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AbbVie to Submit Venetoclax for Approval for the Treatment of Patients with Chronic Lymphocytic Leukemia (CLL) Harboring the 17p Deletion
In August 2015, AbbVie reported that, according to an independent review analysis, a phase II clinical trial (protocol ID: M13-982; 2012-004027-20; NCT01889186) with venetoclax met its primary endpoint of ORR in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia (CLL) with the 17p deletion. This open label trial evaluated the efficacy and safety of venetoclax, an inhibitor of the B-cell lymphoma-2 (BCL-2) protein, being developed in partnership with Genentech and Roche. Data from this trial will be presented at an upcoming medical conference and will serve as the pivotal registration data to be submitted to the FDA and the European Medicines Agency (EMA) before the end of 2015.

The multicenter (n=48), international, open label phase II clinical trial was designed to evaluate the efficacy and safety of venetoclax in either treatment-naïve patients with CLL harboring the 17p deletion or those with relapsed or refractory disease to existing therapies. The trial enrolled 157 patients, 107 patients in the main cohort evaluating efficacy, and 50 patients in the safety expansion cohort. The primary efficacy endpoint is ORR and the primary safety endpoints are the number and percentage of patients who experienced treatment-related AE, changes in physical exam findings, including vital signs, changes in clinical laboratory test results and changes in cardiac assessment findings. Secondary efficacy outcome measures include CR and PR rate, duration of response, PFS and OS, among others. The safety profile of venetoclax was similar to that seen in previous trials and no unexpected safety signals have been reported.

In May 2015, the FDA granted Breakthrough Therapy Designation to venetoclax for the evaluation of treatment of patients with relapsed or refractory CLL harboring the 17p deletion genetic mutation. The 17p deletion mutation is a genomic alteration in which a part of chromosome 17 is absent. CLL with the 17p deletion is a slow progressing hematologic malignancy associated with excessive lymphocyte production. It is the most common leukemia diagnosed in adults in western countries. In the USA, ~ 14,620 new cases of CLL are diagnosed annually. The incidence of CLL with the 17p deletion is ~ 3%-10% among newly diagnosed patients and 30%-50% in patients with relapsed/refractory CLL. The median life expectancy of patients with CLL with the 17p deletion is less than 2-3 years.

A multicenter (n=165), randomized, open label, parallel assignment, phase III clinical trial (protocol ID: GO28667; NCT02005471) was initiated in December 2013, in the USA, Australia, Canada, Europe (Austria, Belgium, Czech Republic, Denmark, France, Germany, Hungary, Italy, Netherlands, Poland, Russia, Spain, Sweden, Switzerland, UK), South Korea, New Zealand, Taiwan, to evaluate the efficacy of ABT-199 plus rituximab compared with bendamustine plus rituximab in treating adult patients with relapsed or refractory CLL who have been treated with 1-3 prior lines of therapy including at least one standard chemotherapy-containing regimen.

FDA’s ODAC Backs Lilly’s Necitumumab BLA for the Treatment of Metastatic Squamous NSCLC
In July 2015, the majority of the members of an FDA ODAC panel agreed that necitumumab provides some benefits for the treatment of locally advanced or metastatic (Stage IV) squamous non-small cell lung cancer (nsclc) despite safety concerns over the potentially increased risk of thrombolytic events. In clinical trials, median OS with necitumumab improved survival by an average 1.6 months, which was statistically significant, and PFS by 0.2 months. However, an FDA briefing document had raised safety concerns regarding the incidence of thromboembolic events.

The BLA submission is based on efficacy data for the proposed indication from the SQUIRE multicenter, international, randomized, controlled, open label, phase III clinical trial (protocol ID: CP11-0806, EudraCT No. 2009-013838-25; NCT00981058) that enrolled 1,093 patients with advanced squamous nsclc who had not been previously treated with chemotherapy for metastatic disease. Patients were randomized 1:1 to either necitumumab with gemcitabine and cisplatin (n=545) or gemcitabine and cisplatin alone (N=548) alone. Randomization was stratified by ECOG performance status and geographic region. The primary efficacy endpoint of the trial is OS. Secondary endpoints include PFS, and ORR. The addition of necitumumab resulted in a 1.6 month improvement in OS, which was statistically significant. Median OS was 11.5 months in the necitumumab arm compared to 9.9 months in the comparison arm (HR=0.84; p=0.012). Median PFS was 5.7 months in the necitumumab arm versus 5.5 months in the control arm (HR=0.85; p=0.02); ORR was 31% versus 29% (p=0.40), respectively.

The submission also included data from INSPIRE, a randomized, controlled, phase III clinical trial (protocol ID: CP11-0805, EudraCT 2009-012574-12; NCT00982111) with necitumumab in combination with pemetrexed and cisplatin versus pemetrexed and cisplatin alone in chemotherapy naïve patients with advanced non-squamous nsclc. This trial was closed prematurely at the request of the data monitoring committee (DMC) because of an imbalance on the number of deaths attributed to potential thromboembolic events and deaths of all causes observed in the necitumumab arm.

Necitumumab’s safety profile is in general consistent with that observed with anti-EGFr MAb agents. In the SQUIRE trial, significant Grade ≥ 3 AE are hypomagnesemia (9%), skin rash (7%) and hypersensitivity/infusion reaction (0.4%). Fatal cardiopulmonary arrest and/or sudden death occurred in 2.2 % of the patients in the necitumumab arm compared to 0.5 % in the control arm. Incidence of thromboembolic events was higher in the necitumumab-containing arms in both the SQUIRE and INSPIRE trials; incidence of Grade ≥3 thromboembolic events were 9% versus 5% in the SQUIRE trial and 11% versus 6% in the INSPIRE trial. The most common venous thromboembolic events, some fatal, were pulmonary emboli (PE) and deep vein thrombosis (DVT) while the most common arterial thromboembolic events were myocardial infarction (MI) and cerebrovascular accidents (CVA).

Inotuzumab Ozogamicin Special Report
In April 2015, Pfizer reported that the INO-VATE ALL multicenter (n=250), international, open label, randomized, phase III clinical trial (protocol ID: B1931022; NCT01564784) with inotuzumab ozogamicin met its first primary endpoint of demonstrating a higher hematologic CR rate in adult patients with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL) compared to that with standard of care chemotherapy. The trial is continuing to allow for the data on OS to mature. No new or unexpected safety issues were identified. Efficacy and safety data from this trial will be submitted for presentation at an upcoming medical meeting. Pfizer plans to discuss these data with the FDA and other regulatory

Opdivo Special Report
In April 2015, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion recommending that Opdivo (nivolumab) be granted approval for use in both first line and previously treated patients with advanced inoperable metastatic melanoma. The application supports the use of Opdivo in patients with both BRAF wild-type and mutation-positive melanoma. This is the first positive opinion given by the CHMP for a PD-1 immune checkpoint inhibitor. The EMA granted Bristol-Myers Squibb accelerated assessment of Opdivo based on current regulations that fulfill its guidance about “medicinal products of major interest from the point of view of public health and in particular from the view point of therapeutic innovation. CHMP’s positive opinion is based on data from two phase III clinical trials CheckMate-037 (protocol ID: CA209-037, 2012-001828-35; NCT01721746), and CheckMate-066 (protocol ID: CA209-066; 2012-003718-16; NCT01721772), demonstrating the efficacy and safety of Opdivo in patients with advanced melanoma with important unmet needs. CheckMate-066, a randomized double blind phase III clinical trial comparing Opdivo with dacarbazine is the first to demonstrate an overall survival benefit in advanced melanoma, as well as a higher objective response rate. In CheckMate-037, a randomized, controlled, open label, clinical trial with Opdivo versus investigator’s choice chemotherapy in patients with advanced melanoma previously treated with Yervoy (ipilimumab), there was an improvement in objective response rates. These data are supported by results from a phase Ib clinical trial (protocol ID: CA209-003; MDX1106-03; NCT00730639) in relapsed advanced or metastatic melanoma, which characterized Opdivo benefit/risk in advanced melanoma. Opdivo was administered at a dose of 3 mg/kg every two weeks across all these three trials.

Bristol-Myers Squibb also reported that according to results from a phase II clinical trial (protocol ID: CA209-069; 2013-002018-11; NCT01927419), evaluating the Opdivo (nivolumab) plus Yervoy (ipilimumab) regimen versus Yervoy alone in patients with previously untreated advanced melanoma, a higher objective response rate (ORR) of 61% (n=44/72), the primary study endpoint, was noted in patients with BRAF wild-type mutation status treated with the combination regimen compared to 11% (n=4/37) for those administered Yervoy monotherapy (p < 0.001). There were 16 (22%) CR in patients with BRAF wild-type mutation status administered the Opdivo plus Yervoy regimen and in no patients treated with Yervoy alone. Similar results were also observed in patients with BRAF mutation-positive melanoma. The Opdivo plus Yervoy regimen decreased risk of melanoma progression or death compared to Yervoy alone by 60%, based upon hazard ratio (HR) of 0.4; median PFS for the regimen has not been not reached with a minimum follow-up of 11 months. The safety profile was consistent with previously-reported trials evaluating the Opdivo plus Yervoy regimen and included Grade 3-4 colitis (17%), diarrhea (11%), and increased alanine aminotransferase (11%).

In April 2015, the open label, randomized CheckMate-057 phase III clinical trial (protocol ID: CA209-057; 2012-002472-14; NCT01673867) evaluating Opdivo (nivolumab) versus docetaxel in previously treated patients with advanced non-squamous non-small cell lung cancer (nsclc) was stopped early because an assessment conducted by the independent Data Monitoring Committee (DMC) concluded that the trial met its endpoint, demonstrating superior OS in patients treated with Opdivo compared to the control arm. The trial’s investigators are being informed of the decision to stop the comparative portion of the trial. Bristol-Myers Squibb is working to ensure that eligible patients will be informed of the opportunity to continue or start treatment with Opdivo in an open label extension trial. The company will complete a full evaluation of the final CheckMate-057 data and work with investigators on the future presentation and publication of the results. The trial randomized 582 patients to either IV nivolumab (3 mg/kg) administered every two weeks or IV docetaxel (75 mg/m2) administered every3 weeks. The primary endpoint is OS. Secondary endpoints include ORR and PFS.

The Ultimate Personalized Cancer Therapy? Cancer Vaccines Targeting Neoantigens in a Given Patient’s Tumors
Tumor-specific antigens (neoantigens) derived from mutated proteins that are present only in a given patient’s tumors appear to represent a promising new immunotherapy approach (Hacohen N, et al., Cancer Immunol Res, Jul 2013;1(1):11-5 and Fritsch EF, et al., Oncoimmunology, 25 Jun 2014;3:e29311). These vaccines target the unique immunogenic mutations present in each patient’s tumor, thus marshaling the immune system against a very specific offender.

Several groups are working on such an approach, including investigators at the Broad Institute of Harvard and MIT (Cambridge, MA); Dana-Farber Cancer Institute (Boston, MA); Brigham and Women's Hospital, Harvard Medical School (Boston, MA); and Massachusetts General Hospital (Boston, MA). Recently, investigators from Washington University School of Medicine (St. Louis, MO), in collaboration with the University of Oklahoma Health Sciences Center (Oklahoma City, OK), reported results from 3 patients with surgically removed malignant melanoma that had spread to the lymph nodes who were administered vaccines targeting neoantigens present in their tumor cells. The team identified a unique set of mutated proteins in a patient's tumor that would be most likely to be recognized by the immune system as foreign. This is a departure from the standard immunotherapy approaches that target proteins overexpressed in melanoma cells but also present in normal cells, thus diluting the effects of the vaccine. Each individualized vaccine incorporated a set of 7 unique neoantigens. Dendritic cells (DC) derived from the patient presented the neoantigens to the immune system. The investigators are planning a phase I clinical trial approved by the FDA that will enroll 6 patients (Carreno BM, etal, Science, 2 Apr 2015; epub ahead of print).

Metformin in Combination with Plk1 Inhibitor BI2536 in the Treatment of Hormone-refractory Prostate Cancer
There is increasing evidence that the antidiabetic metformin exerts strong antineoplastic effects on numerous tumor types, including prostate cancer.  Additionally, it helps to lower the risk of developing castration-resistant prostate cancer.  Investigators at Purdue University (West Lafayette, IN) and colleagues report that inhibition of polo-like kinase 1 (Plk1) with BI2536 enhances the antineoplastic activity of low dose metformin in prostate cancer in vitro and in vivo.  Overexpression of Plk1 can trigger the synthesis of androgen.  BI2536, a specific Plk1 inhibitor, acts synergistically with metformin in inhibiting prostate cancer cell proliferation and also renders prostate cancer cells harboring wild type p53 much more sensitive to treatment with low dose metformin.  The combination of BI2536 and metformin induced p53-dependent apoptosis and further activated the p53/Redd-1 pathway.

Metformin may directly affect prostate cancer cells by altering their metabolism.  Treatment with BI2536 inhibited metformin-induced glycolysis and glutamine anaplerosis, both of which are survival responses of cells against mitochondrial poisons.  Metformin decreases glucose oxidation and increases dependency on reductive glutamine metabolism in both cancer cell lines and in a mouse model of prostate cancer.  Inhibition of glutamine anaplerosis (replenishment) in the presence of metformin further attenuates proliferation.  Therefore, interfering with glutamine may synergize with metformin to improve outcomes in patients with prostate cancer (Fendt SM, etal, Cancer Res, 15 Jul 2013;73(14):4429-38).  The combination of metformin and BI2536 appears to help prevent androgen synthesis without impacting healthy prostate cells.  These findings support a potentially promising therapeutic strategy combining two well tolerated drugs against prostate cancer proliferation and the progression of androgen-dependent prostate cancer to the castration-resistant stage (Shao C, etal, J Biol Chem, 23 Jan 2015;290(4):2024-33). 

BI2536 was the first Plk1 inhibitor to enter clinical trials; the first phase I clinical trial with BI2536 was initiated in August 2004.  Since then, BI2536 has been evaluated in phases I and II clinical trials in various cancer indications and proved to be safe and well tolerated but was not sufficiently effective as monotherapy in prostate cancer.  The last trial was initiated in 2007 and, as of now, there are no ongoing trials in any indication.  It is expected that the metformin/BI2536 combination will be tested in clinical trials in prostate cancer.  In addition, PLK1 inhibition appears to be as an attractive therapeutic approach, in association with conventional chemotherapy, for the management of patients with triple negative breast cancer (TNBC), a particularly aggressive form of the disease (Maire V, etal, Cancer Res, 15 Jan 2013;73(2):813-823).

England's National Cancer Drugs Fund Removes 25 Cancer Indications Involving 16 Separate Drugs from its FY16 Covered List
In January 2015, the CDF removed 25 cancer treatment indications involving 16 separate agents from its annual funding list beginning on March 15, 2015.  The fund exceeded its budget by ~ £100 million in FY15.  This decision eliminates ~ £80 million ($121.3 million) from the FY16 budget for these indications which is nevertheless increased to £340 million in FY16, with its mandate ending on March 15, 2016.  In addition the CDF rejected outright another 33 indications involving 19 separate approved anticancer agents.  The CDF covered list now includes 62 approved indications.  The most telling aspect of the removals is the incredible variety of highly specific indications, some approved and others off label, associated with these drugs that illustrate the complexity of this disease.  In addition to the basic cancer type, the clinical indications specify disease stage, biomarker expression, line of treatment often specifying previous exposure by agent, performance status, distinct agent combinations, etc.  Each of these specific indications has been evaluated in clinical trials providing the regulators with base line information as to their cost effectiveness.

The UK approach to cancer treatment reimbursement has created considerable controversy at home and abroad.  Although the CDF funding and Britain’s NHS reimbursement guidelines may be condemned as rationing, the serial treatment of patients with refractory disease after the standard approved first line therapy with regimens providing minimal benefit is problematic both in terms of patient outcomes and in terms of exorbitant costs.  Whatever the reaction, the UK regulators’ dilemma in this area highlights the fundamental problem associated with the state of cancer treatment in 2015; we still do not know why or how it happens and, therefore, we cannot prevent it or effectively treat it.  Better diagnostic tools have enabled early detection to allow surgical intervention that prevents the disease from advancing to a lethal state but little has been done to treat advanced disease at presentation, particularly solid tumor malignancies affecting vital organs.  Also, there is considerable spin about lives saved by advances in the last 20 years.  Better in vitro diagnostic and imaging modalities have been detecting disease unlikely to kill a patient in his/hers lifetime, including various types of early breast cancer, localized prostate cancer in the elderly, superficial malignant melanoma, and others that are estimated to account for up to 30% of all cases of cancer incidence in the USA.  Actually, there is a movement to refrain from calling these diagnoses as cancer.  The American Cancer Society estimates that 1,658,370 new cancer cases will be diagnosed in the USA in 2015 and 589,430 patients will die from the disease.  By any measure, these are sobering statistics. 

FDA Approves Avastin in Combination with Chemotherapy for the Treatment of Platinum-resistant Ovarian Cancer in the Third Line Setting
In November 2014, the FDA approved Avastin in combination with chemotherapy with paclitaxel, pegylated liposomal doxorubicin or topotecan, for the treatment of women with platinum-resistant, recurrent, epithelial ovarian, fallopian tube, or primary peritoneal cancer, previously treated with no more than two chemotherapy regimens. In August 2014, Avastin was approved in the EU for this indication. Approval was based on results from AURELIA, a phase III clinical trial (protocol ID: MO22224; 2009-011400-33; NCT00976911), in which participants were randomized to one of six treatment arms (paclitaxel, topotecan or pegylated liposomal doxorubicin with or without Avastin). The primary endpoint of the trial was investigator-assessed PFS.

According to trial results, Avastin plus chemotherapy reduced the risk of disease worsening or death by 62% compared to chemotherapy alone; median PFS was 6.8 with Avastin plus chemotherapy versus 3.4 months with chemotherapy alone (HR=0.38; p<0.0001). AE were consistent with those seen in previous trials with Avastin across tumor types for approved indications, but also included high blood pressure and pain, redness or swelling of the hands or feet. Survival gains are modest. Among the 3 chemotherapy plus Avastin combinations in this trial, treatment with paclitaxel plus Avastin produced the best median OS at 22.4 months, a 10.1 month improvement over paclitaxel alone as well median PFS of 9.6 months, a 5.7 month improvement over paclitaxel monotherapy.

Neratinib Reduces CNS Metastases in Patients With HEr2-positive Locally Recurrent or Metastatic Breast Cancer
In November 2014, top line results were presented from the multicenter, international (n=33), randomized, 2-arm, NEfERTT phase II clinical trial (protocol ID: 3144A2-3005; NEFERTT; NCT00915018) with PB272 (neratinib) plus paclitaxel versus trastuzumab (Herceptin) plus paclitaxel for the treatment of patients withHEr2-positive locally recurrent or metastatic breast cancer in the first line setting. The trial enrolled 479 patients. As expected, there was no statistically significant difference in PFS and ORR between the paclitaxel plus neratinib arm compared to the paclitaxel plus trastuzumab arm but there was a significant decrease in the incidence of CNS metastases in the neratinib arm compared to the trastuzumab arm. This represents the first randomized trial with a HEr2 targeted agent that statistically significantly reduced the incidence of CNS metastases, which may provide a meaningful point of differentiation for neratinib in the treatment of HEr2 positive breast cancer. While other HEr2 targeted drugs provide a clinically meaningful benefit to patients with HEr2 positive breast cancer, these drugs have had little impact on CNS metastases. There is an unmet clinical need for reducing the incidence of CNS metastases which may be filled with neratinib.

The primary endpoint of the trial was PFS. Secondary endpoints included objective response rate (ORR) and the incidence of central nervous system (CNS) metastases, including brain metastases. According to safety findings from the trial, the most frequently observed AE in the neratinib arm was diarrhea, with ~ 30% of the patients experiencing Grade 3 diarrhea compare to ~ 4% in the trastuzumab arm. Patients treated with neratinib in this trial did not receive any prophylaxis with antidiarrheal agents to prevent the neratinib-related diarrhea. It has seen observed that high dose loperamide greatly reduces the rate of Grade 3 diarrhea associated with neratinib. In all of its current ongoing trials Puma is instituting the use of high dose loperamide in order to continue to reduce neratinib related diarrhea. PFS among patients treated with the combination of paclitaxel plus neratinib was 16.6 months compared to 16.7 months with the combination of paclitaxel plus trastuzumab (p=0.35). The ORR was 74.8% in the neratinib arm compared to 75.1% in the trastuzumab arm (p=0.94). These results did not demonstrate a statistically significant difference between the PFS and ORR results between the two treatment arms, which was consistent with expectations. With respect to the incidence of CNS metastases (e.g., brain metastases), treatment with the combination of paclitaxel plus neratinib resulted in a 52.6% reduction in the incidence of CNS metastases compared to the incidence of CNS metastases in patients treated with the combination of paclitaxel plus trastuzumab. The incidence of CNS metastases was 7.4% in the neratinib arm compared to 15.6% (p=0.006).in the trastuzumab arm. These results reflect a statistically significant difference between the two treatment arms. Full results of the NEfERTT trial for PB272 will be presented at a future scientific meeting in 2015.

Merck KGaA Discontinues Clinical Development of Tecemotide (L-BLP25) as Monotherapy in Stage III Non-small Cell Lung Cancer
In September 2014, Merck KGaA decided to discontinue the worldwide clinical development program with MUC1 antigen-specific cancer immunotherapy tecemotide (L-BLP25) as a monotherapy in Stage III non-small cell lung cancer (nsclc).  Those patients on active treatment with tecemotide can undergo an individual assessment by their treating physician and apply to be treated outside of the trials.  The company will continue to supply tecemotide for ongoing investigator-sponsored trials in other indications in accordance with Merck KGaA’s agreements with the sponsors of these trials.

The decision to discontinue the current clinical program in nsclc, which includes the phase III START2 (protocol ID: EMR 63325-021; 2013-003760-30; NCT02049151) and INSPIRE (protocol ID: EMR63325-012; NCT01015443) trials, stems from recent results from a planned analysis of a randomized, double blind, placebo-controlled phase I/II clinical trial (protocol ID: EMR063325_009; NCT00960115) in Japanese patients with Stage III inoperable locally advanced nsclc who had had been previously treated with concurrent or sequential chemoradiotherapy (CRT) with a minimum of two cycles of platinum-based chemotherapy and radiation ( ≥50 Gy); the majority of the patients included in the phase II part of the trial had been treated  with concurrent CRT.  According to results no effect has been observed for either the primary endpoint of OS, or for any of the secondary endpoints of PFS, TTP and time to treatment failure.  Although data from the exploratory subgroup analysis in the START trial  (protocol ID: EMR 63325-001; NCT00409188) appeared to warrant additional evaluation of tecemotide (Butts C, etal, Lancet Oncol, Jan 2014;15(1):59-68), results from the trial in Japanese patients lessened the probability of current trials to reach their goals.  Therefore, Merck KGaA’s biopharmaceutical division made the recommendation to stop the investigational treatment in patients in Japan, which led to the discontinuation of the development of tecemotide as a monotherapy in nsclc.  The company is currently focusing its efforts on other promising candidates in its pipeline, including its anti-PD-L1 antibody MSB0010718C.

FDA Grants Merck Accelerated Approval for Keytruda (Pembrolizumab) for the Treatment of Patients With Inoperable or Metastatic Melanoma in the Second Line Setting
In September 2014, the FDA granted accelerated approval to Keytruda (pembrolizumab) dosed at 2 mg/kg every 3 weeks for the treatment of patients with inoperable or metastatic melanoma that progressed following administration of ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.  Accelerated approval was based on tumor response rate and durability of response.  An improvement in survival or disease-related symptoms has not yet been established.  Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. Keytruda is the first anti-PD-1 (programmed death receptor-1) therapy to be granted by the FDA Breakthrough Therapy designation and approval for advanced melanoma.  Merck plans to make Keytruda available within one week from the date of FDA approval.

Approval of Keytruda was based on data from a multicenter, open label, randomized, dose-comparative trial cohort within the ongoing KEYNOTE-001 phase Ib clinical trial (protocol ID: P07990, MK-3475-001; KEYNOTE-001; NCT01295827) in patients with inoperable or metastatic melanoma with disease progression.  Key eligibility criteria included prior treatment with ipilimumab (two or more doses at 3 mg/kg or higher) and a BRAF or MEK inhibitor, if BRAF V600 mutation-positive and disease progression within 24 weeks following the last dose of ipilimumab.  Patients were randomized to either 2 mg/kg (n=89) or 10 mg/kg (n=84) of Keytruda every 3 weeks until unacceptable toxicity or disease progression that was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at 4 to 6 weeks with repeat imaging.  The major efficacy outcome measures were confirmed overall response rate (ORR) as assessed by blinded independent central review using RECIST 1.1 and duration of response.  Tumor response was assessed every 12 weeks.  Omid Hamid, MD, Director of the Melanoma Center at the Angeles Clinic and Research Institute (Los Angeles, CA), is the PI for the pembrolizumab melanoma clinical program. 

Among 89 patients treated with the recommended 2 mg/kg dose, ORR was 24% (21/89), including 1 CR and 20 PR.  At the time of analysis, responses were ongoing in 86% (18/21) of patients with objective responses with durations ranging from 1.4+ to 8.5+ months, including 8 patients with ongoing responses of 6 months or longer.  Disease progressed in 14% (3/21) of patients at 2.8, 2.9, and 8.2 months after initial response.  Immune-mediated AE related to treatment with Keytruda include pneumonitis, colitis, hepatitis, hypophysitis, nephritis, hyperthyroidism, and hypothyroidism.  Based on the severity of AE, Keytruda should be withheld or discontinued and corticosteroids administered.  Based on its mechanism of action, Keytruda may cause fetal harm when administered to a pregnant woman.   The most common adverse reactions, reported in >=20% of patients, were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%).

Pfizer Submits NDA for Palbociclib as First Line Treatment in Combination with Letrozole in Advanced Breast Cancer
In August 2014, Pfizer completed an NDA submission to the FDA requesting approval of palbociclib in combination with letrozole for the treatment of postmenopausal women with estrogen receptor positive (Er+), human epidermal growth factor receptor 2 negative (HEr2-) advanced breast cancer who have not been previously systemically treated for advanced disease.  Palbociclib is an investigational oral targeted agent that selectively inhibits cyclin-dependent kinases CDK4 and CDK6 to re-establish cell cycle control and block tumor cell proliferation.  The submission is based on the final results of PALOMA-1, a randomized, phase II clinical trial (protocol ID: A5481003; NCT00721409) comparing palbociclib plus letrozole versus letrozole alone in this setting.

In PALOMA-1, palbociclib (125 mg) was administered once daily for 3 out of 4 weeks in repeated cycles, in combination with letrozole versus letrozole alone (2.5 mg) once daily on a continuous regimen.  PALOMA-1 achieved its primary endpoint by significantly prolonging PFS compared with letrozole alone in post-menopausal women with estrogen receptor positive (Er+), HEr2-negative locally advanced or metastatic breast cancer.  Median PFS was 20.2 months among women treated with the combination, a statistically significant improvement compared to the 10.2 months in women treated with letrozole alone (HR=0.488; p=0.0004).  At the time of this assessment, treatment with palbociclib plus letrozole also resulted in a median OS of 37.5 months compared to 33.3 months with letrozole alone, a 4.2-month survival benefit (HR=0.813), which was not statistically significant.  A follow-up OS analysis will be conducted following the accrual of additional events.  The combination of palbociclib and letrozole was generally well tolerated and the safety profile of the combination was consistent with previously reported data. The most common AE in the combination arm were neutropenia, leukopenia, fatigue and anemia. The neutropenia observed with the combination in this trial was non-cumulative and clinically manageable; there no cases of febrile neutropenia in either arm of the trial. Neutropenia is an on-target, antiproliferative side effect of palbociclib and signifies inhibition of CDK4 and its effect on bone marrow (Finn RS, AACR14, Abs. CT101).

Neratinib is Headed for Regulatory Filing in 2015
In July 2014, Puma Biotechnology reported top line results from ExteNET, a double blind, placebo-controlled, phase III clinical trial (protocol ID: 3144A2-3004; NCT00878709) with PB272 (neratinib) versus placebo that enrolled 2,821 patients in 41 countries with early stage HEr2-positive breast cancer who had undergone surgery and adjuvant treatment with trastuzumab. After completion of adjuvant treatment with trastuzumab, patients were randomized to extended adjuvant treatment with either neratinib or placebo for a period of one year. Patients were then followed for recurrent disease, ductal carcinoma in situ (DCIS), or death for a period of two years after randomization in the trial.

The primary endpoint of the trial was disease free survival (DFS). Secondary endpoints include DFS specific to ductal carcinoma in situ (DFS-DCIS) and overall survival (OS). Treatment with continuous PO neratinib (240 mg) daily resulted in a 33% improvement in DFS versus placebo (HR=0.67; p=0.0046) and a 37% improvement in DFS including DCIS versus placebo (HR=0.63; p=0.0009), with both being statistically significant.

Based on results from the ExteNET trial, Puma plans to file for regulatory approval of neratinib in the extended adjuvant setting in the first half of 2015. Full results of the ExteNET trial for PB272 will be presented at a future scientific meeting. At this point, no data has been reported from this trial regarding the incidence/severity of side effects or the impact of the addition of neratinib on overall survival (OS). In a phase II clinical trial (protocol ID: 11-344; TBCRC 022; NCT01494662) in patients with breast cancer and brain metastases the most serious adverse event (SAE) was diarrhea.

A multicenter (n=202), international, randomized, open label, parallel assignment, phase III clinical trial (protocol ID: PUMA-NER-1301; 2012-004492-38; NCT01808573) is also ongoing to evaluate the safety and efficacy of neratinib plus capecitabine versus lapatinib plus capecitabine in treating patients with metastatic (Stage IV) HEr2-positive breast cancer previously treated with two or more HEr2-directed regimens. The trial's primary objectives are to determine the PFS and OS. Secondary objectives are to determine the ORR, CBR, duration of response, time to intervention for symptomatic CNS disease, safety, health outcomes assessments, and population PK. According to the protocol, patients are randomized 1:1 to one of two arms. Patients in arm A are treated with neratinib (240 mg), once daily, in combination with PO capecitabine (1500 mg/m²), daily on days 1-14 of each 21-day cycle. Patients in arm B are treated with PO lapatinib (1250 mg), once daily, continuously in 21-day cycles and capecitabine (2000 mg/m²), daily. Treatment continues until disease progression, unacceptable toxicity, or other specified withdrawal criteria. The trial is to enroll about 600 patients.

Pfizer to Submit an NDA to the FDA for Palbociclib
Pfizer expects to submit early in the third quarter of 2014 an NDA with the FDA for palbociclib, combined with letrozole, as first line treatment of post-menopausal women with estrogen receptor positive (Er+), HEr2-negative locally advanced or metastatic breast cancer. This decision is based on discussions with the FDA regarding the final results of PALOMA-1, a randomized phase I/II clinical trial (protocol ID: A5481003; NCT00721409), comparing palbociclib plus letrozole versus letrozole alone in this setting. Palbociclib is an investigational oral targeted agent that selectively inhibits cyclin-dependent kinases CDK4 and CDK6 to re-establish cell cycle control and block tumor cell proliferation.

PALOMA-1 achieved its primary endpoint by significantly prolonging PFS compared with letrozole alone in post-menopausal women with estrogen receptor positive (Er+), HEr2-negative locally advanced or metastatic breast cancer. Median PFS was 20.2 months among women treated with the combination, a statistically significant improvement compared to the 10.2 months in women treated with letrozole alone (HR=0.488; p=0.0004). At the time of this assessment, treatment with palbociclib plus letrozole also resulted in a median OS of 37.5 months compared to 33.3 months with letrozole alone, a 4.2-month survival benefit (HR=0.813), which was not statistically significant. A follow-up OS analysis will be conducted following the accrual of additional events. The combination of palbociclib and letrozole was generally well tolerated and the safety profile of the combination was consistent with previously reported data. The most common AE in the combination arm were neutropenia, leukopenia, fatigue and anemia. The neutropenia observed with the combination in this trial was non-cumulative and clinically manageable; there no cases of febrile neutropenia in either arm of the trial. Neutropenia is an on-target, antiproliferative side effect of palbociclib and signifies inhibition of CDK4 and its effect on bone marrow (Finn RS, AACR14, Abs. CT101).

The PROCEED Phase III Clinical Trial with Vintafolide (Vynfinit) Fails to Meet its Primary Endpoint
Unexpectedly, the Data Safety Monitoring Board (DSMB) after completing a pre-specified, interim futility analysis of the PROCEED phase III clinical trial (protocol ID: EC-FV-06; NCT01170650) evaluating vintafolide (Vynfinit) in combination with pegylated liposomal doxorubicin (PLD) compared to PLD plus placebo for the treatment of folate receptor (FOLr)-positive, platinum-resistant ovarian cancer, recommended that the trial be stopped because vintafolide did not demonstrate efficacy on the pre-specified outcome of PFS in this setting. The DSMB did not identify any safety concerns. The trial has been suspended while further review of the data is conducted. This is a surprising turn of events as in March 2014, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued positive opinions for the Conditional Marketing Authorizations of Vynfinit (vintafolide) and companion imaging components, imaging agent Folcepri (etarfolatide), and Neocepri (IV folic acid), for the treatment of patients with FOLr-positive, platinum-resistant ovarian cancer in combination with PLD. The applications for Conditional Marketing Authorization for vintafolide, etarfolatide and IV folic acid were submitted based on results in patients with platinum-resistant ovarian cancer expressing FOLr on all target lesions as evaluated in the PRECEDENT phase II clinical trial (protocol ID: EC-FV-04; NCT0072259). In this trial, that enrolled 149 patients, median PFS was 5.0 and 2.7 months for the vintafolide plus PLD and PLD-alone arms, respectively (HR=0.63; p=0.031). The greatest benefit was observed in patients with 100% of lesions positive for FOLr, with median PFS of 5.5 months compared with 1.5 months for PLD alone (HR=0.38; p=0.013).

Vintafolide (Vynfinit) Headed for Approval in the EU for the Treatment of Patients with Folate Receptor (FOLr)-positive, Platinum-resistant Ovarian Cancer
After 12 years in development vintafolide (Vynfinit), under development by Endocyte in collaboration with Merck, and companion imaging components Folcepri (etarfolatide), and Neocepri (IV folic acid), are headed for approval in the European Union (EU) for the treatment of folate receptor (FOLr)-positive platinum-resistant ovarian cancer in combination with pegylated liposomal doxorubicin (PLD). Vintafolide, a conjugate of folic acid (B9) and the potent microtubule inhibiting agent, desacetylvinblastine hydrazide (DAVLBH), targets tumor cells expressing FOLr. Etarfolatide is a peptide derivative of folic acid designed to efficiently coordinate with 99mTc for in vivo imaging by predominantly accumulating in folate receptor (FOLr)-positive tumors. Folate receptors, primarily folate receptor alpha or FOLr1 (FOLr) that participate in the internalization of folates into cells are overexpressed in a wide range of cases of primary and metastatic ovarian, lung, breast, endometrial, kidney and brain cancer.

Over the years several projects have been undertaken to conjugate FOLr with a cytotoxic payload including the antibody-drug conjugate IMGN853 currently in early clinical development. Another MAb-based drug in clinical development is farletuzumab (MORAb-003) that blocks FOLr. Also, immunotherapies based on FOLr in clinical development include FBP-E39 (GALE-301), and TPIV200.

In March 2014, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued positive opinions for the Conditional Marketing Authorizations of Vynfinit (vintafolide) and companion imaging components, imaging agent Folcepri (etarfolatide), and Neocepri (IV folic acid), for the treatment of patients with folate receptor-positive, platinum-resistant ovarian cancer in combination with pegylated liposomal doxorubicin (PLD). FOLr status should be assessed by a diagnostic medicinal product approved for the selection of adult patients for treatment with vintafolide, using Single Photon Emission Computed Tomography (SPECT) imaging, in combination with either Computed Tomography (CT) or Magnetic Resonance Imaging (MRI). Etarfolatide, following radiolabeling with sodium pertechnetate (99mTc) solution, is proposed for SPECT imaging in combination with CT or MRI, for the selection of patients for treatment with vintafolide. IV folic acid is administrated prior to 99mTc-etarfolatide for the enhancement of SPECT image quality. The applications for Conditional Marketing Authorization for vintafolide, etarfolatide and IV folic acid were submitted based on results in patients with platinum-resistant ovarian cancer expressing the folate receptor on all target lesions as evaluated in the PRECEDENT phase II clinical trial (protocol ID: EC-FV-04; NCT0072259). In this trial, that enrolled 149 patients, median PFS was 5.0 and 2.7 months for the vintafolide plus PLD and PLD-alone arms, respectively (HR=0.63; p=0.031). The greatest benefit was observed in patients with 100% of lesions positive for FOLr, with median PFS of 5.5 months compared with 1.5 months for PLD alone (HR=0.38; p=0.013).

Vintafolide is an investigational conjugate of folic acid (vitamin B9) linked to the potent vinca alkaloid desacetylvinblastine hydrazide (DAVLBH). Cancer cells generally consume higher levels of folate than normal cells to fuel their growth. Certain malignancies like ovarian cancer have high concentrations of the folate receptor (FOLr) on their surface. Vintafolide selectively targets FOLr to deliver the anticancer agent to tumor cells. Tumors with high concentrations of FOLr are identified by 99mTc-etarfolatide, a non-invasive imaging diagnostic agent whose image quality is enhanced by the simultaneous administration of IV folic acid. Vintafolide, etarfolatide and IV folic acid have been granted orphan drug status by the EMA. The FDA has also granted orphan drug status to vintafolide and etarfolatide.

Vintafolide and etarfolatide are also being investigated in the PROCEED phase III clinical trial (protocol ID: EC-FV-06; NCT01170650) in FOLr-positive, platinum-resistant ovarian cancer. The randomized TARGET phase IIb clinical trial (protocol ID: 8109-003; 2012-000966-40; NCT01577654) with vintafolide in non-small cell lung cancer (nsclc) completed enrollment in September 2013, and a phase II clinical trial (protocol ID: 8109-004; 2012-005170-65; NCT01953536) in triple negative breast cancer (TNBC) is expected to be initiated in the second quarter of 2014.

An estimated 40,000 new cases of ovarian cancer were diagnosed in the European Union in 2012. Overall, approximately 80% of patients with ovarian cancer relapse after first line, platinum-based chemotherapy, the standard of care for ovarian cancer. Platinum-resistant ovarian cancer recurs within 6 months of completion of a platinum-containing regimen. An estimated 80% of patients with platinum-resistant ovarian cancer have FOLr-positive disease, and approximately 40% express FOLr, as detected by etarfolatide, in all target tumor lesions. Patients with tumors expressing FOLr have a poorer overall prognosis than those with tumors that do not express this receptor.

Ramucirumab Headed for FDA Approval in Gastric Cancer
Eli Lilly has completed submissions to USA and EU regulators for approval of for ramucirumab as monotherapy in patients with advanced gastric cancer in the second line setting based on results from the multicenter (n=161), international, randomized phase III clinical trial (protocol ID: 13893; 2008-005964-15; CP12-0715; I4T-IE-JVBD; NCT00917384), dubbed REGARD, with ramucirumab monotherapy (Fuchs CS, etal, ASCOGI13, Abs. LBA5). In addition, based on results from the RAINBOW phase III clinical trial, median OS in patients with metastatic gastroesophageal junction (GEJ) or gastric adenocarcinoma treated with ramucirumab plus paclitaxel in the second line setting was 2 months longer than in those treated with paclitaxel alone. The survival gain is considered significant in this difficult to treat disease. Results of the RAINBOW trial, combined with findings from the REGARD trial support the use of this drug as second line therapy in patients with advanced gastric cancer who can tolerate these regimens. In these two trials in the second line setting, ramucirumab was effective as monotherapy and in a combination regimen.

In February 2014, Eli Lilly also reported that in the REVEL global phase III clinical trial (protocol ID: 13852; I4T-MC-JVBA; 2010-021297-11; CP12-1027; NCT01168973), ramucirumab in combination with docetaxel in patients with non-small cell lung cancer (nsclc), in the second line setting statistically significantly improved OS, the trial's the primary endpoint compared to the control arm of placebo plus docetaxel. There was also a statistically significant improvement in PFS in the ramucirumab arm compared to the control arm. The company did not report further details. Ramucirumab is currently being evaluated in ongoing clinical trials in colorectal, liver and bladder cancer and non-squamous nsclc. Ramucirumab (IMC-1121B), an antiangiogenesis agent, is a human monoclonal antibody (MAb) that blocks the vascular endothelial growth factor receptor 2 (VEGFr2).

According to results from the multicenter (n=167), global, placebo-controlled, double blind, phase III clinical trial (protocol ID: 13894; 14-IE-JVBE; CP12-0922; 2010-020426-18; NCT01170663), dubbed RAINBOW, that randomized 665 patients with metastatic gastroesophageal junction (GEJ) or gastric adenocarcinoma following disease progression after first line platinum and fluoropyrimidine-containing combination therapy, to ramucirumab plus paclitaxel (n=330) or paclitaxel plus placebo (n=335), median OS was 9.63 months for ramucirumab plus paclitaxel and 7.36 months for paclitaxel plus placebo (HR=0.87; p=0.0169). Median PFS was 4.40 months and 2.86 months (HR=0.635 (p<0.0001); median TTP was 5.5 months versus 3.0 months (p <0.0001); and the ORR was 28% versus 16% (p=0.0001, respectively. Neutropenia was more frequently reported in the ramucirumab plus paclitaxel arm but incidence of febrile neutropenia was comparable between the arms The trial met its primary endpoint of improved OS represented by a significant and clinically meaningful benefit of >2 months with ramucirumab plus paclitaxel versus paclitaxel in gastric and GEJ cancer after progression on first line therapy, as were significant benefits in PFS and ORR (Wilke H, etal, ASCOGI14, Abs. LBA7). This is the only trial to date to demonstrate a 2-month improvement in survival.

Ramucirumab, however, did not improve outcomes in metastatic breast cancer. According to results from the ROSE multicenter, international, randomized, double blind, phase III clinical trial (protocol ID: CP12-0606; TRI0-CIRG-012; TRIO-012; EUDRACT Number: 2008-001727-65; NCT00703326) that enrolled 1,144 women with HEr2-negative, inoperable locally recurrent or metastatic breast cancer who were treated with ramucirumab and docetaxel versus placebo and docetaxel as a first line regime, the trial did not meet its primary endpoint of PFS. Median PFS was 9.5 months with the combination compared with 8.2 months on chemotherapy alone (p=0.077). No subgroups showed an advantage for PFS in his trial. OS was 27 months in both groups (p=0.915). However, the ORR was 45% with the combination compared with 38% with chemotherapy alone. The most common (>5% incidence) >Grade 3 AE occurring at a higher rate on the ramucirumab plus docetaxel arm compared to the control arm included fatigue/asthenia, neutropenia, febrile neutropenia, hypertension and stomatitis (Mackey JR, etal, SABCS13, Abs. S5-04).

Speeding the Time it Takes to Evaluate Novel Anticancer Treatments: the I-SPY-2 Adaptive Clinical Trial
Clinical evaluation of novel anticancer agents/treatments routinely takes over 10 years and costs nearly $1 billion.  Currently, numerous agents are in development for even longer lengths of time.  This situation prompted the rethinking of how to evaluate the results of clinical trials in real time rather than wait until the trial’s conclusion.  In this approach, referred to as adoptive design, the effectiveness of a treatment addressing a narrow clinical indication selected on validated science, is evaluated in a small patient population in real time using statistical techniques (Barker AD, etal, Clin Pharmacol Ther, Jul 2009;86(1):97-100) based on a Bayesian model to identify regimens with ≥85% predictive probability of success.  In this manner, a decision can be quickly arrived at as to the treatment’s effectiveness.  The first attempt to employ this approach is represented by the I-SPY 2 TRIAL (Investigation of Serial studies to Predict Your Therapeutic Response with Imaging And moLecular analysis 2), a phase II clinical trial (protocol ID: 097517; NCT01042379) in women with newly diagnosed locally advanced breast cancer to test whether adding investigational drugs to standard chemotherapy is better than standard chemotherapy alone in the neoadjuvant setting (http://www.ispy2.org).  In this trial, various agents are used to treat a small number of patients with several types of breast cancer in the adjuvant setting to determine which are most effective in which patient based on disease characteristics and biomarker expression.  The trial’s primary endpoint is pathologic complete response (pCR).  The trial employs a rigorous patient profile based on the biology of each participant’s tumor and the outcome of each participant who completes treatment is used to decide treatment for women who subsequently join the trial.  Drugs that provide a benefit are then entered into late stage evaluation.

The multicenter (n=21) I-SPY-2 clinical trial, being conducted in the USA under the sponsorship of the Foundation for the National Institutes of Health Biomarkers Consortium under PI Laura Esserman, MD, at the University of California, San Francisco (UCSF), is investigating the following neoadjuvant treatment options in patients with locally advanced breast cancer versus a control arm of standard chemotherapy.

Neratinib monotherapy
Veliparib (ABT-888) plus carboplatin:
Paclitaxel, doxorubicin and cyclophosphamide
AMG 386 alone or in combination with trastuzumab
Ganitumab (AMG 479) plus metformin
MK-2206 with or without trastuzumab
Ado-trastuzumab emtansine (T-DM1) and pertuzumab
Pertuzumab and trastuzumab

At the 2013 San Antonio Breast Cancer Symposium (SABCS), investigators reported findings from the portion of the I-SPY-2 trial investigating veliparib, a PARP inhibitor in development by Abbvie, in combination with carboplatin, in the treatment of patients with HEr2-negative, operable locally advanced breast cancer in the neoadjuvant setting.  The 71 patients (TNBC=38 and Hr-positive=33) in the experimental arm were treated with veliparib (50 mg) twice daily for 12 weeks, and carboplatin (AUC=6) every 3 weeks for 4 doses; all patients in the experimental arm and the control arm (n=44) were also treated with weekly paclitaxel followed by anthracycline-based chemotherapy.  Overall, the estimated pCR rate was 22% for the control group and 33% for those treated with veliparib and carboplatin.  Among patients with TNBC, the estimated pCR rate was 26% in the control group and 52% in the veliparib/carboplatin group, for a 99% probability of superiority and 90% predicted success in a phase III clinical trial.  In contrast, the superiority among HEr2-negative, Hr-positive patients was 28%.  Additional response predictors are under evaluation (Rugo HS, etal, SABCS13, Abs. S5-02).  In addition to the veliparib/carboplatin combination, treatment results with neratinib, under development by Puma Biotechnology, were also positive.

Note: all highlighted items link to complete profiles in nm|OK.

EU Funded Consortium to Develop an Actively Personalized Vaccine (APVAC) for the Treatment of Glioblastoma
In November 2013, immatics Biotechnologies and the newly EU-funded Glioma Actively Personalized Vaccine Consortium (GAPVAC; http://gapvac.eu) selected the HLA-A*02-restricted peptides and completed GMP manufacturing, which is a prerequisite for the GAPVAC clinical trial. Patients enrolling in this trial will be vaccinated with two personalized vaccines, APVAC 1 composed of off-the-shelf pre-manufactured peptides binding to different human leukocyte antigen (HLA) receptors highly overexpressed in a patient's tumor and APVAC 2 consisting of de novo manufactured peptides from tumor-specific mutations.

GAPVAC represents 14 organizations in Europe and the USA that joined forces to develop an APVAC, a completely novel approach used to develop a fully personalized therapeutic vaccine to treat patients with glioblastoma multiforme (GBM). The EU supports GAPVAC with a €6 million grant. The consortium is being led by immatics biotechnologies as the Coordinator and BioNTech as the Vice Coordinator. The project is designed to create, develop and manufacture vaccines tailored for each patient based on the individual aspects of the patient's tumor and immune system by employing next-generation sequencing (NGS), high sensitivity mass spectrometry and innovative immunomonitoring approaches. The aim is to demonstrate that the APVAC approach is feasible, well tolerated and will induce a strong and specific immune response against cancer.

A phase I clinical trial is to be initiated in 2014, under PI Wolfgang Wick, MD, at the University of Heidelberg and Pierre-Yves Dietrich, MD, at University of Geneva, to enroll ~30 patients with newly diagnosed GBM to be treated with an individualized cancer vaccine in combination with standard chemotherapy. immatics will use its XPRESIDENT platform technology to generate tumor-associated peptides (TUMAP) from which the most suitable APVAC are to be selected for each patient based on transcriptomic and peptidomic analysis. BioNTech will add proprietary GBM-expressed tumor-associated antigens to the TUMAP. Mass spectrometry analysis, provided by immatics, and NGS expertise, provided by BioNTech, will be used to identify immunogenic tumor mutations to create a personalized vaccine that incorporates patient-specific tumor mutated peptides. According to BioNTech, the integrated use of NGS to generate the mutanome followed by mutation-targeting vaccination is feasible and leads to tumor control in preclinical models. Manufacturing will be performed by the GMP-unit at the Department of Immunology at the University Tuebingen, under the direction of Prof. Dr. Hans-Georg Rammensee, a co-founder of immatics, and by BCN Peptides in Spain. The clinical trial's biomarker program is being led by the Association of Cancer Immunotherapy (CIMT; http://www.cimt.eu) and by immatics to confirm the mechanism of action and to identify biomarker signatures to guide patient selection.

Also, in November 2013, immatics Biotechnologies and Roche signed a cancer vaccine and immunotherapy collaboration that will focus on the research, clinical development and commercialization of a number of new tumor-associated peptide (TUMAP)-based cancer vaccines and other immunotherapies in oncology, targeting primarily gastric, prostate and non-small cell lung cancer. The most advanced cancer vaccine candidate covered by the agreement is IMA942, for the treatment of gastric cancer, which is ready for phase I trials. In addition to IMA942, immatics is investigating in clinical trials 3 other vaccines for renal cell carcinoma (RCC), glioblastoma multiforme and colorectal cancer.

Yale-Novogen Venture to Develop Treatment for Ovarian Cancer by Targeting Cancer Stem Cells
In November 2013, Novogen and Yale3 University formed CanTx, a joint venture (JV) that combines research advances by Gil Mor, MD, PhD, Professor of Obstetrics, Gynecology, and Reproductive Sciences at Yale University who was the first to isolate and clone ovarian cancer stem cells, with Novogen's expertise in anticancer drug development. The JV is headquartered in New Haven and early R&D operations will take place in Dr. Mor's lab under the Novogen's Sponsored Research Agreement with the university. Novogen owns 85% of CanTx, which is headed by Graham Kelly, PhD, the CEO of Novogen. The arrangement was facilitated by the Yale Office of Cooperative Research. The focus of CanTx is to target ovarian cancer stem cells.

Dr. Mor isolated ovarian cancer stem cells over 10 years ago and formed a company, Mazor Oncology that provided a service to pharmaceutical companies that submitted their compounds to test their ability to kill these cells. The only drug that killed these cells was Novogen's phenoxodiol, which was entered into clinical trials in women with late stage ovarian cancer. Although the OVATURE (OVArian TUmor REsponse) phase III clinical trial (protocol ID: NV06-0039; NCT00382811) with phenoxodiol ultimately failed in this indication, the underlying family of drugs appeared to be active against this disease so the company went on to develop a new generation of drugs that are thousands of times more powerful and can kill cancer stem cells as well as the more prevalent somatic cancer cells.

In December 2012, Novogen completed the acquisition of 100% of the outstanding shares of Triaxial Pharmaceuticals, an unlisted Australian-based company developing a new family of potent anticancer drugs known as super benzopyrans. Trilexium (CS-6), a compound that belongs to this class of agents, kills both ovarian cancer stem and somatic cells. Currently, Novogen's immediate strategy is to develop an injectable formulation of CS-6 that can be administered intraperitoneally. One avenue pursued is to deliver the drug in nanoparticles coated with a peptide that targets tumor cells. A similar approach may be applicable to other malignancies involving the peritoneal cavity including endometrial, colorectal and pancreatic cancer. Eventually, the collaborators plan to use personalized strategies to match an individual's cancer with the appropriate drug. The ultimate goal is personalized chemotherapy using a panel of Novogen drugs to target individual tumor genotypes. In addition to developing markers to match the patient with the appropriate treatment, CanTx also plans to use markers identified in tumor biopsies or in blood tests to track how a patient responds to treatment.

FDA Approves Gazyva (Obinutuzumab or GA101) in Combination With Chlorambucil for the Treatment of Patients with Previously Untreated (First Line) Chronic Lymphocytic Leukemia (CLL)
In November 2013, the FDA approved Gazyva (obinutuzumab or GA101) in combination with oral chlorambucil chemotherapy for the treatment of patients with previously untreated (first line) chronic lymphocytic leukemia (CLL). Gazyva is the first drug approved under the FDA's Breakthrough Therapy designation and the fifth Roche oncology drug to be approved by the FDA in the past 3 years.

Approval is based on PFS results from the pivotal multicenter, open label, randomized, 3-arm phase III clinical trial (protocol ID: BO21004, 2009-012476-28; CLL1; NCT01010061), conducted in cooperation with the German CLL Study Group (GCLLSG), investigating the efficacy and safety profile of either Gazyva plus chlorambucil or MabThera/Rituxan plus chlorambucil compared to chlorambucil alone in 781 previously untreated people with CLL and co-existing medical conditions.

A total of 356 patients were randomized (2:1) to the Gazyva arm (n=238) and chlorambucil monotherapy arm (n=118). Patients randomized to the combination arm were treated with doses of IV obinutuzumab (1000 mg) on day 1 (later divided into 100 mg on day 1, followed by 900 mg on day 2), and on days 8 and 15 of the first cycle. Chlorambucil (0.5 mg/kg) was administered on days 1 and 15. During treatment cycles 2 to 6, patients were treated with obinutuzumab (1000 mg) in combination with chlorambucil (0.5 mg/kg) on days 1 and 15. Patients were also pre-medicated with a glucocorticoid, acetaminophen and anti-histamine prior to initial obinutuzumab infusions, and subsequently as needed. Patients assigned to single agent chlorambucil (0.5 mg/kg) were treated on days 1 and 15 during cycles 1 to 6. Cycles were repeated every 28 days.

According to results from this trial, median PFS was 23.0 months with obinutuzumab in combination with chlorambucil compared to 11.1 months with chlorambucil monotherapy (HR=0.16, p<0.0001). ORR was 75.9% among patients treated in the Gazyva arm compared to 32.1% in the chlorambucil monotherapy arm; CR was noted in 27.8% of patients versus 0.9% of patients, respectively.

The most common Grade 3/4 AE with the combination regimen compared to chlorambucil alone were infusion-related reactions during the first infusion (21%), thrombocytopenia (11% versus 3%) and neutropenia (34% versus 16%); higher levels of hematologic AE in the Gazyva arm did not result in an increased rate of infections.

This trial also investigated Gazyva plus chlorambucil versus MabThera/Rituxan plus chlorambucil. Final data from this portion of the trial will be presented at the annual meeting of the American Society of Hematology (ASH) in December 2013.

Marketing applications have also been submitted to other regulatory authorities, including the European Medicines Agency (EMA).

Gazyva is a third generation, humanized and optimized type II anti-CD20 IgG1 monoclonal antibody (MAb) that mediates superior caspase-independent cell death induction and enhanced antibody-dependent cellular cytotoxicity (ADCC) in comparison to other CD20 antibodies. Gazyva is being investigated in a large clinical program, including multiple phase III clinical trials comparing it to MabThera/Rituxan in indolent non-Hodgkin's lymphoma (NHL) and diffuse large B-cell lymphoma (DLBCL).

In the USA, Gazyva is being developed as part of a collaboration between Genentech and Biogen Idec.

Chronic lymphocytic leukemia (CLL) is a common hematologic malignancy. Approximately 5,000 deaths from CLL are expected in the USA 2013. About 95% of cases of CLL originate in B cells that express CD20 on their surface.

Over the past 10 years, at least 65 novel agents have entered clinical trials in CLL; 54 of these were targeted, often multi-targeted, agents addressing over 45 distinct molecular markers.

In addition to Gazyva, Roche's pipeline of potential hematology medicines includes two antibody-drug conjugates (ADC), anti-CD79b (RG7596) and anti-CD22 (RG7593), a small molecule antagonist of MDM2 (RG7112) and, in collaboration with AbbVie, a small molecule BCL-2 inhibitor (RG7601/GDC-0199/ABT-199).

Priority Review Granted to the BLA Seeking FDA Approval for Ramucirumab Monotherapy in Gastric Cancer in the Second Line Setting
In October 2013, the FDA granted Priority Review to the regulatory submission for Lilly’s anticancer drug ramucirumab (IMC-1121B) as monotherapy for advanced gastric cancer following disease progression after initial chemotherapy. If approved, ramucirumab will be the first FDA-approved therapy for patients in this setting. Stomach cancer is the second leading cause of cancer death globally.  It is anticipated that the FDA will act on this application in the second quarter of 2014. This BLA for ramucirumab was based on data from REGARD, a global, randomized, double blind phase III clinical trial that evaluated ramucirumab plus best supportive care (BSC) compared to placebo plus BSC as a treatment in patients with advanced gastric cancer, including adenocarcinoma of the gastro-esophageal junction, following progression after initial chemotherapy. A registration dossier is also under regulatory review by the European Medicines Agency (EMA) for a Marketing Authorization Application (MAA).

Lilly filed a rolling BLA in April 2013 for ramucirumab as second line monotherapy in gastric cancer based on results from REGARD, a multicenter (n=161), international, randomized phase III clinical trial (protocol ID: 13893; 2008-005964-15; CP12-0715; I4T-IE-JVBD; NCT00917384) in patients with gastric cancer. According to data reported from this trial, PFS at 12 weeks was 40% with ramucirumab versus 16% with placebo, and overall response rate was 3.4% versus 2.6%, and disease control rate was 49% versus 23%, respectively (Fuchs CS, etal, ASCOGI13, Abs. LBA5). 

Separate regulatory submissions are anticipated for the use of ramucirumab in combination with paclitaxel in the treatment of advanced gastric cancer stemming from data from the RAINBOW phase III clinical trial (protocol ID: 13894; 14-IE-JVBE; CP12-0922; 2010-020426-18; NCT01170663) that evaluated the efficacy of paclitaxel with or without ramucirumab in treating patients with locally advanced or metastatic, inoperable gastric adenocarcinoma refractory to or progressive after first line therapy with platinum and/or fluoropyrimidine agents. 

Ramucirumab is a human monoclonal antibody (MAb) that specifically blocks the vascular endothelial growth factor receptor 2 (VEGFr2) thus inhibiting downstream signaling involved in angiogenesis, the formation and maintenance of blood vessels that supply blood to tumors.

Lilly obtained ramucirumab via its acquisition of ImClone in 2008. Clinical development of ramucirumab hails from 2000 when ImClone entered the drug in a phase I clinical trial in patients with advanced solid tumors. Since then the drug has been clinically evaluated in over 30 trials. Currently, three phase II clinical trials are ongoing with ramucirumab in combination with standard chemotherapy in urinary tract and non-small cell lung cancer. Top-line results from three closed phase III clinical trials, in colorectal, hepatocellular and lung cancer, are expected in 2014.

In a set-back, ROSE, a separate multicenter (n=234), international, randomized, double blind, phase III clinical trial (protocol ID: CP12-0606; TRI0-CIRG-012; TRIO-012; EUDRACT Number: 2008-001727-65; NCT00703326), conducted in collaboration with the international cancer research group TRIO (Translational Research in Oncology), with ramucirumab in women with locally recurrent or metastatic breast cancer did not meet its primary endpoint of PFS. The trial compared ramucirumab and docetaxel to placebo and docetaxel as a first line treatment in patients with inoperable, locally recurrent or metastatic HEr2-negative breast cancer. Although PFS, the trial’s primary endpoint favored ramucirumab, the result was not statistically significant. Also, no benefit in OS was noted with ramucirumab in an interim analysis. The most common (>5% incidence) Grade >3 adverse events occurring at a higher rate on the ramucirumab-plus-docetaxel arm compared to the control arm included fatigue/asthenia, neutropenia, febrile neutropenia, hypertension and stomatitis.

Ramucirumab is one of over 30 distinct vascular endothelial growth factor receptor 2 (VEGFr2) inhibitors that have entered clinical trials. Owing to the fundamental mechanism of action, namely angiogenesis inhibition, clinical trials with these agents, the majority of which are small molecule drugs, have addressed numerous cancer indications, including all common malignancies.

The Incredible Complexity of Drug Development and Personalized Medicine in Oncology-Triple Negative Breast Cancer (TNBC)
Triple negative breast cancer (TNBC) is only one of the hundreds of distinct types of cancer.  It accounts for about 15% to 25% of all cases of breast cancer.  TNBC, characterized by a lack of expression of the hormone receptors for estrogen and progesterone and HEr2, is an aggressive form of breast cancer with no effective treatment options.  The severity of the disease and the commercial opportunity for an effective treatment that rivals the $1.5 billion market for Herceptin in triple positive breast cancer, has intensified research in this area.  Most novel agents in TNBC are in early clinical development with no standouts having emerged to date.

Worldwide, more than 1.3 million women are diagnosed with breast cancer every year and over 500,000 die of the disease.  Like all organ-originating malignancies, breast cancer is not a single disease but rather consists of a heterogeneous group of tumors with unique molecular features, prognostic outlook, and response to treatment.  Based on genomic analysis, breast cancer has been classified into 4 categories, each behaving differently in the clinic.  Triple negative breast cancer (TNBC) is a subtype of breast cancer that overlaps with basal-like breast cancer, characterized by the lack of expression of the estrogen receptor (Er) and the progesterone receptor (Pgr) and amplification of the human epidermal growth factor receptor 2 (HEr2).  In the USA, TNBC accounts for 10%-25% of all cases of breast cancer and is more frequently diagnosed in younger patients, and is more prevalent in African-American women.  Even this highly specified disease is heterogeneous in nature with certain subtypes responding differently to standard treatment protocols.

Owing to disease heterogeneity and lack of well defined molecular targets, patients with TNBC are not effectively treated with standard chemotherapy used against breast cancer.  Because TNBC does not express hormone receptors or the oncogene HEr2, it is imperative to identify other putative markers that play a role in this disease in order to design targeted anticancer therapies.   There is convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that TNBC and other subtypes likely arise through distinct etiologic pathways.

More than 24 distinct molecular markers have been described linked to TNBC based on screenings performed by various investigators on TNBC cell lines and in TNBC specimens derived from patients.  Each of these markers is also associated with other malignancies.  Although linked to some aspect of TNBC, only a handful of these molecular signatures have been tested in the clinic, either as therapeutics or as in vitro tests.  Most targeted agents currently in clinical trials in TNBC address molecular effectors with generalized involvement in cancer, such as antiangiogenesis agents, epidermal growth factor (EGF) family members, synthetic lethality modulators and other moieties that have been shown to be effective in the treatment of other malignancies.

Owing to disease heterogeneity and absence of well-defined molecular targets, specific treatments against TNBC are lacking.  Thus, patients with TNBC are treated with options generally recommended for other types of breast cancer.  Despite responding at higher rates to neoadjuvant and often adjuvant chemotherapy, TNBC recurs at a higher rate at distant sites and is associated with a poorer prognosis than other breast cancer subtypes. 

The lack of specific treatment options for patients with advanced or metastatic TNBC has intensified the search for effective therapeutic strategies.  Two distinct approaches are being pursued based on the molecular profile of TNBC, either single or multi-targeted inhibitors of specific markers/oncogenes, or inhibitors of pathways known to play a role in malignancy, in general.  Currently, over 125 trials have been initiated to investigate anticancer agents (mostly approved drugs) alone and in various combinations in TNBC; about 86 of these are ongoing and 13, almost all involving combinations of approved drugs, have advanced to phase III.   Approximately 23 agents are also being evaluated in closed and/or ongoing clinical trials in this indication.  The majority are single or multi-targeted drugs addressing over 21 distinct markers.

FDA Approves Roche's Perjeta in the Neoadjuvant Setting in Patients With HEr2-positive Breast Cancer
 In September 2013, the FDA granted accelerated approval to Roche's Perjeta (pertuzumab) in combination with Herceptin (trastuzumab) and docetaxel for the treatment of patients with high risk, HEr2-positive early stage breast cancer in the neoadjuvant setting. This approval is based primarily on data from a phase II clinical trial in which a pathologic complete response (pCR) was noted in nearly 40% of patients treated with this combination. The Perjeta regimen is the first neoadjuvant breast cancer treatment approved by the FDA and also the first to be approved based on pCR data. A full review of data from the ongoing phase III APHINITY clinical trial (protocol ID: BO25126; 2010-022902-41; BIG 04-11; TOC4939G; NCT01358877) will be required for the accelerated approval to be converted to a full approval. APHINITY compares Perjeta, Herceptin and chemotherapy with Herceptin and chemotherapy for the adjuvant treatment of patients with HEr2-positive early stage breast cancer.

Data from APHINITY are expected in 2016. The FDA had accepted the sBLA for the use of a Perjeta regimen in this setting in July 2013. The sBLA is based primarily on results from NEOSPHERE (protocol ID: WO20697; NCT00545688), and TRYPHAENA (protocol ID: BO22280; 2009-012019-17; NCT00976989), two phase II clinical trials with Perjeta in HEr2-positive early stage breast cancer, as well as on longer term safety data from the CLEOPATRA phase III clinical trial (protocol ID: TOC4129g; WO20698; NCT00567190) with Perjeta in HEr2-positive metastatic breast cancer.

Breakthrough Therapy Designation
Section 902 of the FDA Safety and Innovation Act (FDASIA), signed into law on July 9, 2012, provides for a Breakthrough Therapy designation for a drug that is intended alone or in combination with one or more other drugs to treat a serious or life threatening disease or condition and, according to preliminary clinical evidence, the drug appears to substantially improve one or more clinically significant endpoints over existing therapies as observed early in the drug's clinical development. The FDA will expedite the development and review of any drug with this designation. All requests for this designation are reviewed within 60 days of receipt, with the FDA either granting or denying the request. Additionally, a draft guidance (link) that includes qualifying criteria for breakthrough therapy designation, as well as features of the breakthrough therapy program, and guidelines on how to submit a breakthrough therapy designation request, was published on June 25, 2013. To date, the FDA granted Breakthrough Therapy designations to 7 novel oncology drugs, 3 monoclonal antibodies (MAb) and 4 orally available small molecule drugs, all having entered phase II clinical trials for the indication in consideration, and to one approved dug for an unapproved indication.

Although both developers and investors have viewed this designation as a way to quickly launch lucrative products into the market, many issues remain unresolved as there is no provision in the regulation for monitoring the performance of drugs approved under this process after they enter the market.  It is unclear how this process will work in the oncology sector, where the same drug is in development for a variety of cancer indications, as a monotherapy or in combination with other anticancer drugs, and approval of a minimally tested drug under the Breakthrough Therapy indication would make it applicable as an off-label treatment for other cancer subtypes.

NICE Evaluates 10 Methodologies Used to Detect EGFr Mutations in Lung Cancer
In August 2013, after a thorough review of 10 methodologies used to detect epidermal growth factor receptor (EGFr) tyrosine kinase mutations in the tumors of adults with previously untreated, locally advanced or metastatic non-small-cell lung cancer (nsclc), NICE recommended the use of 5 while there was insufficient evidence to make recommendations on the remaining 5 approaches (link...). 

The 5 recommended methodologies include Qiagen's therascreen EGFR RGQ PCR kit; Sanger sequencing of samples with >30% tumor cells and therascreen EGFR RGQ PCR kit for samples with lower tumor cell contents; Roche's cobas EGFR Mutation test; Sanger sequencing of samples with >30% tumor cells and cobas EGFR Mutation test for samples with lower tumor cell contents; and Sanger sequencing followed by fragment length analysis and polymerase chain reaction (PCR) of negative samples. The remaining 5 tests were high resolution melt analysis; pyrosequencing combined with fragment length analysis; single strand conformation polymorphism analysis; next-generation sequencing (NGS); and Qiagen's therascreen EGFR Pyro kit. The MALDI-TOF test was not reviewed by NICE. In the UK, test costs vary from £130.00 to £187.50.   Based on the review, NICE recommends that studies be performed to directly compare the various testing methods by re-testing stored nsclc tumor samples, and linking the results to patient outcomes. In addition, NICE recommends the design of a multivariate model to predict the response to EGFR TK inhibition of previously untreated patients with advanced or metastatic nsclc.

SCOTUS Rules That Human Genes Cannot be Patented
In June 2013, the Supreme Court overturned a lower Federal court decision that allowed Myriad Genetics' patent of two human genes, BRCA-1 and BRCA-2. Despite alarmist forecasts that the inability to patent naturally existing genes would stifle innovation in the biotechnology sector, this groundbreaking decision rendered unanimously by the Supreme Court is expected to open up this area to uninhibited development of novel and superior technologies and products. Myriad's patents on its tests to detect BRCA-1 and BRCA-2 are unaffected by this decision and remain valid through to their normal date of expiration These patents were originally granted by the USPTO in 1997. In May 2004, an opposition division at the European Patent Office (EPO) had decided to revoke the Myriad patents, which parenthetically were rarely enforced in Europe by Myriad. The Court, however allowed Myriad's patents on complementary DNA (cDNA), which refers to DNA synthesized from a messenger RNA (mRNA) template in a reaction catalyzed by the enzymes reverse transcriptase and DNA polymerase to produce gene clones.

Additional news items are summarized in the News Module.

  

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