Stephen Y. Chui

Adaptive Randomization of Veliparib–Carboplatin Treatment in Breast Cancer

BACKGROUND The genetic and clinical heterogeneity of breast cancer makes the identification of effective therapies challenging. We designed I-SPY 2, a phase 2, multicenter, adaptively randomized trial to screen multiple experimental regimens in combination with standard neoadjuvant chemotherapy for breast cancer. The goal is to match experimental regimens with responding cancer subtypes. We report results for veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin. METHODS In this ongoing trial, women are eligible for participation if they have stage II or III breast cancer with a tumor 2.5 cm or larger in diameter; cancers are categorized into eight biomarker subtypes on the basis of status with regard to human epidermal growth factor receptor 2 (HER2), hormone receptors, and a 70-gene assay. Patients undergo adaptive randomization within each biomarker subtype to receive regimens that have better performance than the standard therapy. Regimens are evaluated within 10 biomarker signatures (i.e., prospectively defined combinations of biomarker subtypes). Veliparib-carboplatin plus standard therapy was considered for HER2-negative tumors and was therefore evaluated in 3 signatures. The primary end point is pathological complete response. Tumor volume changes measured by magnetic resonance imaging during treatment are used to predict whether a patient will have a pathological complete response. Regimens move on from phase 2 if and when they have a high Bayesian predictive probability of success in a subsequent phase 3 neoadjuvant trial within the biomarker signature in which they performed well. RESULTS With regard to triple-negative breast cancer, veliparib-carboplatin had an 88% predicted probability of success in a phase 3 trial. A total of 72 patients were randomly assigned to receive veliparib-carboplatin, and 44 patients were concurrently assigned to receive control therapy; at the completion of chemotherapy, the estimated rates of pathological complete response in the triple-negative population were 51% (95% Bayesian probability interval [PI], 36 to 66%) in the veliparib-carboplatin group versus 26% (95% PI, 9 to 43%) in the control group. The toxicity of veliparib-carboplatin was greater than that of the control. CONCLUSIONS The process used in our trial showed that veliparib-carboplatin added to standard therapy resulted in higher rates of pathological complete response than standard therapy alone specifically in triple-negative breast cancer. (Funded by the QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.).

The Neoadjuvant Model is Still the Future for Drug Development in Breast Cancer

The many improvements in breast cancer therapy in recent years have so lowered rates of recurrence that it is now difficult or impossible to conduct adequately powered adjuvant clinical trials. Given the many new drugs and potential synergistic combinations, the neoadjuvant approach has been used to test benefit of drug combinations in clinical trials of primary breast cancer. A recent FDA-led meta-analysis showed that pathologic complete response (pCR) predicts disease-free survival (DFS) within patients who have specific breast cancer subtypes. This meta-analysis motivated the FDAs draft guidance for using pCR as a surrogate endpoint in accelerated drug approval. Using pCR as a registration endpoint was challenged at ASCO 2014 Annual Meeting with the presentation of ALTTO, an adjuvant trial in HER2-positive breast cancer that showed a nonsignificant reduction in DFS hazard rate for adding lapatinib, a HER-family tyrosine kinase inhibitor, to trastuzumab and chemotherapy. This conclusion seemed to be inconsistent with the results of NeoALTTO, a neoadjuvant trial that found a statistical improvement in pCR rate for the identical lapatinib-containing regimen. We address differences in the two trials that may account for discordant conclusions. However, we use the FDA meta-analysis to show that there is no discordance at all between the observed pCR difference in NeoALTTO and the observed HR in ALTTO. This underscores the importance of appropriately modeling the two endpoints when designing clinical trials. The I-SPY 2/3 neoadjuvant trials exemplify this approach. Clin Cancer Res; 21(13); 2911–5. ©2015 AACR.

Intratumor mapping of intracellular water lifetime: metabolic images of breast cancer?

Shutter‐speed pharmacokinetic analysis of dynamic‐contrast‐enhanced (DCE)‐MRI data allows evaluation of equilibrium inter‐compartmental water interchange kinetics. The process measured here – transcytolemmal water exchange – is characterized by the mean intracellular water molecule lifetime (τi). The τi biomarker is a true intensive property not accessible by any formulation of the tracer pharmacokinetic paradigm, which inherently assumes it is effectively zero when applied to DCE‐MRI. We present population‐averaged in vivo human breast whole tumor τi changes induced by therapy, along with those of other pharmacokinetic parameters. In responding patients, the DCE parameters change significantly after only one neoadjuvant chemotherapy cycle: while Ktrans (measuring mostly contrast agent (CA) extravasation) and kep (CA intravasation rate constant) decrease, τi increases. However, high‐resolution, (1 mm)2, parametric maps exhibit significant intratumor heterogeneity, which is lost by averaging. A typical 400 ms τi value means a trans‐membrane water cycling flux of 1013 H2O molecules s−1/cell for a 12 µm diameter cell. Analyses of intratumor variations (and therapy‐induced changes) of τi in combination with concomitant changes of ve (extracellular volume fraction) indicate that the former are dominated by alterations of the equilibrium cell membrane water permeability coefficient, PW, not of cell size. These can be interpreted in light of literature results showing that τi changes are dominated by a PW(active) component that reciprocally reflects the membrane driving P‐type ATPase ion pump turnover. For mammalian cells, this is the Na+,K+‐ATPase pump. These results promise the potential to discriminate metabolic and microenvironmental states of regions within tumors in vivo, and their changes with therapy.

Early Prediction and Evaluation of Breast Cancer Response to Neoadjuvant Chemotherapy Using Quantitative DCE-MRI

The purpose is to compare quantitative dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) metrics with imaging tumor size for early prediction of breast cancer response to neoadjuvant chemotherapy (NACT) and evaluation of residual cancer burden (RCB). Twenty-eight patients with 29 primary breast tumors underwent DCE-MRI exams before, after one cycle of, at midpoint of, and after NACT. MRI tumor size in the longest diameter (LD) was measured according to the RECIST (Response Evaluation Criteria In Solid Tumors) guidelines. Pharmacokinetic analyses of DCE-MRI data were performed with the standard Tofts and Shutter-Speed models (TM and SSM). After one NACT cycle the percent changes of DCE-MRI parameters Ktrans (contrast agent plasma/interstitium transfer rate constant), ve (extravascular and extracellular volume fraction), kep (intravasation rate constant), and SSM-unique τi (mean intracellular water lifetime) are good to excellent early predictors of pathologic complete response (pCR) vs. non-pCR, with univariate logistic regression C statistics value in the range of 0.804 to 0.967. ve values after one cycle and at NACT midpoint are also good predictors of response, with C ranging 0.845 to 0.897. However, RECIST LD changes are poor predictors with C = 0.609 and 0.673, respectively. Post-NACT Ktrans, τi, and RECIST LD show statistically significant (P < .05) correlations with RCB. The performances of TM and SSM analyses for early prediction of response and RCB evaluation are comparable. In conclusion, quantitative DCE-MRI parameters are superior to imaging tumor size for early prediction of therapy response. Both TM and SSM analyses are effective for therapy response evaluation. However, the τi parameter derived only with SSM analysis allows the unique opportunity to potentially quantify therapy-induced changes in tumor energetic metabolism.

Abstract CT227: Neratinib plus standard neoadjuvant therapy for high-risk breast cancer: Efficacy results from the I-SPY 2 TRIAL

Background: I-SPY 2 is a multicenter, phase II neoadjuvant trial in women with high-risk stage II/III breast cancer using adaptive randomization within biomarker subtypes to evaluate novel agents added to standard chemotherapy. Primary endpoint is pathologic complete response (pCR). Goal is to identify regimens that meet a high Bayesian predictive probability of statistical significance in a neoadjuvant 300-patient phase III trial defined by hormone-receptor (HR), HER2 status, and MammaPrint (MP). Experimental regimens may “graduate” in 1 of 10 signatures, with a maximum of 120 patients. We report efficacy results for neratinib (N). Methods: Tumors ≥2.5cm by clinical exam & ≥2cm by imaging are eligible for screening. MP low risk/HR+/HER2- tumors are ineligible for randomization. Patients receive chemotherapy (paclitaxel qwk x 12, doxorubicin and cyclophosphamide q2-3 wk x 4, T->AC). HER2- pts were randomized to N+T->AC vs. T->AC and HER2+ pts to N+T->AC vs. trastuzumab+T->AC. Analysis is intent-to-treat with pts who switch to non-protocol therapy regarded as non-pCRs. We provide estimated pCR rates (95% Bayesian probability intervals), probabilities of superiority of neratinib over control, and Bayesian predictive probabilities of success in an equally randomized phase III trial. Results: Neratinib met the predictive probability criterion in HR-/HER2+, “graduated”, and accrual ceased [115 N patients (65 HER2+), 78 concurrently randomized controls (22 HER2+)]. The table shows results for all 10 signatures. Two patients (1 N and 1 control) withdrew consent and are not included. Conclusion: I-SPY 29s standing trial mechanism efficiently evaluates agents in biomarker-defined patient subsets. In a modest number of patients, adaptive randomization successfully identified a biomarker signature (HR-/HER2+) for neratinib9s further development. All HER2+ and MP+ tumors may also benefit from this regimen, consistent with preclinical data. Evaluation in I-SPY 3, a phase III registration trial, is planned. Citation Format: John W. Park, Minetta C. Liu, Douglas Yee, Angela DeMichele, Laura van 9t Veer, Nola Hylton, Fraser Symmans, Meredith B. Buxton, A. Jo Chien, Amy Wallace, Michelle Melisko, Richard Schwab, Judy Boughey, Debashish Tripathy, Hank Kaplan, Rita Nanda, Stephen Chui, Kathy S. Albain, Stacy Moulder, Anthony Elias, Julie E. Lang, Kirsten Edminston, Donald Northfelt, David Euhus, Qamar Khan, Julia Lyandres, Sarah E. Davis, Christina Yau, Ashish Sanil, Laura J. Esserman, Donald A. Berry. Neratinib plus standard neoadjuvant therapy for high-risk breast cancer: Efficacy results from the I-SPY 2 TRIAL. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT227. doi:10.1158/1538-7445.AM2014-CT227

Abstract OT1-01-06: A phase III randomized trial of atezolizumab in combination with nab-paclitaxel as first line therapy for patients with metastatic triple-negative breast cancer (mTNBC)

Background: The management of mTNBC is a therapeutic challenge, and chemotherapy remains the mainstay of treatment. Atezolizumab (atezo; MPDL3280A) is a humanized anti-PDL1 antibody that inhibits PD-L1 binding to PD-1 and B7.1 but leaves PD-L2/PD-1 binding intact. mTNBC has high levels of tumor-infiltrating immune cells (IC), increased PD-L1 expression and high mutation rates that may generate immunogenic neoantigens, making it an attractive candidate for PD-L1–targeted therapy with atezo. Accordingly, atezo monotherapy has demonstrated durable responses in mTNBC (Emens et al, AACR 2015). In addition, atezo combined with nab-paclitaxel has shown promising tolerability and activity in mTNBC (Adams et al, SABCS 2015; pending). Nab-paclitaxel has high anti-tumor activity that may favorably alter the immune microenvironment. Based on these preliminary results, a Phase III multicenter, randomized, double-blind, placebo-controlled trial (IMpassion130) was designed to evaluate the efficacy and safety of nab-paclitaxel combined with atezo as first-line therapy for mTNBC. Methods: Patients are randomized 1:1 to receive atezo (840 mg) or placebo on days 1 and 15 plus nab-paclitaxel (100 mg/m2) on days 1, 8 and 15; all treatments are given on a 28-day cycle. Patients are stratified by the presence of liver metastases, prior taxane therapy and the PD-L1 status of IC (IC0 vs IC1/2/3). PD-L1 expression is centrally evaluated by immunohistochemistry using the SP142 assay. To capture pseudoprogression and delayed responses to atezo, patients with radiographic progression may continue to receive open-label atezo alone or with nab-paclitaxel until unacceptable toxicity or loss of clinical benefit. Eligibility criteria: This study will enroll patients with histologically documented locally advanced or metastatic TNBC, no prior systemic therapy for advanced TNBC, ECOG PS 0-1 and measurable disease per RECIST v1.1. Patients with significant cardiovascular or CNS disease (except asymptomatic treated CNS metastases), autoimmune disease or prior immune checkpoint blockade therapy are excluded. Endpoints: The co-primary efficacy endpoints are progression-free survival (PFS) in all patients and in PD-L1–selected patients. Secondary endpoints include overall survival, objective response rate, response duration, safety/tolerability, pharmacokinetics and health-related quality of life. Tumor biopsies are obtained at baseline and at progression to evaluate potential biomarkers associated with therapeutic response and resistance. Statistical methods/target accrual: PFS will be compared between treatment arms (nab-paclitaxel vs. nab-paclitaxel plus atezo) using the stratified log-rank test. The hazard ratio for disease progression or death will be estimated using a stratified Cox proportional hazards model. Kaplan-Meier methodology will be used to estimate the median PFS for each treatment arm. About 350 patients will be enrolled at ≈ 120 sites globally. Sponsor: Genentech, Inc. ClinicalTrials.gov identifier NCT02425891. Citation Format: Emens L, Adams S, Loi S, Schmid P, Schneeweiss A, Rugo H, Chui S, Winer E. A phase III randomized trial of atezolizumab in combination with nab-paclitaxel as first line therapy for patients with metastatic triple-negative breast cancer (mTNBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-01-06.

Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer

Background Unresectable locally advanced or metastatic triple‐negative (hormone‐receptor–negative and human epidermal growth factor receptor 2 [HER2]–negative) breast cancer is an aggressive disease with poor outcomes. Nanoparticle albumin‐bound (nab)–paclitaxel may enhance the anticancer activity of atezolizumab. Methods In this phase 3 trial, we randomly assigned (in a 1:1 ratio) patients with untreated metastatic triple‐negative breast cancer to receive atezolizumab plus nab‐paclitaxel or placebo plus nab‐paclitaxel; patients continued the intervention until disease progression or an unacceptable level of toxic effects occurred. Stratification factors were the receipt or nonreceipt of neoadjuvant or adjuvant taxane therapy, the presence or absence of liver metastases at baseline, and programmed death ligand 1 (PD‐L1) expression at baseline (positive vs. negative). The two primary end points were progression‐free survival (in the intention‐to‐treat population and PD‐L1–positive subgroup) and overall survival (tested in the intention‐to‐treat population; if the finding was significant, then it would be tested in the PD‐L1–positive subgroup). Results Each group included 451 patients (median follow‐up, 12.9 months). In the intention‐to‐treat analysis, the median progression‐free survival was 7.2 months with atezolizumab plus nab‐paclitaxel, as compared with 5.5 months with placebo plus nab‐paclitaxel (hazard ratio for progression or death, 0.80; 95% confidence interval [CI], 0.69 to 0.92; P=0.002); among patients with PD‐L1–positive tumors, the median progression‐free survival was 7.5 months and 5.0 months, respectively (hazard ratio, 0.62; 95% CI, 0.49 to 0.78; P<0.001). In the intention‐to‐treat analysis, the median overall survival was 21.3 months with atezolizumab plus nab‐paclitaxel and 17.6 months with placebo plus nab‐paclitaxel (hazard ratio for death, 0.84; 95% CI, 0.69 to 1.02; P=0.08); among patients with PD‐L1–positive tumors, the median overall survival was 25.0 months and 15.5 months, respectively (hazard ratio, 0.62; 95% CI, 0.45 to 0.86). No new adverse effects were identified. Adverse events that led to the discontinuation of any agent occurred in 15.9% of the patients who received atezolizumab plus nab‐paclitaxel and in 8.2% of those who received placebo plus nab‐paclitaxel. Conclusions Atezolizumab plus nab‐paclitaxel prolonged progression‐free survival among patients with metastatic triple‐negative breast cancer in both the intention‐to‐treat population and the PD‐L1–positive subgroup. Adverse events were consistent with the known safety profiles of each agent. (Funded by F. Hoffmann–La Roche/Genentech; IMpassion130 ClinicalTrials.gov number, NCT02425891.)