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Ferdinandos Skoulidis
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MA03 - Clinomics and Genomics (ID 119)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:Heather A Wakelee, Wilfried Ernst Erich Eberhardt
- Coordinates: 9/08/2019, 10:30 - 12:00, Colorado Springs (1994)
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MA03.05 - BRAF Mutations Are Associated with Increased Benefit from PD1/PDL1 Blockade Compared with Other Oncogenic Drivers in Non-Small Cell Lung Cancer (Now Available) (ID 1472)
10:30 - 12:00 | Author(s): Ferdinandos Skoulidis
- Abstract
- Presentation
Background
PD-1/PD-L1 immune checkpoint blockade (ICB) has revolutionized the treatment of non-small cell lung cancer (NSCLC), but only a minority of patients achieve durable clinical benefit. Although classic EGFR/ALK alterations are correlated with ICB resistance, it is unknown if patients with other molecular subtypes of NSCLC also derive poorer outcomes from ICB. We investigated if there are oncogene-driven NSCLC associated with higher response rates (RR) and progression-free survival (PFS) to ICB.
Method
Two independent retrospective cohorts of oncogene-driven NSCLC treated with ICB monotherapy were analyzed for clinical outcome: MD Anderson (MDACC) and Flatiron Health-Foundation Medicine Clinico-Genomic Database (FH-CGDB). PD-L1 expression (Dako 22C3 - FoundationCore) and tumor mutational burden (TMB - FoundationCore; TCGA and MSK-IMPACT – cbioportal.org) were compared across distinct molecular subtypes of NSCLC to determine differences in clinical outcome.
Result
Among five oncogene defined groups from the MDACC cohort, BRAF-mutant NSCLC had the highest response rate (RR) (RECIST 1.1) (P<0.01) and PFS (P<0.01) when treated with ICB (Table). These differences remained significant after adjusting for PD-L1 expression. Classic EGFR and HER-2 mutant NSCLC had the lowest RR and PFS (Table). Similar results were observed in the independent FH-CGDB cohort where BRAF-mutant NSCLC had longer real-world (rw) PFS and OS to ICB monotherapy (Table). PD-L1 expression (tumor score ≥1% and ≥50%) and TMB were higher in BRAF-mutant NSCLC compared to EGFR and HER-2 (P<0.01). BRAF V600E NSCLC had lower TMB compared to non-V600E (5.9 vs 13.7 mut/Mb, P<0.01), but both had high PD-L1 expression (≥1%: 72% vs 61%; ≥50%: 42% vs 32%).
ConclusionKRAS
BRAF
Classic EGFR
EGFR exon 20
HER2
MDACC cohort
Patients – N
87
10 (V600E 3 / non-V600E 7)
28
25
15
RR – %
24.3
62.5
4.5b
10b
8.3
Median PFS – mo (95% CI)
2.76
(2.23-3.30)
7.37 (not estimable)a
1.78 (1.18-2.37)
2.73 (1.71-3.75)
1.88 (1.63-2.12)
FH-CGDB
Patients – N
503
68 (V600E 32 / non-V600E 36)
52
42
25
Median rwPFS -
mo (95% CI)
3.55
(3.15-4.24)
6.0
(2.89-11.6)
2.17b
(1.77-2.63)
2.66b
(2.23-5.13)
1.87b (1.31-4.34)
Median rwOS – mo (95% CI)
10.28
(8.51-12.02)
16.07
(8.64-NA)
5.29b
(3.25-17.68)
9.89b
(3.68-20.86)
10.81
(4.17-NA)
FoundationCore cohort – N
NA
188 (V600E 74 / non-V600E 114)
386
96
57
TMB – mean (mut/Mb)
NA
10.6a
3.7
3.8
5.8
PD-L1 TPS ≥ 50% (%)
NA
36a
19
23
16
a: P<0.01 vs all groups; b: P<0.05 for pairwise comparison vs BRAF.
NSCLCs with BRAF mutations are associated with increased benefit from ICB when compared to tumors harboring other targetable oncogenic drivers. Oncogene driver mutations are associated with distinct patterns of TMB and PD-L1 expression. These findings highlight the importance of developing mutation-specific clinical trials in NSCLC.
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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): Ferdinandos Skoulidis
- 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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MA17 - Molecular Mechanisms and Therapies (ID 143)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:Eloisa Jantus-Lewintre, Hongbin Ji
- Coordinates: 9/09/2019, 15:45 - 17:15, Melbourne (1991)
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MA17.10 - Lactate Transporter Blockade as a Strategy to Overcome VEGF Inhibitor-Resistance in LKB1-Deficient NSCLC (Now Available) (ID 2647)
15:45 - 17:15 | Author(s): Ferdinandos Skoulidis
- Abstract
- Presentation
Background
STK11/LKB1 alterations are found in 20-30% of NSCLC and used to co-occur with KRAS mutations. Because LKB1 activates AMPK, many of the best known functions of LKB1 are attributed to its ability to control metabolic alterations in cells. Our laboratory have previously reported that loss of LKB1 promotes enhanced glycolysis and elevated lactate production and more recently we demonstrated that STK11/LKB1 mutations are the strongest predictors of de novo resistance to immunotherapy in NSCLC. Prior studies have revealed an association between alterations in the LKB1/AMPK pathway and worse clinical outcomes in NSCLC and in patients treated with chemotherapy and bevacizumab. Given the roles of LKB1 in the regulation of cell metabolism and resistance to immunotherapy, it is feasible that LKB1 also impacts on the response to anti-angiogenic therapies.
Method
Xenograft mouse models were established by subcutaneous injection of H460 cells (LKB1-deficient) and H460 LKB1-expressing in nude mice and LKR10 (KRASG12D) LKB1 wild-type (K) or LKB1- knockout (KL) into 129Svmice. Mice were randomized to vehicle or B20-4.1.1 anti-VEGF antibody. Glycolytic activity of LKB1-intact and -deficient NSCLC cells was measured by Seahorse assay. We analyzed gene expression of SLC16A3 (MCT4) by qPCR and Western blot. Genetic disruption of MCT4 in the K and KL cell lines was done using CRISPR-Cas9 and mouse models were established by subcutaneous injection into mice.
Result
Mice bearing LKB1-expressing H460 xenografts treated with anti-VEGF antibody showed a significant decrease in tumor volume (p<0.05) compared with their vehicle-treated counterparts. However, mice bearing LKB1-deficient H460 xenografts showed markedly reduced efficacy of anti-VEGF therapy compared with that in LKB1-expressing xenografts. Anti-VEGF therapy significantly reduced growth of LKR10 K tumors (p<0.001) but not in LKR10 KL tumors. Microvascular density was not increased in KL tumors following anti-VEGF treatment compared to K. Human isogenic LKB1-deficient cells showed a significantly increased rate of glycolysis and lactate secretion compared with cells expressing LKB1. Human and murine LKB1-deficient cells also had increased MCT4 expression compared to K cells. Immunofluorescence and RPPA analysis of tumor samples from the K and KL mouse models showed that KL tumors upregulated MCT4 protein expression compared with K tumors (p<0.0001). The genetic disruption of MCT4 KL tumors significantly improved tumor volume reduction to anti-VEGF therapies in vivo (p<0.001).
Conclusion
LKB1 loss is associated with increased lactate secretion and resistance to VEGF inhibition in NSCLC. The targeting of the lactate transporter MCT4 enhance the sensitivity of LKB1-deficient NSCLC to anti-VEGF therapy.
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OA13 - Ideal Approach to Lung Resection and Novel Perioperative Therapy (ID 146)
- Event: WCLC 2019
- Type: Oral Session
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Now Available
- Moderators:Tomasz Grodzki, Kenji Suzuki
- Coordinates: 9/10/2019, 11:30 - 13:00, Toronto (1985)
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OA13.06 - Surgical Outcomes Following Neoadjuvant Nivolumab or Nivolumab Plus Ipilimumab in Non-Small Cell Lung Cancer - NEOSTAR Study (Now Available) (ID 2041)
11:30 - 13:00 | Author(s): Ferdinandos Skoulidis
- Abstract
- Presentation
Background
Surgical outcomes following neoadjuvant immune checkpoint inhibitors (ICIs) are limited. We report 90-day perioperative results of the NEOSTAR phase II trial of neoadjuvant nivolumab or nivolumab/ipilimumab in resectable non-small cell lung cancers (NSCLCs).
Method
44 pts with stage I-IIIA NSCLC (AJCC 7th) were randomized to nivolumab (3 mg/kg IV, days 1, 15, 29, n=23) or nivolumab/ipilimumab (1 mg/kg IV, day 1, n=21) with resection planned between 3-6 weeks after last dose. Surgical approach and extent of resection were at surgeons’ discretion.
Result
39 (89%) patients underwent R0 resection, of those 2 (5%) were resected off trial after additional induction chemotherapy (1 nivolumab, 1 nivolumab/ipilimumab). Among 37 patients, 21 underwent surgery following nivolumab and 16 following nivolumab/ipilimumab. Median age 66 (43-83) years, 24 (65%) male, 33 (89%) white, 22 (59%) adenocarcinoma, 22 (59%) stage I, 9 (24%) stage II, 6 (16%) stage IIIA.
5 (11%) were not resected, 1 (1/23, 4%) after nivolumab (stage II), 4 (4/21, 19%) after nivolumab/ipilimumab (1 stage I, 1 stage II, 2 stage IIIA). Reasons for unresectability were change in surgeon’s judgement (n=2), toxicity (n=1), progression (n=1), and declining pneumonectomy (n=1). Median time to surgery was 31 days (range 21-87). 8 (22%) operations were delayed beyond 42 days, 5 after nivolumab/ipilimumab (5/16, 31%) and 3 after nivolumab (3/21, 14%).
33 (89%) underwent lobectomy, 2 (5%) pneumonectomy, 1 (3%) segmentectomy and 1 (3%) wedge resection. 27 (73%) had thoracotomy, 7 (19%) thoracoscopy, 3 (8%) robotic approach. 2 (5%) were electively converted from thoracoscopy to thoracotomy. Median operative time was 147 minutes (71-315), median blood loss was 100cc (50-1000), and median length of stay was 4 days (1-18).
Perioperatively, pulmonary complications occurred in 8 (22%) patients: 8 (22%) prolonged air leak, 2 (5%) pneumonitis/pneumonias, 1 (3%) empyema, and 1 (3%) bronchopleural fistula (BPF). 1 (3%) died from complications of BPF and steroid therapy for pneumonitis. 4 (11%) developed atrial fibrillation, 1 (3%) diarrhea, 1 (3%) ileus, and 1 (3%) transient ischemic attack.
Surgeons subjectively judged 15/37 (40%) of operations to be more complex than usual with 7/37 (19%) lasting > 4 hours.
Conclusion
Following three cycles of neoadjuvant ICIs 89% of patients underwent complete R0 resection, including two patients who received additional induction chemotherapy off trial. Five marginally operable patients who didn’t proceed to resection, and one perioperative mortality highlight the importance of cautious patient selection for neoadjuvant ICIs in the management of operable NSCLC.
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