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ASCO 2010
Competitor Intelligence
Report
page 1
CONFIDENTIAL
ASCO 2010 coverage by Wolters Kluwer Health
The 46th ASCO annual meeting was held 4–8 June 2010 in Chicago, Illinois
ASCO is considered the premier educational and scientific event in the oncology community and this year’s theme
was “Advancing Quality Through Innovation”
The meeting attracts a wide audience of oncologists, oncology nurses, pharmacists, genetic counsellors, and other
healthcare professional from around the world; ASCO continues to grow each year with more than 29,000 delegates
attending in 2009, a large proportion of which were from outside the US
Four medical writers from Wolters Kluwer Health attended the conference to obtain competitor intelligence relevant
to the following products:
ARQ-197
CS-1008
U3-1287
CS-7017
U3-1565
DS-5272
DS-2248
DS-7423
BRAF inhibitors
Tumor types relevant to the pipeline agents are: hepatocellular carcinoma (HCC), non-small cell lung cancer
(NSCLC), colorectal cancer (CRC), breast cancer, gastric cancer, ovarian cancer, and acute myeloid leukemia
(AML)
Information was obtained from posters, oral presentations, press releases, conversations with
delegates/authors/key opinion leaders, exhibit stands, and other materials available at the meeting. General news
items were also searched for using Google News, both during and after the meeting. ASCO Annual Meeting Daily
News was collected each day
Many publication-only abstracts (abstract numbers preceded by an 'e') were published in conjunction with the 2010
Annual Meeting. Although not presented at the meeting, these abstracts are available online
page 2
CONFIDENTIAL
Targeted agents - General comments
• There seemed to be consensus opinion amongst investigators that highly
specific targeted agents appear to be better than “dirty inhibitors”
– Many of the targets (e.g. MEK, BRAF) require complete and sustained
inhibition to be effective
– Off-target effects of non-specific TKIs frequently compromise
continuous administration at effective dose levels and, therefore,
compromise maintenance of target inhibition
• There is mounting support for the idea that targeted agents with “obvious”
benefit in phase II trials should not have to provide phase III results for
approval (specific examples discussed were crizotinib and PARP inhibitors)
– However, approval would have to be restricted to selected patients with
relevant mutations
– Phase III trials would still need to be conducted post-approval to
determine effects in unselected patients and comparative efficacy
versus other standard therapies in various treatment settings
– Typically, these agents demonstrate obvious benefits in all
treatment settings, as long as the relevant mutation is present
page 3
CONFIDENTIAL
Key findings relevant to
ARQ-197 (c-MET inhibitor)
page 4
CONFIDENTIAL
C-Met inhibitors
• Attendees were really excited about the results of ARQ 197-209
• A number of concerns and questions were raised by attendees:
–
Tumor biopsy and imaging correlative studies are needed to identify targets, mechanisms of
resistance and predictors of response
–
Can EML4-ALK positivity be considered diagnostic of adenocarcinoma in NSCLC?
» Does knowledge of the precise translocations matter?
» Is there a cost-effective manner to test for this translocation?
–
Is there a need for phase III studies for agents like crizotinib?
–
The best setting for use of c-Met inhibitors in NSCLC is currently unknown
» Should c-Met inhibitors like crizotinib be used as primary therapy, on relapse or in combination with
other agents?
• Recommendations
page 5
–
Consider testing NSCLC patients for EGFR mutations and/or EML4/ALK fusion, and
including biomarkers in clinical study design
–
Consider utilizing easy-to-use assays for predictive biomarkers such as cMET amplification
–
Because KRAS mutations occur most frequently in pancreatic cancer, CRC and NSCLC,
consider additional efficacy studies of ARQ-197 in EGFR wild-type and KRAS mutationpositive patients with pancreatic cancer and NSCLC
–
In view of the synergy demonstrated between the mTOR inhibitor sirolimus and the cMET
inhibitor PHA665752 in reducing cell growth of H441 NSCLC cells, consider studies that
examine ARQ-197 in combination with mTOR inhibitors.
CONFIDENTIAL
ARQ-197
Agent
Data presented and buzz
ARQ 197-209
One hundred and sixty-seven patients with inoperable locally advanced or metastatic NSCLC were
randomized to receive erlotinib alone or in combination with ARQ-197 in this phase II trial (abstract
LBA7502). After treatment with ARQ-197 and erlotinib the most commonly reported TEAEs were
acneiform rash/dermatitis and diarrhea. Median PFS was prolonged after treatment with ARQ-197
and erlotinib compared with erlotinib alone (16.1 weeks vs 9.7 weeks). Median PFS and OS were
most pronounced in patients with tumors of non-squamous histology.
This study was very well received. But there were concerns about the lack of biomarker studies in
this trial: “Predictive biomarker development with careful patient selection will be important for further
development of ARQ-197” (Ravi Salgia). MET (at the gene and protein level) and circulating level are
important potential biomarkers in lung cancer.
ARQ 197-114
ARQ-197 had manageable tolerability and showed preliminary signs of clinical activity (median TTP
107 days) in a phase Ib study in 21 cirrhotic patients with HCC (abstract #4137). AEs were reported
in more than 95% of patients and the most common drug-related AEs were asthenia, anemia,
neutropenia and leukopenia. Bone marrow toxicity led to study discontinuation in 2 patients and
septic shock that occurred during untreated drug-related leukopenia caused the death of one patient.
All patients’ biopsies were positive for total c-MET and at least weakly positive for HGF.
Interest in this poster was low. The presenter admitted that his poster wasn’t receiving as much
attention as ARQ-197 combination therapy (ARQ-197 and sorafenib) poster.
page 6
CONFIDENTIAL
ARQ-197
Agent
Data presented and buzz
ARQ-197
Preliminary data from a phase I study shows that ARQ-197 + sorafenib is well tolerated in patients
with advanced solid tumors (abstract #3024). The MTD has not yet been reached despite dosing at
full single-agent doses of both drugs. Sorafenib had no effect on the pharmacokinetics of ARQ-197.
Preliminary evidence of anti tumor activity ahs been observed with the combination.
One of the attendees stated that being able to administer full doses was a benefit of this treatment.
This comment was repeated in the discussion panel.
Twenty-five patients with advanced solid tumors received gemcitabine + ARQ-197 in a phase Ib study
to evaluate safety, pharmacokinetics, biomarkers and efficacy (abstract e13008). The combination
therapy was well tolerated and there was no evidence of drug-drug interactions.
ARQ 197-215
In this phase II study (abstract #TPS215), patients with HCC will be randomized in a 2:1 fashion to
receive either oral ARQ-197 360mg BID or placebo. The primary endpoint is TTP; the secondary
endpoint is OS. Overall disease rate will also be measured and biomarkers (including c-MET) will be
evaluated. The study design requires 99 patients at multiple sites. Presently, only 33 patients have
been enrolled in the study and are being treated with ARQ-197. Study enrollment is ongoing.
Delegates commented that the major toxicity observed in this study (G4 neutropenia) is cause for
concern. A lack of opportunity to scale down the dose is also a concern. One attendee said that just
looking for disease stability is not a good goal when the compound is so toxic.
page 7
CONFIDENTIAL
C-Met inhibitors
Agent
Data presented and buzz
XL184
(Exelixis)
Currently in development for glioblastoma (phase III), thyroid cancer (phase III) and NSCLC (phase
I/II).
XL184 was studied in 195 patients with progressive glioblastoma (abstract #2006). Durable
responses were observed in patients naïve to anti-angiogenic agents. Interestingly, the 125mg dose
of XL184 showed improved tolerability compared with the 175mg dose. Although these findings were
interesting, they are not conclusive as the study was not randomized.
XL184 was also studied in combination with erlotinib (abstract #3017).
A phase Ib/II study studied XL184 + erlotinib in 54 patients with previously treated advanced NSCLC.
Patients received various levels of XL184 and erlotinib in two different arms of the study (A and B). In
Arm A, the objective was to maintain high doses of XL184 and in Arm B, high doses of erlotinib. The
MTD in Arm A has not been established; the MTD in Arm B was XL184 at 50mg and erlotinib 150mg.
The diarrhea experienced by patients was not dose limiting. There was no evidence of a drug-drug
interaction between XL184 and erlotinib. Clinical activity observed was in the erlotinib pretreated
population, in patients with EGFR T790M mutations and MET amplification.
XL184 showed promising efficacy in a phase I study in patients with advanced malignancies,
including 37 patients with medullary thyroid cancer (abstract #5502). The ORR was 29%, and 49%
of patients experienced tumor shrinkage >30%;
Some attendees expressed concern about this study and the compound. Firstly, the presentation did
not include any discussion of dose reduction related to treatment. It was also not clear if G3–4 AEs
were related to XL184. Finally, the details of 2 deaths were not reported. The presenter admitted that
XL184 was a highly active drug that may be toxic at higher doses.
There is an on-going trial evaluating activity of XL184 in various tumors (abstract #TPS188).
Approximately 600 patients have been enrolled in this study so far. The response in patients with
prostate cancer has been reported as “impressive” however, the study design has been described as
time-consuming.
page 8
CONFIDENTIAL
C-Met inhibitors
Agent
Data presented and buzz
Crizotinib
(Pfizer)
Currently in phase III development for NSCLC.
Eighty-two patients with no history of smoking and NSCLC with ALK fusions received crizotinib
250mg BID (abstract #3). The most common AEs were nausea, diarrhea and vomiting. Almost all
patients enrolled in the study had a degree of tumor shrinkage; ORR 57% and a disease control rate
of 87%. The response duration lasted from 1 to 15 months. (Attendees were really excited about
these findings).
In an open-label phase I dose-escalation study, PK data from 145 patients with cancer were collected
(abstract #2596). Exposure to crizotinib increased in a dose-proportional manner. BID dosing resulted
in a 4 to ~6 fold accumulation in AUC. Steady state was reached in 15 days, with trough
concentrations exceeding levels needed to inhibit c-MET and ALK. Food had no impact on exposure.
Crizotinib is a moderate inhibitor of CYP3A.
MetMab
(Genentech)
page 9
Currently in phase II development for NSCLC.
A phase Ib study designed to evaluate the safety of MetMAb + bevacizumab demonstrated that this
combination therapy was well tolerated at the recommended dose of 15mg/kg Q3W for each agent
(abstract #13050).
CONFIDENTIAL
C-Met inhibitors
Agent
Data presented and buzz
MGCD265
(MethylGene)
Currently in phase I development for cancer.
MGCD265 was well tolerated in a phase I study in 21 patients with advanced malignancies (abstract
#3108). The MTD was not reached. Of the evaluable patients, 33% achieved SD and 13% stayed on
the drug for 4 cycles or more.
In a related study that examined daily dosing of MGCD265 in patients with solid tumors, 150 mg/m2
was found to be well tolerated and will be considered for use in phase II studies (abstract # 3106).
MK2461
(Merck)
TAK-701
(Millennium)
page 10
Development discontinued.
Parallel PK studies of MK2416 conducted in Korea and Japan and the US were performed to
compare potential ethnic differences in drug metabolism (abstract #2549). The drug was found to be
well tolerated in each group and there were no reported differences in PK. Comparing parallel PK
studies in Asia and the US may be one way of evaluating ethnic differences.
Currently under phase I development for cancer.
TAK-701 was well tolerated in patients with advanced solid tumors (abstract #3081). SD was reported
in ~53% of response-evaluable patients.
CONFIDENTIAL
ARQ197 upstream competitors
Agent
Data presented and buzz
Erlotinib
(OSI)
Approved for treatment of NSCLC in 2005.
Combination therapy with gefitinib and erlotinib showed anti-tumor activity and a tolerable AE profile
as second-line treatment in NSCLC (abstract # 7551).
The MTD of erlotinib and cetuximab in a phase II study in patients with cetuximab-resistant lung
adenocarcinoma was 100mg and 500 mg/m2 q2w, respectively. Toxicities observed included fatigue,
rash and hypomagnesemia (abstract # 7557).
Pemetrexed and erlotinib were associated with comparable efficacy in terms of TTP, OS and ORR in
pretreated patients with advanced NSCLC (abstract #7519). Patients with squamous cell NSCLC
receiving erlotinib experienced a significantly better TTP than patients treated with pemetrexed.
In a study evaluating erlotinib ± everolimus, the combination arm performed better with an 11%
difference in disease control rate at 3 months (abstract #7524).
For patients treated in the first-line setting for locally advanced, recurrent, or metastatic NSCLC, the
addition of bevacizumab to erlotinib after chemotherapy significantly improved PFS (abstract #7526).
Compared with erlotinib or sorafenib monotherapy, the combination therapy of sorafenib and erlotinib
was effective in patients with previously treated NSCLC; median PFS=3.6 months (abstract # 7547).
Sunitinib
(Pfizer)
page 11
Currently in phase III development for NSCLC.
Sunitinib 37.5mg was tolerated in patients with NSCLC and brain metastases (abstract #7581).
Sunitinib was associated with only marginal antitumor activity; however, PFS was 9.4 weeks and TTP
was 15.1 weeks.
CONFIDENTIAL
Key findings relevant to
CS-1008 (Anti-DR5 mAb)
page 12
CONFIDENTIAL
Targeting the death receptor pathway
• Relatively quiet MoA at the meeting – only 8 abstracts, although a number of these were
presented in clinical science symposia or poster discussion sessions (rather than general
posters)
• Results were mixed – positive for conatumumab in pancreatic cancer, negative for
mapatumumab, drozitumab and dulanermin in NSCLC
• Discussant Suresh Ramalingam, talking about the “disappointing” results of the NSCLC
trials of mapatumumab, drozitumab and dulanermin, said “These studies did not fail due to
`bad luck’… This raises the question if targeting the death receptor pathway has reached a
`dead end’? Why?” Ramalingam proposed 2 hypotheses to understand why these trials
might have failed:
–
1) Chemotherapy induces death receptor expression via a p53-dependent mechanism; since
NSCLC has a high prevalence of p53 mutation, this may abrogate the synergistic interactions
between platinum agents and death receptor agonists. It could be interesting to examine
outcomes by p53 status
–
2) A role for c-FLIP, a negative regulator of TRAIL-induced apoptosis, which is
overexpressed in the majority of NSCLCs; “perhaps we’re activating the receptor but if the
tumor had a break in the form of c-FLIP, one may not have seen the potential benefits of this
combination”
–
“I think moving forward with similar approaches is not recommended. Studying more and
thinking of other ways to improve and target TRAIL pathways may be more suited for future
strategies”
• Death receptor agonists do not appear to be active as single agents, and this seems to be
common to the class
page 13
CONFIDENTIAL
Targeting the death receptor pathway
• Sensitivity to death receptor agonists is probably dependent on receptor expression, but few
trials have collected this data. Presenters emphasized the importance of collecting such
data. “One should be thoughtful about correlative preclinical and clinical studies to identify
candidate biomarkers based on the pathogenesis of the pathway associated with antitumor activity”
said Bruce E. Johnson, who discussed the mapatumumab trial. “I think these studies point to the
importance of trying to identify things ahead of time”
• Companies still highlighting death receptor agonists in their pipeline: Amgen
(conatumumab), Genentech (dulanermin), Human Genome Sciences (mapatumumab,
lexatumumab; no booth at ASCO). Drozitumab (PRO95780/Apomab) has been
discontinued, apparently because of disappointing results (NSCLC and NHL results
presented at ASCO)
• Recommendations
–
Prospectively collect biomarker data to determine which patients are most likely to benefit
from treatment with CS-1008, including death receptor expression at the minimum, possibly
also p53 mutational status, c-FLIP expression and Fc gamma receptor type 2 polymorphisms
–
In light of negative results with other death receptor agonists added on to standard
chemotherapy with carboplatin + paclitaxel in unselected patients with NSCLC, consider
conducting future trials of CS-1008 in:
» Selected patient populations (need to determine predictive biomarkers)
» And/or in combination with agents more likely to interact synergistically with CS-1008
page 14
Radiotherapy or chemoradiotherapy in radiation-sensitive tumor types
Agents that activate the intrinsic apoptosis pathway, such as camptothecins or Bcl2 inhibitors (ongoing trials of CS1008 in combination with irinotecan in colorectal cancer may be informative)
CONFIDENTIAL
Death receptor 4 agonists
Agent
Data presented and buzz
Dulanermin
(Amgen/
Genentech)
Genentech and Amgen are co-developing dulanermin for colorectal cancer. Genentech has
terminated co-development in NHL and NSCLC. Reverted back to phase I for CRC in 2009,
probably because of disappointing phase II results in NSCLC and NHL (as presented at ASCO).
DR 4 and 5
agonist
Addition of dulanermin to first-line therapy with carboplatin + paclitaxel +/- bevacizumab did not
improve outcomes in patients with advanced NSCLC in a randomised phase II trial (abstract #7534).
There were no differences between groups in ORR, PFS or OS. In fact, “The control arms did the
best compared to all other experimental arms in the trial”.
In a randomised phase II trial, addition of dulanermin to rituximab was “well tolerated”, but did not
improve ORR in patients with follicular NHL (abstract #8104).
Mapatumumab
(Human
Genome
Sciences)
Mapatumumab is currently in phase II development. Trials are ongoing in multiple myeloma, liver
cancer, and cervical cancer; positive results were obtained in NHL and CRC (results reported in
2005, but phase III development has not yet been initiated), while negative results were obtained in
NSCLC (presented at ASCO).
DR 4 agonist
“No evidence of antitumor activity” was observed with mapatumumab at 10 or 30 mg/kg when
added to first-line carboplatin + paclitaxel in a randomized phase II trial in patients with advanced
NSCLC (abstract #LBA7501). Neither dosage of mapatumumab improved ORR, PFS or OS over
treatment with chemotherapy alone. “One piece of optimism is that there does appear to be a
subset of patients with long PFS” commented Discussant Bruce E. Johnson. However, no biomarker
data were collected.
“One of the things that is somewhat disappointing … given that mapatumumab has now been in
trials for longer than 5 years without the identification of patients more likely to benefit from therapy
as a single agent or when combined with chemotherapy; this was an unselected trial either by
histology, serum or biomarkers.”
page 15
CONFIDENTIAL
Death receptor 5 agonists
Agent
Data presented and buzz
Conatumumab
(Amgen)
Conatumumab is currently in phase II trials for CRC, NSCLC, lymphoma, sarcoma.
DR 5 agonist
Conatumumab showed a trend towards improved overall and progression-free survival when given
in combination with gemcitabine versus gemcitabine alone in a phase II randomized trial in patients
with metastatic pancreatic cancer (abstract #4035). The trial also included a gemcitabine + AMG
479 (Amgen’s IGF-1R receptor mAb) arm, which obtained similar results, although Discussant
Milind M. Javle (University of Texas M. D. Anderson Cancer Center) commented that response rate
seemed slightly higher in the AMG 479 arm. Study agents were both tolerable. Physicians and the
presenter were “surprised” that there was not more grade 3-4 thrombocytopenia. Javle commented
that this was probably because of the schedule used. Poster presenter Hedy Lee Kindler (University
of Chicago Medical Center) was very open and enthusiastic about results. Kindler was certain that
one or both agents would progress to phase III, but Amgen staff were unable or unwilling to confirm
this. The poster attracted thick crowds, with many asking questions; Kindler mentioned that 300
reprints of the poster had been provided; all of these were gone within a half hour.
Conatumumab was well tolerated in combination with AMG 479 in the dose-escalation phase of a
phase I trial in patients with advanced solid tumours, with no serious AEs or DLTs and no evidence
of drug-drug interaction (abstract #3102). Recommended phase II doses of the agents were AMG
479 at 18 mg/kg + conatumumab 15 mg/kg. Among 9 patients, 4 had SD, 3 were not evaluable, 2
had PD. Part 2 of the trial is ongoing and enrolling patients with NSCLC (squamous or nonsquamous), CRC, pancreatic, ovarian and sarcoma. Primary endpoint is ORR.
page 16
CONFIDENTIAL
Death receptor 5 agonists
Agent
Data presented and buzz
Drozitumab
PRO95780,
Apomab
(Genentech)
Drozitumab was in phase II development for NHL, NSCLC, CRC and chondrosarcoma. However,
development of drozitumab has been discontinued, apparently because of disappointing phase II
results (results in NSCLC and NHL were presented at ASCO).
DR 5 agonist
Drozitumab did not appear to be effective in combination with carboplatin + paclitaxel + bevacizumab
as first-line therapy in patients with advanced NSCLC (abstract #7535). Compared with carboplatin +
paclitaxel + bevacizumab alone, there were no differences in median progression-free survival or
response rate, while overall survival appeared better in the control arm. AEs more common in
drozitumab arm were neutropenia, liver function abnormalities and supraventricular tachycardia.
Exploratory analyses suggested a favorable effect of drozitumab in certain polymorphisms of Fc
gamma receptor type 2, but the “implications of this are not clear”.
Addition of drozitumab to rituximab did not appear to improve efficacy in patients with follicular NHL
(abstract #e18511). ORR was 50% - similar to that expected with rituximab alone. Drozitumab well
tolerated; the most common AEs were neutropenia and liver function abnormalities.
Lexatumumab
(Human
Genome
Sciences)
DR 5 agonist
page 17
Lexatumumab is in phase I development.
Lexatumumab showed “some evidence of activity” in a phase I trial in pediatric patients with solid
tumors (abstract #9500). “May be exciting” combined with radiotherapy, with anecdotal cases of
response in radiotherapy fields when given before or after radiotherapy. MTD was 8 mg/kg (versus
adult MTD of 10 mg/kg); DLTs were pneumonia with hypoxia and pleural effusion. No evidence of
human anti-human antibody production in response to study drug. Care was taken not to give drug
during active infection, as DLTs and one treatment-related death in the adult phase I study all
occurred in the setting of active infection.
CONFIDENTIAL
PARP inhibition
• PARP inhibition continues to generate enthusiasm in breast and ovarian cancers. An
educational session and a clinical science symposium were dedicated to PARP
inhibition and these sessions were very well attended. Heralded as a “really
extraordinary advance in therapeutics”
– PARP inhibitors have single-agent activity in patients with defects in homologous
repair (i.e. BRCA-deficient tumors) through the concept of “synthetic lethality”
» Several investigators posed the question of whether PARP inhibition may
have utility as chemoprevention in patients with BRCA mutations, however,
“there are no data yet, and it is quite controversial”
– The PARP enzyme is activated by single-strand breaks. Therefore, PARP
inhibitors act synergistically with agents that cause single-strand breaks, such as
topoisomerase I inhibitors, alkylating agents, DNA methylating agents and
ionizing radiation
» These agents are commonly used in a wide variety of tumor types –
perhaps one third of common tumors are likely to benefit from PARP
inhibition
» “Very promising” activity has been observed in combination with DNAdamaging agents in sporadic (BRCA-competent) triple-negative breast
cancer; a phase III trial of gemcitabine + carboplatin ± iniparib is complete
and results are eagerly anticipated
» There is some interest in combining PARP inhibition with
chemoradiotherapy; investigation is underway, but no data yet – there was
initial reluctance for this approach because of concerns about late toxicity,
“which I think is a great shame” (Nicola Curtin)
page 18
CONFIDENTIAL
PARP inhibition
• Need to identify biomarkers associated with sensitivity to PARP inhibition due to the heterogeneity
of tumors likely to respond
–
PTEN loss is common in triple-negative breast cancer and leads to a reduction in homologous
repair, which may increase sensitivity to PARP inhibition
–
High-grade serous (“BRCA-like”) sporadic ovarian tumors tend to have deficiencies in homologous
repair – this “an important therapeutic focus for the future”
• Potential problems with PARP inhibition:
–
Enhancement of toxicity in combination with cytotoxic agents may make it difficult to maintain effective
doses
»
There is general surprise among investigators that PARP inhibition has not been associated with greater systemic toxicity,
though they are careful to note that “toxicity is not trivial”
»
“You don’t necessarily want to escalate the dose until there is dose-limiting toxicity”
–
Development of resistance
–
Genotoxicity
• Future challenges:
–
What is the right dose and schedule for PARP inhibitors?
–
To what extent does PARP need to be inhibited to obtain clinical benefit?
–
What is the optimal duration of PARP inhibition?
–
Who do we treat?
• A number of PARP inhibitors are in development (AG014699, veliparib, olaparib, iniparib, BSI401,
CEP9722, INO1001, GPI21026, BMN673), but there are very little data to help us decide which
PARP inhibitor to use.
page 19
CONFIDENTIAL
PARP inhibitors
Agent
Data presented and buzz
Iniparib
(sanofi-aventis)
Iniparib is currently in phase III development for the treatment of metastatic breast cancer and lung cancer,
and in phase II trials for ovarian and endometrial cancers.
Iniparib was well tolerated with conventionally prescribed doses of temozolomide given during and following
radiotherapy in newly diagnosed malignant glioma (abstract #2010). The MTD was not reached.
MK 4827
(Merck)
Olaparib
(AstraZeneca)
MK 4827 is currently in phase I development for solid tumors.
In a first-in-human study, MK 4827 had dose-proportional PK and significantly inhibited PARP at doses of 80
mg/day or higher; γ-H2AX induction was also observed (abstract #3001). Multiple responses were observed in
patients with ovarian and breast cancers – most were found to have BRCA1/2 mutations. Enrolment in an
expansion cohort enriched for BRCA mutation carriers is ongoing. DLT was thrombocytopenia – not observed
as a DLT with other PARP inhibitors.
Olaparib is in phase II development for the treatment of breast, colorectal and ovarian cancers.
Single-agent olaparib demonstrated ”encouraging” single-agent activity in patients with advanced serous
ovarian cancer, regardless of BRCA mutational status (ORR 40%) in a phase II trial (abstract #3002) - the first
trial to show activity of single-agent PARP inhibition in serous ovarian cancer without BRCA mutation. No
responses were observed in triple-negative breast cancer patients. Discussant James H. Doroshow
commented: “this is one of the most important abstracts that you will hear at this meeting”.
Olaparib + paclitaxel was associated with partial response in 33-40% of patients with triple negative mBC
(abstract #1018). The combination was well tolerated, but toxicity was "not trivial", with neutropenia in 58% of
patients. Diarrhea was also common.
Chemoresponsiveness appears to be maintained after treatment with olaparib in patients with advanced
BRCA-deficient ovarian cancer (abstract #5041).
Colorectal cancer cell lines proficient in DNA mismatch repair (MMR) are more sensitive to PARP inhibition
with olaparib as a single agent than are cell lines with microsatellite instability. The addition of PARP inhibitor
to the traditional cytotoxic agent oxaliplatin did not potentiate cell death in either cell line (abstract #e13644).
page 20
CONFIDENTIAL
PARP Inhibitors
Agent
Data presented and buzz
Veliparib
(Abbott)
Veliparib is in phase II development for the treatment of breast, colorectal and ovarian cancers and melanoma.
Veliparib did not appear to affect the PK of cyclophosphamide in a phase I trial in patients with advanced solid
tumors (abstract #3000). Evidence of activity was observed in patients with prostate cancer and breast cancer,
with disease stabilization also observed in patients with bladder, colon and non-small cell lung cancer. The
maximum tolerated dose was not reached using an intermittent dosing schedule. Questions remain about the
recommended dose going forward and an extended dosinq schedule will be evaluated – might have more
activity if the tumor has less time to repair.
Veliparib + temozolomide was associated with an ORR of 7% in a heterogeneous group of patients with mBC
in a phase II trial (abstract #1019). Activity appeared to be limited to BRCA mutation carriers; the ORR among
patients with BRCA mutations was 38%. This finding “calls into question the concept of BRCA-ness for at least
this PARP”. Toxicity was “not inconsiderable”, consisting of myelosuppression, nausea, electrolyte
disturbances and fatigue.
page 21
CONFIDENTIAL
Predictive/prognostic
biomarkers
page 22
CONFIDENTIAL
Non-small cell lung cancer
• Attendees and presenters both stressed the importance of the need for tumor biopsies
for testing
• A number of abstracts presented at the meeting focused on predictive and prognostic
markers
• There still appears to be confusion regarding the definition of prognostic and predictive
markers
• Future directions
–
Gene expression and genotype signatures should be developed in parallel with biomarkers
–
Clinical trials should integrate biomarkers (EGFR and ALK at the minimum)
• Prognostic markers
–
In the absence of ALK-targeted therapies, ALK rearrangement is not a positive prognostic
factor in NSCLC (abstract #7606)
–
VEGF levels are a negative prognostic indicator in advanced NSCLC (abstract #7614)
–
Transcriptomic-based strategies may identify cohorts of patients who may be candidates for
adjuvant therapy with IGF-1R-targeted therapies (abstract #7012)
–
Patients with brain metastases at diagnosis of advanced NSCLC had a higher risk of
subsequent CNS progression, despite receiving prior CNS therapy (abstract #7543)
» Significant predictors of development of CNS progression included age younger than 63 years and
EGFR mutation genotype
page 23
CONFIDENTIAL
Non-small cell lung cancer, cont.
• Predictive markers
–
EGFR polymorphisms do not have a predictive effect on OS and PFS after treatment with erlotinib (abstracts
#7538 and #7549)
»
Another study suggested improved OS for erlotinib-treated patients whose tumors contain wild-type EGFR and E-cadherin
expression (abstract #7550)
–
High serum HGF levels could be useful in predicting response to EGFR-TKI (abstract #7563)
–
VEGF polymorphisms may predict disease control rate and PFS in patients treated with sorafenib (abstract
#7607)
–
KRAS mutated, KRAS wild-type or EGFR wild-type tumors may derive benefit from treatment with sorafenib,
whereas those with EFGR mutation/amplification may have a worse prognosis (abstract #7609)
»
Another study showed that KRAS and EGFR mutations are not predictive of outcomes (abstract #7526)
–
T790M mutation at baseline was more common with L858R than del(19) and was associated with worse
PFS in erlotinib-treated patients (abstract #7514)
–
EGFR FISH+ or mutation+ may have some predictive value in identifying patients who receive benefit from
docetaxel and vandetanib treatment (abstract #7516)
–
EML4-ALK fusion transcripts can be detected and measured in NSCLC FFPE specimens by RT-PCR
(abstract #10535)
–
Patients with KRAS mutations may derive less benefit from chemotherapy (especially) if tumor sizes are
larger than 4cm (although, this interaction did not reach statistical significance) (abstract #7008)
–
In a biomarker analysis of pertuzumab combined with erlotinib in patients with NSCLC, high tumor
expression levels of PTEN positively correlated with PFS (abstract #7540)
page 24
»
High tumor mRNA expression levels for EFGR, HER2 and HER3 positively correlated with longer PFS
»
mRNA combination scores for EGFR, HER2 and HER3 were associated with longer PFS in patients when more than one
receptor had an elevated mRNA level
CONFIDENTIAL
Colorectal cancer
• Use of genetic biomarkers predictive of adjuvant
chemotherapy benefit in stage II disease
– Microsatellite instability (MSI)/mismatch-repair (MMR) assays cheap
and easy to do; recommended for use for all stage II patients
– Oncotype DX gene expression assay predictive of recurrence risk now
validated and recommended for use for T3 stage II patients
– ColoPrint gene expression assay still undergoing validation but looks
promising
• BRAF mutation appears to be independently prognostic rather
than a predictive biomarker of response to EGFR-targeted
therapy (abstracts #3505, #3506, #3591, #3592, #3517)
– Not clear whether responses are shorter in patients with BRAF
mutations or these patients simply don’t respond
– Awaiting results from biomarker-enriched trials such as FOCUS III,
which stratified patients on the basis of KRAS, BRAF and topo-I status
page 25
CONFIDENTIAL
Hepatocellular cancer
•
•
TIMP metallopeptidase inhibitor 1 (TIMP-1), monocyte chemotactic protein-1 (MCP-1), and prolactin may potentially
be complementary biomarkers for the early detection of HCC in patients at risk of developing this disease, and may
predict for a worse relapse-free survival (abstract #4131)
–
All three of these proteins were elevated in the serum of patients with HCC, particularly in those with stage
III vs stage II disease or non-HCC patients
–
Patients with TIMP-4 levels ≥ ULN had a significantly shorter median relapse-free survival than those with
levels <ULN, as did those with TIMP-4 + MCP-1 + prolactin levels ≥ ULN
–
Combined analysis of alphafetoprotein (AFP) + TIMP-4 had a high sensitivity (90%) and increased specificity
(100%) of predicting HCC compared with AFP analysis alone
Results of other studies (mostly phase II) investigating predictive (and/or prognostic) biomarkers in advanced HCC:
–
A significant correlation was shown between higher baseline angiopoietin-2 levels and decreased OS, and
higher baseline VEGFR-2 levels and decreased PFS, in patients receiving bevacizumab + erlotinib (abstract
#4046)
–
Higher baseline circulating endothelial progenitor cells predicted poorer PFS and OS in patients receiving
sorafenib + tegafur + uracil (abstract #4063)
–
Early hematopoietic toxicity (occurring during first cycle of treatment) predicted more favorable survival
outcomes in patients receiving sunitinib (abstract #4081)
–
Multi-drug resistance-associated protein 4 expression was significantly increased in tissue from patients with
HCC relative to healthy normal tissue, particularly in the early stages of portal vein invasion, and may be a
potential target of HCC treatment (abstract #4146)
–
Serum PIVKA (plasma proteins induced by vitamin K antagonism or absence) levels were reduced by
linifanib in 11 of 33 evaluable patients, and these reductions were associated with improved OS (abstract
#4038); there was no association between change in AFP levels and OS in this study
–
Hypertension was a positive predictive marker of OS in patients receiving sorafenib (abstract #e14536)
–
PET-CT-assessed early response to sorafenib (i.e. >20% reduction in change in standardized uptake value
(SUV) response) appeared to be a biomarker of predictive and/or prognostic value, with early-response
patients having a significantly longer median TTP and OS than non-early-response patients (i.e. patients
with increased or stable SUV responses) (abstract #e14567)
page 26
CONFIDENTIAL
Gastric cancer
• High tumoral matrix metallopeptidase 9 (MMP9) mRNA expression significantly predicted poorer
survival in patients with metastatic gastroesophageal cancer (particularly those in the highest
quartile of MMP9 expression) (abstract #4017)
–
Discussant described results as “impressive” and found two agents in the literature that target
MMP9: all-trans retinoic acid and epigallocatechin-3-gallate
• Patients with localized gastric cancer (GC) or colorectal cancer carrying at least one T allele of the
GRP78_415 polymorphism had a significantly shorter median time to relapse and OS than patients
not carrying this allele, indicating that this polymorphism may be useful in identifying patients at risk
of tumor recurrence. The GRP78 may also serve as a drug target in these pt populations (abstract
#10524)
• In patients receiving neoadjuvant treatment with S-1 + irinotecan for advanced GC, high expression
of uridine monophosphate synthetase, sodium/hydrogen exchanger 2, uracil-DNA glycosylase, and
tyrosyl-DNA phosphodiesterase 1, and low expression of cyclin-dependent kinase inhibitor 1 was
significantly correlated with tumor response (abstract #4122)
• The efficacy of first-line treatment for GC or gastroesophageal junction cancer with cetuximab +
cisplatin + docetaxel was correlated with negative or low EGFR score, high ERK, and positive
mTOR expression; KRAS and BRAF mutations were not common in this population and were not
correlated with response (abstract #4133)
• Low primary tumor ERCC1 expression was associated with significantly longer median OS and 1year survival rates than high ERCC1 expression in patients receiving cisplatin + epirubicin +
leucovorin + 5-FU in a phase I study, indicating that ERCC1 testing might be useful in predicting
outcome in GC patients (abstract #e14603)
• DNA polymerase η protein expression was a predictive marker of treatment response and survival
in patients with metastatic GC receiving first-line FOLFOX (5-FU + oxaliplatin + folinic acid) or
XELOX (capecitabine + oxaliplatin) chemotherapy (abstract #e14632)
page 27
CONFIDENTIAL
Breast cancer
•
•
•
•
HER2 overexpression is an established predictor of benefit from HER2-directed therapy, but the extent of
overexpression may also be important:
–
Higher HER2 expression by mRNA expression, total protein levels or FISH ratio predicts higher ORR and
longer PFS on HER2-directed therapy (abstracts #1016, #1036, #1088, #1011)
–
“Unless you are genuinely HER2 overexpressing, you don’t respond to the drug” (David Cameron,
Edinburgh University)
A number of other markers are being investigated as predictors of response to HER pathway inhibitors:
–
PTEN positivity was associated with improved PFS on cetuximab therapy in patients with triple-negative
mBC (abstract #1056), while no clear association was found between PTEN expression and response to
trastuzumab-DM1 (abstract #1016)
–
High EGFR copy number was predictive of response to lapatinib in a phase II trial (abstract #1059), while
low EGFR extracellular domain was an independent predictive factor for response to lapatinib in combination
with capecitabine (abstract #1102)
Early markers of response:
–
Lapatinib-induced reductions in pAKT were associated with response in inflammatory breast cancer patients
(abstract #10572)
–
Reductions in serum uPA during trastuzumab therapy predicted longer PFS and OS (abstract #1050)
–
Early changes in sKIT and VEGF during sunitinib therapy were predictive of longer OS, PFS and TTP
(abstract #1055)
Circulating tumor cells (CTCs) are becoming established as prognostic in breast cancer of all stages:
–
CTCs ≥5 per 7.5 mL of blood is prognostic of worse OS and PFS in patients with mBC (abstracts #1000,
#1001, #1033, #10544), while very high CTCs (≥100) are an “oncologic emergency” (abstract #1094).
Patients with high CTCs require more aggressive therapy.
–
CTCs predict higher risk of recurrence after adjuvant therapy in patients with early breast cancer (abstracts
#579, #1003)
–
CTC enumeration should become a standard part of disease assessment, but more sensitive methods of
detection are required
page 28
CONFIDENTIAL
Ovarian cancer
• There are no validated molecular biomarkers in epithelial ovarian cancer which correlate
with prognosis or chemosensitivity – `biomarkers’ is “an abused 10-letter word”
• BRCA protein expression appears to be prognostic in patients with ovarian cancer
–
Patients with BRCA-associated ovarian cancer have better survival than those with sporadic
disease. Additionally, those with BRCA2 mutations appear to live longer than those with
BRCA1 mutations, possibly due to greater platinum sensitivity? (abstract #5017)
–
Among patients with BRCA1-positive ovarian tumors, those who were carriers of
polymorphisms in BRCA1 had significantly worse OS than non-carriers (abstract #5019)
–
Patients with sporadic ovarian cancer and low BRCA1 expression had longer PFS than
those with high BRCA1 expression (abstract #5018)
–
A “BRCA-ness” gene profile was found to identify a subset of patients with sporadic ovarian
cancer who had an improved outcome. The profile also appeared to correlate with
responsiveness to platinum therapy and PARP inhibitors (abstract #5004)
–
Need to develop and easy and reliable test to determine if a patient has high BRCA (treat
with PARP inhibitors?)
• The KRAS-variant (variation in the allele at rs61764370) predicts an increased risk of
developing ovarian cancer and a worse outcome
–
The variant was found in 30% of patients with BRCA-positive tumors and 61% of those with
BRCA-negative hereditary ovarian cancers in a case control study. In addition, presence of
the KRAS variant appeared to be associated with worse outcome in patients aged ≥60 years
(abstract #5016)
–
These findings need to be validated in larger patient cohorts
page 29
CONFIDENTIAL
Headline news by tumor type
page 30
CONFIDENTIAL
Non-small cell lung cancer
• A new paradigm for treating advanced NSCLC in the elderly was provided by
combined monthly carboplatin with weekly paclitaxel (abstract #2)
–
The combination was shown to be superior to single-agent treatment with vinorelbine or
gemcitabine, with longer PFS, OS and a higher response rate reported
–
The study confirms that age (per se) should not be used as a criteria to choose
chemotherapy
• Identification of driver mutations may result in treatments that negate the impact of
those drivers
–
Treatment with crizotinib in patients with no history of smoking and NSCLC with ALK fusions
resulted in an ORR of 57% and a disease control rate of 87%. Response durations lasted
from 1 to 15 months (abstract #3)
• C-met inhibitors showed promising clinical efficacy in NSCLC (abstracts #LBA7502
and #3017)
–
Addition of ARQ-197 to erlotinib prolonged PFS (median 16.1 weeks vs 9.7 weeks) in
previously treated patients naïve to EGFR-targeted therapy. Improvements in PFS and OS
were most pronounced in patients with non-squamous disease
» Benefits in EGFR wild-type and KRAS mutation-positive tumors were observed
» But delegates were concerned that there were a number of lost opportunities to conduct tumor biopsy
and imaging correlative studies to identify targets, mechanisms of resistance and predictors of
response
–
A degree of clinical activity was observed after treatment of XL184 and erlotinib in patients
with previously treated advanced NSCLC
» Study population included patients with EGFR T790M mutations and MET amplified tumors
page 31
CONFIDENTIAL
Non-small cell lung cancer
• Disappointing phase III results for the IGF-1R inhibitor figitumumab (abstract
#7500)
– Addition of figitumumab to standard chemotherapy regimen of paclitaxel and
carboplatin did not improve OS in advanced non-adenocarcinoma NSCLC
– AEs of figitumumab (including infection, hemorrhage, and renal failure)
undermine the benefit of the treatment
– The levels of free IGF-1 play a crucial role in the decision to use figitumumab
» It is unclear whether baseline levels of free IGF-1 should be used as a biomarker for
toxicity or efficacy
• Discussant Ross Camidge doubted that similar IGF-1R inhibitors would result
in different outcomes and he did not believe that avoiding patients with nonadenocarcinoma would be the only answer
• Disappointing results were also presented for the DR4 agonist
mapatumumab in a phase II study (abstract LBA7501)
– Addition of mapatumumab to paclitaxel and carboplatin did not provide any
benefit in patients with advanced NSCLC
– Fatigue, nausea and alopecia were commonly reported AEs. The AE profile was
similar between treatment groups
page 32
CONFIDENTIAL
Non-small cell lung cancer
Strengths
Weaknesses
Platinum-based doublets remain standard therapy for
advanced disease
A lack of prospective pharmacogenomic-driven trials continue to
lead to negative results of phase III studies of targeted therapy
Several targeted agents show efficacy in advanced
disease
Diagnostic test needed for free IGF-1
Prognostic and predictive biomarkers are evolving
rapidly and beginning to allow personalized treatment,
e.g. mutations in EGFR, Kras or ALK, RRM1 and
ERCC1 overexpression
Biomarkers needed for anti-angiogenesis
PFS as an endpoint is subjective, with variable definitions; use of
disease stability is not a good endpoint in the presence of severe
toxicity
Limited randomized data for cancer vaccines for NSCLC (e.g, LBLP25, TGF-b, and TG4010)
Opportunities
Threats
Adjuvant use of biologics
Crizotinib (c-MET/ALK inhibitor in EML4-ALK mutant NSCLC; in
phase III development)
Effective therapies for EML4-ALK mutant, EGFR wildtype, and KRAS mutant subgroups of NSCLC are
needed
Therapies that can be used across multiple
histological subtypes are needed
Other c-MET inhibitors (XL184, MGCD265, TAK701)
Agents that overcome resistance to EGFR inhibitors (PF299804,
BIBW2992 and HSP inhibitors)
Combination therapies to overcome resistance to
EGFR inhibitors are needed (for example: c-MET
inhibitors + EGFR inhibitors)
page 33
CONFIDENTIAL
Non-small cell lung cancer – agents in phase III
Angiogenesis inhibitors
c-Met/ALK inhibitors
Cytotoxic agents
• Aflibercept
• Crizotinib
• Canfosfamide
• BIBF 1120
• Paclitaxel poliglumex
• Cediranib
Immunostimulants
• Motesanib
• Astuprotimut-R
• Sorafenib
• Belagenpumatucel-L
• Vadimezan
• Emepepimut-S
• Sunitinib
• Racotumomab
• Talactoferrin alfa
HER pathway inhibitors
• BIBW 2992
• Necitumumab
• PF 299804
page 34
CONFIDENTIAL
Non-small cell lung cancer – agents in phase II
Angiogenesis inhibitors
c-MET/HGF inhibitors
Death receptor agonists
• Alacizumab pegol
• MetMab
• Conatumumab
• Axitinib
• MGCD 265
• Dulanermin
• Bavituximab
• SCH 900105
• Mapatumumab
• CT 322
• XL 184
• Fosbretabulin
HSP90 inhibitors
• ORA 101
HER pathway inhibitors
• Retaspimycin
• Pazopanib
• Canertinib
• STA 9090
• Ramucirumab
• Icotinib
• Tivozanib
• Neratinib
mTOR inhibitors
• Volociximab
• BMS 690514
• Ridaforolimus
• WST 11
• XL 647
• Salirasib
IGF-1R inhibitors
• Cixutumumab
page 35
CONFIDENTIAL
Non-small cell lung cancer – agents in phase II, cont.
CTLA-4 inhibitors
Cytotoxic agents
• Ipilimumab
• BI 2536
• Tremelimumab
• EC 145
• KOS 1584
Apoptosis stimulants
• Patupilone
• Bortezomib
• Plinabulin
• Sagopilone
page 36
CONFIDENTIAL
Colorectal cancer
• EGFR-targeted agents do not appear to be effective in stage III disease (abstracts
#CRA3507) and may even drive chemotherapy resistance in patients with KRAS
mutated tumors (#3508)
– Surprising negative results from the large NNCTG N0147 phase III study of
cetuximab plus mFOLFOX6
» Presenter suggested that this may be because of decreased tolerance with
cetuximab resulting in a reduction in chemotherapy dose intensity
– However, Discussant Louis M. Weiner had a more interesting theory
» He described the process of epithelial-mesenchymal transition, during which
malignant epithelial cells temporarily lose their epithelial biomarkers until
they have fully metastasized at distant sites, and postulated that during
stage III, when micrometastasis begins, tumor cells are less sensitive to
cetuximab because the EGFR target has “temporarily gone into hiding”
• Subanalyses of randomized phase III studies of first-line panitumumab + FOLFOX4
and second-line panitumumab + FOLFIRI in patients with mCRC were presented:
– G2–4 rash was associated with improved ORR, PFS and OS compared with
grade 0–1 rash (abstracts #3528 and #3529)
– Expression of EGFR (by IHC) was not predictive of response to panitumumab
(abstracts #3566 and #3565)
page 37
CONFIDENTIAL
Colorectal cancer
• There are no conclusive answers on the role of bevacizumab in maintenance
therapy
–
Results were inconclusive from the phase III MACRO trial, designed to assess whether
maintenance therapy with single-agent bevacizumab is as effective as XELOX-bev after 6
cycles of induction XELOX-bev in patients with mCRC (abstract #3501)
» A priori-specified non-inferiority could not be statistically confirmed, but there were no major
differences between treatment arms in response rates, PFS (1°endpoint) or OS
» More SAEs with single-agent bevacizumab
» David Olsen (Memorial Sloan Kettering) asked how the results from this study could be interpreted
when there wasn’t a no-treatment arm, given the brief time that patients received maintenance therapy
(median 3 cycles)? He remarked, “Bevacizumab is very expensive compared with no treatment at all”
» Discussant Dr Alan Venook stated that we still do not have conclusive answers about the role of
bevacizumab in maintenance therapy, and that we need to “go back to the drawing board”
» Results of other studies of maintenance bevacizumab are awaited with interest (DREAM, CAIRO-3,
AIO-ML21768)
• Phase II data presented for:
–
Novel agents: GDC-0449 (Genentech), perifosine (AEterna)
» However, a recent press release (dated 16 Jun 2010) announced that a phase II trial of first-line GDC0449 in combination with bevacizumab and FOLFOX or FOLFIRI in patients with metastatic CRC
failed to meet the primary endpoint of PFS. It appears that development of this agent will no longer
continue in CRC.
–
page 38
Combinations of targeted therapies: sunitinib + bevacizumab, cetuximab + erlotinib,
bevacizumab + everolimus, E7820 + cetuximab, motesanib + panitumumab
CONFIDENTIAL
Colorectal cancer
Strengths
Weaknesses
Biomarkers predictive of response to adjuvant therapy
for stage II disease validated and moving into the clinic:
MSI/MMR, Oncotype DX
Other than KRAS mutation testing, no predictive biomarkers
to identify responders to targeted therapies identified so far
Detection of predictive and prognostic markers
recommended by treatment guidelines
Good phase II results often do not translate into success at
phase III
Limited regulatory approval based on tumor genotype
Opportunities
Threats
Identification of patient subpopulations most likely to
respond to targeted therapies
Agents in phase III development: aflibercept, cediranib,
erlotinib, sunitinib
Identification of new targeted therapies for stage II and III
disease
A number of targeted agents in phase II development
Identification of effective combinations of targeted
therapies with manageable tolerability
Effective therapies for KRAS-mutant CRC
Effective therapies for BRAF-mutant CRC
EGFR-targeted therapies appear to be ineffective in
stage III disease
page 39
CONFIDENTIAL
Colorectal cancer – agents in phase III
Angiogenesis inhibitors
Immunostimulants
• Aflibercept
• AMT 2003*
• Brivanib alaninate
• Cediranib
Apoptosis stimulants
• Ursodeoxycholic acid
BRAF inhibitors
• Regorafenib
HER pathway inhibitors
• Erlotinib
AKT/MAPK/PI3K/JNK
inhibitors
• Perifosine
* Phase II/III
page 40
CONFIDENTIAL
Colorectal cancer – agents in phase II
Angiogenesis inhibitors
IGF-1R inhibitors
Death receptor agonists
• AMG386
• AMG 479
• Conatumumab
• Axitinib
• Cixutumumab
• Tigatuzumab
• BIBF 1120
• Dalotuzumab
• IMC 18F1
• F 50035
PPAR-gamma agonists
• Linifanib
• Figitumumab
• CS 7017
• NGR-TNF
• Robatumumab
• Ramucirumab
• Recombinant human
endostatin
HER pathway inhibitors
PI3K inhibitors
• BIBW 2992
• Enzastaurin
• Lapatinib
• Sorafenib
• Sunitinib
• Vandetanib
page 41
• Necitumumab
MAPK inhibitors
• Selumetinib
CONFIDENTIAL
• Nimotuzumab
Colorectal cancer – agents in phase II, cont.
c-MET/HGF inhibitors
Other targeted agents
Immunostimulants
• AMG 102
• Adecatumumab (antiEpCAM mAb)
• NAcGM3-VSSP vaccine
PARP inhibitors
• Olaparib
• Veliparib
HSP90 inhibitors
• STA 9090
• CT 011 (anti-PD-1 mAb)
• DRF 7295 (signal
transduction modulator)
•GDC 0449 (Hedgehog
pathway agonist)
• Labetuzumab I-131 (antiCEA mAb)
• Resveratrol (SIRT1 protein
stimulant)
HDAC inhibitors
• Panobinostat
• Sodium phenylybutyrate
page 42
• Sibrotuzumab (FAPα
antagonist)
• Tremelimumab (CTLA4
inhibitor)
CONFIDENTIAL
• OncoVax®
• PGG glucan
• PV 701
• TroVax®
• Vitespen
Apoptosis stimulants
• Aviscumine
• Ispinesib
• LOR 2040
• TAS 109
Colorectal cancer – agents in phase II, cont.
Cytotoxic agents
• AR 726
• EZN 2208
• Fosfluridine tidoxil
• Hyaluronan irinotecan
• Irinotecan/floxuridine
• mAb TNT-1
• Nanoliposomal vinorelbine
• NKTR 102
• Paclitaxel poliglumex
• Picoplatin
• TAS 102
• TNF-α gene therapy
• TP 300
page 43
CONFIDENTIAL