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Rafael Rosell
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MA04 - Novel Approaches with IO (ID 900)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Immunooncology
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 13:30 - 15:00, Room 107
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MA04.03 - Immunotherapy for Non-Small Cell Lung Cancers (NSCLC) with Oncogenic Driver Mutations: New Results from the Global IMMUNOTARGET Registry (ID 13187)
13:40 - 13:45 | Author(s): Rafael Rosell
- Abstract
- Presentation
Background
Prospective data on immunotherapy for NSCLC with oncogenic driver mutations are limited. We recently reported first results from the global IMMUNOTARGET registry (Mazières, ASCO 2018). Here, we present new data for PD-L1 and mutation subgroups.
a9ded1e5ce5d75814730bb4caaf49419 Method
In 2017, we started an international retrospective registry study ("IMMUNOTARGET") for patients with advanced NSCLC, known driver mutations (KRAS, EGFR, ALK, ROS1, BRAF, HER2, MET and RET) and PD-L1 immune checkpoint inhibitor therapy. The registry is approved by University of Toulouse and Swissethics, and funded by University of Toulouse and Cantonal Hospital of Lucerne. Anonymized real-world data submitted to the coordinating center include: patient and tumor characteristics, mutation test methods and results, systemic therapy lines, immune related adverse events, best response by RECIST, survival, and tumor PD-L1 expression (optional). Statistical calculations including best response, median PFS and OS are done at University of Toulouse.
4c3880bb027f159e801041b1021e88e8 Result
In April 2018, the registry included 551 pts from Europe, USA, Israel and Australia. Patients were 50% male/female, 28% current smokers, median age 60 years (range 28-83), 85% had PS0/1. Most (73%) tumors were stage IV at diagnosis, almost all (96%) were adenocarcinomas. Molecular classification by dominant driver mutation: KRAS=271 (49%), EGFR=125 (23%), BRAF=43 (8%), MET=36 (7%), HER2=29 (5%), ALK=23 (4%), RET=16 (3%), ROS1=7 (1%), 1 (0.2%) not classified (ALK+RET+MET). Most pts received nivolumab (466) or pembrolizumab (48) and were treated with immunotherapy in second or third line (67%). The median number of cycles was 5 (range 1-68). Fifty (11%) pts had grade 3-5 toxicity. Median OS from start of immunotherapy was 13.3 months, median PFS was 2.8 months. Best response was PR/CR in: KRAS=26%, BRAF=24%, ROS1=17%, MET=16%, EGFR=12%, HER2=7%, RET=6%, ALK=0%. Percentage of PD-L1 positive cells was available for 177 pts: 0%=71 (40%), 1-49%=46 (26%), 50-100%=60 (34%). Median % of positive cells was highest for ROS1 (90%), BRAF (50%), MET (30%) and RET (26%) mutant tumors. PD-L1 positivity was predictive for improved PFS in KRAS and EGFR mutant tumors. PD-L1 status was known in 18 tumors with ALK, ROS1 or RET rearrangements: 5 had 0%, 4 had 1-49% and 9 had 50%-100%. No tumor remissions were observed in this subgroup. The registry remains open, updated results will be presented at the conference.
8eea62084ca7e541d918e823422bd82e Conclusion
Although response rates were lower than in KRAS mutant NSCLC, individual tumors with other driver mutations responded to immunotherapy. PD-L1 expression may not accurately predict clinical benefit from immunotherapy in some molecular subgroups, better markers are needed.
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MA26 - New Therapies and Emerging Data in ALK, EGFR and ROS1 (ID 930)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 13:30 - 15:00, Room 201 BD
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MA26.11 - Effects of Dose Modifications on the Safety and Efficacy of Dacomitinib for EGFR Mutation-Positive NSCLC (ID 13318)
14:40 - 14:45 | Author(s): Rafael Rosell
- Abstract
- Presentation
Background
In patients with EGFR mutation-positive advanced stage NSCLC, first-line dacomitinib significantly improved PFS, OS, DoR and time to treatment failure vs gefitinib (ARCHER 1050; NCT01774721).1,2 Dacomitinib starting dose was 45 mg QD for all patients, with reductions to 30 or 15 mg QD permitted. We explored effects of dacomitinib dose reduction on safety and efficacy in this ongoing study.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with newly diagnosed stage IIIB/IV or recurrent NSCLC harboring an EGFR mutation (exon 19 del or exon 21 L858R) randomized to dacomitinib received 45 mg PO QD. Study endpoints and protocol-defined dose reduction parameters were previously described.1 We evaluated reasons for dose reductions, and their effects on incidence and severity of common adverse events (AEs) and key efficacy endpoints (PFS, OS, ORR). Data cutoff dates: 17-Feb-2017 (OS), 29-Jul-2016 (other endpoints).
4c3880bb027f159e801041b1021e88e8 Result
Overall, 150 (66.1%) patients dose reduced for AEs (87 and 63 reduced to 30 and 15 mg QD as lowest dose, respectively); most commonly for skin toxicities (62.6%) and diarrhea (14.0%). Median time to each successive dose reduction was ~12 weeks. Incidence and severity of AEs declined following dose reduction, including grade ≥3 diarrhea (11.3% before vs 4.0% after), dermatitis acneiform (15.3% vs 6.7%), stomatitis (3.3% vs 2.7%) and paronychia (7.3% vs 4.7%).
PFS was similar in dose-reduced and all dacomitinib-treated patients (Figure).
Median OS results were also similar (dose-reduced patients: 36.7 mo [95% CI: 32.6, NR]; all dacomitinib-treated patients: 34.1 mo [95% CI: 29.5, 37.7] as were ORRs (dose-reduced patients: 79.3% [95% CI: 72.0, 85.5]; all dacomitinib-treated patients: 74.9% [95% CI: 68.7, 80.4]).
8eea62084ca7e541d918e823422bd82e Conclusion
Efficacy was similar in the dose-reduced patients and the overall study population. Incidence/severity of dacomitinib-related AEs decreased with dose reduction, thereby allowing patients to continue treatment.
References:
Wu, et al. Lancet Oncol. 2017.
Mok, et al. J Clin Oncol. 2018.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.13-01 - Anti-EGF Antibodies Increase the Effect of ALK and MEK Inhibitors in ALK and KRAS NSCLC and CRC Cell Lines (ID 13160)
16:45 - 18:00 | Author(s): Rafael Rosell
- Abstract
Background
Immunization against Epidermal Growth Factor (EGF) has demonstrated efficacy in a phase III trial including unselected NSCLC patients, and we have recently shown that antibodies generated by vaccination (anti-EGF VacAbs) potentiate the effects of TKIs in EGFR-mut cells growing in vitro. In this study, we aimed to determine if anti-EGF VacAbs show antitumor activity in KRAS-mutant (mut) and Anaplastic Lymphoma Kinase (ALK) translocated non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) cells, alone or in combination.
a9ded1e5ce5d75814730bb4caaf49419 Method
Anti-EGF VacAbs were generated in rabbits. Cell lines were treated with anti-EGF VacAbs alone and in combination with ALK TKIs, trametinib and standard chemotherapeutic agents in ALK translocated (H3122, E13;A20 (v1) and H2228, E6;A20 (v3)) and lung (A549 and H23) and colon (DLD1 and LS174T) KRAS-mut cell lines. Cell viability was analyzed by MTT, changes of total and phosphorylated proteins by Western blot and emergence of resistance by direct microscopic examination in low density cultures.
4c3880bb027f159e801041b1021e88e8 Result
Anti-EGF VacAbs suppressed EGF-induced cell proliferation and inhibited EGFR phosphorylation signaling in all cell lines tested. In combination, the anti-EGF VacAbs significantly enhanced the antitumor activity of alectinib and crizotinib in H2228 cells and trametinib in A549, H23 and DLD1 cells. In these cell lines, the antibodies decreased Erk ½ and Akt phosphorylation. Finally, the addition of the anti-EGF VacAbs to the culture medium significantly delayed the emergence of resistant clones to alectinib and crizotinib in H2228 cells. In previous experiments, H2228 cells had shown a stronger dependency on the EGF/EGFR pathway than H3122. Results for the combination with standard chemotherapy in KRAS-mut cell lines will be presented at the meeting.
8eea62084ca7e541d918e823422bd82e Conclusion
Anti-EGF VacAbs decreased cell proliferation and inhibited EGFR activation in lung and colon ALK translocated and KRAS-mut cell lines. In addition, they potentiated the effects of trametinib in KRAS-mut cells and TKIs in ALK translocated cells (v3), where they also prevented the emergence of resistance to alectinib and crizotinib. Two clinical trials are currently testing anti-EGF vaccination in advanced NSCLC; the Epical Phase I/II trial, in combination with EGFR TKIs in EGFR-mut patients; and the BV-NSCLC-002 Phase III trial, in combination with chemotherapy in EGFR-wt.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P2.03 - Biology (Not CME Accredited Session) (ID 952)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 3
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.03-02 - Cell-Free DNA (cfDNA) Testing in Lung Adenocarcinoma (LUAC) Patients: Spanish Lung Liquid Versus Invasive Biopsy Program (SLLIP) (ID 12561)
16:45 - 18:00 | Author(s): Rafael Rosell
- Abstract
Background
Liquid biopsies are a revolution in cancer diagnostics as a minimally invasive alternative to tissue biopsy. cfDNA is used for the detection of biomarkers in LUAC patients if a tumor tissue sample is not available. We conducted the SLLIP study to prospectively validate Guardant360 for the detection of 7 targetable activating alterations (EGFR, ALK, ROS1, BRAF, MET, RET, and ERBB2) in LUAC.
a9ded1e5ce5d75814730bb4caaf49419 Method
Blood samples from treatment-naïve stage IIIB-IV LUAC patients were analyzed using Guardant360, a next-generation sequencing panel covering 73 genes. The assay includes complete exon sequencing for 19 cancer genes, sequencing of critical exons in 54 genes, and detection of amplifications (18 genes), fusions (6 genes), and indels (23 genes) with high overall clinical sensitivity rates (85%) and ultra-high specificity (>99.9%). Indels and point mutations can be detected at a mutant allele fraction as low as 0.1%. Guardant360 was compared with tissue genotyping performed as standard of care, using a variety of “real life” techniques. The primary objective was to demonstrate the non-inferiority of Guardant360 versus tissue analysis for the detection of the 7 genetic alterations. The study is registered with ClinicalTrials.gov, number NCT03248089.
4c3880bb027f159e801041b1021e88e8 Result
186 LUAC patients were enrolled over a period of 11 months (August 2016-July 2017). Median age 64, 65% male, 72% smoker/ex-smokers, 85% ECOG performance status 0-1. Targetable activating alterations were detected by the Guardant360 assay and by tissue analysis in 25% (n=47) and 26% (n=49) of patients, respectively (non-inferiority P=0.268). Thirty patients (16%) had alterations identified by both modalities. None of the 186 patients was successfully tested in tissue for all 7 alterations. Of the 17 patients who were negative in tissue but for whom Guardant360 identified targetable alterations, 3 had BRAF V600E mutations. For none of these patients was BRAF tested in tissue. Clinical efficacy per biomarker and treatment modality are awaited.
8eea62084ca7e541d918e823422bd82e Conclusion
Guardant360 cfDNA and tissue analysis detect relevant somatic tumor alterations at similar rates in LUAC patients. Under-genotyping in tissue is common but can be mitigated by the use of cfDNA next generation sequencing assays.
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P2.03-14 - PKCι-PAK1 Pathway Modulates Sensitivity to Therapy in EGFR, KRAS Mutant and Squamous Cell Non-Small Cell Lung Cancer (NSCLC) (ID 12342)
16:45 - 18:00 | Author(s): Rafael Rosell
- Abstract
Background
To understand intrinsic and acquired resistance to different MAPK signaling inhibitors, we explored PKCι-PAK1 signaling in EGFR, KRAS and Squamous cell carcinoma (SCC) cell lines.
a9ded1e5ce5d75814730bb4caaf49419 Method
Three lung cancer cell lines were used: HCC827 and H23 lung adenocarcinoma cells that carry EGFR and KRAS mutations, respectively, and H520 PAK1 amplified squamous NSCLC cells. Cell viability assays and western blotting were applied to evaluate the effect of auranofin (PKCi inhibitor) plus IPA-3 (PAK1 inhibitor). Since IPA-3 is only for laboratory use, we also tested auranofin in combination with OTSSP167 (a MELK inhibitor in phase I trials), which, in our experience, inhibits pPAK1 (Thr423 and Thr212 in the HCC827 cell line).
4c3880bb027f159e801041b1021e88e8 Result
Auranofin plus IPA-3 was highly synergistic (CI less than 0.4) in EGFR mutant (HCC827), KRAS mutant (H23) and SCC with PAK1 amplification (H520 cells). Similar synergism was found with the combination of auranofin plus OTSSP167 in the 3 cell lines (Figure). the combination of auranofin with either IPA-3 or OTSSP167 ablated EGFR phosphorylation and downstream signaling pathways: ERK, AKT, STAT3, YAP1 and inhibited the expression of RTKs: AXL, MET and CDCP1. We created EGFR mutant gefitinib and osimertinib resistant cell lines (PC9-GR3, GR4, OR2, OR4). Auranofin plus IPA-3 was highly synergistic in all cell lines.
8eea62084ca7e541d918e823422bd82e Conclusion
These observations suggest that the combination of auranofin with OTSSP167 can be used for treatment of different subclasses NSCLC with driver EGFR or KRAS mutations, as well as SCC with PAK1 amplification.
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P2.03-15 - Integrin-Linked Kinase (ILK), Protein Tyrosine Phosphatase SHP2 and B lymphoma Mo-MLV Insertion Region 1 Homolog (Bmi-1) in EGFR-Mutant NSCLC (ID 12557)
16:45 - 18:00 | Author(s): Rafael Rosell
- Abstract
Background
The clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) is jeopardized by the activation of multiple signaling pathways. ILK regulates the expression of Bmi-1, a well-known epithelial mesenchymal transition-inducing transcription factor. SHP2 function is required for MAPK pathway activation, and also plays a role in receptor tyrosine kinase signaling pathways.
a9ded1e5ce5d75814730bb4caaf49419 Method
Clinical data were assessed in accordance with the protocol approved by the institutional review board and de-identified for patient confidentiality. Pretreatment tumor specimens from advanced EGFR-mutant NSCLC patients (pts) were collected from eight sites in Spain, France, Italy and Colombia. mRNA gene expression analysis was performed by TaqMan (qRT-PCR). We examined the mRNA levels of ILK, SHP2 and Bmi-1.
4c3880bb027f159e801041b1021e88e8 Result
With a median follow-up of 26.7 months, median progression-free survival (PFS) was 9.3 (95% CI, 7.6-14.2) and 15.7 months (95%CI, 12.3-30.1) for pts with high and low ILK mRNA, respectively (P=0.0002), (HR for disease progression, 2.4; 95% CI, 1.3-4.5; P=0.002). Median PFS was 11.4 (95% CI, 8.2-14) and 24.1 months (95% CI, 8.2-30.9) for pts with high and low SHP2 mRNA, respectively (P=0.009), (HR, 2.4; 95% CI, 1.2-4.7; P=0.01). Median PFS was 8.2 (95% CI, 4.8-13.1) and 24.1 months (95% CI, 14.2-36.5) for pts with high and low SHP2 mRNA, respectively (P=0.001), (HR, 2.9; 95% CI, 1.4-5.9; P=0.002). Median overall survival (OS) was 17.9 (95% CI, 13.2-33) and 34.4 months (95% CI, 18.5-44.2) for pts with high and low ILK mRNA, respectively (P=0.200), (HR, 1.5; 95% CI, 0.79-3; P=0.200). Median OS was 18.5 (95% CI, 14-33) and 36.7 months (95% CI, 16.7-47.1) for pts with high and low SHP2 mRNA, respectively (P=0.018), (HR, 2.5; 95% CI, 1.1-5.8; P=0.020). Median OS was 17.6 (95% CI, 8.6-39.1) and 36.7 months (95% CI, 19.1-64.1) for pts with high and low Bmi-1 mRNA, respectively (P=0.004), (HR, 2.2; 95% CI, 1.0-5.1; P=0.040).
8eea62084ca7e541d918e823422bd82e Conclusion
The disturbance of RTKs, including ILK-SHP2-Bmi-1 axis, occurs frequently in EGFR mutant NSCLC patients, significantly limiting the PFS and OS. The levels of ILK, SHP2 and Bmi-1 could be predictive for upfront combinatory therapy of EGFR TKI plus a MAPK pathway inhibitor (SHP2 or MEK inhibitors).
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P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.13-11 - EGFR Amplification and Sensitizing Mutations Correlates with Survival from Erlotinib in Lung Adenocarcinoma Patients (MutP-CLICAP¶) (ID 14305)
16:45 - 18:00 | Author(s): Rafael Rosell
- Abstract
Background
Tumor heterogeneity causes different EGFR mutation abundances, and is believed to be responsible for varied progression-free survival (PFS) in lung adenocarcinoma (ADC) patients receiving EGFR-TKI treatment. EGFR amplification and its common presence in EGFR mutant allele might be determined by the EGFR copy number variation. Examination of EGFR amplification status in EGFR mutant patients could predict the efficacy of EGFR-TKI treatment
a9ded1e5ce5d75814730bb4caaf49419 Method
72 lung ADC patients, who harbored EGFR activating mutations and received erlotinib as first line treatment, were examined for EGFR amplification by FISH. We analyzed the relationship between the EGFR mutational status and copy number profile with clinical outcomes including response rate, overall-survival (OS), and PFS.
4c3880bb027f159e801041b1021e88e8 Result
Median age was 62-yo (r, 20-87 years), 53 patients were females (73%), and 89% had common mutations. Twenty-two (30.6%) samples with EGFR activating mutations were identified as having EGFR amplification. EGFR amplification was more frequent in patients with exon 19 deletion (p=0.05) and in those with better performance status (p=0.01). Patients with EGFR gene amplification had a significantly longer PFS than those without [(25.2 months, 95%CI 22.0-38.5) vs. (12.4 months, 95%CI 5.3-19.5); p=0.002] as well as better OS [(EGFR amplified 37.8 months, 95%CI 30.9-44.7) vs. (EGFR non-amplified 27.1 months, 95%CI 12.8-41.3); p=0.009]. EGFR amplification significantly influenced the response to erlotinib (p=0.0001).
8eea62084ca7e541d918e823422bd82e Conclusion
EGFR amplification occurs in one third of patients with lung ADC harboring EGFR activating mutations, and could serve as an indicator for better response and survival from EGFR-TKI treatment.
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SH02 - Highlight of the Previous Day Sessions (ID 994)
- Event: WCLC 2018
- Type: Highlight of the Day Session
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 07:00 - 08:00, Room 202 BD
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SH02.04 - Pathology/Biology/Diagnostics (ID 14784)
07:36 - 07:48 | Presenting Author(s): Rafael Rosell
- Abstract
- Presentation
Abstract not provided
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