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Pharmaceutical and Biotech News


19 January 2012

Data from the Phase 3 study of regorafenib (BAY 73-4506) in metastatic colorectal cancer 

Onyx Pharmaceuticals, Inc. and Bayer HealthCare announced results from the  Phase 3 CORRECT clinical study from the investigational compound regorafenib (BAY 73-4506) in metastatic colon cancer.

Regorafenib (BAY 73-4506) is a multikinase inhibitor that binds to and inhibits VEGFR-2 and -3, and tumor cell signaling kinases including RET, KIT, PDGFR, and Raf.  This activity inhibits tumor angiogenesis and tumor cell proliferation.

The CORRECT trial is an international, multicenter, randomized, double-blind, placebo-controlled study that enrolled 760 patients with mCRC whose disease has progressed after approved standard therapies. Patients were randomized to receive either regorafenib plus best supportive care (BSC) or placebo plus BSC. Treatment cycles consisted of 160 mg of regorafenib (or matching placebo) once daily for three weeks on / one week off plus BSC. The primary endpoint of this trial was overall survival. Secondary endpoints included progression-free survival, objective tumor response rate and disease control rate. The safety and tolerability of the two treatment groups were also compared.

The CORRECT study was unblinded in late 2011 by the recommendation of an independent Data Monitoring Committee following a pre-planned interim analysis that determined that the regorafenib arm showed significant improvement in overall survival.  The patients on the placebo arm were offered treatment with regorafenib.

The study met its primary endpoint, showing statistically significant improvement in overall survival (OS) by 29% (HR=0.77, p=0.0052, median OS: 6.4 months vs. 5.0 months for the placebo group). Additionally, findings from the secondary endpoints of the CORRECT study showed statistically significant improvement in progression-free survival (PFS) (HR=0.49, p<0.000001, median PFS: 1.9 months vs. 1.7 months) and an improvement in disease control rate (44.8% vs. 15.3%) in patients treated with regorafenib compared to those treated with placebo. The difference in objective response rate between the two arms (1.0% vs. 0.4%) did not reach statistical significance. The most common drug-related treatment-emergent adverse events included fatigue (47.4% vs. 28.1%), hand-foot skin reaction (46.6% vs. 7.5%), diarrhea (33.8% vs. 8.3%), anorexia (30.4% vs. 15.4%), hypertension (27.8% vs. 5.9%), oral mucositis (27.2% vs. 3.6%) and rash/desquamation (26.0% vs. 4.0%) for patients receiving regorafenib as compared to placebo.

According to the public releases, Bayer plans to submit regorafenib for marketing authorization in mCRC in 2012. In the US, the potential market is approximately 15,000 metastatic colorectal cancer patients who fail treatment with Avastin, Erbitux or Vectibix.


June 21, 2011

Positive data in a Phase 2 study with Roche's Vismodegib in advanced basal cell carcinoma (BCC)

The reason for including a brief analysis of these data of a phase 2 study (although the company is describing the study as "pivotal") is because of the compound being tested.  Vismodegib is a small molecure inhibitor of the Hedgehog pathway, a pathway involved in the tumorigenesis and a target in advanced malignancies.

The phase 2 study was a multicenter, open label, single arm, uncontrolled clinical trial.  The study enrolled 104 patients with advanced BCC including 71 patients with locally advanced BCC and 33 patients with metastatic BCC (mBCC).  The principal endpoint was objective response.  The study demonstrated that vismodegib substantially shrank tumors or healed visible lesions in 43% of patients with locally advanced BCC and 30% of patients with metastatic BCC. The median duration of progression-free survival (PFS) was 9.5 months. Since the study has been uncontrolled, it is really difficult to objectively evaluate these results.  One would have to wait for more advanced, fully controlled studies to estimate the possible utility of vismodegib.

June 14, 2011

Micromet's Blinatumomab Produces High Single-Agent Activity in Patients with Relapsed Acute Lymphoblastic Leukemia

Usually, I do not cover early studies (Phase 1 and 2).  But I am somewhat partial to Micromet's BiTE antibody technology, and these early results have captured my attention.  BiTE stands for "Bi-specific T-cell Engagers" and describes antibodies that bind to specific targets on malignant cells and also to the CD3 receptor of T-cells, sequestering them to the site of the tumor or type of cell/

Blinatumomab (MT103) is a BiTe antibody binds to the CD19 receptor of B-cells and to the CD3 receptor of T-cells.  It is being investigated in non-Hodskins Lymphoma, in acute lymphoblastic leukemia (ALL), in lung and gastrointestinal cancers.  The recent announcement concerned interim results of a phase 2 trial in relapsed ALL.  The study is expected to enroll 25 patients.  It is investigating the effects of two doses 15 and 30 μg/m²/day by continuous intravenous infusion.  The interim results, 9 of 12 patients showed either full or full hematologic remission (CR or CRh).  Of the patients in this study, 4 with genotypes associated with poor outcome, achieved full (CR or CRh) remission.

May 6, 2011

Overall Survival Benefit in the Intergroup Phase III Study (CALGB 100104) of Revlimid® (Lenalidomide) As Continuous Therapy for Patients with Multiple Myeloma following Autologus Stem Cell Transplantation

Revlimid® (lenalidomide) is a derivative of thalidomide marketed by Celgene for the treatment of previously treated patients with multiple myeloma and patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q abnormality. It is not indicated for patients newly diagnosed with multiple myeloma.

Researchers in the Cancer and Leukemia Group B (CALGB) -a research group sponsored by the National Cancer Institute- announced data from the ongoing study of Revlimid® as continuous therapy in myeloma (CALGB 100104) at the 2011 International Myeloma Workshop in Paris, France.

The Phase 3 CALGB 100104 clinical trial is a randomized, double-blind study of maintenance therapy with Lenalidomide (CC 5013) or placebo following autologous stem cell transplantation (ASCT) for multiple myeloma.  The study accessed 568 patients in 46 investigative sites. The independent Data and Safety Monitoring Committee (DSMC) conducted a planned interim analysis in November 2009 which included 418 pts, 210 randomized to lenalidomide and 208 to placebo. This analysis led to the announcement the study had met its primary endpoint and was subsequently unblinded. The data reported in Paris are derived from a continuing analysis of the subjects post-unblinding through April 2011.

As of April 2011, at a median follow-up of 28 months, patients receiving continuous lenalidomide following ASCT demonstrated a statistically significant improvement in overall survival (OS), with an OS rate of 90% (208/231) compared to 83% (190/229) for patients randomized to receive placebo (unadjusted p=0.018) hazard ratio 0.51 (95% CI = 0.26 to 1.014), despite nearly 80% (86/110) of patients crossing over to receive continuous lenalidomide at the time of study unblinding. Additional analyses of the original OS data at time of study unblinding demonstrated an OS rate of 94% (218/231) in the continuous lenalinomide arm compared to 89% (204/229) in the placebo arm (p=0.05). At a median follow-up of 28 months, the median time to progression (TTP) was significantly higher for the lenalidomide arm at 48 months versus the median TTP of 30.9 months for the placebo arm (p<0.0001) HR 0.44 (95% CI = 0.32 to 0.60). This translated to a 56% reduction in the risk of disease progression in the lenalidomide arm.

In prospectively defined subgroup analyses, TTP was significantly higher in all subgroups of patients that received continuous lenalidomide post ASCT. Within these subgroups TTP was longest in the group of patients that received lenalidomide both as induction therapy and continuous therapy following ASCT. Also, at a median follow-up of 28 months, the median event-free survival for patients in the lenalidomide arm was 43.4 months, versus 30.9 months in the placebo arm (p<0.0001) with an estimated HR of 0.51 (95% CI = 0.38 to 0.68) In this Phase III, controlled, double-blind, multi-center study, newly diagnosed multiple myeloma patients who achieved at least stable disease (SD) following autologous stem cell transplant (ASCT) were randomized to receive continuous daily treatment with lenalidomide 10 mg (n=231) or placebo (n=229) until relapse.

The most common grade 3-4 adverse events experienced by patients receiving lenalidomide or placebo in the study were neutropenia (43% 89/208 vs. 9% 17/197), thrombocytopenia (13% 26/208 vs. 4% 7/197) and infections (16% 33/208 vs. 5% 11/197). There were no grade 5 hematologic adverse events. The rate of grade 5 non-hematologic adverse events was similar between the two arms of the study (1% 3/208 vs. 2% 3/197). An increase in second primary malignancies (SPMs), mainly hematological malignancies, was observed in patients receiving lenalidomide compared to patients receiving placebo. However, the event free survival analysis, where SPM was included as an event, in addition to death and progression, demonstrated that there was no significant impact of SPMs on the observed TTP or OS benefit.

In addition to data from the CALGB 100104 study, Celgene announced data from additional studies of lenalinomide in multiple myeloma as well as a combined analysis of the use of lenalidomide as maintenance treatment in this disease.

March 14, 2011

Aflibercept Fails as 2nd-Line Treatment in Combination with Docetaxel of Non-Small Cell Lung Cancer

Aflibercept, developed jointly by Regeneron Pharmaceuticals  and Sanofi-Aventis, is a fusion protein  that combines portions of human VEGFR1 and VEGFR2 [Vascular Endothelial Growth Factor (VEGF) Receptors] and the constant region of human IgG1.  This fusion protein was designed as an inhibitor of VEGF in blood and in the extravascular space. The efficacy of this molecule in lung cancer was investigated in a Phase 3 study.  The primary objective of the study (called VITAL) was to determine if  overall survival for aflibercept + docetaxel was superior to that of docetaxel + placebo when applied as second line treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC).  At least 900 subjects were to be enrolled in both arms of this study.  Top line results indicated that the study did not achieve pre-specified criteria for the primary endpoint of improvement in overall survival.  The companies stated that the addition of aflibercept to docetaxel demonstrated activity as measured by key secondary endpoints of the study: progression free survival (PFS) (HR=0.82, CI: 0.716 to 0.937) and an overall objective response rate (ORR) of 23.3% (utilizing RECIST criteria) in the aflibercept arm compared to 8.9 percent in the placebo arm.  It should be noted that PFS has been shown not to correlate very well with overall survival, and it should not be taken as an indicator of efficacy in most cases.  Aflibercept is also been tested as first- and second-line treatment in metastatic colorectal cancer and as a first line treatment in hormone-resistant, metastatic prostate cancer.

March 10, 2011

BioSante's Pancreatic Cancer Vaccine Prolongs Survival in a Phase II Study

The pancreatic GVAX vaccine by BioSante is a member of similar vaccines developed by this company for an array of cancers such as prostate, breast, pancreatic, colorectal cancers, leukemia and melanoma.  GVAX (granulocyte-macrophage colony-stimulating factor [GM-CSF] gene transduced irradiated cancer cells) offers the possibility of a "host versus cancer" immune responses possibly generated in patients receiving the vaccine.  The theory behind these vaccines that the GM-CSF expressed by the vaccined cells would induce the activation dendritic cells and antigen presentation to both the B-cell and T-cell arms.  As such, these vaccines are similar to Dendreon's Provenge which is approved by the FDA.

The study that BioSante is touting as showing that its GVAX vaccine extents survival in pancreatic cancer was a single-center, uncontrolled, non-randomized phase II study performed at the Sidney Kimmel Comprehensive cancer center.  It accessed sixty (60) patients diagnosed with stage I or II of pancreatic adenocarcinoma.  The vaccine was given in combination with chemoradiotherapy.  The median disease-free survival of patients was 17.3 months (95% CI, 14.6–22.8) with median survival of 24.8 months (95% CI, 21.2–31.6). The administration of immunotherapy was well tolerated.

Despite BioSante's positive message here about the vaccine, this open-label, non-randomized, single-center study cannot really serve an indication that the vaccine is efficacious. Such studies are not good foundations for a Phase 3 progam. Considering the extent of efficacy of the Provenge in advanced, metastatic prostate cancer, it is likely that the vaccine has similar capabilities.  Obviously, a step forward, but hardly a definitive one when one considers the high costs of these vaccines (taking Provenge as the pricing model).

February 18, 2011

Exelixis Announces  Phase 2 Data for Cabozantinib (XL184) that Show Evidence of Efficacy in Patients with Castration-Resistant Prostate Cancer

Cabozantinib (XL184) is an inhibitor of certain tyrosine kinases, notabaly MET and VEGFR2.  Mutated, overexpressing and highly active versions of these receptor tyrosine kinases contribute to angiogenesis, proliferation and metastasis of malignant cells. Partial data from an open-label, adaptive discontinuation Phase 2 study in patients diagnosed with castration-resistant prostate cancer were announced in the ASCO Genitourinary Cancers  2011 Symposium in Orlando, FL.  The study examined the effect of this drug on metastatic bone lesions that are very painful. The subjects received cabozantinib orally for 12 weeks.   In the preliminary analysis, of the 72 patients enrolled, 63 had bone scans.  Of these, 52 (85%)  showed partial or full response in metastatic bone lessions by RECIST criteria (assessement performed by independent radiologists).  Also, the majority of patients with anemia showed increases in hemoglobin during the study. The patients received cabozantinib orally for 12 weeks.  [The reason that this announcement is included here is because the information provided by the company is difficult to decode. In an adaptive discontinuation study, patients are administered the experimental treatment immediately after enrollment.  Those that respond to treatment are then randomized to either continue receiving the experimental treatment or to placebo.  The data announced probably refer to the pre-randomization assessment, but a direct statement was not included.  In any case, such studies result in the enrichment of responsive study population and their results should be interpreted with caution] Cabozantinib is being studied in a variety of other malignancies including medullary thyroid cancer, non-small cell lung cancer, gliobalstoma multiforme and others.

January 21, 2011

Plexxikon's/Genentech's  PLX4032 Meets Overall Survival and Progression-Free Endpoint for Melanoma Patients in  Phase 3 Trial Study

 PLX4032 is a B-RAF inhibitor that disrupts the B-Raf/MEK step on the B-Raf/MEK/ERK pathway if the B-RAF contains the V600E mutation common in melanoma patients.  PLX4032 is being co-developed by Plexxikon and Genentech/Roche.

Plexxikon Inc. today announced positive data from an interim analysis of the BRIM3 trial, a large multi-center Phase 3 clinical study of PLX4032 (RG7204) in patients with previously untreated metastatic melanoma with the common B-RAF V600E mutation.  The BRIM3 analysis showed that the study met the pre-specified criteria for co-primary endpoints of overall survical (OS) and progression-free survival (PFS). Patients treated with PLX4032 had an improved OS compared to patients treated with dacarbazine, the current standard of care. In addition, these patients showed increased PFS. It should be noted that having OS and PFS as co-primary endpoints is very important in melanomal studies, as PFS is highly influenced in this cancer by a high spontaneous remission rate.  The safety profile was generally consistent with the previous PLX4032 studies. Based on these results, patients on the dacarbazine arm of the study will have the option to crossover to receive PLX4032. Additionally, an Expanded Access Program also will now be opened to previously untreated melanoma patients with the BRAF mutation.   Combination trials with PLX4032, as well as trials in other BRAF-mutated cancers, are also planned.

 January 19, 2011

ARIAD's Ridaforolimus Prolongs Progression-Free Survival in Patients with Metastatic Soft-Tissue or Bone Sarcomas:

Ridaforolimus, co-developed by Merck and Ariad Pharmaceuticals, Inc., is is a targeted small-molecule inhibitor of the protein mTOR. mTOR, a popular target of anti-neoplastic drugs, acts as a central regulator of protein synthesis, cell proliferation, cell cycle progression and cell survival. 

The Phase 3 clinical study (named SUCCEED) is examining the effect of ridaforolimus treatment in progression-free survival (PFS) in patients with metastatic soft-tissue or bone sarcomas who demonstrated a favorable response to prior conventional chemotherapy. In this multicenter, randomized (1:1), double-blind, placebo controlled study, oral ridaforolimus ws administered at 40 mg/day (five of seven days/week)

Analysis of 552 progression events in  711 patients, performed by an independent review committee showed that the study met its primary endpoint, with a statistically significant  28% (p=0.0001)reduction by ridaforolimus in the risk of progression compared to placebo (hazard ratio=0.72). Determination of median PFS for each arm of the trial demonstrated that ridaforolimus treatment resulted in a statistically significant 21 percent (3.1 week) improvement in median PFS (ridaforolimus, 17.7 weeks vs. placebo, 14.6 weeks). Based on the full analysis of PFS determined by the investigative sites, there also was a statistically significant (p<0.0001) 31 percent reduction by ridaforolimus in the risk of progression compared to placebo (hazard ratio=0.69). Ridaforolimus treatment resulted in a statistically significant 52% (7.7 week) improvement in median PFS (ridaforolimus, 22.4 weeks vs. placebo, 14.7 weeks). The most common side effects observed in the study included stomatitis (e.g., mouth sores), fatigue, diarrhea and thrombocytopenia. This trial remains active, and study participants continue to be followed to gather additional data on secondary endpoints, including overall survival and the safety profile of ridaforolimus. Merck, which is developing this agent in association with ARIAD Pharmaceuticals Inc, currently plans to file for marketing approval of oral ridaforolimus in 2011. 

Ridaforolimus is being developed for a number of other challenging oncology indications.  In October 2010, we reported here interim results from a Phase 2 study in advanced endometiral cancer.

December 20, 2010

FDA Proceeds to Remove the Breast Cancer indication from bevacizumab (Avastin®)

The FDA announced on December 16, 2010 that it is beginning the process to remove from bevacizumab the indication for the treatment of breast cancer.  The agency stated that the review of the results of four clinical studies of Avastin in breast cancer showed that the drug does not prolong overall survival and does not provide a sufficient benefit in slowing disease progression although it does possess significant risks and possible adverse reactions such as severe high blood pressure, bleeding, the development of perforations in the body (including in the nose, stomach, and intestines), and heart attack or heart failure. As we indicated here in a prior posting,  in July 2010, an independent advisory committee voted 12-1 to remove the breast cancer indication from Avastin’s label.   This has not been the only negative assessment of bevacizumab.  The UK-based National Institute of Health and Clinical Excellence (NICE) in a well-documented assessment also found no evidence to support the use of bevacizumab in combination with taxanes in the treatment of breast cancer.  The US FDA process of removing the indication would certainly be lengthy, including consultations with Roche/Genentech.

October 25, 2010

Interim Results from Randomized Phase 2 Trial of Oral Ridaforolimus in Advanced Endometrial Cancer

Ariad Pharmaceuticals announced interim of a randomized, open-label, active-control multicenter Phase 2 study of oral ridaforolimus, in patients with metastatic or recurrent endometrial cancer. Ridaforolimus, developed in association with Merck, is a targeted small-molecule inhibitor of the protein mTOR. mTOR, a popular target of anti-neoplastic drugs, acts as a central regulator of protein synthesis, cell proliferation, cell cycle progression and cell survival.

The interim analysis was based on 114 patients enrolled at 39 sites in North America and Europe. Patients in the trial were randomized to receive either oral ridaforolimus (n=57), or oral progestin (n=48) or chemotherapy (n=9), both standard treatments in patients with advanced endometrial cancer. Progression-free survival (PFS) was determined by evaluating tumor shrinkaged utilizing RECIST criteria based on radiologic studies conducted every two months. An independent review committee evaluated all of the radiologic studies. The interim analysis demonstrated a significant improvement in the study’s primary endpoint, PFS, with a statistically significant 1.7 month difference in median PFS (ridaforolimus, 3.6 months; standard of care, 1.9 months, p=0.007) and a hazard ratio of 0.52.  It should be, however, noted that improvements in PFS often fail to translate to improvements in overall survival (OS), the clinical benefit endpoint utilized in pivotal clinical studies.

The interim analysis also showed that the most common adverse events observed with ridaforolimus were mucositis (38.2%), stomatitis (21.8%) and hyperglycemia (27.3%), which have been observed in previous studies and are considered to be class effects of mTOR inhibitors. Overall, patients treated with ridaforolimus had significantly more serious adverse events (23.6%) than patients treated with the standard of care (3.8%).

August 24, 2010

Pfizer's Sutent® fails to increase overall survival in previously treated patients diagnosed with non-small cell lung cancer (NSCLC):

Sutent® (sunitinib malate) is a multiple receptor tyrosine kinase inhibitor that has been approved for the treatment of kidney cell carcinoma and certain gastrointenstinal stromal tumors. In a Phase III study (SUN 1087) in which the efficacy and safety of sunitib plus erlotinib (Tarceva® - Genentech/OSI Oncology) was compared to that of erlotinib plus placebo, there was no statistical difference in overall survival.  A statistical difference was detected in a secondary endpoint, progression-free survival (PFS).  Patients enrolled in the SUN 1987 study were diagnosed with metastatic or locally advanced NSCLC and had received previous treatment including platinum chemotherapy. 

Sutent® has recently failed in Phase III studies in advanced breast cancer and advanced hepatocellular carcinoma.

August 11, 2010

Amgen's Vectibix fails in a Phase III study in head and neck cancer:

Vectibix (panitumumab injection) is a monoclonal antibody that binds to the epidermal growth factor receptor (EGFR) and inhibits or slows down malignant cell proliferation.  Vectibix was  approved in 2006 by the FDA for the treatment of metastatic colon carcinoma.

Amgen's SPECTRUM study evaluated the safety and efficacy of Vectibix as a first-line treatment in patients with recurrent and/or metastatic squamous cell head and neck cancer. The study accessed 658 patients who were randomized to receive a standard platinum-based chemotherapy (cisplatin and 5-FU), with or without Vectibix (9 mg/kg) every three weeks. The primary endpoint was overall survival. The secondary endpoints included progression-free survival, objective response rate, duration of response, time to progression, time to response, patient reported outcomes and safety.

Analysis of the data showed the addition of Vectibix to platinum-based chemotherapy did not result in a statistically significant improvement in overall survival, the primary endpoint, compared to chemotherapy alone [median 11.1 months versus 9.0 months, hazard ratio 0.87 (95% CI: 0.73, 1.05)]. Therefore, the study did not meet its primary endpoint. Secondary endpoints of progression-free survival [median 5.8 months versus 4.6 months, hazard ratio 0.78 (95% CI: 0.66, 0.92)] and objective response rate (36 percent versus 25 percent) were numerically improved but were not tested for statistical significance.

 The most frequently reported adverse events in the Vectibix plus chemotherapy arm included nausea, rash, neutropenia and vomiting, as anticipated for this combination therapy.

July 27, 2010

Announcement of data from the Phase 2b study in multiple myeloma with Onyx' Carfilzomib

Carfilzomib is a novel, irreversible, epoxomicin-related proteasome inhibitor. Proteasomes are very large protease complexes inside cells that degrade no longer required or damaged proteins.  Proteasome inhibitors induce apoptosis of malignant cells by disrupting the degradation of pro-growth proteins in these cells. 

Onyx's 003-A1 clinical study with carfilzomib was an open-label, single-arm Phase 2b trial. It evaluated 266 heavily-pretreated patients with relapsed and refractory multiple myeloma whose disease did not respond to their last treatment regimen and who had received at least two prior therapies, including bortezomib (another proteasome inhibitor by a reversible one), either thalidomide or lenalidomide, an alkylating agent, glucocorticoids and an anthracycline. Refractory disease was defined as ≤ 25% response or progression during therapy or within 60 days after completion of therapy. Patients enrolled in the trial had received a median of five prior therapeutic regimens, corresponding to a median of 13 anti-myeloma agents. Patients received carfilzomib at 20mg/m2 for the first cycle followed by 27mg/m2 thereafter for up to 12 cycles. Patients who completed the 12 cycles were eligible to enter an extension study. Responses and progression were determined according to the International Myeloma Working Group (IMWG) criteria. 

Following an independent review of the data, carfilzomib achieved an overall response rate (partial response or greater) of 24% and a median duration of response of 7.4 months. The clinical benefit rate (minimal response or greater) in the study population was 36%. Carfilzomib was well-tolerated and there were no new or unexpected toxicities observed.  Onyx announced that based on these results it is continuing discussions with the U.S. Food and Drug Administration (FDA) regarding filing a new drug application (NDA) for carfilzomib, which the company expects to submit by year-end 2010 for potential accelerated approval in the U.S.

July 27, 2010

The FDA's Oncologic Drug Advisory Committee recommends against the approval of Avastin in metastatic breast cancer:

 Bevacizumab (Avastin) is a humanized monoclonal antibody that blocks the vascular endothelial growth factor A (VEGF-A), a compound that stimulates the growth of new blood vessels (angiogenesis). It is approved for the treatment metastatic colon, non-small cell lung and renal cancers. The FDA granted accelerated approval for bevacizumab as first line treatment in metastatic breast cancer but this approval was contingent on additional positive results from ongoing clinical trials.

 In meeting on July 20, the advisory committee voted 12 to 1 to recommend against the use of Avastin in combination with chemotherapy as a first line treatment in metastatic breast cancer.  The data from the additional studies (AVADO and RIBBON1) failed to confirm the data from study E2100 that served as the basis of the original approval in metastatic breast cancer. The additional trials performed by Genentech, together enrolled almost 2,500 women. The women in AVADO were randomly assigned to receive chemotherapy with docetaxel plus placebo or docetaxel plus bevacizumab. The patients in the bevacizumab arm of AVADO had a median improvement in PFS of less than a month. In RIBBON1, patients were assigned at the discretion of their physicians to receive chemotherapy with a taxane, an anthracycline, or capecitabine (Xeloda). Within those three groups, the researchers randomly assigned women to receive additional bevacizumab or a placebo. The improvement in PFS was minor: just 1.2 months in the taxane and anthracycline groups and 2.9 months in the capecitabine group. In both trials, the bevacizumab groups exhibited an increased risk of death. According to the FDA presentation, FDA, 0.8 percent of the women in AVADO and 1.2 percent of the women in RIBBON1 who received bevacizumab died from side effects thought to be related to the drug.  Significantly, the meeting underlined the difficulty of interpreting Progression-Free Survival (PFS) as the primary endpoint of trials in oncology.

June 4 - 8, 2010

ASCO 2010

There were various announcements at the recent ASCO meeting (June 4 -8, Chicago, IL) regarding existing and novel drugs for the treatment of various malignancies.  I have emphasized selectively specific agents and clinical studies that provide substantial promise for new or improved therapeutic approaches in a special page called  ASCO 2010. In that page, I have included a general summary -from my perspective, of course- as well as selected announcements for which my usual approach is applied (pertinent facts are selected, company spin is discounted and my comments are clearly indicated). 

June 3, 2010

Pivotal Phase III Trial of Afinitor Met Primary Endpoint in Study of Patients With Advanced Pancreatic Neuroendocrine Tumors:

 Afinitor (everolimus) is an inhibitor of the the mTOR protein, an important target in various cancers.  It is being developed by Novartis.  In 2009, it obtained approval in the treatment of kidney cancer resistant to sorafenib (Nexavar) or sunitinib (Sutent). The phase III study (RADIANT-3) in pancreatic endocrine tumors (a rare but aggressive malignancy with few treatment options) was  double-blind, randomized, parallel group, placebo-controlled, multicenter study. The trial compared the efficacy and safety of everolimus plus best supportive care against placebo plus best supportive care in 410 patients with advanced pancreatic NET. Patients who met the study's entry criteria were randomized 1:1 to receive either daily everolimus (10 mg) or daily placebo orally.  Progression-free survival was the main endpoint of the study, with objective response and overall survival as secondary endpoints.

May 7, 2010

Bayer Schering Pharma commences Phase III clinical study with regorafenib in metastatic colorectal carcinoma:

 Regorafenib (or BAY 73-4506) is a small molecule inhibitor of endothelial growth factor receptors (VEGFRs) 2 and 3, and Ret, Kit, PDGFR and Raf kinases.  Regorafenib has shown substantial promise in the treatment of previously untreated patients with metastatic or unresectable renal cell carcinoma.  Regorafenib is structurally very similar to sorafenib (Nexavar®) which Bayer is marketing (and developing) in association with Onyx Pharmaceuticals. The close similarity in structure (the addition of a single fluorine atom in Regorafenib) prompted a legal challenge by Onyx. The upcoming Phase III clinical study in metastatic colorectal carcinoma will enroll approximately 690 patients who have failed standard treatment and compare overall survival of patients treated with regorafenib vs. those treated with placebo.

April 30, 2010

FDA approves PROVENGE® for the treatment of asymptomatic of minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer:

PROVENGE® (sipuleucel-T) is a autologous cellular immunotherapy in which the patient's own CD54+ cells are utilized after treatment with a recombinant protein, PAP-GM-CSF.  PAP-GM-CSF consists of the prostatic acid phosphatase (PAP), an enzyme expressed in prostate cancer tissue, linked to granulocyte-macrophage colony stimulating factor (GM-CSF).  In two pivotal studies utilizing 639 patients, PROVENGE® extended overall survival by approximately 5 months.   PROVENGE® is marketed by Dendreon, a Seattle, WA -based company.

April 22, 2010

Pfizer ends trial of Sutent in liver cancer

(sunitinib malate) is a receptor tyrosine kinase inhibitor that has been approved for the treatment of kidney cell carcinoma and certain gastrointenstinal stromal tumors. In a Phase 3 study (SUN 1170) of Sutent® vs. Nexavar® (sorafenib) in patients diagnosed with advanced hepatocellular carcinoma, Sutent® failed to demonstrate either superiority or non-inferiority to Nexavar® in overall survival. In addition, there was a higher incidence of serious adverse events in the Sutent® arm. Recently, Sutent® failed in Phase 3 studies in advanced breast cancer, but pivotal studies in advanced non-small cell lung cancer, advanced castration-resistant prostate cancer, and as an adjuvant treatment in kidney cancer are ongoing.

April 19, 2010

FDA Approves Tarceva as a Maintenance Therapy for Advanced Non-Small Cell Lung Cancer:


Tarceva®(erlotinib) is a tyrosine kinase inhibitor acting on the epidermal growth factor receptor (EGFR). Tarceva® has been previously approved for the treatment of locally advanced (metastatic) non-small cell lung cancer (NSCLC) and, in combination with gemcitabine, in metastatic pancreatic cancer.  It is co-marketed by OSI Pharmaceuticals and Genetech. The latest approval was based on the results of the Phase 3 SATURN clinical study.  In that study, patients diagnosed with NSCLC were treated with four cycles of standard first-line platinum-based chemotherapy and then randomized to Tarceva® or placebo if the cancer did not progress. The primary endpoint of the study was progression-free survival (PFS).  It was defined as the length of time from randomization to disease progression or death from any cause. Patients randomized to Tarceva® showed 41% improvement in the likelihood of living without the disease getting worse (PFS, the primary endpoint) compared to placebo (hazard ratio=0.71, 29 percent reduction in the risk of cancer progression or death, p<0.0001). Overall survival (OS) was improved by 23% with compared to placebo (hazard ratio=0.81, 19 percent reduction in the risk of death, p=0.0088). The most common reported adverse events associated with Tarceva® as maintenance therapy were rash (49%) and diarrhea (20%).

April 13, 2010

ChemGenex Receives a Complete Response Letter from the FDA for Omapro™:

Omapro™ (Omacetaxine mepesuccinate)  induces apoptosis by inhibition of protein synthesis, particularly Mcl-1. It is being evaluated in clinical trials in a range of hematological malignancies.  ChemGenex submitted an NDA for the use of Omapro™ in chronic myeloid leukemia (CML) in September 2009.  The company did not reveal details regarding the contents of the Complete Response letter, although it stated that the FDA did not request additional studies.  Some of the criticism of the Omapro™ pivotal study in CML can be found in minutes of the meeting of the Oncologic Drugs Advisory Committee held in March 22, 2010.  The main concerns during this meeting were (a) a small, incomplete and single trial in support of the indication, (b) one third of the patients in the study did not meet enrollment criteria, (c) low response rates, (d) variability in assays testing eligibility and (e) certain safety concerns.

April 9, 2010

Roche and Biogen-Idec apply to expand Rituxan label

 Rituxan® (rituximab) is a genetically engineered chimeric murine/human monoclonal IgG antibody directed against the CD20 antigen expressed in B lymphocytes.  It is approved for the treatment of Non-Hodgkin's Lymphoma, Chronic Lymphocytic Leukemia (CLL) and Rheumatoid Arthritis.  Roche and Biogen-Idec submitted a supplemental Biologics License Application (sBLA) to FDA to expand the usage of Rituxan in the maintenance therapy of previously untreated patients with advanced follicular lymphoma.  The data for the supplemental application were derived from the Phase 3 PRIMA study, the results of which were announced last September.

April 8, 2010

Aeterna Zentaris Announces Initiation of Phase 3 Registration Trial with Perifosine in Refractory Advanced Colorectal Cancer:

  Perifosine is an alkylphospholipid exhibiting antitumor properties by acting on the Akt and other signal transduction pathways such as JNK and MAPK.  It induces apoptosis although its mechanism of action is still undefined.  The Phase 3 study protocol will compare overall survival of patients with refractory advanced colorectal cancer treated with perifosine + Xeloda vs those treated with placebo + Xeloda. Perifosine is also developed in multiple myeloma (a Phase 3 study is ongoing).  Aeterna Zendaris has outlicensed perifosine in North America to Keryx Biopharmaceuticals, which oversees the clinical development program.

March 29, 2010

GenVeC discontinues Phase 3 clinical trial of TNFerade™ after interim analysis of the data in pancreatic cancer.  

TNFerade is an adenovirus vector which contains the gene for tumor necrosis factor-alpha (TNFα), an immune system protein with anti-tumor activity.  TNFerade is directly injected into the tumor where it stimulates expression of TNFα.  This agent is utilized in conjunction with standard chemotherapy or radiation.  TNFerade was also being tested in head and neck cancer, but it appears that this program is discontinued.  The company announced that it will focus in the development of its vaccines.

Regulus Therapeutics Publish Pre-clinical In Vivo Efficacy Data on microRNA Therapeutics targeting microRNA-10b in Models of Breast Cancer Metastasis.  MicroRNAs are recently-discovered non-coding RNAs of about 22 nucleotides in length that regulate the expression of specific genes. There is intense interest in positively defining the role of microRNAs in cancer and developing blocking or modulating agents.  So far, progress has been less than spectacular.  Regulus Therapeutics, a Carlsbad, California -based company, is developing oligonucleotide-based therapeutic agents that modulate the activity of microRNAs. The published data showed that treatment of breast tumor-bearing mice with a microRNA therapeutic inhibited metastasis.  

March 23, 2010

Merck Serono suspends trials with Oncothyreon's Stimuvax

 Stimuvax is a cancer vaccine designed to induce immune response to tumors expressing the MUC1 antigen. The suspension occurred because a multiple myeloma patient in one of the exploratory studies developed encephalitis. Phase 3 clinical trials in non-small cell lung carcinoma and breast cancer have also been suspended. 

March 22, 2010

Advaxis Immunotherapeutic ADXS11-001 Phase 1 Survival Data Extended (through BusinessWire):


ADXS1-001 is under development in patients with advanced cervical cancer who have failed prior chemotherapy. Advaxis is a biotechnology company developing proprietary immunotherapeutics that deliver engineered tumor antigens, which stimulate multiple, simultaneous, immunological mechanisms to fight cancer.  The company has a number of these constructs under development.

FDA Advisory Panel votes unanimously against approval of Cell Therapeutics pixantrone. 

Pixantrone is currently being developed for the treatment of patients with relapsed or refractory aggressive non-Hodgkin's lymphoma ("NHL") that have failed at least two previous courses of treatment. It is is a topoisomerase II inhibitor with an aza-anthracenedione molecular structure.  Regarding the rejection by the advisory panel, it is important to note that Cell Therapeutics, Inc. discontinued the Phase III study of pixantrone at an unscheduled time point due to poor enrollment.  The FDA's re-analysis of the data submitted by the company did not support a statistically significant treatment effect.  Apparently, the advisory panel shared the FDA's reservations.

March 17, 2010

ABRAXANE Meets Primary Endpoint in Phase 3 Trial for Advanced Non-Small Cell Lung Cancer (through BusinessWire)


ABRAXANE® is protein-bound paclitaxel marketed by Abraxis Bioscience, Inc.   ABRAXANE®
has already been approved for the treatment of metastatic breast cancer.