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N. Leighl
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OA21 - Palliative and Supportive Care for Lung Cancer Patients (ID 405)
- Event: WCLC 2016
- Type: Oral Session
- Track: Palliative Care/Ethics
- Presentations: 1
- Moderators:C.A. Silva, H. Watzke
- Coordinates: 12/07/2016, 11:00 - 12:30, Schubert 5
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OA21.02 - ALK-Rearranged Non-Small Cell Lung Cancer is Associated with a High Rate of Venous Thromboembolism (ID 4290)
11:10 - 11:20 | Author(s): N. Leighl
- Abstract
- Presentation
Background:
Patients with lung cancer are at increased risk for venous thromboembolism (VTE), particularly those receiving chemotherapy. It is estimated that 8-15% of patients with advanced non-small cell lung cancer (NSCLC) experience a VTE in the course of their disease. The incidence in patients with specific molecular subtypes of NSCLC is unknown. We undertook this review to determine the incidence of VTE in patients with ALK-rearranged NSCLC.
Methods:
We identified all patients with ALK-rearranged NSCLC, diagnosed and/or treated at the Princess Margaret Cancer Centre (PM CC) in Canada between July 2012 and January 2015. Retrospective data were extracted from electronic medical records. We then included a validation cohort comprising all consecutive patients with ALK-rearranged NSCLC treated in two tertiary centers in Israel.
Results:
Within the PM CC cohort, of 55 patients with ALK-rearranged NSCLC, at a median follow-up of 22 months, 23 (42%) experienced VTE. Patients with VTE were more likely to be Caucasian (p=0.006). The occurrence of VTE was associated with a trend towards worse prognosis (overall survival HR=2.88, p=0.059). Within the validation cohort (N=43), VTE rate was 28% at a median follow-up of 13 months. Combining the cohorts (N=98) the VTE rate was 36%. Patients with VTE were younger (age 52 vs 58, p=0.04) and had a worse ECOG performance status (p=0.04). VTE was associated with shorter OS (HR=5.71, p=0.01)Figure 1.
Conclusion:
We found the rate of VTE in our ALK-rearranged cohort is 3-5-fold higher than previously reported for the general NSCLC population. This warrants confirmation in larger cohorts.
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OA22 - Novel Trials and Biomarkers in Malignant Pleural Mesothelioma (ID 403)
- Event: WCLC 2016
- Type: Oral Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:H. Pass, N. Van Zandwijk
- Coordinates: 12/07/2016, 14:20 - 15:50, Strauss 3
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OA22.02 - Nintedanib plus Pemetrexed/Cisplatin in Patients with MPM: Phase II Findings from the Placebo-Controlled LUME-Meso Trial (ID 4191)
14:30 - 14:40 | Author(s): N. Leighl
- Abstract
- Presentation
Background:
Standard first-line treatment for patients with unresectable malignant pleural mesothelioma (MPM) is pemetrexed/cisplatin, yielding a median overall survival (OS) of only ~1 year, thus new approaches are required. As demonstrated by the bevacizumab MAPS study, inhibition of the VEGF pathway is of interest as a treatment approach for MPM. Nintedanib is an oral, triple angiokinase inhibitor of VEGFR, PDGFR and FGFR. This study will evaluate the efficacy and safety of nintedanib plus pemetrexed/cisplatin in patients with advanced MPM.
Methods:
Patients with unresectable MPM (chemo-naïve, ECOG PS 0–1) were stratified by histology (epithelioid/biphasic) and randomised (1:1) to receive up to 6 cycles of pemetrexed (500 mg/m[2])/cisplatin (75 mg/m[2]) on Day 1 plus nintedanib (200 mg bid)/placebo on Days 2–21. Patients without disease progression received maintenance treatment with nintedanib/placebo. The primary endpoint was progression-free survival (PFS).
Results:
87 patients were randomised to receive pemetrexed/cisplatin, plus nintedanib/placebo. Patient characteristics were comparable between the groups. PFS was longer in the nintedanib vs the placebo arm, in both the overall study population and in epithelioid patients (Table 1). Preliminary OS data also favour nintedanib. All patients experienced at least one adverse event (AE, any grade), with 7% of patients in the nintedanib arm discontinuing due to AEs, vs 15% with placebo. Serious AEs occurred in 36% vs 42% of patients in the nintedanib and placebo arms, respectively. The most common ≥grade 3 AEs occurring in nintedanib vs placebo patients were neutropenia (34% vs 10%), ALT increase (14% vs 2%) and gamma glutamyltransferase increase (14% vs 0%).
Conclusion:
Nintedanib plus pemetrexed/cisplatin demonstrated clinical efficacy with improved PFS and a tolerable safety profile in patients with unresectable MPM. Based on these promising findings, this Phase II study was extended to a confirmatory Phase III trial, which is currently enrolling patients. Clinical trial identifier: NCT01907100.
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P3.02a - Poster Session with Presenters Present (ID 470)
- 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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P3.02a-013 - Brigatinib in Crizotinib-Refractory ALK+ NSCLC: Central Assessment and Updates from ALTA, a Pivotal Randomized Phase 2 Trial (ID 4046)
14:30 - 14:30 | Author(s): N. Leighl
- Abstract
Background:
Brigatinib, an investigational next-generation ALK inhibitor, has yielded promising activity in crizotinib-treated ALK+ NSCLC patients in a phase 1/2 trial (NCT01449461). As responses and adverse events (AEs) varied with starting dose, two brigatinib regimens are under evaluation in ALTA (NCT02094573).
Methods:
Patients with crizotinib-refractory advanced ALK+ NSCLC were randomized 1:1 to receive brigatinib at 90 mg qd (arm A) or 180 mg qd with a 7-day lead-in at 90 mg (arm B) and stratified by presence of brain metastases at baseline and best response to prior crizotinib. Primary endpoint was investigator-assessed confirmed ORR per RECIST v1.1.
Results:
222 patients were enrolled (arm A, n=112/arm B, n=110). Median age (A/B) was 51/57 years, 55%/58% were female, 74%/74% previously received chemotherapy, and 71%/67% had brain metastases. As of February 29, 2016, 64/112 (57%) patients in arm A and 76/110 (69%) patients in arm B were receiving brigatinib; median follow-up was 7.8/8.3 months. The Table shows investigator-assessed endpoints by arm and subgroup for select baseline characteristics. Independent review committee–assessed endpoints (A/B, n=112/n=110; as of May 16, 2016): confirmed ORR 48%/53%, median PFS 9.2/15.6 months. Any-grade treatment-emergent AEs (≥25% overall frequency; A/B, n=109/n=110 treated): nausea (33%/40%), diarrhea (19%/38%), headache (28%/27%), cough (18%/34%); grade ≥3 events (excluding neoplasm progression; ≥3% frequency): hypertension (6%/6%), increased blood CPK (3%/9%), pneumonia (3%/5%), increased lipase (4%/3%). A subset of pulmonary AEs with early onset (median onset: Day 2) occurred in 14/219 (6%) treated patients (3%, grade ≥3); 7/14 patients were successfully retreated. No such events occurred after escalation to 180 mg in arm B.
Conclusion:
In each arm, brigatinib yielded substantial responses and prolonged PFS, with an acceptable safety profile. 180 mg with 90 mg lead-in was not associated with increased early pulmonary events and showed a consistent improvement in efficacy, compared with 90 mg, particularly with respect to PFS.Investigator-Assessed Endpoints by Arm and Subgroup
Confirmed ORR, n/N(%) Median PFS, months Arm A B A+B A B A+B All patients 50/112(45) 59/110(54) 109/222(49) 9.2 12.9 11.1 Prior chemotherapy Yes 35/83(42) 44/81(54) 79/164(48) 8.8 12.9 11.8 No 15/29(52) 15/29(52) 30/58(52) 9.2 8.1 9.2 Race Asian 18/39(46) 18/30(60) 36/69(52) 8.8 11.1 11.1 Non-Asian 32/73(44) 41/80(51) 73/153(48) 9.2 12.9 11.8 Brain metastases at baseline Yes 31/80(39) 43/74(58) 74/154(48) 9.2 11.8 11.1 No 19/32(59) 16/36(44) 35/68(51) 7.4 15.6 15.6 Best response to prior crizotinib Partial+complete 36/71(51) 47/73(64) 83/144(58) 11.1 15.6 15.6 Other 14/41(34) 12/37(32) 26/78(33) 7.4 12.9 9.2 ORR=objective response rate PFS=progression-free survival
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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-028 - Characterizing Residual Erlotinib-Tolerant Population Using EGFR-Mutated NSCLC Primary Derived Xenografts: The Last Holdouts (ID 5455)
14:30 - 14:30 | Author(s): N. Leighl
- Abstract
Background:
Three generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have led to multi-fold improvements in progression free survival of advanced stage non-small cell lung cancer (NSCLC) patients carrying EGFR kinase domain mutations. However, cure is not yet achievable with any EGFR TKI monotherapy, as patients will eventually progress due to acquired resistance. In vitro evidence suggests that minor populations of epigenetically modified drug tolerant cells (DTCs) may be one important mechanism for tumor cells surviving the TKI. We hypothesize that characterizing the genomic and epigenomic alterations observed in DTCs in vivo and comparing them to the bulk tumour will delineate a number of mechanisms of tolerance exhibited by DTCs.
Methods:
DTCs were induced via chronic erlotinib treatment of a lung adenocarcinoma primary derived xenograft (PDX) harbouring an erlotinib sensitive exon 19 deletion. Molecular profiles of DTCs are compared to untreated controls via immunohistochemistry (IHC) and gene expression array. We are now undertaking exome-sequencing, assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), methylated DNA immunoprecipitation and sequencing (MeDIP-seq).
Results:
When compared to untreated tumours, DTCs exhibit decreased apoptosis (CC3 IHC) and proliferation (Ki67 IHC). DTCs maintained strong signaling via the EGFR pathway (pERK, pAKT, pS6). DTCs exhibited 2437 significantly differentially expressed genes (DEGs; >1.5-fold change and adjusted p-value <0.05) including multiple cancer stem cell markers (ALDH1A1, ALDH1A3, CD44). DEGs also were involved in vesicle-mediated transport (including lysosomes, exosomes and endosomes), autophagy, stress/unfolded protein response, cytoskeleton organization, chromatin organization, ion pumps and transporters, cell adhesion, WNT, NOTCH, PI3K and MAPK pathways. DTCs remained resistant to three cycles of cisplatin/vinorelbine either alone or when combined with erlotinib. Genomic and epigenomic profiling are on-going and results will be presented.
Conclusion:
DTCs may be a major impediment to cure by single-agent EGFR targeted therapies. Understanding the mechanisms and developing strategies to overcome DTCs may give insights on therapeutic strategy to further improve the survival of EGFR-mutated NSCLC patients.
