asco 2010 final report (edited) -...

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ASCO 2010Competitor Intelligence Report

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� 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

ASCO 2010 coverage by Wolters Kluwer Health

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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

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ARQ-197 (c-MET inhibitor)

Key findings relevant to

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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– 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 mutation-positive 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.

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ARQ-197Agent 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.

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ARQ-197Agent 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.

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C-Met inhibitorsAgent 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.

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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)

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).

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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)

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.

TAK-701(Millennium)

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.

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ARQ197 upstream competitorsAgent 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)

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.

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CS-1008 (Anti-DR5 mAb)

Key findings relevant to

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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

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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� Radiotherapy or chemoradiotherapy in radiation-sensitive tumor types

� Agents that activate the intrinsic apoptosis pathway, such as camptothecins or Bcl2 inhibitors (ongoing trials of CS-1008 in combination with irinotecan in colorectal cancer may be informative)

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Death receptor 4 agonistsAgent Data presented and buzz

Dulanermin (Amgen/ Genentech)

DR 4 and 5 agonist

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).

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)

DR 4 agonist

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).

“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.”

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Conatumumab (Amgen)

DR 5 agonist

Conatumumab is currently in phase II trials for CRC, NSCLC, lymphoma, sarcoma.

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 non-squamous), CRC, pancreatic, ovarian and sarcoma. Primary endpoint is ORR.

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DrozitumabPRO95780, Apomab (Genentech)

DR 5 agonist

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).

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

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.

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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 be nefit from PARP inhibition

» “Very promising” activity has been observed in combination with DNA-damaging 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)

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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.

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PARP inhibitorsAgent 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)

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(AstraZeneca)

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).

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PARP InhibitorsAgent 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.

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Predictive/prognostic biomarkers

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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

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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)

» 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

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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

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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)

CONFIDENTIALpage 27

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 1-year 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)

CONFIDENTIALpage 28

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

CONFIDENTIALpage 29

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

CONFIDENTIALpage 30

Headline news by tumor type

CONFIDENTIALpage 31

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

CONFIDENTIALpage 32

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 non-adenocarcinoma 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

CONFIDENTIALpage 33

Strengths

Platinum-based doublets remain standard therapy for advanced disease

Several targeted agents show efficacy in advanced disease

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

Weaknesses

A lack of prospective pharmacogenomic-driven trials continue to lead to negative results of phase III studies of targeted therapy

Diagnostic test needed for free IGF-1

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, L-BLP25, TGF-b, and TG4010)

Opportunities

Adjuvant use of biologics

Effective therapies for EML4-ALK mutant, EGFR wild-type, and KRAS mutant subgroups of NSCLC are needed

Therapies that can be used across multiple histological subtypes are needed

Combination therapies to overcome resistance to EGFR inhibitors are needed (for example: c-MET inhibitors + EGFR inhibitors)

Threats

Crizotinib (c-MET/ALK inhibitor in EML4-ALK mutant NSCLC; in phase III development)

Other c-MET inhibitors (XL184, MGCD265, TAK701)

Agents that overcome resistance to EGFR inhibitors (PF299804, BIBW2992 and HSP inhibitors)

Non-small cell lung cancer

CONFIDENTIALpage 34

Non-small cell lung cancer – agents in phase III

Angiogenesis inhibitors

• Aflibercept

• BIBF 1120

• Cediranib

• Motesanib

• Sorafenib

• Vadimezan

• Sunitinib

HER pathway inhibitors

• BIBW 2992

• Necitumumab

• PF 299804

c-Met/ALK inhibitors

• Crizotinib

Immunostimulants

• Astuprotimut-R

• Belagenpumatucel-L

• Emepepimut-S

• Racotumomab

• Talactoferrin alfa

Cytotoxic agents

• Canfosfamide

• Paclitaxel poliglumex

CONFIDENTIALpage 35

Non-small cell lung cancer – agents in phase II

Angiogenesis inhibitors

• Alacizumab pegol

• Axitinib

• Bavituximab

• CT 322

• Fosbretabulin

• ORA 101

• Pazopanib

• Ramucirumab

• Tivozanib

• Volociximab

• WST 11

• XL 647

c-MET/HGF inhibitors

• MetMab

• MGCD 265

• SCH 900105

• XL 184


• Canertinib

• Icotinib

• Neratinib

• BMS 690514

IGF-1R inhibitors

• Cixutumumab

Death receptor agonists

• Conatumumab

• Dulanermin

• Mapatumumab

HSP90 inhibitors

• Retaspimycin

• STA 9090

mTOR inhibitors

• Ridaforolimus

• Salirasib

CONFIDENTIALpage 36

Non-small cell lung cancer – agents in phase II, con t.

CTLA-4 inhibitors

• Ipilimumab

• Tremelimumab

Apoptosis stimulants

• Bortezomib

Cytotoxic agents

• BI 2536

• EC 145

• KOS 1584

• Patupilone

• Plinabulin

• Sagopilone

CONFIDENTIALpage 37

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)

CONFIDENTIALpage 38

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 GDC-0449 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.

– Combinations of targeted therapies: sunitinib + bevacizumab, cetuximab + erlotinib, bevacizumab + everolimus, E7820 + cetuximab, motesanib + panitumumab

CONFIDENTIALpage 39

Strengths

Biomarkers predictive of response to adjuvant therapy for stage II disease validated and moving into the clinic: MSI/MMR, Oncotype DX

Detection of predictive and prognostic markers recommended by treatment guidelines

Weaknesses

Other than KRAS mutation testing, no predictive biomarkers to identify responders to targeted therapies identified so far

Good phase II results often do not translate into success at phase III

Limited regulatory approval based on tumor genotype

Opportunities

Identification of patient subpopulations most likely to respond to targeted therapies

Identification of new targeted therapies for stage II and III disease

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

Threats

Agents in phase III development: aflibercept, cediranib, erlotinib, sunitinib

A number of targeted agents in phase II development

Colorectal cancer

CONFIDENTIALpage 40

Colorectal cancer – agents in phase IIIAngiogenesis inhibitors

• Aflibercept

• Brivanib alaninate

• Cediranib

BRAF inhibitors

• Regorafenib


• Erlotinib

AKT/MAPK/PI3K/JNK inhibitors

• Perifosine

Immunostimulants

• AMT 2003*


• Ursodeoxycholic acid

* Phase II/III

CONFIDENTIALpage 41

Colorectal cancer – agents in phase IIAngiogenesis inhibitors

• AMG386

• Axitinib

• BIBF 1120

• IMC 18F1

• Linifanib

• NGR-TNF

• Ramucirumab

• Recombinant human endostatin

• Sorafenib

• Sunitinib

• Vandetanib

IGF-1R inhibitors

• AMG 479

• Cixutumumab

• Dalotuzumab

• F 50035

• Figitumumab

• Robatumumab

PI3K inhibitors

• Enzastaurin

MAPK inhibitors

• Selumetinib

Death receptor agonists

• Conatumumab

• Tigatuzumab

PPAR-gamma agonists

• CS 7017


• BIBW 2992

• Lapatinib

• Necitumumab

• Nimotuzumab

CONFIDENTIALpage 42

Colorectal cancer – agents in phase II, cont .c-MET/HGF inhibitors

• AMG 102

PARP inhibitors

• Olaparib

• Veliparib

HSP90 inhibitors

• STA 9090

HDAC inhibitors

• Panobinostat

• Sodium phenylybutyrate

Other targeted agents

• Adecatumumab (anti-EpCAM mAb)

• CT 011 (anti-PD-1 mAb)

• DRF 7295 (signal transduction modulator)

•GDC 0449 (Hedgehog pathway agonist)

• Labetuzumab I-131 (anti-CEA mAb)

• Resveratrol (SIRT1 protein stimulant)

• Sibrotuzumab (FAPαantagonist)

• Tremelimumab (CTLA4 inhibitor)

Immunostimulants

• NAcGM3-VSSP vaccine

• OncoVax®

• PGG glucan

• PV 701

• TroVax®

• Vitespen


• Aviscumine

• Ispinesib

• LOR 2040

• TAS 109

CONFIDENTIALpage 43

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

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