Two recent phase III trials, BOLERO-1 and BOLERO-3 (Breast Cancer Trials of Oral Everolimus), evaluated the addition of everolimus to trastuzumab and chemotherapy in human epidermal growth factor receptor 2-overexpressing advanced breast cancer. The current analysis aimed to identify biomarkers to predict the clinical efficacy of everolimus treatment.
Archival tumor samples from patients in BOLERO-1 and BOLERO-3 were analyzed using next-generation sequencing, immunohistochemistry, and Sanger sequencing.
Biomarker data were available for 549 patients. PIK3CA activating mutations and PTEN loss were reported in 30% and 16% of BOLERO-1 samples and in 32% and 12% of BOLERO-3 samples, respectively. PI3K pathway was hyperactive (PIK3CA mutations and/or PTEN loss and/or AKT1 mutation) in 47% of BOLERO-1 and 41% of BOLERO-3 samples. In both studies, differential progression-free survival (PFS) benefits of everolimus were consistently observed in patient subgroups defined by their PI3K pathway status. When analyzing combined data sets of both studies, everolimus was associated with a decreased hazard of progression in patients with PIK3CA mutations (hazard ratio [HR], 0.67; 95% CI, 0.45 to 1.00), PTEN loss (HR, 0.54; 95% CI, 0.31 to 0.96), or hyperactive PI3K pathway (HR, 0.67; 95% CI, 0.48 to 0.93). Patients with wild-type PIK3CA (HR, 1.10; 95% CI, 0.83 to 1.46), normal PTEN (HR, 1.00; 95% CI, 0.80 to 1.26), or normal PI3K pathway activity (HR, 1.19; 95% CI, 0.87 to 1.62) did not derive PFS benefit from everolimus.
This analysis, although exploratory, suggests that patients with human epidermal growth factor receptor 2-positive advanced breast cancer having tumors with PIK3CA mutations, PTEN loss, or hyperactive PI3K pathway could derive PFS benefit from everolimus.
© 2016 by American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper).

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Follicular lymphoma (FL) is the second most common type of lymphoid cancer in Western Europe.
The aim of this study was to evaluate the cost utility of rituximab-bendamustine treatment compared with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) treatment as a first-line therapy for patients with advanced FL in Spain.
A Markov model was developed to estimate the cost effectiveness of rituximab-bendamustine compared with R-CHOP as first-line treatment for patients with advanced FL in the Spanish National Health System (NHS). Transitions between health states (progression-free, including induction and maintenance; first relapse; second relapse; and death) were allowed for the patient cohort in 4-week-long cycles. Clinical data for the extrapolation of progression-free survival curves were obtained from randomized trials. Mortality rates and utilities were obtained from the literature. Outcomes were measured as quality-adjusted life-years (QALYs). The total costs (€, 2013) included drug costs (ex-factory prices with mandatory deductions), disease management costs and adverse event-associated costs. Costs and outcomes were discounted at a 3 % annual rate. Probabilistic sensitivity analysis was performed using 10,000 Monte Carlo simulations to assess the model robustness.
Treatment and administration costs during the induction phase were higher for rituximab-bendamustine (€17,671) than for R-CHOP (€11,850). At the end of the 25-year period, the rituximab-bendamustine first-line strategy had a total cost of €68,357 compared with €69,528 for R-CHOP. Health benefits were higher for rituximab-bendamustine treatment (10.31 QALYs) than for R-CHOP treatment (9.82 QALYs). In the probabilistic analysis, rituximab-bendamustine was the dominant strategy over treatment with R-CHOP in 53.4 % of the simulations.
First-line therapy with rituximab-bendamustine in FL patients was the dominant strategy over treatment with R-CHOP; it showed cost savings and higher health benefits for the Spanish NHS.

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On April 20, 2016 Spectrum Pharmaceuticals (NasdaqGS: SPPI), a biotechnology company with fully integrated commercial and drug development operations with a primary focus in Hematology and Oncology, reported that the U.S. Food and Drug Administration (FDA) Office of Orphan Products Development (OOPD) has granted 7 years of Orphan Drug Exclusivity for EVOMELA for use as a high-dose conditioning treatment prior to hematopoietic progenitor (stem) cell transplantation in patients with multiple myeloma (Press release, Spectrum Pharmaceuticals, APR 20, 2016, View Source [SID:1234511152]). EVOMELA has also been recently listed in the Orange Book, including two composition of matter patents that do not expire until March 2029.

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"We are pleased to receive FDA Orphan Drug Exclusivity for EVOMELA, another important regulatory milestone for Spectrum," said Rajesh C. Shrotriya, MD, Chairman and Chief Executive Officer of Spectrum Pharmaceuticals. "EVOMELA is reconstituted with normal saline and does not contain propylene glycol. EVOMELA’s formulation is based on Captisol technology and is stable at room temperature for 1 hour following reconstitution and for an additional 4 hours after further dilution. We believe EVOMELA has the potential to become an important therapy for multiple myeloma patients undergoing high-dose conditioning treatment prior to hematopoietic stem cell transplantation and fits very well with our existing Hematology/Oncology infrastructure. Revenues from our niche products like EVOMELA help us develop our late-stage drugs that target blockbuster markets."

The FDA Orphan Drug Designation program provides a special status to drugs and biologics intended to treat, diagnose or prevent so-called orphan diseases and disorders that affect fewer than 200,000 people in the U.S. Orphan Drug Designation provides the sponsor certain benefits and incentives, including a period of marketing exclusivity if regulatory approval is ultimately received for the designated indication, potential tax credits for certain activities, eligibility for orphan drug grants, and the waiver of certain administrative fees.

Spectrum Pharmaceuticals gained global development and commercialization rights to EVOMELA from Ligand Pharmaceuticals Incorporated (NASDAQ: LGND) in March 2013. Spectrum assumed responsibility for completing the pivotal Phase 2 clinical trial, and was responsible for filing the NDA. Under the license agreement, Ligand received a license fee, and NDA approval milestone, and is eligible to receive further potential milestones and royalties in connection with commercialization.

About Multiple Myeloma

Multiple Myeloma is a systemic malignancy of plasma cells that accumulate in the bone marrow, usually associated with monoclonal antibody secretion, and results in bone marrow failure and bone destruction. It is the second most common hematologic disease with nearly 30,000 new cases projected in the US in 2016 and over 11,000 deaths annually (American Cancer Society Stats, 2016). The rate of autologous stem cell transplantation (ASCT) for patients with MM is growing by approximately 3.3% annually.

Melphalan is the most commonly used IV agent for high-dose conditioning for patients undergoing ASCT for MM. The current IV melphalan market is approximately $100 million annually, with predominant use in ASCT; EVOMELA is the only intravenous melphalan product that is approved for use in the high-dose conditioning indication.

About EVOMELA

EVOMELA was approved by FDA based on its bioequivalence to the standard melphalan formulation (Alkeran) in a Phase 2 clinical study (Aljitawi et al, Bone Marrow Transplant, 2014) via the 505(b)(2) regulatory pathway. EVOMELA has been granted Orphan Drug Designation by the FDA for its use as a high-dose conditioning regimen for patients with MM undergoing ASCT.

EVOMELA’s melphalan formulation does not contain propylene glycol. The use of the Captisol technology to reformulate also contributes to the 4-hour admixture stability of EVOMELA at room temperature. This is in addition to the 1 hour stability of reconstituted EVOMELA drug product at room temperature and 24 hour stability at refrigerated temperature (5°C).

Please see the Important Safety Information below and the full prescribing information, including BOXED WARNINGS, for EVOMELA at www.evomela.com.

Important Safety Information

WARNING: SEVERE BONE MARROW SUPPRESSION,
HYPERSENSITIVITY, and LEUKEMOGENICITY

Severe bone marrow suppression with resulting infection or bleeding may occur. Controlled trials comparing intravenous (IV) melphalan to oral melphalan have shown more myelosuppression with the IV formulation. Monitor hematologic laboratory parameters.

Hypersensitivity reactions, including anaphylaxis, have occurred in approximately 2% of patients who received the IV formulation of melphalan. Discontinue treatment with EVOMELA for serious hypersensitivity reactions.

Melphalan produces chromosomal aberrations in vitro and in vivo. EVOMELA should be considered potentially leukemogenic in humans.

Contraindications

History of serious allergic reaction to melphalan.
Warnings and Precautions

Nausea, vomiting, diarrhea or oral mucositis may occur. Provide supportive care using antiemetic and antidiarrheal medications as needed.

Hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice have been reported after treatment with melphalan. Hepatic veno-occlusive disease has also been reported. Monitor liver chemistries.
EVOMELA can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to avoid pregnancy during and after treatment with EVOMELA. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, advise the patient of potential risk to the fetus.

Melphalan-based chemotherapy regimens have been reported to cause suppression of ovarian function in premenopausal women, resulting in persistent amenorrhea in approximately 9% of patients. Reversible or irreversible testicular suppression has also been reported.

Adverse Reactions

The most common adverse reactions observed in at least 50% of patients with multiple myeloma treated with EVOMELA were neutrophil count decreased (100%), white blood cell count decreased (100%), lymphocyte count decreased (98%), platelet count decreased (98%), diarrhea (93%), nausea (90%), fatigue (77%), hypokalemia (74%), anemia (66%), and vomiting (64%).
In a single-arm clinical study, twelve (20%) patients with multiple myeloma who received EVOMELA conditioning for ASCT experienced a treatment emergent serious adverse reaction. The most common serious adverse reactions ( > 1 patient, 1.6%) were pyrexia, hematochezia, febrile neutropenia, and renal failure.

In a randomized clinical trial studying the palliative treatment of patients with multiple myeloma, severe myelotoxicity (WBC ≤1,000 and/or platelets ≤25,000) was more common in the IV melphalan arm (28%) than in the oral melphalan arm (11%).
Drug Interactions

No formal drug interaction studies have been conducted. When nalidixic acid and IV melphalan are given simultaneously, the incidence of severe hemorrhagic necrotic enterocolitis has been reported to increase in pediatric patients.
Use in Specific Populations

It is not known whether melphalan is present in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from melphalan, breastfeeding is not recommended during treatment with EVOMELA.

Advise females of reproductive potential to avoid pregnancy, which may include the use of effective contraception methods, during and after treatment with EVOMELA.

For Palliative Treatment, consider dose reduction for patients with renal impairment receiving EVOMELA.
About Captisol

Captisol is a patent-protected, chemically modified cyclodextrin with a structure designed to optimize the solubility and stability of drugs. Captisol was invented and initially developed by scientists in the laboratories of Dr. Valentino Stella at the University of Kansas’ Higuchi Biosciences Center for specific use in drug development and formulation. This unique technology has enabled six FDA-approved products, including Onyx Pharmaceuticals’ Kyprolis, Baxter International’s Nexterone and Merck’s NOXAFIL IV. There are also more than 30 Captisol-enabled products currently in clinical development.

On April 20, 2016 Puma Biotechnology, Inc. (NYSE: PBYI), a biopharmaceutical company, reported that its drug candidate neratinib was highlighted in three poster presentations at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 (Press release, Puma Biotechnology, APR 20, 2016, View Source [SID:1234511151]). The AACR (Free AACR Whitepaper) Annual Meeting was held at the Ernest N. Morial Convention Center in New Orleans from April 16 to April 20.

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Abstract Number 298: Amplification of mutant ERBB2 drives resistance to the irreversible kinase inhibitor neratinib in ERBB2-mutated breast cancer patients.

On Sunday April 17th, preclinical data was presented from studies performed to identify possible mechanisms of acquired resistance to neratinib therapy in ERBB2-mutated breast cancers. Data from three breast cancer patients in the ongoing phase II SUMMIT basket study of neratinib in ERBB2-mutant cancers who progressed following initial benefit from neratinib treatment identified a common genomic alteration in their tumors. More specifically, targeted exome sequencing of biopsies collected at time of disease progression revealed increased copy number of the ERBB2-mutant allele. In addition, enhanced receptor activity in the ERBB2-mutant cells correlated with increased formation of ERBB2/ERBB3 dimers, activation of the PI3K/AKT pathway and in vivo tumorigenic potential. Combined ERBB2 and ERBB3 inhibition efficiently inhibited phosphorylation of ERBB2/ERBB3 and cell proliferation. These studies indicate that amplification of mutated ERBB2 may promote increased ERBB2/ERBB3 dimerization, ERBB3 activation, and subsequent downstream signaling activation and that dual ERBB2/ERBB3 blockade may be a potential strategy to delay or prevent resistance to neratinib in ERBB2-mutant breast tumors.

Abstract Number 3140: Differential clonal selection in tumor tissue and cell-free DNA from a neratinib-treated refractory breast cancer patient harboring an activating ERBB2 (HER2) mutation.

On Tuesday April 19th, data was presented from a patient who was part of the ongoing Copenhagen Prospective Personalized Oncology (CoPPO) research program. This program aims to offer patients with limited treatment options targeted treatments against actionable driver mutations that have been identified in circulating cell free DNA in patients by using whole exome sequencing. The poster presented data from a patient with metastatic HER2-negative and estrogen receptor (ER)-positive breast cancer (Luminal A) who had previously been exposed to seven lines of chemotherapy as well as ER antagonists and aromatase inhibitors. After examination by whole exome sequencing, an activating mutation in ERBB2 (S310Y) was found and consequently the patient was treated with neratinib through a compassionate use program. Neratinib caused a rapid decrease in the allelic frequency of ERBB2 (S310Y) cell free DNA after 2 days, with a continuous decline during the next 7 days. Consistent with this neratinib treatment effect, MRI scans showed regression of the liver metastases. After 5 months on neratinib, the patient progressed with the appearance of brain metastases, which were surgically removed and subject to whole exome sequencing. The ERBB2 mutation observed in the liver metastasis could not be identified in the brain metastases. However, more than 300 new variants were exclusively identified in the brain metastases, among these ERBB3 as well as new PIK3CA, and ESR1 mutations, that were not present in the pre-treatment cell free DNA samples. In conclusion, neratinib was able to suppress an activating ERBB2 mutation in a heavily pre-treated ER+ breast cancer patient. However, refractory tumor clones harboring ERBB3, PIK3CA and ESR1 mutations developed in brain. The poster indicated that combining neratinib with fulvestrant or inhibitors of the HER3/PI3K/AKT/mTOR pathway might prove beneficial to overcome potential resistance mechanisms to therapy.

Abstract Number 4760: Efficacy of EGFR/HER2 duel-kinase inhibitors in PDX models harboring known and novel HER2-mutations.

On Wednesday April 20th, preclinical studies to better understand effects of HER2 mutations were presented. Patient-derived xenograft (PDX) tumor models representing colorectal, ovary, pancreas and endometrial cancers were evaluated in vivo, testing the antitumor activity of neratinib, afatinib, lapatinib, trastuzumab and T-DM1 administered on standard treatment regimens. In vivo treatment with neratinib or afatinib resulted in tumor growth inhibition in some tested models including ST022 (HER2G366R/R678Q) ovary and ST204 (HER2A386D) pancreas and tumor regressions were reported with either agent in the ST427 (HER2V777L) colorectal line. Neratinib or afatinib were also found active in one each of four tested endometrial models. Lapatinib, trastuzumab and T-DM1 were inactive in all tested HER2-mutant models.

The abstracts of the three presentations described above are available online at: View Source;DetailItemID=363#.Vusrr-IrKUk.

On April 20, 2016 Peregrine Pharmaceuticals, Inc. (NASDAQ:PPHM) (NASDAQ:PPHMP), a biopharmaceutical company focused on developing therapeutics to stimulate the body’s immune system to fight cancer, reported the presentation of preclinical study data demonstrating enhanced anti-tumor activity and immune activation for a combination of the preclinical bavituximab equivalent (ch1N11) and anti-PD-1 therapy in models of breast cancer including triple negative breast cancer (TNBC) (Press release, Peregrine Pharmaceuticals, APR 20, 2016, View Source [SID:1234511150]). Additionally, new analysis conducted using the nCounter PanCancer Immune Profiling Panel from NanoString Technologies further validated previously reported findings showing that the combination treatment induced a shift in the tumor microenvironment from immunosuppressive to immune active. This was evidenced by a distinct change in immune cell phenotypes, as well as an increase in immune activating cytokines and decrease in immunosuppressive cytokines. These study results, which were presented at the 2016 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, provide further support for Peregrine’s strategy of evaluating bavituximab in combination with a range of novel immuno-oncology (I-O) agents for the treatment of various cancers.

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"These presented study results, particularly the significant increase in overall survival and immunity to tumor re-challenge seen with the treatment combination as compared to anti-PD-1 therapy alone, continue to strengthen our collection of translational and preclinical data supporting the potential for bavituximab to enhance the therapeutic impact of I-O agents in the treatment of cancer. In doing so, these data provide further rationale for our clinical strategy focused on studying bavituximab in combination with I-O agents targeting the PD-1/PD-L1 pathway in a range of cancers," stated Jeff T. Hutchins, Ph.D., Peregrine’s vice president, preclinical research. "With a wealth of supportive research in hand, we look forward to the continued advancement of our clinical collaborations with AstraZeneca, the National Comprehensive Cancer Network and Memorial Sloan Kettering Cancer Center, to further evaluate the therapeutic potential of bavituximab with novel I-O agent combinations."

Bavituximab is an investigational immunotherapy designed to assist the body’s immune system by targeting and modulating the activity of phosphatidylserine (PS), a highly immune-suppressive signaling molecule expressed broadly on the surface of cells in the tumor microenvironment. Peregrine’s PS signaling pathway inhibitor candidates, including bavituximab, reverse the immunosuppressive environment that many tumors establish in order to proliferate, while also activating immune cells that target and fight cancer. The preclinical equivalent of bavituximab, ch1N11, is used in animal model studies as a guide for clinical development.

As part of the study that was presented at AACR (Free AACR Whitepaper), researchers evaluated the combination of ch1N11 and anti-PD-1 therapy versus anti-PD-1 stand-alone therapy in two well-characterized murine models of TNBC (EMT-6 and E0771). Study data showed that the combination therapy significantly enhanced overall survival (p=0.0155) and was capable of mediating complete tumor regressions in a greater number of subjects compared to single agent treatments (60% vs. 20%). Data also demonstrated that animals receiving combination treatment had significant increases in tumor associated indicators of immune system activation, including CD45+, CD8+ and CD3+ T-cells. Importantly, the combination treatment led to a prolonged anti-tumor immune response which protected the animals that achieved a complete tumor regression against a re-challenge with the same E0771 TNBC model tumor cells. This sustained anti-tumor response demonstrates the ability of the combination treatment to trigger immune system memory and support adaptive immune responses against reemerging disease in this TNBC model. All study animals experienced no signs of adverse effects or weight loss following repeated doses of all therapeutic agents.

About Bavituximab: A Targeted Investigational Immunotherapy
Bavituximab is an investigational chimeric monoclonal antibody that targets phosphatidylserine (PS). Signals from PS inhibit the ability of immune cells to recognize and fight tumors. Bavituximab is believed to override PS mediated immunosuppressive signaling by blocking the engagement of PS with its receptors as well as by sending an alternate immune activating signal. PS targeting antibodies have been shown to shift the functions of immune cells in tumors, resulting in multiple signs of immune activation and anti-tumor immune responses.