Introduction: The cell cycle cyclin-dependent kinases (CDKs) play a critical role in controlling the transition between cell cycle phases, as well as cellular transcription. Aberrant CDK activation is common in cancer, and deregulation of the cell cycle a key hallmark of cancer. Although CDK4/6 inhibitors are now a standard-of-care option for first- and second-line HR+/HER2- metastatic breast cancer, resistance inevitably limits their clinical benefit.Areas covered: Early pan-CDK inhibitors targeted the cell cycle and RNA polymerase II phosphorylation, but were complicated by toxicity, providing a rationale and need for the development of selective CDK inhibitors. In this review, we highlight selected recent literature to provide a narrative review summarizing the current CDK inhibitor therapeutic landscape. We detail the challenges associated with targeting CDKs for the treatment of breast and other cancers and review emerging biomarkers that may aid response prediction. We also discuss the risk-benefit ratio for CDK therapy and explore promising combination approaches.Expert opinion: Although CDK inhibitors may stem the proliferation of cancer cells, resistance remains an issue, and currently there are limited biomarkers to predict response to therapy. Ongoing research investigating CDK inhibitors in cancer is of paramount importance to define appropriate and effective treatment regimens.
9016 Background: Teliso-V is an antibody-drug conjugate composed of a c-Met antibody (ABT-700) and a microtubule inhibitor (monomethyl auristatin E). The phase 2 M14-239 trial (LUMINOSITY, NCT03539536) aims to identify the c-Met OE NSCLC populations best suited to Teliso-V (Stage 1) and expand selected groups for further evaluation of efficacy (Stage 2). In Stage 1, pts were enrolled into cohorts defined by histopathology (non-squamous [NSQ] or squamous [SQ]) and EGFR mutation status (mutant or wild type [WT]); NSQ cohorts were further divided in groups on the basis of c-Met expression (high or intermediate). Updated data from the fourth interim analysis (IA4) are presented. Methods: Pts had locally advanced/metastatic NSCLC, ≤2 prior lines of systemic therapy, ≤1 line of chemotherapy, and tumors that were c-Met OE by central immunohistochemistry (IHC; Ventana; Tucson, AZ). c-Met OE was defined for the NSQ cohort as ≥25% 3+ by IHC (high, ≥50% 3+; intermediate, 25 to <50% 3+) and for the SQ cohort as ≥75% 1+ by IHC. The planned enrollment was up to approximately 150 pts in Stage 1 and 160 pts in Stage 2. Teliso-V was dosed at 1.9 mg/kg IV Q2W. The primary endpoint is objective response rate (ORR) by independent central review. Secondary endpoints include duration of response (DOR). Results: As of data cutoff (27 May 2021), 136 pts were treated with Teliso-V; 122 were evaluable for ORR. ORR was 36.5% in the NSQ EGFR WT cohort (52.2% in c-Met high group and 24.1% in c-Met intermediate group), but was modest in the NSQ EGFR mutant and SQ cohorts. Efficacy data in groups/cohorts are in the Table. The most common any-grade adverse events (AEs) were peripheral sensory neuropathy (25.0%), nausea (22.1%), and hypoalbuminemia (20.6%). Grade 5 AEs considered possibly related to Teliso-V occurred in 2 pts (sudden death and pneumonitis in 1 pt each in the SQ cohort). Conclusions: Teliso-V demonstrated a promising ORR in pts with previously treated c-Met OE NSQ EGFR WT NSCLC; this cohort is currently expanding in Stage 2. ORR was modest in the cohorts of pts with c-Met OE NSQ EGFR mutant NSCLC and with c-Met OE SQ NSCLC; both cohorts have now met the protocol-specified stopping criteria and are no longer enrolling. The safety profile observed was consistent with IA3. Clinical trial information: NCT03539536. [Table: see text]
// James Che 1,2 , Victor Yu 1 , Manjima Dhar 1 , Corinne Renier 2,3 , Melissa Matsumoto 1 , Kyra Heirich 3 , Edward B. Garon 4 , Jonathan Goldman 4 , Jianyu Rao 5 , George W. Sledge 6 , Mark D. Pegram 6 , Shruti Sheth 6 , Stefanie S. Jeffrey 3,6 , Rajan P. Kulkarni 1,7 , Elodie Sollier 1,2,3 and Dino Di Carlo 1,8,9 1 Department of Bioengineering, University of California, Los Angeles, California, USA 2 Vortex Biosciences, Menlo Park, California, USA 3 Department of Surgery, Stanford University School of Medicine, Stanford, California, USA 4 Department of Hematology & Oncology, UCLA Medical Center, Los Angeles, California, USA 5 Department of Pathology & Laboratory Medicine, UCLA Medical Center, Los Angeles, California, USA 6 Stanford Women’s Cancer Center, Stanford, California, USA 7 Division of Dermatology, UCLA Medical Center, Los Angeles, California, USA 8 California NanoSystems Institue, Los Angeles, California, USA 9 Jonsson Comprehensive Cancer Center, Los Angeles, California, USA Correspondence to: Dino Di Carlo, email: // Keywords : circulating tumor cells, immunofluorescent staining, rare cell enrichment, size based cell isolation, Vortex Received : January 18, 2016 Accepted : January 21, 2016 Published : February 06, 2016 Abstract Circulating tumor cells (CTCs) are emerging as rare but clinically significant non-invasive cellular biomarkers for cancer patient prognosis, treatment selection, and treatment monitoring. Current CTC isolation approaches, such as immunoaffinity, filtration, or size-based techniques, are often limited by throughput, purity, large output volumes, or inability to obtain viable cells for downstream analysis. For all technologies, traditional immunofluorescent staining alone has been employed to distinguish and confirm the presence of isolated CTCs among contaminating blood cells, although cells isolated by size may express vastly different phenotypes. Consequently, CTC definitions have been non-trivial, researcher-dependent, and evolving. Here we describe a complete set of objective criteria, leveraging well-established cytomorphological features of malignancy, by which we identify large CTCs. We apply the criteria to CTCs enriched from stage IV lung and breast cancer patient blood samples using the High Throughput Vortex Chip (Vortex HT), an improved microfluidic technology for the label-free, size-based enrichment and concentration of rare cells. We achieve improved capture efficiency (up to 83%), high speed of processing (8 mL/min of 10x diluted blood, or 800 μL/min of whole blood), and high purity (avg. background of 28.8±23.6 white blood cells per mL of whole blood). We show markedly improved performance of CTC capture (84% positive test rate) in comparison to previous Vortex designs and the current FDA-approved gold standard CellSearch assay. The results demonstrate the ability to quickly collect viable and pure populations of abnormal large circulating cells unbiased by molecular characteristics, which helps uncover further heterogeneity in these cells.
9000 Background: The third generation EGFR tyrosine kinase inhibitor (TKI) rociletinib has demonstrated activity in non-small cell lung cancer (NSCLC) patients (pts) who progressed on prior EGFR TKIs due to an acquired T790M resistance mutation. Additional work is needed to understand the mechanisms of resistance to rociletinib and other third generation EGFR TKIs. Methods: We employed circulating tumor DNA analysis using Cancer Personalized Profiling by deep Sequencing (CAPP-Seq) to study putative mechanisms of innate and acquired resistance to rociletinib. CAPP-Seq was applied to a total of 115 serial plasma samples from T790M-positive NSCLC pts (n = 43) enrolled in the TIGER-X (n = 42) (NCT01526928) and TIGER-2 (n = 1) (NCT02147990) clinical trials. Results: Rociletinib resistance was diverse, with mutations and/or copy number gains affecting 9 genes involved in bypass pathway activation and tumor suppressor pathways. Multiple resistance mechanisms were observed in 23% of pts. Examples of emergent alterations included activating KRAS mutations in three pts, a novel tertiary mutation in EGFR (L798I) in one patient, and an EGFRC797S mutation in one patient. Increased MET copy number was the most frequently observed mechanism of resistance, occurring in 26% of cases. Pts with heterogeneity of resistance mechanisms at baseline (both T790M and increased MET copy number) displayed inferior responses and significantly shorter progression free survival (P < 0.05). In agreement with these clinical findings, erlotinib-resistant xenografts treated with rociletinib reproducibly developed MET amplification. Importantly, sensitivity to rociletinib could be reinstated by combined therapy with the METinhibitor crizotinib. Conclusions: We observed diverse and heterogeneous resistance mechanisms to rociletinib. The association of inferior outcomes with multiple resistance mechanisms at baseline emphasizes the clinical importance of tumor heterogeneity in these pts. Our results demonstrate that non-invasive profiling using ctDNA analysis can define patterns of resistance to targeted therapies and potentially allows for personalization of combination therapies to overcome resistance.
<div>AbstractPurpose:<p>Immune checkpoint inhibitors (ICI) have revolutionized the treatment of non–small cell lung cancer (NSCLC), but predictive biomarkers of their efficacy are imperfect. The primary objective is to evaluate circulating immune predictors of pembrolizumab efficacy in patients with advanced NSCLC.</p> Experimental Design:<p>We used high-dimensional mass cytometry (CyTOF) in baseline blood samples of patients with advanced NSCLC treated with pembrolizumab. CyTOF data were analyzed by machine-learning algorithms (Citrus, tSNE) and confirmed by manual gating followed by principal component analysis (between-group analysis).</p>Results:<p>We analyzed 27 patients from the seminal KEYNOTE-001 study (median follow-up of 60.6 months). We demonstrate that blood baseline frequencies of classical monocytes, natural killer (NK) cells, and ICOS<sup>+</sup> CD4<sup>+</sup> T cells are significantly associated with improved objective response rates, progression-free survival, and overall survival (OS). In addition, we report that a baseline immune peripheral score combining these three populations strongly predicts pembrolizumab efficacy (OS: HR = 0.25; 95% confidence interval = 0.12–0.51; <i>P</i> < 0.0001).</p>Conclusions:<p>As this immune monitoring is easy in routine practice, we anticipate our findings may improve prediction of ICI benefit in patients with advanced NSCLC.</p></div>
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