Robert McCormack

Considerations in the development of circulating tumor cell technology for clinical use

This manuscript summarizes current thinking on the value and promise of evolving circulating tumor cell (CTC) technologies for cancer patient diagnosis, prognosis, and response to therapy, as well as accelerating oncologic drug development. Moving forward requires the application of the classic steps in biomarker development–analytical and clinical validation and clinical qualification for specific contexts of use. To that end, this review describes methods for interactive comparisons of proprietary new technologies, clinical trial designs, a clinical validation qualification strategy, and an approach for effectively carrying out this work through a public-private partnership that includes test developers, drug developers, clinical trialists, the US Food & Drug Administration (FDA) and the US National Cancer Institute (NCI).

Circulating Tumor Cell Biomarker Panel As an Individual-Level Surrogate for Survival in Metastatic Castration-Resistant Prostate Cancer

PURPOSE Trials in castration-resistant prostate cancer (CRPC) need new clinical end points that are valid surrogates for survival. We evaluated circulating tumor cell (CTC) enumeration as a surrogate outcome measure. PATIENTS AND METHODS Examining CTCs alone and in combination with other biomarkers as a surrogate for overall survival was a secondary objective of COU-AA-301, a multinational, randomized, double-blind phase III trial of abiraterone acetate plus prednisone versus prednisone alone in patients with metastatic CRPC previously treated with docetaxel. The biomarkers were measured at baseline and 4, 8, and 12 weeks, with 12 weeks being the primary measure of interest. The Prentice criteria were applied to test candidate biomarkers as surrogates for overall survival at the individual-patient level. RESULTS A biomarker panel using CTC count and lactate dehydrogenase (LDH) level was shown to satisfy the four Prentice criteria for individual-level surrogacy. Twelve-week surrogate biomarker data were available for 711 patients. The abiraterone acetate plus prednisone and prednisone-alone groups demonstrated a significant survival difference (P = .034); surrogate distribution at 12 weeks differed by treatment (P < .001); the discriminatory power of the surrogate to predict mortality was high (weighted c-index, 0.81); and adding the surrogate to the model eliminated the treatment effect on survival. Overall, 2-year survival of patients with CTCs < 5 (low risk) versus patients with CTCs ≥ 5 cells/7.5 mL of blood and LDH > 250 U/L (high risk) at 12 weeks was 46% and 2%, respectively. CONCLUSION A biomarker panel containing CTC number and LDH level was shown to be a surrogate for survival at the individual-patient level in this trial of abiraterone acetate plus prednisone versus prednisone alone for patients with metastatic CRPC. Additional trials are ongoing to validate the findings.

Breaking a Vicious Cycle

New tumor-biomarker diagnostics will emerge along with changes in regulation, development, reimbursement, and investment practices. Despite prodigious advances in tumor biology research, few tumor-biomarker tests have been adopted as standard clinical practice. This lack of reliable tests stems from a vicious cycle of undervaluation, resulting from inconsistent regulatory standards and reimbursement, as well as insufficient investment in research and development, scrutiny of biomarker publications by journals, and evidence of analytical validity and clinical utility. We offer recommendations designed to serve as a roadmap to break this vicious cycle and call for a national dialogue, as changes in regulation, reimbursement, investment, peer review, and guidelines development require the participation of all stakeholders.

Decline in Circulating Tumor Cell Count and Treatment Outcome in Advanced Prostate Cancer

Background Treatment response biomarkers are urgently needed for castration-resistant prostate cancer (CRPC). Baseline and post-treatment circulating tumor cell (CTC) counts of ≥5 cells/7.5 ml are associated with poor CRPC outcome. Objective To determine the value of a ≥30% CTC decline as a treatment response indicator. Design, setting, and participants We identified patients with a baseline CTC count ≥5 cells/7.5 ml and evaluable post-treatment CTC counts in two prospective trials. Intervention Patients were treated in the COU-AA-301 (abiraterone after chemotherapy) and IMMC-38 (chemotherapy) trials. Outcome measures and statistical analysis The association between a ≥30% CTC decline after treatment and survival was evaluated using univariable and multivariable Cox regression models at three landmark time points (4, 8, and 12 wk). Model performance was evaluated by calculating the area under the receiver operating characteristic curve (AUC) and c-indices. Results Overall 486 patients (122 in IMMC-38 and 364 in COU-AA-301) had a CTC count ≥5 cells/7.5 ml at baseline, with 440, 380, and 351 patients evaluable at 4, 8, and 12 wk, respectively. A 30% CTC decline was associated with increased survival at 4 wk (hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.36–0.56; p < 0.001), 8 wk (HR 0.41, 95% CI 0.33–0.53; p < 0.001), and 12 wk (HR 0.39, 95% CI 0.3–0.5; p < 0.001) in univariable and multivariable analyses. Stable CTC count (<30% fall or <30% increase) was not associated with a survival benefit when compared with increased CTC count. The association between a 30% CTC decline after treatment and survival was independent of baseline CTC count. CTC declines significantly improved the AUC at all time-points. Finally, in the COU-AA-301 trial, patients with CTC ≥5 cells/7.5 ml and a 30% CTC decline had similar overall survival in both arms. Conclusions A 30% CTC decline after treatment from an initial count ≥5 cells/7.5 ml is independently associated with CRPC overall survival following abiraterone and chemotherapy, improving the performance of a multivariable model as early as 4 wk after treatment. This potential surrogate must now be prospectively evaluated. Patient summary Circulating tumor cells (CTCs) are cancer cells that can be detected in the blood of prostate cancer patients. We analyzed changes in CTCs after treatment with abiraterone and chemotherapy in two large clinical trials, and found that patients who have a decline in CTC count have a better survival outcome.

Codevelopment of Genome-Based Therapeutics and Companion Diagnostics Insights From an Institute of Medicine Roundtable

More than 100 therapeutics, mostly for oncology, have biomarker tests recommended in their US Food and Drug Administration (FDA) labels.1 Moreover, a strategy to codevelop and cosubmit to the FDA a diagnostic test (companion diagnostic [CoDx]) that specifically targets a drug to patients predicted to respond has had success recently with vemurafenib, targeting the BRAF V600 mutation in metastatic melanoma, and with crizotinib, targeting the EML4-ALK mutation in non–small cell lung cancer.2 Companion diagnostic tests define the subset of patients who are most likely to benefit from a therapy or who should not receive the therapy because of ineffectiveness or predicted adverse effects.3 Genome-based, targeted therapeutics and codeveloped CoDx tests are the foundation of personalized medicine and have potential for contributing to high-value health care.

Circulating Tumor Cell Number as a Response Measure of Prolonged Survival for Metastatic Castration-Resistant Prostate Cancer: A Comparison With Prostate-Specific Antigen Across Five Randomized Phase III Clinical Trials

Purpose Measures of response that are clinically meaningful and occur early are an unmet need in metastatic castration-resistant prostate cancer clinical research and practice. We explored, using individual patient data, week 13 circulating tumor cell (CTC) and prostate-specific antigen (PSA) response end points in five prospective randomized phase III trials that enrolled a total of 6,081 patients-COU-AA-301, AFFIRM, ELM-PC-5, ELM-PC-4, and COMET-1- ClinicalTrials.Gov identifiers: NCT00638690, NCT00974311, NCT01193257, NCT01193244, and NCT01605227, respectively. Methods Eight response end points were explored. CTC nonzero at baseline and 0 at 13 weeks (CTC0); CTC conversion (≥ 5 CTCs at baseline, ≤ 4 at 13 weeks-the US Food and Drug Administration cleared response measure); a 30%, 50%, and 70% decrease in CTC count; and a 30%, 50%, and 70% decrease in PSA level. Patients missing week-13 values were considered nonresponders. The discriminatory strength of each end point with respect to overall survival in each trial was assessed using the weighted c-index. Results Of the eight response end points, CTC0 and CTC conversion had the highest weighted c-indices, with smaller standard deviations. For CTC0, the mean (standard deviation) was 0.81 (0.04); for CTC conversion, 0.79 (0.03); for 30% decrease in CTC count, 0.72 (0.06); for 50% decrease in CTC count, 0.72 (0.06); for 70% decrease in CTC count, 0.73 (0.05); for 30% decrease in PSA level, 0.71 (0.03); for 50% decrease in PSA level, 0.72 (0.06); and for 70% decrease in PSA level, 0.74 (0.05). Seventy-five percent of eligible patients could be evaluated with the CTC0 end point, compared with 51% with the CTC conversion end point. Conclusion The CTC0 and CTC conversion end points had the highest discriminatory power for overall survival. Both are robust and meaningful response end points for early-phase metastatic castration-resistant prostate cancer clinical trials. CTC0 is applicable to a significantly higher percentage of patients than CTC conversion.