Bone Scan Lesion Area Research Articles

Pretreatment visceral metastases in castration resistant metastatic prostate cancer: role in prediction versus actual site of disease progression

BackgroundTo evaluate the anatomic site(s) of initial disease progression in patients with castration resistant metastatic prostate cancer (mCRPC) in the presence or absence of pre-treatment visceral metastases while on systemic therapy. MethodsThis is a retrospective cohort study of mCRPC patients who have baseline and at least one follow up bone scan and CT chest, abdomen and pelvis (CAP). Disease progression was determined by RECIST and/or ≥ 30% increase in automated bone scan lesion area score. Kaplan–Meier plot was used to estimate the median progression free survival and log-rank tests were used to compare anatomic sites.ResultsOf 203 patients, 61 (30%) had pre-treatment visceral metastases. Patients with baseline visceral disease were 1.5 times more likely to develop disease progression (HR = 1.53; 95% CI, 1.03–2.26). Disease progression was a result of worsening bone scan disease (42% (16/38)) versus visceral (32% (12/38)) or lymph node disease (3% (1/38)) by CT or a combination thereof (23% (9/38)). Median time to progression (TTP) did not differ by anatomic location of initial progression (p = 0.86). Development of new lesions occurred in 50% of those visceral patients with soft tissue only progression and was associated with a significantly longer TTP (3.1 months (2.8–4.3 months) than those with worsening of pre-existing lesions (1.8 months (1.6–2.7 months); p = 0.04.ConclusionsPatients with pre-treatment visceral metastases in mCRPC are more likely to experience disease progression of bone disease with the initial anatomic site of progression similar to those without baseline visceral involvement.

A randomized phase IIa study of quantified bone scan response in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with radium-223 dichloride alone or in combination with abiraterone acetate/prednisone or enzalutamide

BackgroundIn metastatic castration-resistant prostate cancer (mCRPC), assessing treatment response and bone lesions with technetium-99m is limited by image resolution and subjectivity. We evaluated bone scan lesion area (BSLA), a quantitative imaging assessment of response in patients with mCRPC receiving radium-223 alone or in combination with androgen receptor pathway inhibitors (abiraterone/prednisone or enzalutamide).Patients and methodsThis randomized, non-comparative phase IIa three-arm trial (NCT02034552) evaluated technetium-99m-based BSLA response rate (RR), safety, radiologic progression-free survival (rPFS), and time to first symptomatic skeletal event (SSE) in men with mCRPC and bone metastases receiving radium-223 with/without abiraterone/prednisone or enzalutamide. The primary endpoint was week 24 BSLA RR.ResultsOverall, 63 patients received treatment (abiraterone/prednisone combination, n = 22; enzalutamide combination, n = 22; radium-223 monotherapy, n = 19). Median treatment duration (first to last dose of any study treatment) was 12 months (abiraterone/prednisone combination), 10 months (enzalutamide combination), and 3 months (radium-223 monotherapy). Week 24 BSLA RR was 58% [80% confidence interval (CI) 41% to 74%; one-sided P < 0.0001; 11/19 patients] with abiraterone/prednisone combination, 50% (32% to 68%; one-sided P < 0.0001; 8/16 patients) with enzalutamide combination, and 22% (10% to 40%; one-sided P = 0.0109; 4/18 patients) with radium-223 monotherapy. Median rPFS was not evaluable for combination arms and 4 months (80% CI 4 to 12) for monotherapy. SSEs were reported in 32% of patients; median time to first SSE was not estimable. Fatigue and back pain were the most commonly reported treatment-emergent adverse events (TEAEs); more patients receiving combination therapy than monotherapy had TEAEs. Fractures were reported in 18% receiving abiraterone/prednisone, 32% receiving enzalutamide, and 11% receiving radium-223 monotherapy. Fracture rates were lower in patients taking bone health agents versus not taking bone health agents at baseline.ConclusionsTechnetium-99m imaging BSLA may offer objective, quantifiable assessment of isotope uptake changes, and potentially treatment response, in patients with mCRPC and bone metastases treated with radium-223 alone or in combination with abiraterone/prednisone or enzalutamide. In this largely treatment-naive population, BSLA RR was numerically lower with radium-223 monotherapy versus combination therapy, indicating a limited role as first-line treatment. Use of radium-223 should follow evidence-based treatment guidelines and the licensed indication.

Pre-therapy visceral metastases in castrate resistant metastatic prostate cancer: Role in tumor progression.

e17586 Background: Visceral metastases in castrate resistant metastatic prostate cancer (mCRPC) are known to develop late in the course of disease and portend a poor prognosis. As patients with visceral metastases still derive a clinical benefit to treatment, understanding patterns of progressive disease (PD) may help differentiate important disease phenotypes in mCRPC. The aim of our study was to evaluate the differences in anatomic sites of PD in patients with pretreatment visceral or bone metastases on time to progression (TTP). Methods: A retrospective review of anonymized patients enrolled in phase 2 and 3 clinical trials was performed. Patients were excluded if lacked Tc bone scan or CT chest, abdomen and pelvis (CT CAP) at baseline. Bone disease was defined by automated bone scan lesion area (BSLA) criteria. All CT CAPs per clinical trial protocol were assessed by RECIST 1.1. Soft tissue PD was noted as target, non-target lesion growth and/or presence of new lesions by anatomic site. Bone PD was defined by &gt; 20% increase in BSLA score. Results: Of the 169 subjects that met our selection criterion, visceral disease was present at baseline in 90 patients (53%). Baseline BSLA score was 90474 mm² in visceral and 80348 mm² in non-visceral patients (p = 0.395). Disease progression occurred in 93 patients (55%). With baseline visceral disease, PD was a result of BSLA in 26 (51%) and visceral disease only in 11 (22%) of patient. Lacking visceral disease at baseline resulted in PD by BSLA in 26 (62%) and visceral disease only in 3 (7%) of patients. There was no significant difference in PFS for baseline visceral/non-visceral involvement; median PFS = 4.5 months in visceral; median PFS = 4.34 months in non-visceral (HR = 1.28; p = 0.244). Conclusions: Patients with visceral disease may still derive a similar clinical benefit from treatment to those without. While the presence of baseline visceral disease was associated with higher rates of PD by visceral involvement, PD by bone disease remained the most common cause of PD regardless of presence of baseline visceral metastases.

870P - A phase IIa study of radium-223 dichloride (Ra-223) alone or in combination with abiraterone acetate or enzalutamide in metastatic castration-resistant prostate cancer (mCRPC)

870P - A phase IIa study of radium-223 dichloride (Ra-223) alone or in combination with abiraterone acetate or enzalutamide in metastatic castration-resistant prostate cancer (mCRPC)

Cabozantinib for Progressive Metastatic Castration-resistant Prostate Cancer Following Docetaxel: Combined Analysis of Two Phase 3 Trials

Two phase 3 trials, COMET-1 and COMET-2, have reported that cabozantinib did not significantly extend overall survival (OS) compared to prednisone and prednisone plus mitoxantrone, respectively, in post-docetaxel patients with metastatic castration-resistant prostate cancer (mCRPC). We conducted a retrospective analysis of a combined data set from these trials to identify a benefit in subsets of patients according to prognostic risk factors. The prognostic ability of factors to predict survival was evaluated using Cox proportional hazards regression models. Evaluation of potential beneficial subsets was performed using interaction terms between factors and cabozantinib. All tests were two-sided and p≤0.05 was considered statistically significant. A total of 1147 post-docetaxel patients with mCRPC were available (1028 from COMET-1 and 119 from COMET-2). The following factors were prognostic for OS: age, disease-free interval, hemoglobin, prostate-specific antigen, alkaline phosphatase, albumin, bone scan lesion area, lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, and pain (all p<0.05). There was no interaction effect on survival between cabozantinib versus comparator arms and any prognostic group. After adjusting for prognostic factors, cabozantinib was associated with better OS (hazard ratio 0.80, 95% confidence interval 0.67–0.95; p=0.012). Further investigation of cabozantinib in a better-powered trial or a rational patient population based on a molecular biomarker may be warranted. Patient summaryTwo phase 3 trials have reported no survival benefit for cabozantinib, a multitarget oral drug, in metastatic castration-resistant prostate cancer. This analysis pooled 1147 patients from these trials to identify a survival benefit for cabozantinib. This study suggests that further rational development may be justified.

Cabozantinib for metastatic castration-resistant prostate cancer (mCRPC) following docetaxel: Combined analysis of two phase III trials.

225 Background: Two phase III trials, COMET-1 and COMET-2, have reported that cabozantinib did not extend overall survival (OS) outcomes compared to prednisone and prednisone plus mitoxantrone respectively, in unselected post-docetaxel patients with mCRPC. We conducted a retrospective analysis of a combined dataset of these trials in an attempt to identify a benefit in subsets of patients based on prognostic risk factors. Methods: Baseline characteristics and survival data were combined for COMET-1 and COMET-2. Prognostic ability of baseline factors on survival was evaluated using Cox proportional hazards regression models, which incorporated the factors in the modern post-docetaxel nomogram and overall bone scan lesion area (BSLA) by computer-assisted analysis. Regression models included trial as a stratification factor. Evaluation of potentially benefited subsets was performed by the use of interaction terms between the factors and cabozantinib. The hazard ratio between cabozantinib and comparator arms was evaluated after adjusting for baseline prognostic factors. All tests were 2-sided and a p-value ≤0.05 was considered statistically significant. Results: A total of 1147 post-docetaxel patients with mCRPC were available (1028 from COMET-1 and 119 from COMET-2). Age, albumin, LDH and BSLA were statistically significant prognostic factors in addition to variables from the Halabi model (site of metastases, pain, docetaxel-free interval, ECOG-PS, hemoglobin, alkaline phosphatase, PSA). There was no consistent interaction effect on survival between cabozantinib vs. comparator arms for any prognostic group. After adjusting for multiple potential prognostic factors, treatment with cabozantinib vs. comparator was associated with an observed hazard ratio of 0.77 (95% CI = 0.65 to 0.92, p = 0.003) for survival. Conclusions: After combining data from both COMET-1 and COMET-2 trials, no differential effect of cabozantinib on survival was observed for any prognostic risk factor. A modest treatment effect of cabozantinib on OS was observed after controlling for multiple potential prognostic factors.

Quantitative bone scan lesion area as an early surrogate outcome measure indicative of overall survival in metastatic prostate cancer.

.A clinical validation of the bone scan lesion area (BSLA) as a quantitative imaging biomarker was performed in metastatic castration-resistant prostate cancer (mCRPC). BSLA was computed from whole-body bone scintigraphy at baseline and week 12 posttreatment in a cohort of 198 mCRPC subjects (127 treated and 71 placebo) from a clinical trial involving a different drug from the initial biomarker development. BSLA computation involved automated image normalization, lesion segmentation, and summation of the total area of segmented lesions on bone scan AP and PA views as a measure of tumor burden. As a predictive biomarker, treated subjects with baseline BSLA had longer survival than those with higher BSLA ( and ). As a surrogate outcome biomarker, subjects were categorized as progressive disease (PD) if the BSLA increased by a prespecified 30% or more from baseline to week 12 and non-PD otherwise. Overall survival rates between PD and non-PD groups were statistically different ( and ). Subjects without PD at week 12 had longer survival than subjects with PD: median 398 days versus 280 days. BSLA has now been demonstrated to be an early surrogate outcome for overall survival in different prostate cancer drug treatments.

Quantitative bone scan lesion area as an early surrogate outcome measure indicative of overall survival in metastatic castration-resistant prostate cancer.

179 Background: Bone Scan Lesion Area (BSLA) is a biomarker that can be computed semi-automatically from whole-body scintigraphic imaging as a measure of overall bone tumor burden. Initial development and validation, including correlation with outcomes, was performed in trial cohorts from a single drug treatment with controls in subjects with metastatic castrate-resistant prostate cancer (CRPC). A 30% increase/decrease in BSLA was defined as progression/response on bone scan. We hypothesize that, when applied to an independent treatment trial cohort with a different mechanism of drug action, baseline BSLA and Week 12 change post-treatment are predictive of a subject's overall survival. Methods: From an anonymized imaging research database a cohort of 198 CRPC subjects was identified who enrolled in a treatment trial (127 treated, 71 placebo). This cohort was independent of those used for biomarker development and initial validation, and involved a different mechanism of drug action. Subjects underwent standard of care whole-body bone scintigraphy with 99mTc-Methyl diphosphonate (99mTc-MDP). BSLA was calculated at baseline and response at Week 12. Multivariate Cox regression was used to test whether (1) baseline BSLA, and (2) early changes in BSLA (12 weeks post treatment) were predictive of overall survival. Results: BSLA &lt; 2000 mm2 at baseline was a prognostic factor (HR=0.6; p=0.003) and predictive of longer survival (HR=0.4; p&lt;0.001). Subjects without PD by BSLA at Week 12 had significantly longer survival than subjects with PD: median 170 days vs. 186 days in the placebo group and 260 days vs. 392 days in the treatment group. The overall survival rates between non-PD and PD subjects were statistically different (HR=0.64, p=0.007). Conclusions: BSLA is calculated semi-automatically from bone scans and provides a quantitative and objective treatment response assessment. Baseline BSLA and early changes post treatment were found to be predictive of overall survival in patients with metastatic castration-resistant prostate cancer. BSLA has now been demonstrated to be an early surrogate outcome for overall survival in different drug treatments.

Final analysis of COMET-1: Cabozantinib (Cabo) versus prednisone (Pred) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) previously treated with docetaxel (D) and abiraterone (A) and/or enzalutamide (E).

139 Background: Cabo inhibits tyrosine kinases including MET and VEGFRs. In a phase 2 study in mCRPC pts, Cabo was associated with improvements in bone scans, pain, measurable disease, and circulating tumor cells. COMET-1 compared the effects of Cabo versus Pred on overall survival (OS) in men with progressive mCRPC and prior D and A and/or E. Methods: In this randomized, double-blind, controlled phase 3 study (NCT01605227), pts with mCRPC and prior D and A and/or E were randomized 2:1 to receive Cabo (60 mg qd) or Pred (5 mg bid). Pts were stratified by prior treatment with cabazitaxel, ECOG status, and presence of moderate to severe pain. The primary endpoint was OS. The study was designed to observe 578 deaths to provide 90% power to detect a hazard ratio (HR) of 0.75. A secondary endpoint was bone scan response at Week 12 (BSR) determined by central independent radiology committee, defined as a ≥30% decrease in the bone scan lesion area compared to baseline. Exploratory endpoints include PFS and OS subgroup analyses. Results: 1,028 pts were randomized between Jul 2012 and Nov 2013. In the final analysis after 614 deaths, the estimated median OS was 11.0 months for Cabo vs 9.8 months for Pred (HR 0.90; 95% CI: 0.0.76-1.06; P = 0.212). The secondary endpoint of BSR was 41% for Cabo vs 3% for Pred (P &lt;0.001). Median PFS per investigator was 5.5 months for Cabo vs 2.8 months for Pred (HR 0.50; P &lt;0.001). For 191 pts with visceral disease median OS was 7.1 months for Cabo vs 4.8 months for Pred (HR 0.65; P = 0.0215). 371 (54.4%) and 233 (67.3%) pts received salvage therapy in the Cabo and Pred arms, respectively. Subsequent cabazitaxel and/or D was reported in 107 (15.7%) and 104 (30.1%) Cabo and Pred pts, respectively. Serious adverse events of pulmonary embolism, nausea, dehydration and fatigue were more frequent with Cabo. Conclusions: Compared to prednisone, Cabo improved BSR and PFS but did not significantly increase OS. The improvement in OS was greatest in the subset of patients with visceral metastases. The activity and safety profile of Cabo was similar to that observed in phase 2 studies in mCRPC. Clinical trial information: NCT01605227.

A dose-ranging study of cabozantinib in men with castration-resistant prostate cancer and bone metastases.

Cabozantinib is an oral MET/VEGFR2 inhibitor. A recent phase II study of cabozantinib (100 mg daily) showed improved bone scans in subjects with metastatic castration-resistant prostate cancer (mCRPC), but adverse events (AE) caused frequent dose reductions. This study was designed to determine the efficacy and tolerability of cabozantinib at lower starting doses. An adaptive design was used to determine the lowest active daily dose among 60, 40, and 20 mg. The primary endpoint was week 6 bone scan response, defined as ≥30% decrease in bone scan lesion area. The secondary endpoint was change in circulating tumor cells (CTC). Among 11 evaluable subjects enrolled at 40 mg, there were 9 partial responses (PR), 1 complete response, and 1 stable disease (SD). Of 10 subjects subsequently enrolled at 20 mg, there were 1 PR, 5 SDs, and 4 with progressive disease. Among 13 subjects enrolled on the 40 mg expansion cohort, there were 6 PRs and 7 SDs. No subjects required dose reduction or treatment interruption at 6 or 12 weeks; 3 subjects at dose level 0 discontinued due to AEs by 12 weeks. At 40 mg, median treatment duration was 27 weeks. 58% of subjects with ≥5 CTCs/7.5 mL at baseline converted to <5. Cabozantinib 40 mg daily was associated with a high rate of bone scan response. Cabozantinib 40 mg daily was associated with better tolerability than previously reported for cabozantinib 100 mg daily. These observations informed the design of phase III studies of cabozantinib in mCRPC.

Computer-aided bone scan lesion area quantitation: Inter-reader measurement variability.

e16019 Background: Bone scan is essential for response assessment in subjects with metastatic prostate cancer. However, visual assessment is subjective and prone to inter-reader variability. A commercial computer-aided (CAD) system for bone scan lesion area (BSLA) calculation has been developed (MedQIA, LLC). BSLA provides an objective and sensitive measure for response assessment. New VEGF treatments showing promising results in reducing lesion burden on bone scan present an urgent need for validated systems capable of accurately assessing treatment response. Measurement of inter reader variability is fundamental to such a validation. In this work we measure inter-reader variability in quantitation of BSLA change using the CAD system. Methods: In a multi-center clinical trial of cabozantinib (Exelixis, Inc), bone scans were acquired according to a standardized imaging protocol. Scans at baseline and Week 12 were available for 113 subjects for this analysis. Automated CAD lesion detection was performed following image intensity normalization to increase consistency between subject time points. Two nuclear medicine physicians independently edited and approved the CAD result as needed, primarily to remove false positives due to degenerative joint disease. The system then calculated the percent change in BSLA at Week 12 from baseline (BSLAPCT). The BLSAPCT values from the two readers were compared to assess inter-reader variability. Additional analytic validation of the BSLA measure was performed in which the readers provided a categorical assessment of responder vs non-responder, using the CAD-normalized images, and the classification performance of BSLAPCT was assessed using ROC analysis. Results: The median (IQR) difference in BSLAPCT between the two readers was -1.8 (20.0) percentage points. The absolute difference was 9.4 (23.9) percentage points. The BSLAPCT response classification had an ROC area under curve (AUC) of 0.96 for both readers. Conclusions: Computer-aided quantitative assessment of change using bone scan lesion area demonstrated low variability between two readers. This is an important step toward the validation of an objective, quantitative, and sensitive response assessment technique.

An exploratory analysis of bone scan lesion area (BSLA), circulating tumor cell (CTC) change, pain reduction, and overall survival (OS) in patients (pts) with castration-resistant prostate cancer (CRPC) treated with cabozantinib (cabo): Updated results of a phase II nonrandomized expansion (NRE) cohort.

5026 Background: The results of 144 pts with metastatic CRPC treated in a phase II NRE cohort with daily cabo 100 mg and 40 mg starting doses have been previously reported. Substantial rates of bone scan improvement, reductions in CTC counts and pain relief were observed. To better understand the implication of these effects, the association with OS was explored. Methods: Relevant baseline variables (LDH, BSLA, visceral disease, pain, hemoglobin, CTCs) and post-treatment changes at week 6: ≥30% reduction in BSLA using computer-aided assessment, CTC conversion (&gt;5 vs. 4 or less/7.5 ml of blood), and pain intensity (7 day averaged worst pain score; BPI scale; using an IVR system) were associated with OS in 144 CRPC pts with bone metastasis who progressed within 6 months of docetaxel (D) treatment (≥225 mg/m2) in either bone or soft tissue. Median OS was compared between responders and non-responders for each of the above outcomes categories using a Cox proportional hazard model. The findings were examined further after adjusting for significant baseline covariates selected from a stepwise Cox regression model. Results: See Table. Conclusions: Recognizing the limitations of associating response with survival, this retrospective analysis of decreases in BSLA, CTC conversions and reductions in pain intensity support further study in ongoing phase III trials. Clinical trial information: NCT00940225. [Table: see text]

897O - Cabozantinib (XL184) At 40 Mg in Patients with Metastatic Castration Resistant Prostate Cancer (MCRPC): Results of a Phase 2 Non-Randomized Expansion Cohort (NRE)

ABSTRACT Background Cabozantinib (cabo) inhibits MET & VEGFR2. In a phase 2 NRE cohort of patients (pts) with mCRPC, cabo at 100 mg daily was associated with high rates of bone scan resolution, pain relief & overall disease control, independent of PSA changes. We now report the activity & safety of cabo 40 mg daily. Methods Docetaxel (D)-pretreated (≥225 mg/m) CRPC pts with bone metastasis were required to have progressed within 6 months of last dose of D. Tumor response was assessed q6 wks. Bone scan response used computer-aided assessment of bone scan lesion area (BSLA). Diffusion Weighted MRI was performed in some pts. Pain intensity (worst pain over the past 24 hrs; BPI scale 0-10) & interference with sleep & daily activity were prospectively assessed using an IVR system (7 day intervals). Analgesic use was collected by diary. Bone turnover markers & circulating tumor cells (CTCs) were assessed. Results 51 pts were enrolled. Among 30 pts who had ≥6 wks f/u, the median age was 66 yrs. 20% received cabazitaxel, 70% abiraterone, & 20% had visceral disease. 47% (14/30) had pain (BPI ≥4) at baseline (bsl) of which 86% (12/14) were using narcotics. Median bsl CTC count was 17 & 73% had ≥5. Median f/u was 84 days (range, 44-141). 55% (11/20 pts) with a f/u bone scan showed BSLA reduction (range, 1-70%). Increases in Apparent Diffusion Coefficient (suggestive of tumor necrosis) & enhancement reduction were observed in bone & soft tissue metastases. 10/14 pts (71%) evaluable for pain response had a ≥30% reduction from bsl; 7/12 (58%) pts decreased narcotics. Sleep & daily activity improved in pts with pain relief. Among pts with elevated bsl serum levels of CTx, NTx & bALP, 57%, 60% & 33% respectively, had declines ≥30%. In 22 pts with CTCs ≥5, 59% had a decrease of ≥30% at wks 6 or 12, & 23% converted to Conclusions Cabo 40 mg was well tolerated & demonstrated bone scan resolution, substantial pain relief with a narcotic sparing effect, & reductions in bone turnover markers & CTCs in heavily pretreated mCRPC pts. MRI results are consistent with an anti-tumor effect. Disclosure M.R. Smith: Consultant to Exelixis. O.A. Sartor: Consultant for Exelixis. All other authors have declared no conflicts of interest.

Investigator-sponsored trial of efficacy and tolerability of cabozantinib (cabo) at lower dose: A dose-finding study in men with castration-resistant prostate cancer (CRPC) and bone metastases.

4566 Background: Cabo (XL184) is an oral inhibitor of MET and VEGFR2. In a randomized discontinuation trial of cabo 100mg daily, 76% of men with CRPC and bone metastases had partial or complete resolution of bone scan lesions as early as week (wk) 6. However, treatment was limited by adverse events (AEs), with dose reductions in 51% of patients (pts), and discontinuations in 10%. The current study was designed to determine the efficacy and tolerability of cabo at lower starting doses. Methods: An adaptive response scheme was used to determine the lowest active daily cabo dose among dose levels +1 (60mg), 0 (40mg), and -1 (20mg). The primary endpoint was wk 6 bone scan response (BSR) assessed with an automated FDA 510(k) approved computer-aided detection system. A ≥30% decrease in total bone scan lesion area (BSLA) was defined as a response. The first cohort was treated at dose level 0. The number of responses (≥8 vs. &lt;8 among 11 evaluable pts) was used to select the dose level (-1 vs. +1) for the second cohort. Based on the observed BSR rate in the second cohort of 11 pts, a dose was selected for expansion to treat 13 more pts. Results: The study completed planned enrollment of 36 pts. Median age was 66; 44% were docetaxel-pretreated. Among 12 pts enrolled at dose level 0, there were 10 BSRs at wk 6 including 1 complete response (CR), and 1 pt with stable disease (SD). The median decrease in BSLA was 62%. Ten pts evaluated at wk 12 included 9 BSRs (3 CRs), and 1 sustained SD. Among 11 pts then treated at dose level -1, 10 pts were evaluable at wk 6: 1 BSR, 5 SD, and 4 had progressive disease. No pts in the 2 cohorts required dose reduction or treatment interruption at 12 wks; 1 pt discontinued due to grade 3 AEs (anorexia, fatigue). 6/12 pts with ≥6 months follow-up remain on study. 5/5 pts enrolled at 40mg with CTCs ≥5 per 7.5mL converted to &lt;5. Thirteen pts accrued to the expansion cohort at 40mg daily had confirmed high BSR rate. Conclusions: Cabo 40mg daily achieves a high BSR rate in men with CRPC and bone metastases, and is associated with better tolerability than previously reported for cabo 100mg daily.

Cabozantinib (XL184) in chemotherapy-pretreated metastatic castration resistant prostate cancer (mCRPC): Results from a phase II nonrandomized expansion cohort (NRE).

4513 Background: Cabozantinib (cabo) inhibits MET and VEGFR2. High rates of bone scan resolution, pain relief and overall disease control, independent of PSA changes, were previously reported in a phase II study in mCRPC patients (pts). This is a NRE cohort in docetaxel (D)-pretreated pts with a novel primary endpoint of bone scan response based on computer-aided quantitative assessment of bone scan lesion area (BSLA) and a double-reader, independent, blinded review (Nucl Med Commun, in press). Methods: D-pretreated (≥225 mg/m2) CRPC pts with bone metastasis were required to have progressed in soft-tissue or bone within 6 months of last dose of D. Pts received 100 mg cabo qd. Tumor response was assessed q6 wks. Bone scan response (BSR) was defined by a ≥30% decline in BSLA. Pain intensity (worst pain over the past 24 hrs; BPI scale 0-10) and interference with sleep and daily activity were prospectively assessed using an IVR system. Analgesic use was collected by diary. Bone turnover markers and CTCs were assessed. Results: 93 D-pretreated pts were enrolled (89 evaluable with ≥6 wks f/u). Median age was 67, 46% received cabazitaxel and/or abiraterone, 32% had visceral disease, 51% had fatigue, and 18% had anemia. 44% had worst pain ≥4 of which 95% were taking narcotics. Median CTC count was 49 and 80% had ≥5. Median f/u was 125 days (range, 23-305). Of 85 pts evaluable for BSR, 51 (60%) had a PR, 24 (28%) SD, 5 (6%) PD and 5 (6%) d/c’d prior to f/u scan. 21/30 pts (70%) had reduction of measurable disease.16/33 pts (49%) with BPI ≥4 and ≥12 wks f/u had pain reduction durable for ≥6 wks; 46% had decreased narcotic use, including 27% who discontinued use. Sleep and daily activity were improved in pts with pain relief. Among pts with elevated serum levels, 74%, 67% and 47% had declines on treatment of ≥30% in CTx, NTx and bALP, respectively. In 59 pts with CTCs ≥5, 92% had a decrease of ≥30% and 39% converted to &lt;5 CTCs at weeks 6 or 12. 12% discontinued cabo due to AEs. Most common Gr 3/4 AEs were fatigue (19%), nausea (10%) and anemia (10%). Conclusions: Cabo treatment resulted in high rates of bone scan response, durable pain relief, and reductions in bone turnover markers and CTCs in D-pre-treated CRPC pts with bone metastases.

Computer-aided quantitative bone scan assessment of prostate cancer treatment response

The development and evaluation of a computer-aided bone scan analysis technique to quantify changes in tumor burden and assess treatment effects in prostate cancer clinical trials. We have developed and report on a commercial fully automated computer-aided detection (CAD) system. Using this system, scan images were intensity normalized, and then lesions were identified and segmented by anatomic region-specific intensity thresholding. Detected lesions were compared against expert markings to assess the accuracy of the CAD system. The metrics Bone Scan Lesion Area, Bone Scan Lesion Intensity, and Bone Scan Lesion Count were calculated from identified lesions, and their utility in assessing treatment effects was evaluated by analyzing before and after scans from metastatic castration-resistant prostate cancer patients: 10 treated and 10 untreated. In this study, patients were treated with cabozantinib, a MET/vascular endothelial growth factor inhibitor resulting in high rates of resolution of bone scan abnormalities. Our automated CAD system identified bone lesion pixels with 94% sensitivity, 89% specificity, and 89% accuracy. Significant differences in changes from baseline were found between treated and untreated groups in all assessed measurements derived by our system. The most significant measure, Bone Scan Lesion Area, showed a median (interquartile range) change from baseline at week 6 of 7.13% (27.61) in the untreated group compared with -73.76% (45.38) in the cabozantinib-treated group (P=0.0003). Our system accurately and objectively identified and quantified metastases in bone scans, allowing for interpatient and intrapatient comparison. It demonstrates potential as an objective measurement of treatment effects, laying the foundation for validation against other clinically relevant outcome measures.

Abstract B114: Cabozantinib effects on bone metastasis: Computer-aided quantitative bone scan assessment of prostate cancer treatment response.

Abstract Background: Cabozantinib is an oral inhibitor of MET and VEGFR2 and at a dose of 100 mg qd has demonstrated high rates of partial or complete bone scan resolution in CRPC patients with bone metastases, as assessed by manual visual reads. No accepted approach exists for the assessment of bone scan response in prostate cancer patients. An FDA 510(k) approved image analysis package has been developed that includes a computer-aided detection (CAD) system to detect pixels associated with bone lesions on bone scan with high accuracy, thus facilitating quantitative assessment of tumor burden with advantages of objectivity and consistency over manual approaches. A change in total Bone Scan Lesion Area of 30% or greater has been previously established as a cutoff point to distinguish responders from non-responders [1]. Methods: Original Digital Imaging and Communications in Medicine (DICOM) format images of baseline and week 6 bone scan assessments were collected and analyzed by the automated CAD system then reviewed by a physician experienced with bone scan interpretation as part of an ongoing clinical study of single agent cabozantinib at a lower starting dose of 40 mg qd in CRPC subjects with evidence of bone metastases. All subjects had undergone standard of care whole body scintigraphy, 2–4 hours post-injection of 20–25 mCi of Tc MDP. All images underwent intensity normalization to a bone scan reference to account for differences in radiotracer dosing levels and scan timing to improve reproducibility. Lesions consistent with metastatic foci of disease were automatically segmented based on anatomic region-specific intensity thresholds. Each segmented image was reviewed by a nuclear medicine physician for removal of any remaining false positive regions (e.g. areas of degenerative joint disease). Quantitative assessment of lesion burden was then determined. Results: 10 CRPC subjects showing evidence of bone metastasis were treated in an ongoing dose-ranging study with cabozantinib and were evaluable for bone scan response assessment at week 6. Reductions in the following parameters (median and range) were observed at week 6 relative to baseline: total Bone Scan Lesion Area (168.5 cm2 [20, 864] to 54 cm2 [0, 431]; 68% reduction), Bone Scan Lesion Count (34 [3, 74] to 3 [0, 64]; 91% reduction), and mean normalized Bone Scan Lesion Intensity (92.2 [56.5, 155.0] to 57.0 [0, 90.5]; 38% reduction). All 10 subjects had a reduction in Bone Scan Lesion Area, with 9 achieving a bone scan response at the week 6 timepoint as assessed by both the CAD system and visual review by the investigator. Conclusion: A significant reduction in apparent bone scan abnormality was demonstrated by the automated CAD system. The results demonstrate the potential for objective measurement of cabozantinib treatment effects in bone, laying the foundation for further validation against other clinically relevant outcome measures such as pain and overall survival. Reference: 1. G. H. Chu, M. S. Brown, H. J. Kim, M. Auerbach, C. Poon, B. Ramakrishna, A. Vidovic, D. W. Gjertson, M. J. Morris, S. M. Larson, J. G. Goldin, H. I. Scher. Initial analytic validation of automated bone scan measures for treatment response assessment in patients with metastatic castration-resistant prostate cancer (CRPC). J Clin Oncol 29: 2011 (suppl; abstr e15174). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B114.

Abstract A90: Efficacy and tolerability of cabozantinib at lower dose: A dose finding study in men with castration-resistant prostate cancer and bone metastases.

Abstract Background: Cabozantinib is an orally available inhibitor of MET and VEGFR2. In a randomized discontinuation trial of cabozantinib (100 mg daily), 86% of men with mCRPC and bone metastases had partial or complete resolution of lesions on bone scan as early as week 6; dose reductions for AEs occurred in 51% of pts, and discontinuations in 10%.[1] The current study is designed to determine the efficacy and safety of cabozantinib at lower doses. Methods: The study uses an adaptive response scheme based on Sargent one-stage design [2] to determine the lowest effective cabozantinib dose among three dose levels: dose level +1 (60 mg daily), dose level 0 (40 mg daily), and dose level −1 (20 mg daily). Bone scan responses were assessed by comparison of baseline and week 6 bone scans using an automated FDA 510(k) approved computer-aided detection (CAD) system.[3] A decrease in total bone scan lesion area of ≥ 30% was defined as a response The first cohort was treated at dose level 0 (40 mg po QD). Using the adaptive design, the number of bone scan responses at dose level 0 (≥8 responses versus &amp;lt;8 responses among 11 evaluable subjects) was used to select the dose level (−1 versus +1) for the second cohort. By this design, subjects will be treated at two of the three dose levels (dose level 0 and −1, or dose level 0 and +1). Based on the observed bone scan response rate in the second cohort of 11 subjects, a dose level will be selected for expansion to treat an additional 13 subjects. Results: The study has enrolled a total of 23 subjects. Twelve subjects were enrolled in the first study cohort and treated with cabozantinib 40 mg daily. Median followup is 14 weeks. One subject discontinued the study at week 2 because of anorexia and fatigue. Another subject discontinued at week 6 after experiencing a hip fracture. The remaining 10 subjects remain on treatment without dose reduction. Baseline and week 6 bone scans have been centrally reviewed for the first 10 evaluable subjects. There were 9 confirmed bone scan responses at week 6 including complete response. Median decrease in bone lesion area at week 6 was 69%. Eleven subjects were accrued to the second cohort and treated with cabozantinib 20 mg daily; all subjects remain on study. Conclusions: Cabozantinib 40 mg daily results in high rates of bone scan response in men with CRPC and bone metastases. Cabozantinib 40 mg daily is associated with improved tolerability compared to cabozantinib 100 mg daily. Evaluation of the efficacy and tolerability of cabozantinib 20 mg daily is ongoing.