Bettzy Stephen

Survival of 1,181 Patients in a Phase I Clinic: The MD Anderson Clinical Center for Targeted Therapy Experience

Purpose: To determine whether the Royal Marsden Hospital (RMH; London, UK) prognostic score for phase I patients can be validated in a large group of individuals seen in a different center and whether other prognostic variables are also relevant, we present an analysis of 1,181 patients treated in the MD Anderson Cancer Center (MDACC; Houston, TX) phase I clinic. Experimental Design: Medical records of 1,181 consecutive patients who were treated on at least one trial in the phase I clinic were reviewed. Results: The median age was 58 years and 50% were women. The median number of prior therapies was four and median survival 10 months [95% confidence interval (CI), 9.1–10.9 months]. Independent factors that predicted shorter survival in a multivariate Cox model and could be internally validated included RMH score of >1 (P < 0.0001; albumin <3.5 g/dL; lactate dehydrogenase >upper limit of normal, and >two sites of metastases), gastrointestinal tumor type (P < 0.0001), and Eastern Cooperative Oncology Group performance status ≥1 (P = 0.0004). The median survival was 24.0, 15.2, 8.4, 6.2, and 4.1 months for patients with 0, 1, 2, 3, and 4 or 5 of the above risk factors, respectively. Conclusion: The RMH score was validated in a large group of patients at MDACC. Internal validation of the independent prognostic factors for survival led to the development of the MDACC prognostic score, a modification of the RMH score that strengthens it. Clin Cancer Res; 18(10); 2922–9. ©2012 AACR.

Cancer therapy directed by comprehensive genomic profiling: a single center study

Innovative molecular diagnostics deployed in the clinic enable new ways to stratify patients into appropriate treatment regimens. These approaches may resolve a major challenge for early-phase clinical trials, which is to recruit patients who, while having failed previous treatments, may nevertheless respond to molecularly targeted drugs. We report the findings of a prospective, single-center study conducted in patients with diverse refractory cancers who underwent comprehensive genomic profiling (CGP; next-generation sequencing, 236 genes). Of the 500 patients enrolled, 188 (37.6%) received either matched (N = 122/188, 65%) or unmatched therapy (N = 66/188, 35%). The most common reasons that patients were not evaluable for treatment included insufficient tissue, death, or hospice transfer. The median number of molecular alterations per patient was five (range, 1-14); median number of prior therapies, four. The most common diagnoses were ovarian cancer (18%), breast cancer (16%), sarcoma (13%), and renal cancer (7%). Of the 339 successfully profiled patients, 317 (93.5%) had at least one potentially actionable alteration. By calculating matching scores, based on the number of drug matches and genomic aberrations per patient, we found that high scores were independently associated with a greater frequency of stable disease ≥6 months/partial/complete remission [22% (high scores) vs. 9% (low scores), P = 0.024], longer time-to-treatment failure [hazard ratio (HR) = 0.52; 95% confidence interval (CI) = 0.36-0.74; P = 0.0003], and survival (HR = 0.65; 95% CI = 0.43-1.0; P = 0.05). Collectively, this study offers a clinical proof of concept for the utility of CGP in assigning therapy to patients with refractory malignancies, especially in those patients with multiple genomic aberrations for whom combination therapies could be implemented. Cancer Res; 76(13); 3690-701. ©2016 AACR.

Triple-Negative Breast Cancer Patients Treated at MD Anderson Cancer Center in Phase I Trials: Improved Outcomes with Combination Chemotherapy and Targeted Agents

Patients with metastatic triple-negative breast cancer (TNBC) have poor treatment outcomes. We reviewed the electronic records of consecutive patients with metastatic TNBC treated in phase I clinic at MD Anderson Cancer Center (Houston, TX) between Augu st 2005 and May 2012. One hundred and six patients received at least 1 phase I trial. Twelve of 98 evaluable patients (12%) had either complete response (CR; n = 1), partial response (PR; n = 7), or stable disease ≥6 months (SD; n = 4). Patients treated on matched therapy (n = 16) compared with those on nonmatched therapy (n = 90) had improved SD ≥ 6 months/PR/CR (33% vs. 8%; P = 0.018) and longer progression-free survival (PFS; median, 6.4 vs. 1.9 months; P = 0.001). Eleven of 57 evaluable patients (19%) treated with combination chemotherapy and targeted therapy had SD ≥ 6 months/PR/CR versus 1 of 41 evaluable patients (2%) treated on other phase I trials (P = 0.013), and longer PFS (3.0 vs. 1.6 months; P < 0.0001). Patients with molecular alterations in the PI3K/AKT/mTOR pathway treated on matched therapy (n = 16) had improved PFS compared with those with and without molecular alterations treated on nonmatched therapy (n = 27; 6.4 vs. 3.2 months; P = 0.036). On multivariate analysis, improved PFS was associated with treatment with combined chemotherapy and targeted agents (P = 0.0002), ≤2 metastatic sites (P = 0.003), therapy with PI3K/AKT/mTOR inhibitors for those with cognate pathway abnormalities (P = 0.018), and treatment with antiangiogenic agents (P = 0.023). In summary, combinations of chemotherapy and angiogenesis and/or PI3K/AKT/mTOR inhibitors demonstrated improved outcomes in patients with metastatic TNBC. Mol Cancer Ther; 13(12); 3175–84. ©2014 AACR.

Aberrations in the epidermal growth factor receptor gene in 958 patients with diverse advanced tumors: implications for therapy

BACKGROUND Epidermal growth factor receptor (EGFR) mutations are associated with the response to EGFR inhibitors in patients with non-small-cell lung cancer (NSCLC). We sought to investigate EGFR aberrations in patients with diverse advanced cancers. PATIENTS AND METHODS Patients referred to the phase I clinic were evaluated for the presence of EGFR mutations and response to therapy. RESULTS EGFR aberrations were detected in 34 of 958 patients (3.5%). Though EGFR mutations were most frequent in NSCLC (21 of 131, 16%), they were also present in a variety of other solid tumors (13 of 827 patients, 1.6%) including adrenocortical (1/10 patients), skin (1/24), breast (1/55), carcinoid (1/8), cholangiocarcinoma (1/20), head and neck (1/61), ovarian (1/84), parathyroid (1/1), salivary gland (1/20), renal (1/17), sarcoma (2/38), and thymic carcinomas (1/7). Of the 13 EGFR aberration-positive non-NSCLC patients (median number of prior systemic therapies = 3), 6 had treatment with an EGFR inhibitor. Two patients (diagnosis = parathyroid tumor and basal cell carcinoma) achieved stable disease (SD), lasting 6 and 7 months, respectively. CONCLUSION We found EGFR aberrations in 1.6% of a large group of patients with diverse tumors other than NSCLC, and treatment with an EGFR inhibitor could be associated with prolonged SD.

Risk of serious toxicity in 1181 patients treated in phase I clinical trials of predominantly targeted anticancer drugs: the M. D. Anderson Cancer Center experience

BACKGROUND This study assessed toxicity in advanced cancer patients treated in a phase I clinic that focuses on targeted agents. PATIENTS AND METHODS An analysis of database records of 1181 consecutive patients with advanced cancer who were treated in the phase I program starting 1 January 2006 was carried out. RESULTS All patients were treated on at least 1 of the 82 phase I clinical trials. Overall, 56 trials (68.3%) had only targeted agents, 13 (15.9%) only cytotoxics, and 13 (15.9%) targeted and cytotoxic agents. Rates of grade 3 and 4 toxicity that were at least possibly drug related were 7.1% and 3.2%, respectively, and 5 of the 1181 patients (0.4%) died from toxicity that was at least possibly drug related. The most common grade 3 or more toxic effects were neutropenia, thrombocytopenia, anemia, dehydration, infection, altered mental status, bleeding, vomiting, nausea, and diarrhea. Eastern Cooperative Oncology Group (ECOG) performance status greater than zero and use of a cytotoxic agent were selected as independent factors associated with serious toxicity. CONCLUSION Phase I trials of primarily targeted agents showed low rates of toxicity, with 10.3% of patients experiencing grade 3 or 4 toxicity and a 0.4% rate of death, at least possibly drug related.BACKGROUND This study assessed toxicity in advanced cancer patients treated in a phase I clinic that focuses on targeted agents. PATIENTS AND METHODS An analysis of database records of 1181 consecutive patients with advanced cancer who were treated in the phase I program starting 1 January 2006 was carried out. RESULTS All patients were treated on at least 1 of the 82 phase I clinical trials. Overall, 56 trials (68.3%) had only targeted agents, 13 (15.9%) only cytotoxics, and 13 (15.9%) targeted and cytotoxic agents. Rates of grade 3 and 4 toxicity that were at least possibly drug related were 7.1% and 3.2%, respectively, and 5 of the 1181 patients (0.4%) died from toxicity that was at least possibly drug related. The most common grade 3 or more toxic effects were neutropenia, thrombocytopenia, anemia, dehydration, infection, altered mental status, bleeding, vomiting, nausea, and diarrhea. Eastern Cooperative Oncology Group (ECOG) performance status greater than zero and use of a cytotoxic agent were selected as independent factors associated with serious toxicity. CONCLUSION Phase I trials of primarily targeted agents showed low rates of toxicity, with 10.3% of patients experiencing grade 3 or 4 toxicity and a 0.4% rate of death, at least possibly drug related.

Haplotype Analysis of the TRB Locus by TCRB Repertoire Sequencing

Polymorphism within the T cell receptor beta variable gene (TRBV) has been implicated in autoimmune disease and immuneCrelated adverse events (IRAEs) during immunotherapy. Previous efforts to evaluate TRBV polymorphism by whole genome sequencing (WGS) have been hampered by the repetitive nature of the TCRB locus. We present a novel longCamplicon TCRB repertoire sequencing approach to evaluate TRBV polymorphism from peripheral blood, which we use to identify TRBV allele haplotypes in 81 Caucasians.

Overview of Basic Immunology for Clinical Investigators

Tumor exists as a complex network of structures with an ability to evolve and evade the host immune surveillance mechanism. The immune milieu which includes macrophages, dendritic cells, natural killer cells, neutrophils, mast cells, B cells, and T cells are found in the core, the invasive margin, or the adjacent stromal or lymphoid component of the tumor. The immune infiltrate is heterogeneous and varies within a patient and between patients of the same tumor histology. The location, density, functionality, and the cross talk between the immune cells in the tumor microenvironment influence the nature of immune response, prognosis, and treatment outcomes in cancer patients. Therefore, an understanding of the characteristics of the immune cells and their role in tumor immune surveillance is of paramount importance to identify immune targets and to develop novel immune therapeutics in the war against cancer. In this chapter, we provide an overview of the individual components of the human immune system and the translational relevance of predictive biomarkers.