Biomarkers and Bone Imaging Dynamics associated with Clinical … · 2018. 10. 16. · Cabozantinib...
Transcript of Biomarkers and Bone Imaging Dynamics associated with Clinical … · 2018. 10. 16. · Cabozantinib...
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Biomarkers and Bone Imaging Dynamics Associated with Clinical Outcomes of Oral
Cabozantinib Therapy in Metastatic Castrate Resistant Prostate Cancer
Ulka N. Vaishampayan, Izabela Podgorski1, Lance K. Heilbrun, Jawana M.
Lawhorn-Crews, Kimberlee C. Dobson, Julie Boerner, Karri Stark, Daryn W.
Smith, Elisabeth I. Heath, Joseph A. Fontana and Anthony F. Shields.
Department of Oncology Karmanos Cancer Center/Wayne State University, Detroit
MI 48201.
1. Department of Pharmacology and Oncology Wayne State University, Detroit
MI 48201.
Corresponding Author:
Ulka Vaishampayan M.D.
4100 John R
Detroit MI 48201.
Tel 313-576-8718
Fax 3135768487
E mail [email protected]
This study was partially supported by Department of Defense National Oncogenomics
and Molecular Imaging Center (NOMIC) Grant W81XWH-11-1-0050,
Exelixis Inc and by the NIH Cancer Center Support Grant CA-22453.
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Translational Relevance
Radiologic response and progression represent key decision making endpoints in
oncology therapeutics. Decisions to continue or change therapy hinge on changes noted
in imaging. The cabozantinib experience in mCRPC highlights the major challenge of
using imaging response as a surrogate for clinical outcomes in this disease. Due to the
bone targeted, osteoclast inhibitory activity of cabozantinib, bone marker and bone scan
changes were misleading and did not correlate with clinical outcomes. Even novel
imaging methods such as NaF-PET and FMAU-PET scans were unsuccessful in
detecting responses that would predict clinical benefit. Bone markers and tissue c-MET
expression also did not yield prediction of efficacy. Cabozantinib represents a unique
mechanism of action that is distinct from currently approved therapies in mCRPC and is
worthy of deeper investigation with genomic sequencing to evaluate predictive markers
for patient selection and therapy.
Abstract
Background: Cabozantinib is a multitargeted tyrosine kinase inhibitor that demonstrated
remarkable responses on bone scan in metastatic prostate cancer. Randomized trials
failed to demonstrate statistically significant overall survival. We studied the dynamics of
biomarker changes with imaging and biopsies pre- and post-therapy to explore factors
that are likely to be predictive of efficacy with cabozantinib.
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Methods: Eligibility included metastatic castrate resistant prostate cancer patients with
normal organ function and performance status 0-2. Cabozantinib 60 mg orally was
administered daily. Pretherapy and 2 weeks post, 99mTc-labeled bone scans (BS), positron
emission tomography with 18F-sodium fluoride (NaF-PET) and 18F-(1-(2′-deoxy-2′-
fluoro-β-D-arabinofuranosyl) thymine (FMAU-PET) scans were conducted. Pre and post
therapy tumor biopsies were conducted, and serum and urine bone markers were
measured.
Results: 20 evaluable pts were treated. 8 patients had a PSA decline, of which 2 had a
decline > 50%. Median progression free survival (PFS) and overall survival (OS) were
4.1 and 11.2 months, respectively and 3 pts were on therapy for 8, 10 and 13 months. The
NaF-PET demonstrated a median decline in SUVmax of -56% (range -85 to -5%, n = 11)
and -41% (range -60 to -25%, n = 9) for patients who were clinically stable and remained
on therapy for ≥ 4 or < 4 cycles, respectively. The FMAU-PET demonstrated a median
decline in SUVmax of -44% (-60 to -14%) and -42% (-63% to -23%) for these groups.
The changes in bone markers and mesenchymal epithelial transition/MET testing did not
correlate with clinical benefit.
Conclusions: Early changes in imaging and tissue or serum/urine biomarkers did not
demonstrate utility in predicting clinical benefit with cabozantinib therapy.
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INTRODUCTION:
Prostate cancer is the most common cancer in males with an estimated 164,690 new cases
in 2018 in United States with an anticipated mortality of 29,430 [1]. Although most cases
are treated when localized, others present as disseminated disease or become metastatic
after definitive treatment. In metastatic castrate resistant prostate cancer (mCRPC),
various agents like sipuleucel T, abirateraone, enzalutamide, docetaxel, cabazitaxel and
radium-223 have demonstrated survival benefit [2, 3]. Despite demonstrating impressive
efficacy in early trials, cabozantinib encountered a rocky road during the development of
an indication in metastatic prostate cancer. Initial phase I/II study of cabozantinib
revealed tremendous promise with an unprecedented normalization of bone scans which
had never been observed even with the most effective treatment to date such as androgen
deprivation therapy [4,5]. In addition these effects were seen in a refractory pretreated
patient population and measurable disease responses were noted. The phase II trial results
with this agent in prostate cancer led to the conduct of two large registration trials.
Unfortunately the first trial of cabozantinib plus prednisone versus placebo plus
prednisone showed no benefit in overall survival (OS), which was the primary endpoint
[5]. The second trial comparing cabozantinib and prednisone to mitoxantrone and
prednisone with predefined pain palliation endpoint was halted early due to results
demonstrating lack of benefit [6]. These events led to further drug development of
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cabozantinib being put on hold in prostate cancer. The mechanisms underlying the
remarkable bone scan responses associated with significant clinical palliation have not
been studied in depth. In addition the evaluation of biomarker or imaging changes in
correlation with clinical outcomes was not conducted.
Cabozantinib is an inhibitor of tyrosine kinases including MET, AXL, and
VEGFR. that results in abrupt clinical changes in bone metabolism represented as an
abrogation of 99mTc-MDP uptake on bone scan. This is likely due to inhibition of
osteoclast function and decrease in osteoblast activity. We hypothesized that the agent
uniquely targets the cross talk between C-MET and vascular endothelial growth factor
receptor (VEGFR) axis, and modulates bone turnover via downstream cathepsin K driven
pathways and activity of novel receptor tyrosine kinases, such as DDR-1 and DDR-2 [7,8
Figure 1]. We conducted a pilot trial designed to study the pathophysiology and
biomarker changes in bone metastases and correlate these with response and clinical
outcome data in metastatic CRPC patients. The study also explored any mechanistic clues
for a subset within mCRPC that maybe worthy of targeting with cabozantinib therapy,
given the clinical efficacy observed and reported by multiple investigators globally. The
MET receptor tyrosine kinase (RTK) for hepatocyte growth factor (HGF) has been
implicated as a mediator in many important aspects of tumor pathobiology, including
tumor survival, growth, angiogenesis, invasion, and dissemination. [9] Several tyrosine
kinase inhibitors of MET have been reported to show antitumor activity in cell lines and
animal models [10]. The VEGFR2 (vascular endothelial growth factor receptor) is a
central mediator of tumor angiogenesis, and several small molecule and protein
therapeutics targeting this receptor are in clinical development. In addition to their
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individual roles in tumor pathobiology, preclinical data suggest that Met and VEGFR2
play synergistic roles in promoting tumor angiogenesis and subsequent dissemination [9].
Typically anti-VEGF therapies have not been effective in mCRPC. Randomized
trials with bevacizumab or ramucirumab demonstrated lack of benefit when evaluated in
combination with docetaxel. Compounds that simultaneously inhibit VEGF and MET
RTKs may be more effective anticancer agents than agents that target each of these
receptors individually [10]. Cabozantinib is a potent RTK inhibitor that targets primarily
MET and VEGFR2 and by this mechanism is likely to overcome resistance to anti-VEGF
therapy. It has activity against other RTKs that have been implicated in tumor
pathobiology, including KIT, FMS-like tyrosine kinase 3 (FLT3), and Tie-2. It is known
to inhibit RET, a RTK known to be causative for malignancy, such as in hereditary
medullary thyroid cancer [11, 12].
Imaging Studies
The conventional bone scan utilizes Technetium 99mTc methylene diphosphonate (MDP)
and is a most widely used, standard of care method for evaluating skeletal metastases in
prostate cancer. The 99mTc-MDP accumulates in new (woven) bone and is an indicator
of changes in bone metabolism especially associated with prostate cancer-induced
osteoblastic response. However, 99mTc-MDP scan findings are nonspecific and are
indirect markers of response to treatment [13]. 18F-NaF-PET scans have improved
anatomic detail over 99mTc-MDP scans, a higher accuracy in detecting metastases and
potentially allow quantification of the extent of metastatic lesion [14]. This imaging
modality may be superior to 18F-fluorodeoxyglucose (FDG) PET for prostate cancer,
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since the bone metastases in prostate cancer are primary osteoblastic. Osteoblastic
metastases tend to exhibit a high rate of fluoride incorporation [13] and may have low
FDG uptake [14]. Additionally, NaF-PET has improved sensitivity so earlier detection of
changes is feasible and PET imaging offers the potential for rigorous quantification.
Unlike conventional bone scans that delineate the presence of a lesion, [15] imaging
techniques currently being evaluated in association with therapeutic trials in prostate
cancer are designed to detect pharmacodynamic effects of novel agents. We utilized the
18F-fluoride PET in this study to trace the extent of absorption of fluoride ion by bone
tissue and to attempt quantification of response in bone metastases.
PET obtained with the thymidine analog 18F-FMAU scan is used to image tumor
metabolism and is based on incorporation of the tracer by mitochondrial thymidine
kinase- 2 (TK2) [16, 17]. The three modalities complement each other in distinguishing
changes in lesions on imaging. Changes in cellular metabolism effected by therapy were
hypothesized to have increased sensitivity in measurement of anti-tumor effects of
cabozantinib than the more conventional approach of observing changes in size as seen
on CT scans or just detecting areas of bone turnover or lack thereof, as seen with 99mTc-
MDP conventional bone scans. We have previously reported on the use of FMAU scans
for detection of prostate cancer bone metastases from a study conducted at our institution
validating the use of this imaging modality for bone metastases [18].
PATIENTS AND METHODS
Study Design
The primary objective of the study was to evaluate the timing, physiology, and magnitude
of changes in tumor imaging, and pharmacodynamics (PD) markers with cabozantinib
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treatment in mCRPC. The secondary objectives were to evaluate the clinical safety,
progression free survival and overall survival with this agent and to correlate clinical
outcomes with imaging and PD changes observed. This was a single arm, single
institution, pilot trial of Cabozantinib administered at a starting dose of 60 mg orally
daily in patients with mCRPC. The study was approved by the Wayne State University
institutional review board and written informed consent was obtained from all patients
before registration. The study was conducted in accordance with the ethical guidelines of
the Declaration of Helsinki.
Patient selection
Eligible patients were of 18 years or older, with histologically confirmed mCRPC
and objective progression or rising PSA despite androgen deprivation therapy and
antiandrogen withdrawal were eligible. Patients with rising PSA had to demonstrate
a rising trend with 2 successive elevations at a minimum interval of 1 week. A
minimum PSA of 5 ng/ml or new area of bony metastases on bone scan were
required for patients with no measurable disease. No minimum PSA was required for
patients with measurable disease. A maximum of one prior chemotherapy regimen
for mCRPC was allowed. Any radiation therapy had to be completed at least 2 weeks
prior to starting study therapy. All patients had to be documented to be castrate with
a testosterone level < 0.5 ng/ml. Luteinizing hormone releasing hormone (LHRH)
agonist therapy was continued, if required to maintain castrate levels of testosterone.
Patients had to be off antiandrogens for a minimum of 4 weeks for flutamide and 6
weeks for bicalutamide or nilutamide. Patients with ECOG performance status 2
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and life expectancy of 12 weeks or more were eligible. Patients were required to
have adequate bone marrow, liver, and renal function. Other key exclusion criteria
included history of bowel perforation or fistula, uncontrolled brain or leptomeningeal
metastases, uncontrolled hypertension or diabetes mellitus or history of congestive
heart failure.,
Treatment plan
The study consisted of open label daily, oral administration of cabozantinib at a starting
dose of 60 mg to eligible patients. This was administered with a full glass of water
(minimum of 8 oz/ 240 mL) after fasting (with exception of water) for a minimum of 2
hours before and at least one hour after ingestion. Subjects were advised to record dosing
time and doses taken in a study drug dosing diary while on study treatment. The original
schedule of assessments continued even if doses were withheld. The subjects were
instructed to not make up any missed or vomited doses and to adhere to the planned
dosing schedule. The study allowed maximum of two dose reductions of Cabozantinib to
40 mg and 20 mg orally daily respectively. If Grade 3 or 4 toxicities or grade 2 toxicity
lasting for 7 days or greater was noted then medication was held until the toxicity
resolved to grade 1 or pretherapy baseline. Dose reduction could be considered when
resuming therapy. If toxicity persisted after 2 dose reductions and optimal supportive
care, then study therapy had to be discontinued.
Correlative studies:
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Imaging Methods
This study utilized standard of care 99mTc-MDP bone scan using a gamma camera, NaF-
PET to measure effects of cabozantinib treatment on bone tissue, and FMAU-PET to
measure changes in tumor metabolism in response to therapy. Imaging was performed
using a gamma camera and PET/CT scanners.
We proposed evaluating patients with NaF-PET pre and post cabozantinib therapy to
determine the optimal timing when bone scan normalization occurs. So approximately 5
patients were evaluated with NaF-PET imaging pretherapy and 2-3 weeks posttherapy.
The optimal timepoint to perform imaging with FMAU PET scans to evaluate for anti-
tumor effect was determined to be at two weeks and subsequent patients had scans
performed during that timeline. PET imaging was performed using a GE Discovery STE
PET/CT system (GE Medical Systems, Milwaukee, WI), located at the PET Center, Children’s
Hospital of Michigan. Patients were positioned on their back on a PET/CT scanner in a high-
sensitivity mode. Vital signs were monitored at the beginning and end of each scan. Patients
were injected with 18F-FMAU using an intravenous catheter with doses standardized to body
weight (mean, 360 MBq; range, 196-407 MBq) with a specific activity of at least 18500
MBq/microM and a purity greater than 98%. Dynamic images were acquired at 6-11 minutes
with one bed position over the area of interest of 2 frames: (1 x 5 mins and 1 x 6 mins). After
which, a whole-body image was obtained using a 2D/3D modality, of 3 bed positions. For 18F-
NaF scans patients received an intravenous injection with a mean of 340 MBq (range 259-407
MBq) and imaging began 45-60 minutes later. Patients were positioned with their arms down and
scanned from the vertex to upper thigh and then repositioned to scan the patient’s legs. Whole-
body acquisition time consisted of 3 minutes per bed position. Reconstructed images were viewed
and analyzed using Osirix Imaging Software (Geneva, Switzerland). Tumor SUVmax values
were obtained at baseline and follow up scans by drawing a 1 cm diameter region of interest over
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5 of the most active boney lesions on the 18F-NaF scans. We selected no more than 2 active
lesions per bone region; including the skull, thorax, spine, pelvis and extremities. The same
lesions were selected on the 18F-FMAU scans. A decrease in mean SUV by 20% was considered
a PET response and was used as the threshold to detect changes.
Serum and urine markers
Serum bone markers were assessed pre and post therapy. These included serum bone
specific alkaline phosphatase (BSAP) and N-terminal telopeptide of collagen type I
(NTx). High levels of these markers (>146u/Lfor BSAP and > 100nmol/mmol for NTx)
have been reported to be significantly predictive of higher incidence of skeletal
complications (relative risk of 3.32, p< 0.001), prostate cancer progression (RR 2.02,
p<0.001) and death (RR of 4.59, p<0.001) [19].
A number of other bone turnover markers such as osteocalcin, pyridinoline and
deoxypyridinoline, have been implicated to be predictive of therapeutic response. A study
evaluating the efficacy of matrix metalloproteinase inhibitors in prostate cancer reported
that decline of the bone resorption markers including NTx, procollagen I NH2-terminal
propeptide, osteocalcin and deoxypyridinoline correlated with improved progression free
survival and overall survival outcome [19-21]. This led to the hypothesis that detectable
changes in bone markers could act as surrogates of therapeutic effect in prostate cancer
bone metastases.
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We selected the serum NTx and BSAP and urine NTx as the bone turnover markers due
to the validation of these markers in prior large studies utilizing zoledronate therapy [22].
Decline in the levels was predictive of lower incidence of skeletal events as well as PFS
and OS. Hence the measurement of these markers (NTx and BSAP) pre and post therapy
was correlated with PET scan findings and clinical outcomes.
Serum and Urine (24-hour urine collection sample) N-telopeptide were assessed using the
Vitros ECI Immunodiagnostic System competitive assay (Johnson & Johnson Ortho-
Clinical Diagnostics, Raritan, NJ). Serum bone-specific alkaline phosphatase levels were
assessed using a chemical inhibition and differential inactivation assay.
The levels of bone resorption markers in serum were assayed at baseline and at 8, 15, and
28 days post treatment with cabozantinib. Tartrate Resistant Acid Phosphatase (TRAcP)
levels were measured using Human TRAcP ELISA (RayBiotech; Norcross, GA). For the
evaluation of Osteocalcin levels Quantikine® Colorimetric Sandwich ELISA assays
(R&D Systems; Minneapolis, MN) were used. All samples were assayed in triplicate
according to manufacturer’s instructions, and cytokine levels were quantified by
colorimetric detection at 450 nm against appropriate standards.
Circulating Tumor Cell Count
This was measured by the Cell Search method pre therapy, and 2 and 4 weeks post
therapy and at progression.
Immunohistochemistry for MET testing
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Paraffin sections were de-parraffinized in a xylene-ethanol series. Endogenous peroxides
were removed by a methanol/1.2% hydrogen peroxide incubation at room temperature for
30 minutes. HIER antigen retrieval with a pH9 EDTA buffer and the BIOCARE
Decloacking Chamber. A 40-minute blocking step with Super Block Blocking buffer
(Thermo Scientific) was performed prior to adding the primary antibody. Met antibody
from Abcam (ab51067) was used at a dilution of 1:100. Detection was obtained using
HRP/DAB chromogen and counterstained with Mayer’s Hematoxylin. Sections were de-
hydrated through a series of ethanol to xylene washes and cover slipped with Permount.
The staining was evaluated and categorized as 0, 1+, 2+ and 3+ by a qualified pathologist
who was blinded to clinical data and reported.
Statistical methods:
The trial was a prospective pilot adaptive design study to obtain preliminary data. Each
patient would undergo up to four PET scans, using different radiotracers. It was desired
to estimate the mean SUV at any time point to approximately one-third of a standard
deviation (SD) with 80% confidence. With N=15 patients, the mean SUV could be
estimated to within 0.347 SD units of the true mean with 80% confidence. These
preliminary estimates would be of sufficient precision for use in designing a subsequent
larger study. Since not all patients would undergo all PET scans, the mean SUV may be
less precisely estimated at some time points.
The Prostate Cancer Clinical Trials Working Group (PCWG2) criteria were used to
determine a response [23]. For measurable disease response RECIST criteria 1.1 were
used [24]. For the patients imaged on a common schedule the continuous endpoints (e.g.,
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SUV, bone scan measurements, and all continuously distributed correlatives) were
summarized with standard descriptive statistics, separately at each measurement time
point. We hypothesized that biomarker changes in bone metastases and imaging,
correlated with response and clinical outcome data in metastatic CRPC patients treated
with cabozantinib. The categorical endpoints such as toxicities, the clinical response,
IHC expression levels, etc. were summarized via their frequency distribution, point
estimate of the proportion, and the Wilson type 90% confidence interval (CI).
The distributions of percent change in SUV by FMAU and percent change in each bone
marker were quite non-Normal, despite various transformations applied. Accordingly,
the relationship between pre/post therapy changes in imaging (percent change in SUV by
FMAU and by NaF) and changes in each of the 3 bone marker levels (percent change
from Day 1 to Week 4) were first assessed using the Spearman rank correlation
coefficient (rho, and its 90% CI). Fisher’s Z-transformation of rho was required in order
to calculate the confidence limits for the rank correlation coefficient. To explore the
relationships of change in bone markers with change in imaging we used a nonparametric
regression approach. We fit a locally estimated scatterplot smoother (LOESS) curve
using the LOESS procedure in SAS 9.4 software. A LOESS curve was fit to two
selected bivariate relationships of change in bone marker and change in imaging. For
exploratory analysis purposes, the selections were the only two relationships having rho >
0.20. The default smoothing parameter (percent of the total observations used in each
smoothing neighborhood) was used in the LOESS procedure. These nonparametric
LOESS curves better described the nonlinear character of those two relationships.
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The distribution of censored PFS was summarized via the Kaplan-Meier (K-M)
survivorship estimate. Summary statistics (e.g., median, 6-month and 12-month
progression-free rates, etc.) were calculated from the K-M life table. Similar analyses
will be performed for OS as well.
PFS was measured from treatment start date to the first date of documented
progression, whether by PSA or by imaging, or death from any cause, whichever
occurred first. Patients not experiencing progression were censored for PFS as of the
date of their last PSA or imaging result. OS was measured from treatment start date to
the date of death from any cause. Patients were censored for OS as of the last date on
which they were confirmed to be still alive.
RESULTS:
Patient Characteristics, Toxicity and Efficacy:
26 patients were consented of which 20 were eligible and enrolled; one withdrew from
study and 5 were screen failures. The median age was 69 years (range 56-76 years)
[Table S1]. Thirteen patients had bone pain at the time of enrollment. Sixteen patients
discontinued therapy due to progression and four discontinued due to toxicities which
consisted of hand foot syndrome, fatigue, urinary infection and elevated creatinine each
in one patient. No unexpected toxicities or treatment related prolonged morbidity or
mortality were noted. Each cycle consisted of 28 days of therapy. Median number of
cycles received was 4 (Range 1-17 cycles) and 6 (30%) patients received 8 or more
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cycles of therapy. Three patients did not require dose reductions and eleven and six
required 1 and 2 dose reductions respectively.
Efficacy:
Response was assessed in all 20 patients based on PSA as well as measurable disease per
RECIST1.1. 6 of 9 patients with measurable disease showed tumor shrinkage per
RECIST 1.1 criteria (Median -20%, range -10 to -38%). 8 of 20 patients demonstrated a
PSA decline with a median of 21% [Figure 2] with absolute change of 22.3 ng/ml (range
6.4% to 70.8%, absolute decline range 0.9-282.9 ng/ml). Two patients had a 50% or
greater reduction in PSA levels. The PSA decline did not correlate with PFS. Ten
patients received therapy for > 4 cycles and six patients continued on therapy for > 8
cycles (maximum of 17 cycles). All patients were evaluable for PFS and OS. Median
PFS was 4.1 months (90% CI 2.3-5.3 months) and median OS was 11.2 months (90% CI
15.0-29.7 months).
Imaging and Bone Turnover Markers
19 of 20 patients demonstrated a decline in the SUV max and mean pre and post therapy.
17 patients had the FMAU-PET scan pre and post therapy and 14 showed a SUV decline
of >20%. Two patients showed a decline of <20% at 14.2% and 18.7%. Only one patient
showed a 23% increase in SUV max. Maximum SUV decline was 63.7%. Examples are
shown in Figure 3. The NaF-PET scan was evaluated in 19 patients and 18 (one patient
showed a 5% decline) showed a decline in SUV max of >20%. Maximum change in
uptake was a 85.4% decrease. The timeline of changes and decline in tracer activity on
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both imaging techniques was very rapid and seen within 1-2 weeks of therapy. Serum
NTX showed minimal change from pretherapy to week 4 of therapy, median decline of
2.8% from pretherapy median levels of 12.5 to 11.4 at week 4 of therapy. Urine NTX
revealed an appreciable decrease from median of 29 pretherapy to 15 post therapy,
median decrease of 41.2%. Unfortunately no correlation was noted between the
magnitude of decline in SUV max by imaging with clinical benefit. 11 patients had CTC
> 5 pretherapy, of which 5 patients converted to CTC< 5 after therapy. Table 1
summarizes the changes dichotomized by patients receiving less than 8 cycles, or 8 or
more cycles of therapy.
As an exploratory analysis only, Spearman rank correlation coefficients (rho values and
their CI) for all pairs of 5 variables (percent change in each of FMAU SUV, NaF SUV,
BSAP, serum NTx, and urine NTx) are given in Supplementary Appendix Table S2.
The 2 pairs of imaging change and bone marker change with the largest (and positive)
correlation (rho > 0.20) were NaF SUV with BSAP (rho = 0.22), and NaF SUV with
urine NTx (rho = 0.26). The nonparametric LOESS curve fit for percent change in NaF
SUV as a function of percent change in BSAP is shown in Figure 4A. There is a positive
relationship overall, especially in the range of negative percent changes in BSAP. There,
large decreases in BSAP tended to relate to large decreases in NaF SUV. A similar but
weaker positive relationship was found in which large decreases in urine NTx tended to
relate to only modest decreases in NaF SUV (Figure 4B).
Tissue testing
Tumor biopsies were conducted pretherapy and 2 weeks post therapy. C-MET testing
was conducted by IHC on tumor biopsies (Figure 5A and B). No consistent changes in c-
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MET expression were noted pre and post therapy and the extent of CMET expression did
not correlate with clinical benefit (Figure5 C and D).
DISCUSSION:
Radiologic response and progression represent key decision making endpoints in
oncology therapeutics. Frequently decisions to continue or change therapy hinge on
changes noted in imaging. In the case of bone metastases; the predominant site of spread
in prostate cancer, this endpoint is flawed and leads to erroneous decisions. A prime
example of this was noted within the imaging changes after cabozantinib administration.
Conventional (Technetium) 99mTc-MDP bone scans showed remarkable response in
majority of the patients and led to excitement in phase II trials, that was subsequently not
matched by clinical efficacy seen in the randomized setting [25]. The current study was
designed to incorporate other imaging techniques such as NaF-PET and FMAU-PET
scans to evaluate correlation with clinical endpoints. The results reveal that these
scanning methods were not predictive of efficacy. Novel imaging techniques such as
choline/acetate scans and fluciclovine scans based on amino acid radiotracer have
demonstrated exquisite sensitivity to detect recurrent disease at low PSA levels, and high
positive predictive values [26]. These scans are able to detect metastases in both bone and
soft tissue, however they have not yet been assessed for monitoring effects of systemic
therapy [27]. Bone turnover markers have been explored as potential predictors of
response or clinical benefit from therapy. Unfortunately the results of most studies have
been disappointing and these biomarkers are not utilized in routine clinical practice.
Alkaline phosphatase changes have been reported to be predictive of response in radium-
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223 therapy [28] In fact changes in alkaline phosphatase are likely to be better predictors
of benefit than changes in PSA for radium-223 treatment. Cabozantinib had a major
impact on the bone turnover in prostate cancer bone metastases in initial studies. It also
demonstrated promising clinical response rates in measurable disease [5]. Unfortunately
later studies showed that the remarkable efficacy noted did not lead to an OS impact.
Randomized double blind controlled trials revealed lack of OS benefit when compared to
prednisone therapy alone. However investigator assessed PFS which was an exploratory
endpoint of the study was statistically significantly improved by cabozantinib treatment.
(HR=0.48 p<0.001). . The end result was that in randomized trials the clinical efficacy of
cabozantinib could not be proven.
The anti-VEGF therapies have demonstrated a consistent pattern of promising efficacy in
single arm trials, which subsequently did not translate into OS benefit in the randomized
setting. Sunitinib demonstrated lack of OS benefit in a double blind placebo controlled
trial with median OS of 13.1 months with sunitinib and 11.8 months with placebo [29].
CALGB 90401 was a trial that compared the combination of bevacizumab and docetaxel
to docetaxel alone and although the combination showed improved response rates (43.4%
vs 35.4 %) and median PFS of 9.9 versus 7.5 months, (stratified log-rank P < .001) the
OS (median of 22.6 months for the combination vs 21.5 months, p=-.18) was no
different [30]. A meta-analysis of nine randomized control trials of docetaxel and
antiangiogenic therapy as compared to docetaxel and prednisone confirmed lack of
clinical benefit and possibly increased toxicity with combination therapy in mCRPC [31].
The current study was designed to detect the mechanism of the bone changes and to
explore if bone biomarkers and imaging changes could select a patient population that
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was likely to benefit. The results of our study show that initial response and sustained
clinical benefit for over 8 months was noted in 30% of the patients. The observed
reduction in serum marker levels was likely due to the reduced activity of cathepsin K, a
protease highly present in metastatic prostate cancer [32] (PMID:12568399) and the only
enzyme capable of completely degrading helical and non-helical collagen I, the main
component of bone matrix [33](PMID:9822715). We also suspect the involvement of
DDR1 and DDR2, two novel RTKs which are ligands for bone matrix collagen [34, 35]
(PMID: 16626936; PMID: 12611880). Whether cabozantinib mediates its action on bone
turnover via this axis needs further investigations.
Table 1 reveals that the serum and urine biomarkers tested such as CTC, BSAP and
serum and urine Ntx were not distinctly indicative of early prediction of clinical benefit
with cabozantinib therapy. The MET overexpression and phosphorylated MET also did
not reveal any clear trend of being predictive markers of efficacy. C-terminal MET
protein expression was absent in hormone naïve prostate cancer and in contrast was
present in CRPC in 23% of palliative transurethral resection specimens and in 72% of
bone metastases [36]. This was also not related to MET polysomy or amplification. C-
MET is phosphorylated after nuclear translocation and the staining noted indicates the
activity, however the level of expression was not associated with clinical benefit [36]. On
imaging, the decline in SUV was very rapid and occurred within a short period of time; in
less than one week. This was in concordance with that observed in preclinical studies, but
unfortunately no differential emerged to predict clinical outcomes. MET overexpression
on IHC staining was also not predictive of clinical benefit. 30% of patients had a durable
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21
benefit and continued on therapy for longer than 32 weeks. The imaging changes were
seen in majority of the treated patients, regardless of clinical benefit with cabozantinib.
The cabozantinib experience in mCRPC highlights the major challenge of using imaging
response as a surrogate for clinical outcomes in this disease. Bone only as a site of
metastases comprises about 90% of the patients with CRPC. The conventional bone scan
is severely limited in response determination, as the extent of tracer uptake and changes
thereof, do not correlate with clinical response. The MDP bone scan also cannot be
utilized for measurement of lesions. In addition due to the bone targeted, osteoclast
inhibitory activity of cabozantinib, bone marker and bone scan changes were misleading
and not useful to predict clinical outcomes. Our study depicts that even novel imaging
methods such as NaF-PET and FMAU-PET scans were unsuccessful in detecting
responses that would predict clinical benefit with this agent. NaF-PET is thought to detect
bone metabolism and formation and may also bind to calcium phosphate, and hence not
likely to provide a clear measure of treatment response [37]. FMAU-PET was
developed with the intent to image tumor proliferation, but may be trapped in the cell by
mitochondria by TK2, limiting the ability to assess changes in tumor growth [18]. With
advent of genomic testing, next generation sequencing based results should be
investigated as guides to therapeutic decisions.
Cabozantinib based combinations are being explored in mCRPC such as a clinical
trial conducted by the NCI with nivolumab, and an ongoing trial in combination with
atezolizumab [NCT03170960]. Synergy has been reported with multiple agents such as
immune checkpoint inhibitors and with radiation therapy. The phenotype of mCRPC is
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22
likely to change dramatically over the next decade. The advent of early indication and
utilization of chemotherapy and abiraterone in the metastatic hormone naïve setting and
use of agents such as enzalutamide and apalutamide in non-metastatic disease will alter
the configuration of the mCRPC state. Incidence of neuroendocrine features within
mCRPC is likely to increase. Cabozantinib has demonstrated efficacy in neuroendocrine
tumors and is worthy of evaluation in prostate cancers that manifest neuroendocrine
features [38]. Application of next generation sequencing will provide future clues in
predicting clinical benefit with cabozantinib. With review of specific activity of
cabozantinib in medullary thyroid cancer, it can be hypothesized that the RET gene
mutations in prostate cancers could possibly predict for response [39]. Future
investigations of cabozantinib in mCRPC should focus on genomic markers that are
representative of MET upregulation and RET mutations.
In conclusion, cabozantinib represents a unique mechanism of action that is distinct from
currently approved therapies in mCRPC and continues to be worthy of deeper
investigation. It holds potential in the treatment of patients with refractory mCRPC. The
imaging changes occurred indiscriminately, and were unable to indicate clinical benefit
with the agent.
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Table 1 Percent Change in Imaging, Bone Markers and CTC pre and post
Cabozantinib Therapy
Variable
Median
change
Minimum
Maximum
< 8 cycles
(Median
change)
>8 cycles
(Median
change)
FMAU scan -45% -63.4% +23.2% -45% -40.1%
NaF scan -48.1% -85.4% -24.5% -48.1% -58.8%
BSAP 21.3% -55.8% 250.7% 21.3% -7.5%
Serum Ntx -13% -68.2% 522.6% -13.0% 18.5%
Urine Ntx -41.7% -77.4% 66.7% -41.7% 50.0%
CTC (week2) -33.2% -97.8% 100% -66.7% -16.7%
CTC (Prog) 423% -61.5% 2633% 423% 300%
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FIGURE LEGENDS
FIGURE 1: Proposed Mechanism of Action of XL 184 in Prostate Cancer.
XL184 predominantly targets RTKs involved in tumor-induced bone resorption.
Inhibition of osteoclast activity by XL184 results in reduced levels of the key osteoclast
collagenase CTSK and overall inhibition of bone turnover. Inhibition of DDR-1, and -2
directly by XL184 and indirectly by reduced availability of resorbed collagen abrogates
collagen-induced osteoblast differentiation and woven bone deposition. Abbreviations:
RANKL ((Receptor Activator of NF-κB ligand), VEGF (Vascular Endothelial Growth
Factor), VEGFR1-, 2- (VEGF Receptors), HGF (Hepatocyte Growth Factor), cMet (HGF
Receptor), MCSF (Macrophage Colony Stimulating Factor), c-fms (MCSF Receptor),
SCF (Stem Cell Factor), c-kit (SCF Receptor), FLt3 (FMS-like Tyrosine Kinase 3),
DDR-1,2 (Discoidin Domain Receptor), PIGF (Placental Growth Factor), CTSK
(Cathepsin K), TRAcP (Tartrate Resistant Acid Phosphatase), NTx (N-Telopeptide), CTx
(C-Telopeptide), ET-1 (Endothelin-1).
FIGURE 2
Waterfall Plot of PSA levels
Figure 3
Illustrations of imaging changes seen with cabozantinib therapy in mCRPC patients
treated on study. Figures 3A is 18F-NaF scan obtained in a 64 year old male pre and post
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32
treatment. Figures 3B, 3C and 3D were obtained from a 71 year old male using 99mTC-
MDP bone scan, 18F-NaF and 18F-FMAU, respectively.
Figure 4
(A) Nonparametric regression LOESS curve (solid line) of percent change (pre/post XL
184) therapy in NaF SUV as a function of percent change (from Day 1 to Week 4) in
serum BSAP. The shaded area indicates the 90% confidence interval (CI) for the
predicted mean percent change in NaF SUV over the range of observed levels of percent
change in serum BSAP. (B) Nonparametric regression LOESS curve (solid line) of
percent change (pre/post XL 184) therapy in NaF SUV as a function of percent change
(from Day 1 to Week 4) in urine NTx. The shaded area indicates the 90% confidence
interval (CI) for the predicted mean percent change in NaF SUV over the range of
observed levels of percent change in urine NTx.
Figure 5
Changes in membrane and cytoplasmic C-MET expression on tumor tissue by
immunohistochemistry, pre and post Cabozantinib therapy.
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Published OnlineFirst October 16, 2018.Clin Cancer Res Ulka Vaishampayan, Izabela Podgorski, Lance K. Heilbrun, et al. Castrate Resistant Prostate CancerClinical outcomes of Oral Cabozantinib Therapy in Metastatic Biomarkers and Bone Imaging Dynamics associated with
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