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Rafal Dziadziuszko
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PC 03 - 3-1 What is the Optimal Sequence of ALK-TKI for ALK-Positive Lung Cancer? (Alectinib First or Crizotinib First) (ID 583)
- Event: WCLC 2017
- Type: Pros & Cons
- Track: Chemotherapy/Targeted Therapy
- Presentations: 2
- Moderators:Rafal Dziadziuszko, Y.O. Tan
- Coordinates: 10/18/2017, 11:00 - 11:40, Room 303 + 304
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PC 03.01 - Crizotinib First (ID 7831)
11:00 - 11:40 | Presenting Author(s): Sai-Hong Ignatius Ou
- Abstract
- Presentation
Abstract:
Crizotinib is the first ALK TKI that has demonstrated statistically superior progression-free survival over standard of platinum-based chemotherapy in treatment-naïve ALK+ NSCLC patients (PROFILE1014, PROFILE 1029). Since then next generation ALK TKI such as ceritinib (ASCEND-4) has also demonstrated statistically improved PFS over platinum-base chemotherapy (ASCEND-4) and alectinib has demonstrated statistically improved PFS over crizotinib (J-ALEX, ALEX). In ALEX, a global randomized phase 3 study comparing alectinib to crizotnib demonstrated that alectinib achieved an median PFS of 25.7 months compared to median PFS of 10.4 months for crizotinib. Additionally, the cumulative incidence of CNS metastasis was significantly lower over for patients treated with alectinib than patients treated with crizotinib the duration of study period. Crizotinib did achieve higher than expected confirmed overall response rate in patients with CNS metastasis in the ALEX trial than has previously published. In fact the median PFS achieved by patients without CNS metastasis at study enrollment and treated by crizotinib was 14.8 months. There is a retrospective study that demonstrated two-third of the patients treated with crizotinib would continue to benefit from continuation of crizotinib beyond disease progression with local ablative therapy with a median overall survival of additional 16 months from the time of disease progression. Next generation ALK inhibitor such as brigatinib has achieved a median PFS of > 15 months in patients who are crizotinib-refractory or intolerant. Furthermore, “third-generation” ALK inhibitor, lorlatinib, achieved clinically meaningful overall response rate presented at this conference. Thus sequencing crizotinib to brigatinib could potentially achieve the additional 15.3 months of additional PFS achieved by using alectinib first. Finally, one of the major resistance mechanism of alectinib is the generation of ALK G1202R solvent front mutation while the incidence of ALK G1202R resistance mutation in crizotinib-refractory cases are much lower. Currently only lorlatinib and TPX-0005 (next generation ALK inhibitors presented at this WCLC) have shown reliably in vitro inhibitory against solvent front mutation. Thus the up-front use of alectinib could potential generate resistance mechanisms that allow limited further treatment options.
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PC 03.02 - Alectinib First (ID 7832)
11:00 - 11:40 | Presenting Author(s): Kazuhiko Nakagawa
- Abstract
- Presentation
Abstract not provided
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PC 03 - 3-2 Which Do you Prefer: Liquid Biopsy or Tissues Biopsy for Molecular Diagnosis? (ID 596)
- Event: WCLC 2017
- Type: Pros & Cons
- Track: Chemotherapy/Targeted Therapy
- Presentations: 2
- Moderators:Rafal Dziadziuszko, Y.O. Tan
- Coordinates: 10/18/2017, 11:40 - 12:30, Room 303 + 304
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PC 03.03 - Liquid Biopsy (ID 8114)
11:40 - 12:30 | Presenting Author(s): Heather A Wakelee
- Abstract
- Presentation
Abstract:
Tissue biopsy has been the gold standard in cancer diagnosis and molecular diagnosis of NSCLC for years. However, “liquid biopsy” is gaining in popularity as the sensitivity and availability of the assays increase. Plasma testing is now a standard approach for EGFR mutation testing with US FDA approved tests (Cobas), and much broader applications are available. Liquid biopsies are preferred, especially from the patient perspective. Would you prefer a simple blood draw or an invasive biopsy with high complication risk? The answer is obvious. As tumor cells die they shed DNA into peripheral blood. This circulating tumor DNA (ctDNA) is transient in nature, but can be detected in the plasma samples of patients. Plasma assays require simple phlebotomy compared to the risks of tissue biopsy. This technology can be applied to many malignancies, but is of particular interest in NSCLC given the number of known actionable driver mutations. Rapid detection of these mutations, and monitoring for development of resistance is already part of standard practice. Tissue biopsy strategies are significantly hampered by difficult to access tumors such as those in the brain or bone, and risks such as hemorrhage or pneumothorax. The issue of tumor heterogeneity is also of significance, as a biopsy in one lesion may not reflect the resistance biology of another location.[1] The application of ctDNA is best illustrated in the setting of EGFRmutant (EGFRmut) NSCLC. Though most patients have an EGFR activating mutation identified in the initial tumor biopsy, on June 1, 2016 the US FDA approved the cobas Mutation Test v2, a real-time PCR based assay for EGFR mutations, for use with plasma for detection of EGFR exon19del and L858R (and others in exons 18-21). ctDNA testing for the T790M EGFR resistance mutation is of greater practical utility as biopsy can be avoided in this setting with a positive liquid biopsy. AURA3 established the third generation EGFR TKI osimertinib as superior to chemotherapy for patients with T790M mutations, making T790M testing of high clinical significance.[2] In addition to tissue testing AURA3 was designed with an imbedded plasma assay. Based on the trial results the cobas EGFR Mutation Test v2 approval was expanded to include detection of T790M mutation in plasma samples. The Cobas assay established liquid biopsies as a standard approach for EGFRmut NSCLC, but has limited sensitivity and more sensitive liquid biopsy approaches exist including droplet digital PCR (ddPCR) and BEAMing (beads, emulsion, amplification, and magnetics), in addition to broader next generation sequencing (NGS) assays. Osimertinib activity has been demonstrated in T790M+ NSCLC patients regardless of how T790M is detected.[3] In a large analysis of hundreds of matched tissue, plasma and urine samples from EGFRmut NSCLC patients, both plasma and urine T790M detection sensitivity were 81% versus tissue testing. In the 181 patients with matched tissue, plasma and urine specimens there were 23 patients with T790M detected in plasma but not tissue, and 24 patients with T790M found in tissue but not plasma. The study utilized BEAMing technology, and a sensitive urine assay with quantitative NGS focused on EGFRdel 19, L585R and T790M.[4 ] One challenge for liquid biopsy is in the setting where there is limited ctDNA shedding, such as in lung only disease (M1a) in which case EGFRmut detection rates can be <50%,[5] but increasingly sensitive assays will ameliorate this issue. In a comparison across various platforms of Cobas (non-digital PCR), ARMS (therascreen EGFR amplification refractory mutation system (ARMS), digital detection droplet PCR (ddPCR) and BEAMing dPCR, the sensitivity ranged from 78-100% for the sensitizing mutations and 29-81% for T790M with specificity of 93-100% for the activating mutation and 58-100% for the T790M assays.[6] As outlined above, there is variability in the assays available for plasma analyses, however these assays correlate well with the tissue testing. In a meta-analysis of 26 studies comparing EGFR mutation detection in plasma versus tissue the specificity was 0.97 (95% CI 0.93-0.99) and sensitivity was 0.65 (95% CI 0.54-0.74).[7] Sensitivity is increased with more modern techniques such as BEAMing and droplet digital PCR. As this and other comparisons highlight, specificity is exceedingly high in all available assays, but sensitivity varies amongst the tests and thus a positive ctDNA test should be believed and can spare the patient a biopsy, but a negative test should be followed by further evaluation, bearing in mind that tissue testing can also result in false negatives. Another advantage of “liquid biopsy” is the speed of obtaining results. In a comparison of plasma ddPCR versus biopsy the median turnaround time was significantly faster for the plasma testing (3 days versus 12 days, not including time to arrange the biopsy).[8 ] Thus, for EGFRmut NSCLC it is clear that compared to tissue biopsy, liquid biopsy is highly sensitive and specific, faster, and much more convenient and safe for patients. There should be no debate on the utility of liquid biopsy at initial diagnosis and around development of resistance to 1[st]/2[nd] generation EGFR TKIs. We already have an FDA approved assay in these settings with many improved technologies available as well. EGFR testing lays the foundation for ctDNA testing in NSCLC, but the utility of ctDNA has already expanded to testing for BRAF and other actionable mutations, and tumor rearrangements such as ALK. As an example, a commercially available ctDNA NGS assay performed on 362 NSCLC patients with paired tissue samples identified 51 additional actionable driver mutations via ctDNA analysis compared to the tissue assay, demonstrating real world practicality of this approach and theoretically improved patient outcomes.[9] Other highly sensitive NSCLC platforms looking at panels of dozens to hundreds of genes are available and rapidly changing our ability to detect mutations in larger groups of actionable mutations.[10] Utilization of these technologies at the time of diagnosis and for identification of resistance mechanisms is no longer theoretical but practical. Use of these technologies to monitor treatment response may one day replace or at least supplement imaging, and of particular utility, ctDNA analysis is already showing promise as a measure of minimal residual disease after curative therapy in early stage disease and will likely help guide us in decisions regarding adjuvant therapy in the near future. Liquid biopsy is an established, approved standard for EGFR testing, widely available and practical for tumor genotyping for other actionable mutations, and poised to radically change our surveillance strategies and our management of earlier stages of disease and likely even screening, which is far beyond the scope of what can be done with tissue. The preference for liquid biopsy over tissue biopsy should be clear. REFERENCES: 1) Hata A, Katakami N, Yoshioka H, et al. Spatiotemporal T790M Heterogeneity in Individual Patients with EGFR-Mutant Non-Small-Cell Lung Cancer after Acquired Resistance to EGFR-TKI. J Thorac Oncol 10 (2015) 2) Mok TS, Wu YL, Ahn MJ, et al. AURA3 Investigators, Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med (2016) 3) Oxnard GR, Thress KS, Alden RS, et al. Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 34 (2016) 4) Wakelee HA, Gadgeel SM, Goldman JW, et al.. Epidermal growth factor receptor (EGFR) genotyping of matched urine, plasma and tumor tissue from non-small cell lung cancer (NSCLC) patients (pts) treated with rociletinib. J Clin Oncol 34, (abstr 9001) (2016) 5) Karlovich C, Goldman JW, Sun JM, et al. Assessment of EGFR mutation status in matched plasma and tumor tissue of NSCLC patients from a phase I study of rociletinib (CO-1686). Clin Cancer Res 22(10)(2016) 6) Thress KC, Brant R, Carr TH, et al. EGFR mutation detection in ctDNA from NSCLC patient plasma: A cross-platform comparison of leading technologies to support the clinical development of AZD9291. Lung Cancer (2015). 7) Wu Y, Liu H, Shi X, Song Y. Can EGFR mutations in plasma or serum be predictive markers of non-small-cell lung cancer? A meta-analysis, Lung Cancer Amst. Neth. 88 (2015) 8) Sacher AG, Paweletz C, Dahlberg SE, et al. Prospective validation of rapid plasma genotyping for detection of EGFR and KRAS mutations in advanced NSCLC. Jama Oncology (2016) 9) Zill O, Banks K, Mortimer S, et al. Somatic genomic landscape of over 15,000 advanced stage cancer patients from clinical NGS analysis of ctDNA. J Clin Oncol 34, (LBA11501) (2016) 10) Newman AM, Lovejoy AF, Klass DM, et al. Integrated digital error suppression for improved detection of circulating tumor DNA. Nat Biotechnol 34(5) (2016)
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PC 03.04 - Tissues Biopsy (ID 7833)
11:40 - 12:30 | Presenting Author(s): Keith M Kerr
- Abstract
- Presentation
Abstract not provided
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Author of
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ES 10 - Radiation Treatment Update (ID 519)
- Event: WCLC 2017
- Type: Educational Session
- Track: Radiotherapy
- Presentations: 1
- Moderators:Z. Liao, F. McDonald
- Coordinates: 10/18/2017, 14:30 - 16:15, F201 + F202 (Annex Hall)
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ES 10.05 - RT and Targeted Therapies (ID 7865)
14:30 - 16:15 | Presenting Author(s): Rafal Dziadziuszko
- Abstract
- Presentation
Abstract not provided
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JCSE 01 - Joint IASLC/CSCO/CAALC Session: Immunotherapy for Management of Lung Cancer: Ongoing Research from East and West (ID 630)
- Event: WCLC 2017
- Type: Joint Session IASLC/CSCO/CAALC
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:C. Bai, Fred R. Hirsch, Tony SK Mok, Yi-Long Wu
- Coordinates: 10/15/2017, 07:30 - 11:30, F203 (Annex Hall)
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JCSE 01.27 - Patients with ALK IHC-Positive/FISH-Negative NSCLC Benefit from ALK TKI Treatment: Response Data from the Global ALEX Trial (ID 10923)
07:30 - 11:30 | Author(s): Rafal Dziadziuszko
- Abstract
Background:
Patients with ALK-positive NSCLC have seen significant advances and increased options in ALK targeted therapies recently, and therefore rely on high quality, robust ALK status testing. Fluorescence in-situ hybridization (FISH) and immunohistochemistry (IHC) are the most common methods to determine ALK status for ALK tyrosine kinase inhibitor (TKI) treatment. However, availability of clinical outcome data from randomized trials linked directly to specific methods is limited. The ALEX trial (BO28984, NCT02075840) provides a unique dataset to assess ALK IHC- and FISH-based assays regarding clinical outcome for alectinib and crizotinib, particularly for the subset of patients with IHC-positive/FISH-negative NSCLC.
Method:
The VENTANA ALK (D5F3) CDx Assay (ALK IHC) performed in central laboratories was used as an enrollment assay for the selection of patients with ALK-positive NSCLC for inclusion in the ALEX trial. Additional samples from these patients were retrospectively tested in central laboratories with the Vysis ALK Break Apart FISH Probe Kit (ALK FISH).
Result:
Overall, 303 patients all with ALK IHC-positive NSCLC were randomized in the ALEX trial, of those 242 patients also had a valid ALK FISH result, with 203 patients having ALK FISH-positive disease and 39 patients having ALK FISH-negative disease (alectinib, n=21; crizotinib, n=18). For 61 of 303 (20.1%) patients with an ALK IHC-positive result, a valid ALK FISH result could not be obtained due to the test leading to an uninformative FISH result (10.9%), or not having adequate/no tissue available (9.2%). Ventana IHC staining success rates were higher than for Vysis FISH testing for the ALEX samples. Exploratory analysis of investigator-assessed progression-free survival (PFS) in patients with a FISH-positive result (HR 0.40, 95% CI 0.27–0.61; p<0.0001; median not reached [alectinib] versus 12.7 months [crizotinib]) was consistent with the primary endpoint analysis in the Ventana ALK IHC-positive population. Patient outcome data show that 28% of central ALK IHC-positive/ALK FISH-negative samples were from patients who responded to ALK TKI treatment (complete response or partial response) and 33% had stable disease according to investigator assessment.
Conclusion:
This analysis shows that ALK IHC is a robust testing approach, which may identify more patients with a valid ALK testing result who benefit from ALK TKI treatment than ALK FISH testing. While PFS of patients with ALK FISH-positive NSCLC was similar to that of patients with ALK IHC-positive NSCLC, the analysis also revealed that the majority of patients with ALK IHC-positive/ALK FISH-negative NSCLC may derive clinical benefit from ALK TKI treatment.
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MA 06 - Lung Cancer Biology I (ID 660)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Biology/Pathology
- Presentations: 1
- Moderators:N. Motoi, Keith M Kerr
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 501
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MA 06.06 - Assessment of RANK Prevalence and Clinical Significance in the NSCLC European Thoracic Oncology Platform Lungscape Cohort (ID 10006)
15:45 - 17:30 | Author(s): Rafal Dziadziuszko
- Abstract
- Presentation
Background:
Receptor Activator of Nuclear Factor κappa-B (RANK) is a pathway involved in bone homeostasis. Recent evidence suggests that RANK signalling may also play a role in bone metastasis, and primary breast and lung cancers. The European Thoracic Oncology Platform (ETOP) Lungscape project allows evaluation of the prevalence of RANK expression and its clinical significance in a cohort of surgically-resected NSCLCs.
Method:
RANK expression was assessed on tissue microarrays (TMAs) using immunohistochemistry. Up to 4 cores per patient were analysed based on sample acceptance criteria. An H-Score (staining intensity + % cells stained) was used to assess RANK expression (positivity), as defined by at least 1 core with any degree of positive staining. Prevalence of RANK positivity and its association with clinicopathological characteristics, other cancer-related biomarkers (IHC ALK/MET/PTEN/PD-L1 expression and EGFR/KRAS/PIK3CA mutations) and patient outcome [Relapse-free Survival (RFS), Time-to-Relapse (TTR), Overall Survival (OS)] was explored in a subset of the ETOP Lungscape cohort. The prevalence of RANK overexpression (proportion of positive cancer cells ≥50%) was also investigated.
Result:
RANK expression was assessed in patients from 3 centers, a total of 402 from the 2709 patients of the Lungscape cohort, with median follow-up 44 months; 32.6% female, 40.8/54.2/5.0% adenocarcinomas (AC)/squamous cell carcinomas (SCC)/other, 44.8/28.4/26.9% with stage I/II/III, 20.6/57.7/18.9% current/former/never smokers (and 2.7% with unknown smoking status). Median was 74 months for both RFS and OS, while median TTR was not reached. Prevalence of RANK positivity was 26.6% (107 of the 402 cases), with 95% confidence interval (95%CI):22.4%-31.2%; significantly higher in AC: 48.2% (79 of 164 cases), 95%CI:40.3%-56.1%; vs SCC: 9.2% (20 of 218 cases), 95%CI:5.7%-13.8%; (p<0.001). RANK positivity was more frequent in females (38.9% vs 20.7% in males, p<0.001) and tumors≤4cm (30.7% vs 21.1% in tumors>4cm, p=0.031). Significant associations were also detected between RANK and PTEN expression in AC (RANK positivity 57.4% in PTEN expression vs 30.5% in PTEN loss; p=0.0011) and with MET status in SCC (RANK positivity 27.8% in MET+ vs 7.6% in MET-; p=0.016). No association with outcome was found. RANK overexpression was identified in 43 (10.7%; 95%CI: 7.9%-14.1%) cases.
Conclusion:
In this early-stage NSCLC cohort, RANK positivity (26.6% overall) is found to be significantly more common in adenocarcinomas (48.2%), females, patients with tumors of smaller size, with PTEN expression (in SCC) and MET positivity (in AC). No prognostic significance of RANK expression was found. Analysis of additional cases is ongoing and results will be presented.
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MA 07 - ALK, ROS and HER2 (ID 673)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Robert C. Doebele, J.C. Ho
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 316
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MA 07.01 - Patients with ALK IHC-Positive/FISH-Negative NSCLC Benefit from ALK TKI Treatment: Response Data from the Global ALEX Trial (ID 9008)
15:45 - 17:30 | Author(s): Rafal Dziadziuszko
- Abstract
- Presentation
Background:
Patients with ALK-positive NSCLC have seen significant advances and increased options in ALK targeted therapies recently, and therefore rely on high quality, robust ALK status testing. Fluorescence in-situ hybridization (FISH) and immunohistochemistry (IHC) are the most common methods to determine ALK status for ALK tyrosine kinase inhibitor (TKI) treatment. However, availability of clinical outcome data from randomized trials linked directly to specific methods is limited. The ALEX trial (BO28984, NCT02075840) provides a unique dataset to assess ALK IHC- and FISH-based assays regarding clinical outcome for alectinib and crizotinib, particularly for the subset of patients with IHC-positive/FISH-negative NSCLC.
Method:
The VENTANA ALK (D5F3) CDx Assay (ALK IHC) performed in central laboratories was used as an enrollment assay for the selection of patients with ALK-positive NSCLC for inclusion in the ALEX trial. Additional samples from these patients were retrospectively tested in central laboratories with the Vysis ALK Break Apart FISH Probe Kit (ALK FISH).
Result:
Overall, 303 patients all with ALK IHC-positive NSCLC were randomized in the ALEX trial, of those 242 patients also had a valid ALK FISH result, with 203 patients having ALK FISH-positive disease and 39 patients having ALK FISH-negative disease (alectinib, n=21; crizotinib, n=18). For 61 of 303 (20.1%) patients with an ALK IHC-positive result, a valid ALK FISH result could not be obtained due to the test leading to an uninformative FISH result (10.9%), or not having adequate/no tissue available (9.2%). Ventana IHC staining success rates were higher than for Vysis FISH testing for the ALEX samples. Exploratory analysis of investigator-assessed progression-free survival (PFS) in patients with a FISH-positive result (HR 0.40, 95% CI 0.27–0.61; p<0.0001; median not reached [alectinib] versus 12.7 months [crizotinib]) was consistent with the primary endpoint analysis in the Ventana ALK IHC-positive population. Patient outcome data show that 28% of central ALK IHC-positive/ALK FISH-negative samples were from patients who responded to ALK TKI treatment (complete response or partial response) and 33% had stable disease according to investigator assessment.
Conclusion:
This analysis shows that ALK IHC is a robust testing approach, which may identify more patients with a valid ALK testing result who benefit from ALK TKI treatment than ALK FISH testing. While PFS of patients with ALK FISH-positive NSCLC was similar to that of patients with ALK IHC-positive NSCLC, the analysis also revealed that the majority of patients with ALK IHC-positive/ALK FISH-negative NSCLC may derive clinical benefit from ALK TKI treatment.
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OA 05 - Next Generation TKI (ID 657)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:James Chih-Hsin Yang, Fiona Blackhall
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 301 + 302
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OA 05.07 - Efficacy and Updated Safety of Ceritinib (450 Mg or 600 Mg) with Low-Fat Meal vs 750 Mg Fasted in ALK+ Metastatic NSCLC (ID 9366)
15:45 - 17:30 | Author(s): Rafal Dziadziuszko
- Abstract
- Presentation
Background:
Ceritinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of patients with ALK+ non-small cell lung cancer (NSCLC) who are treatment-naive or have progressed on crizotinib at the recommended dose of 750 mg/day under fasted state. Gastrointestinal (GI) adverse events (AEs), eg, diarrhea, nausea, vomiting, are common with ceritinib 750 mg/day under fasting conditions. ASCEND‑8 study, (NCT02299505) evaluated alternative methods of ceritinib administration, utilizing potential benefit of dosing ceritinib with food to reduce GI toxicity, while maintaining the pharmacokinetic exposure at lower doses. Based on the primary pharmacokinetics analysis previously presented (n=137; WCLC 2016), ceritinib 450 mg with food had similar exposure and a more favorable GI safety profile vs ceritinib 750 mg fasted in patients with ALK+ NSCLC.
Method:
This is a multicenter, randomized, 3-arm (450 mg or 600 mg ceritinib taken with low-fat meal vs 750 mg ceritinib taken in fasted state), open-label, phase 1 study (ASCEND-8). Patients were eligible if they had stage IIIB or IV ALK+ advanced NSCLC, were aged 18 years or older, who were either previously treated with chemotherapy and/or crizotinib or treatment naive. We plan to report the updated safety (n=228) and preliminary efficacy for treatment-naïve patients (ALK+ by immunohistochemistry [IHC]) who were randomized at least 18 weeks before the cutoff date (March 28, 2017; n=79). Updated analysis is planned to be made available by August 2017 and the following data will be included at the time of final abstract submission: patient disposition; patient demographics; disease characteristics and prior therapies; overall response rate and duration of response by blinded independent review committee (BIRC; key secondary endpoints) in treatment-naïve patients (ALK+ by IHC) randomized at least 18 weeks prior to the cut-off date; progression-free survival per BIRC in treatment-naïve patients (ALK+ by IHC) randomized at least 18 weeks prior to the cut-off date; updated safety results with detailed information on GI (diarrhea, nausea, vomiting) and liver (alanine transaminase/aspartate transaminase) toxicities.
Result:
LBA shell - not applicable
Conclusion:
LBA shell - not applicable
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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-013 - Patient-Reported Outcomes and Safety from the Phase III ALUR Study of Alectinib vs Chemotherapy in Pre-Treated ALK+ NSCLC (ID 9007)
09:30 - 16:00 | Author(s): Rafal Dziadziuszko
- Abstract
Background:
Alectinib demonstrated superior efficacy versus chemotherapy in ALK+ NSCLC after crizotinib failure (ALUR; NCT02604342). We present PROs and safety in the ITT population and in patients with baseline CNS disease (C-ITT).
Method:
Patients (n=107) with pre-treated ALK+ NSCLC (randomised 2:1) received alectinib (600mg BID) or chemotherapy (pemetrexed 500mg/m[2] or docetaxel 75mg/m[2] q3w) until PD/death/withdrawal. Primary endpoint: investigator-assessed PFS. Secondary endpoints: safety and PROs. Symptoms, functioning, and HRQoL were reported using questionnaires: EORTC QLQ-C30; lung module QLQ-LC13; BN-20 (3 items, CNS symptoms). Pre-specified endpoints included time-to-deterioration (TTD) in lung cancer symptoms, longitudinal analyses of mean score changes from baseline, proportion of patients with clinically meaningful change (≥10-point change from baseline) during treatment.
Result:
High compliance with assessment completion (alectinib 91.7%, chemotherapy 88.6% at baseline); compliance remained ≥70% with alectinib, and decreased with chemotherapy (64.3%, Week 6; ≤70% thereafter). Deterioration of patient-reported fatigue (median TTD 2.7 vs 1.4 months) and arm/shoulder pain (median TTD 8.1 vs 1.9 months) was delayed with alectinib versus chemotherapy. Median TTD in composite symptom endpoint (cough, dyspnoea, chest-pain) was similar between arms. Alectinib patients reported improvement in lung cancer symptoms from baseline (least square [LS] mean) during treatment: fatigue (-6.2), single-item dyspnoea (-6.0), multi-item dyspnoea scale (-2.3), coughing (-4.9), chest pain (-4.2), pain in other parts (-5.3). More patients reported improvement in baseline symptoms (nausea/vomiting, diarrhoea, peripheral neuropathy) with alectinib versus chemotherapy, except constipation. More alectinib patients reported improvements in cognitive function versus chemotherapy (ITT 19% vs 3%; C-ITT 24% vs 4%); average change from baseline in cognitive function favoured alectinib (LS means difference 10.0, 95% CI 2.2–17.7). Median treatment duration: 20.1 weeks alectinib (95% CI 0.4–8.2), 6 weeks chemotherapy (95% CI 1.9–47.1). For alectinib versus chemotherapy: AEs leading to discontinuation, 5.7% vs 8.8%; dose reductions, 4.3% vs 11.8%; dose interruptions due to AEs, 18.3% vs 8.8%. AEs: 77.1% alectinib (grade 3–5, 27.1%); 85.3% chemotherapy (grade 3–5, 41.2%); one fatal AE (chemotherapy); grade ≥3 AEs: 41.2% chemotherapy versus 27.1% alectinib. TEAEs occurring in ≥10% patients: constipation (alectinib 18.6%, all grade 1–2; chemotherapy 8.8% [grade ≥3 2.9%]), nausea (alectinib 1.4%, all grade 1–2; chemotherapy 17.6% [grade ≥3 2.9%]) and fatigue (alectinib 5.7%, all grade 1–2; chemotherapy 26.5% [grade ≥3 8.8%]).
Conclusion:
Alectinib improved HRQoL, functioning, and symptom burden versus chemotherapy (except constipation). Safety of alectinib compared favourably to chemotherapy. Alectinib patients (ITT and C-ITT populations) derived benefit versus chemotherapy.
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P1.04 - Clinical Design, Statistics and Clinical Trials (ID 690)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.04-011 - Development of Novel Blood-Based Biomarker Assays in 1L Advanced/ Metastatic NSCLC: Blood First Assay Screening Trial (BFAST) (ID 8398)
09:30 - 16:00 | Author(s): Rafal Dziadziuszko
- Abstract
Background:
Worldwide it is estimated that 20%-30% of advanced NSCLC patients do not receive a complete molecular diagnosis at baseline and are ineligible for targeted therapies due to tissue biopsy limitations. Blood-based, multiplex testing that analyzes circulating tumor DNA (ctDNA) by targeted next-generation sequencing offers a minimally invasive testing method, but clinical utility has yet to be established. High tumor mutational burden (TMB) measured in tissue is associated with atezolizumab (anti–PD-L1) clinical activity in several tumor types, including NSCLC. Alectinib, a potent, selective ALK/RET kinase inhibitor, has shown activity in 1L and is approved as 2L therapy in patients with ALK- or RET-positive advanced NSCLC but requires tissue for analysis. Here we present an umbrella trial that aims to clinically validate novel blood-based diagnostic assays that measure TMB in the blood (bTMB) and somatic mutations (e.g., ALK/RET), and to determine the efficacy and safety of 1L atezolizumab or alectinib in biomarker-selected NSCLC patients.
Method:
BFAST is a Phase II/III global, multicenter, open-label, multi-cohort screening and interventional umbrella trial designed to evaluate the safety and efficacy of targeted therapies in patients with unresectable, advanced or metastatic NSCLC selected based on the presence of oncogenic somatic mutations or a positive bTMB score. Key eligibility criteria include previously untreated, stage IIIB-IVB NSCLC of any histology and measurable disease per RECIST v1.1. Pre-enrollment blood-based screening will identify patients whose tumors harbor oncogenic somatic mutations (ALK/RET) or a positive bTMB score (above a pre-specified cutoff); patients will be assigned to the appropriate cohort based on the screening results. Study treatment will continue until disease progression (all cohorts) or loss of clinical benefit (atezolizumab only) (Table). The modular trial design allows for additional biomarker-driven BFAST cohorts with distinct screening and treatment requirements, and endpoints such as ORR with highly active drugs.Table. BFAST Study Details Cohort Treatment Planned Enrollment, n Primary Endpoints Key Secondary Endpoints Cohort AALK+ Alectinib 600 mg PO bid 78 ORR per RECIST v1.1 (INV-assessed) DOR, CBR[c] and PFS per RECIST v1.1 (INV-assessed) ORR, DOR, CBR and PFS per RECIST v1.1 (IRF-assessed) OS Cohort B RET+ Alectinib 900 and 1200 mg dose escalation 52-62 ORR per RECIST v1.1 (INV-assessed) DOR, CBR and PFS per RECIST v1.1 (INV-assessed) ORR, DOR, CBR and PFS per RECIST v1.1 (IRF-assessed) OS Cohort C bTMB+ Atezolizumab 1200 mg IV q3w or platinum-based chemotherapy[a] ≈440 (R, 1:1)[b] PFS per RECIST v1.1 (INV-assessed) OS PFS, ORR and DOR per RECIST v1.1 (IRF-assessed) ORR and DOR per RECIST v1.1 (INV-assessed) 6- and 12-month PFS rates [a ]Cisplatin or carboplatin + pemetrexed for non-squamous histology, and cisplatin or carboplatin + gemcitabine for squamous histology. Administered per standard of care. [b ]Stratification factors include tissue availability, ECOG performance status, bTMB level and tumor histology. [c ]CBR is defined as the rate of patients with confirmed CR or PR or stable disease that has been maintained for ≥ 24 weeks. bid, twice a day; bTMB, blood tumor mutational burden; CBR, clinical benefit rate; INV, investigator; IRF, independent review facility; IV, intravenously; PO, orally; q3w, every 3 weeks; R, randomized.
Result:
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Conclusion:
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