Virtual Library

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.

Abstract not provided

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)

Abstract not provided