetrexed (CP)] prolongs overall survival and is a standard of care (SOC) for the 1st line treatment of metastatic EGFR/ALK wild-type (wt) non-squamous non-small cell lung cancer (mnsNSCLC). Despite widespread use of the CPP regimen, molecular determinants of clinical benefit from the addition of P to CP remain poorly defined. We previously identified genomic alterations in STK11/LKB1 as a major driver of primary resistance to PD-1/PD-L1 blockade in mnsNSCLC. Here, we present updated data on the impact of STK11/LKB1 alterations on clinical outcomes with CPP chemo-immunotherapy from a large retrospective multi-institution international study.
Method
620 pts with mnsNSCLC and tumor genomic profiling encompassing STK11/LKB1 from 21 academic institutions in the US and Europe were included in this study. Clinical outcomes were collected for two distinct patient cohorts: a) 468 pts treated with first-line CPP (or >1st line following FDA-approved TKIs) that were alive for 14 days thereafter and b) 152 STK11/LKB1-mt pts that received CP prior to regulatory approval of CPP.
Result
Among 468 CPP-treated pts, STK11/LKB1 genomic alterations (N=118) were associated with significantly shorter PFS (mPFS 5.0m vs 6.8m, HR 1.45, 95% CI 1.11 to 1.91; P=0.007) and shorter OS (mOS 10.6m vs 16.7m, HR 1.46, 95% CI 1.04 to 2.07; P=0.031) compared with STK11/LKB1-wt tumors (N=350). The likelihood of disease progression as BOR to CPP differed significantly between the two groups (29.5% vs 17%, P= 0.006). Similar results were obtained when limiting the analysis to EGFR and ALK-wt tumors (N=435) (mPFS 5.0m vs 6.9m, HR 1.48, 95% CI 1.12-1.95, P=0.006 and mOS 10.6m vs 16.7m, HR 1.45, 95% CI 1.02-2.05, P=0.036). Importantly, in pts with STK11/LKB1-mt mnsNSCLC, addition of pembrolizumab to CP did not result in significant improvement of PFS (mPFS 5.0m vs 3.9m, HR 0.82, 95% CI 0.63 to 1.07, P=0.14) or OS (mOS 10.6m vs 9.1m, HR 0.93, 95% CI 0.67 to 1.30, P=0.69) compared to CP alone.
Conclusion
In mnsNSCLC, STK11/LKB1 alterations define a subgroup of pts with inferior clinical outcomes with CPP and lack of benefit from the addition of pembrolizumab to CP chemotherapy. Novel therapeutic strategies are required to establish effective antitumor immunity in STK11/LKB1-mutant NSCLC.
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P1.04 - Immuno-oncology (ID 164)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.04-33 - Deep Phenotyping of Immune Populations Reveals Baseline Predictors of Pembrolizumab Efficacy in NSCLC on KEYNOTE-001 (Now Available) (ID 2292)
09:45 - 18:00 | Author(s): Amy Lauren Cummings
- Abstract
Background
Medical treatment of lung cancer has irreversibly changed since the development of immune checkpoint inhibitors like pembrolizumab. However, immune biomarkers of efficacy are still lacking. Preliminary data in melanoma showed that a high baseline blood level of classical monocytes was associated with improved outcome in patients treated with programmed cell death-1 (PD-1) inhibitors. This led us to explore the immune landscape of non-small cell lung cancer (NSCLC) patients treated with pembrolizumab on KEYNOTE-001 using high-dimensional mass cytometry.
Method
We analyzed 38 advanced NSCLC patients treated with pembrolizumab on KEYNOTE-001 at UCLA. Mass cytometry (CyTOF) was performed on baseline peripheral blood mononuclear cells (PMBC). We used a panel of 31 antibodies defining major immune populations of myeloid cells (plasmacytoid and myeloid dendritic cells, myeloid-derived suppressor cells, classical and CD16+ monocytes), lymphoid cells (B cells, NK cells, TReg, γδ T-cells, sub-populations of CD4+ and CD8+ T-cells), selected co-stimulatory (CD28, ICOS, 41BB), co-inhibitory molecules (PD-1, PD-L1, TIM3, LAG3, CTLA-4) and cytotoxicity molecules (perforin, granzymeB). Unsupervised clustering combined with predictive regression model (Citrus algorithm, false discovery rate = 1%) was used to detect immune populations differing between patients that experienced an objective response on trial, as assessed by immune-related response criteria (responders) vs those that did not (non-responders). Classical manual gating (FlowJo software) was used to confirm the Citrus results.
Result
Among the 38 patients analyzed via CyTOF, 27 patients had sufficient viable cells for analysis. Citrus algorithm comparing responders (n=7) and non-responders (n=20) revealed significant frequency differences in specific subtypes of three immune populations: monocytes, CD4+ and CD8+ T-cells. Manual gating confirmed that responders (vs non-responders) had increased frequency (%CD45+) of classical monocytes perforin+ granzymeB+ (5.54% vs 2.55%, p=0.029), central memory CD4+ T-cells ICOS+ CD28+ PD1+ (1.29% vs 0.83%, p=0.06) and over-expression of 41BB (mean metal intensity (MMI)=0.15 vs MMI=0.09, p=0.006) and perforin (MMI=108.4 vs MMI=70.7, p=0.004) in effector memory CD8+ T-cells.
Conclusion
Mass cytometry in the blood reveals that a high baseline frequency of activated and cytotoxic monocytes, CD4+ and CD8+ T-cells predicted for pembrolizumab efficacy in advanced NSCLC. Preliminary analyses correlating immune cell populations and overall survival are ongoing and suggest a similar increase in the three immune cell populations found to be higher in responders vs non-responders.
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P1.12 - Small Cell Lung Cancer/NET (ID 179)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.12-22 - A Phase 1b/2 Study of Niraparib Plus Temozolomide Versus Standard Care as Maintenance Therapy in Extensive-Stage Small Cell Lung Cancer Patients (ID 504)
09:45 - 18:00 | Presenting Author(s): Amy Lauren Cummings
- Abstract
Background
Maintenance therapy is a promising therapeutic approach for extensive-stage small cell lung cancer (ES-SCLC), especially in light of IMpower 133 (Horn NEJM 2018). SCLC models of poly (ADP-ribose) polymerase (PARP) protein 1 and 2 inhibition suggested synergy with temozolomide (TMZ) (Wainberg AACR 2016). Combining PARP inhibition with TMZ after first-line therapy for ES-SCLC may improve disease control.
Method
This is a phase 1b/2, randomized, open-label study of TMZ plus niraparib, a PARP inhibitor, versus best supportive care (BSC) as maintenance therapy in adult patients with ES-SCLC after completion of platinum-based first-line chemotherapy. The primary outcome for phase 1b is the RP2D of TMZ in combination with niraparib, and for phase 2, progression-free survival (PFS). Secondary endpoints include safety and overall survival. Exploratory endpoints include patient-reported outcomes on health-related quality of life and adverse events which will be collected electronically through a patient portal. Phase 1b participants are required to have an advanced and incurable solid malignancy. An accelerated lead-in of 12 participants will be treated in cohorts of 6 with an initial dose level of niraparib 200 mg po daily in 28-day cycles in addition to low-dose TMZ 40 mg po daily on days 1-5 of each cycle. For phase 2, participants are required to have ES- SCLC with a complete response or partial response per RECIST 1.1 following 4 to 6 cycles of platinum-based chemotherapy and ability to proceed to randomization within 7 weeks after day 1 of the last cycle of prior chemotherapy. Prophylactic WBRT is allowed prior to study. 52 participants will be stratified by a history of brain metastases and randomized 1:1 to RP2D niraparib plus TMZ versus BSC. There will be no cross-over between arms.
Result
Section not applicable.
Conclusion
Section not applicable.
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P2.12 - Small Cell Lung Cancer/NET (ID 180)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.12-09 - Phase 2 Study of Talazoparib Plus Low-Dose Temozolomide in Patients with Relapsed/Refractory Extensive-Stage Small Cell Lung Cancer (ID 954)
10:15 - 18:15 | Author(s): Amy Lauren Cummings
- Abstract
Background
Talazoparib exhibits cytotoxic effects by inhibiting poly (ADP-ribose) polymerase (PARP) proteins 1 and 2 in addition to “trapping” PARP on DNA. Temozolomide (TMZ) has been shown to increase antitumor response when combined with a PARP inhibitor in small cell lung cancer (SCLC) models (Wainberg AACR 2016). Combining PARP inhibition with TMZ as second-line therapy for ES-SCLC may improve disease-related outcomes.
Method
This is a phase 2, open-label, single-arm study of the safety and efficacy of talazoparib plus TMZ in patients with extensive-stage SCLC. The primary endpoint is objective response rate (ORR) based on RECIST 1.1 criteria. Secondary endpoints include progression-free survival, overall survival, duration of response, and time to response. Exploratory endpoints include biomarker studies such as DNA damage response gene analysis and patient reported outcomes (PRO).
Participants are required to have relapsed (progressed within 6 months) or refractory (progressed
during or within 4 weeks of completing 1stline platinum-based regimen) ES-SCLC. Those with a best response of progressive disease to first-line therapy per RECIST 1.1 or more than one line of cytotoxic therapy are excluded. Prior immunotherapy is allowed. Participants receive talazoparib 0.75 mg po daily on 28-day cycles with TMZ 37.5 mg/m2 po on days 1-5. 15 participants will be enrolled in the first part of a Simon two-stage design; if 3 or more responses are seen, an additional 13 participants will be enrolled. The null hypothesis will be rejected if 8 or more objective responses are observed compared to a historical control of 15% ORR in second-line topotecan (Horita Sci Rep 2015).
Result
As of 8 March 2019, 3 participants were evaluable for treatment response. Median age was 51 (range 46-80). One participant had a confirmed partial response (PR) with 50% reduction in target lesions, one had stable disease with 16% reduction in target lesions, and one had progressive disease (PD). Biomarker and PRO analysis correlated with the radiographic response. In the participant with PR, Guardant circulating tumor DNA testing showed PIK3CA amplification and TP53 mutations at baseline that were not detectable at week 5 of treatment, whereas the other subjects has persistent ctDNA. Patient-reported outcomes similarly noted improvement in the participant with PR within 2 weeks while the one with PD showed no improvement throughout treatment course. Adverse events were hematologic, including one grade 4 thrombocytopenia that resolved within 2 weeks.
Conclusion
Combination talazoparib and TMZ used as second-line therapy in ES-SCLC is tolerable and has shown promising preliminary results. The trial will continue to enroll. Updated response and biomarker data will be presented.