New roles of Jak, PARP, and BTK inhibitors in cancer immunotherapies

FDA presentation focusing on trial designs to accelerate approval of promising new cancer drugs underscores the agency’s continued positive attitude towards industry. Deeper understanding of immune oncology approach. A number of abstracts will focus on correlating clinical responses for Merck & Co.’s PD-1 antibody MK-3475 with PD-L1 expression (melanoma, colorectal, lung). Additional focus includes: PD-L1 role in head/neck cancer, use of peptides to inhibit PD1 pathway, rationale for HDAC6 inhibition in combination with PDL1 blockade, novel TDO/IDO inhibitors, rationale for combining PD1/PD-L1 with IDO inhibitor.

New roles for Jak inhibitors in multiple tumor types. Presentations suggests a rationale for combining a Jak inhibitor with a BTK inhibitor in NHL specially in diffuse large B cell lymphoma (DLBCL), and using Jak2 inhibition in ovarian cancer; a loss of function Jak1 mutation study could provide a broad view of where Jak1 inhibitors may be useful in oncology.

Novel drugs targeting T790M EGFR mutant lung cancer. Multiple companies will have data for their novel inhibitor aimed at targeting lung cancer with the T790M EGFR mutation including: Clovis (CO-1686), AstraZeneca (AZD9291), Astellas (ASP8273), Innova Pharma (KL-ON113), Novartis (EEGF816), Roche/Genentech (series), and ImmunoGen (IMGN289-an ADC).

Role for PARP inhibitors beyond BRCA+ breast cancer. New data could broaden potential areas of interest for PARP inhibitors, including: a subset of lung cancer with overactive PARP, endometrial cancer, gastric cancer, Ewing’s sarcoma, in Herceptin resistant Her2+ breast cancer, head and neck cancer, and as combination therapy with a CDK inhibitor or radiation.

Novel early stage drugs of interest. New data for several products could be worth watching: Additional results for Sanofi’s anti-CD38 antibody SAR’984 in hematologic malignancies, Incyte’s selective delta PI3kinase inhibitor INC‘093, GlaxoSmithKline’s ADC ‘916 licensed from Seattle Genetics for myeloma, myeloma synergies for Celgene’s Revlimid and licensed HDAC6 inhibitor ACY-1215, Amgen’s Ang1/Ang2 antibody AMG-780 for renal cell carcinoma.

Novel roles for ibrutinib, second generation BTK inhibitor. There will be in vitro data for ibrutinib in Her2+ breast cancer cells.


Global cancer cases reach 14 million, World Health Organization says

The number of people being diagnosed with cancer in the world each year has leaped to more than 14 million, the World Health Organization says.

The data for 2012 shows a marked rise on the 12.7 million cases in 2008.

In that time the number of deaths has also increased, from 7.6 million to 8.2 million.

The rising burden of cancer is being driven by a rapid shift in lifestyles in the developing world to more closely reflect industrialised countries.

Rising rates of smoking and obesity as well as people living longer are contributing to the rise.

Lung cancer, which is mainly caused by smoking, was the most common cancer globally, with 1.8 million cases – about 13% of the total.

The WHO also described a « sharp rise » in cases of breast cancer. Both the incidence and mortality have increased since 2008. The disease in now the most common cancer in women in 140 countries.

Dr David Forman, from the WHO’s International Agency for Research on Cancer, said: « Breast cancer is also a leading cause of cancer death in the less developed countries of the world.

« This is partly because a shift in lifestyles is causing an increase in incidence, and partly because clinical advances to combat the disease are not reaching women living in these regions. »

The WHO said there was an « urgent need » for the advances made in detection, diagnoses and treatment of breast cancer to be implemented in developing nations.

The WHO predicts the number of cancer cases will soar to more than 19 million a year by 2025

NICE requests more data on bortezomib for multiple myeloma

NICE requests more data on bortezomib for multiple myeloma

In draft guidance, published today (12 November), NICE has asked Janssen to provide more data on the effectiveness of their product, bortezomib (Velcade) as a treatment for some patients with newly diagnosed multiple myeloma.
This appraisal is examining the use of bortezomib for treating multiple myeloma in combination with dexamethasone and thalidomide. The draft guidance has been issued for consultation and the manufacturer now has an opportunity to respond to the independent Appraisal Committee’s considerations and requests.
NICE has requested further evidence on the clinical and cost effectiveness of bortezomib in combination with dexamethasone compared with current standard treatment of newly diagnosed patients who are suitable for high dose chemotherapy with haematopoietic stem cell transplantation. Standard treatment in the UK is a combination of cyclophosphamide, thalidomide and dexamethasone.
The draft guidance does not currently recommend bortezomib in combination with thalidomide and dexamethasone.
Dr Carole Longson, Health Technology Evaluation Centre Director at NICE said: « The independent Appraisal Committee could not assess whether bortezomib in combination with dexamethasone is a cost-effective treatment option because it did not have sufficient information to do so. The next step in the NICE process is for the manufacturer to consider the Committee’s comments and respond to its request for further evidence. »
Consultees, including the manufacturer, healthcare professionals and members of the public are now able to comment on the preliminary recommendations which are available for public consultation. Comments received during this consultation will be fully considered by the Committee and following this meeting the next draft guidance will be issued.
Until final guidance is issued, NHS bodies should make decisions locally on the funding of specific treatments. Once NICE issues its final guidance on a technology, it replaces local recommendations across the country.
1. The draft guidance will be available from 12 November 2013. Embargoed copies of the draft guidance are available from the NICE press office on request.
2. The cost of bortezomib is £762.38 per 3.5 mg vial. The average cost of a course of treatment with bortezomib given with dexamethasone is estimated to be £12,260.91 and the average cost of a course of treatment with bortezomib given with dexamethasone and thalidomide is estimated to be £24,840.10.
3. The Committee agreed that treatment with bortezomib and dexamethasone was associated with statistically significant improvements in post-induction overall response rates compared with vincristine, adriamycin and dexamethasone, whereas induction treatment with bortezomib, thalidomide and dexamethasone resulted in statistically significant improvements in overall response rates (post-induction and post-stem cell transplantation) and progression-free survival compared with thalidomide and dexamethasone. However, it concluded that no direct evidence was available to compare the efficacy of bortezomib, thalidomide and dexamethasone or bortezomib and dexamethasone with cyclophosphamide, thalidomide and dexamethasone, the comparator regimen considered to be current standard of care in the UK.
4. The most plausible cost per quality-adjusted life year (QALY) for bortezomib, thalidomide and dexamethasone compared with cyclophosphamide, thalidomide and dexamethasone was likely to be substantially higher than the £39,000 per QALY compared with thalidomide and dexamethasone.
5. NICE already recommends bortezomib as an option for the treatment of progressive multiple myeloma in people who are at first relapse having received one prior therapy and who have undergone, or are unsuitable for, bone marrow transplantation. NICE Technology Appraisal 129
6. Thalidomide in combination with an alkylating agent and a corticosteroid is recommended as an option for the first-line treatment of multiple myeloma in people for whom high-dose chemotherapy with stem cell transplantation is considered inappropriate. Bortezomib (Velcade, Janssen) is also recommended under these circumstances, if the person is unable to tolerate or has contraindications to thalidomide. NICE Technology Appraisal 228
7. Lenalidomide in combination with dexamethasone is recommended as a treatment option for people with multiple myeloma who have received two or more prior therapies.
About NICE
The National Institute for Health and Care Excellence (NICE) is the independent body responsible for driving improvement and excellence in the health and social care system. We develop guidance, standards and information on high-quality health and social care. We also advise on ways to promote healthy living and prevent ill health.
Formerly the National Institute for Health and Clinical Excellence, our name changed on 1 April 2013 to reflect our new and additional responsibility to develop guidance and set quality standards for social care, as outlined in the Health and Social Care Act (2012).
Our aim is to help practitioners deliver the best possible care and give people the most effective treatments, which are based on the most up-to-date evidence and provide value for money, in order to reduce inequalities and variation.
Our products and resources are produced for the NHS, local authorities, care providers, charities, and anyone who has a responsibility for commissioning or providing healthcare, public health or social care services.
To find out more about what we do, visit our website: and follow us on Twitter: @NICEComms.


Roche’s medicine Avastin plus chemotherapy improved survival in women with advanced cervical cancer, compared to chemotherapy alone

Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced the results of a large, independent study (GOG240) sponsored by the US National Cancer Institute (NCI) and conducted by the Gynecologic Oncology Group (GOG), which showed that the addition of Avastin (bevacizumab) to chemotherapy (paclitaxel and cisplatin or paclitaxel and topotecan) extended the lives of women with advanced cervical cancer, compared to chemotherapy alone. The study met its primary endpoint of improving overall survival with a statistically significant 29 percent reduction in the risk of death for women who received Avastin plus chemotherapy compared to those who received chemotherapy alone (HR=0.71, p=0.0035).

Women who received Avastin plus chemotherapy lived a median of 3.7 months longer compared to those who received chemotherapy alone; the median overall survival (OS) was 17 months with Avastin plus chemotherapy compared to 13.3 for chemotherapy alone. No new safety signals related to Avastin were observed and overall safety was consistent with that seen in previous pivotal studies of Avastin across different tumour types.

“Worldwide, cervical cancer is the third most common cancer in women, and those who have an advanced form of this cancer need new medicines”, said Hal Barron, M.D., chief medical officer and head, Global Product Development. “We’d like to thank the GOG for their leadership and the NCI for their support of the study. We plan to discuss these encouraging data with regulatory authorities.”

It is estimated that there are more than half a million cases of cervical cancer worldwide each year,1 with approximately 85% of those in developing countries.1 Besides effective treatment, it is also critical that more women have access to vaccination against human papilloma virus (HPV; the cause of the vast majority of cervical cancers) and to screening for precancerous lesions. These approaches can prevent women from developing advanced clinical disease.

Source: Roche

Chronic myelogenous leukemia (CML) Drug Development Opportunities

Leukemia is the neoplastic proliferation of the hematopoietic cells. These cells are undifferentiated or partially differentiated stages of maturation. As a consequence of the immature leukocytes excessive proliferation, these cells eventually replace the normal blood-forming elements, resulting in the patient presenting with clinical and laboratory evidence of leukopenia, anemia, and thrombocytopenia.


In terms of incidence, chronic myelogenous leukemia (CML) is the second most frequent form of myeloid leukemia after acute myeloid leukemia (AML), accounting for approximately the third of all incident cases of myeloid leukemias. However, the CML prognosis is good, resulting in the number of prevalent cases of CML outnumbering those of AML based on survival data analysis from the United States (SEER, 2011). Although, the risk of developing CML is very low, its status as a chronic disease implies a disproportionately large burden of disease and period of treatment, with many CML patients being maintained on a course of drug therapy for many years (Hochhaus A, 2008).

CML is identified by the ICD-10 code C92.1, three phases of CML are defined, in ascending order of severity as follows: chronic, accelerated, blastic. Most patients eventually progress to an accelerated phase and finally develop a blast crisis. The majority of patients who develop a blast crisis have a myeloid lineage to develop acute myeloid lymphoma. In contrast, less than 20% of patients progress through blast crisis with a lymphoid lineage to acute lymphocytic lymphoma.


Therapy Overview

Given the systemic nature of leukemia, the primary treatment modality is chemotherapy. Stem cell transplantation (SCT) is sometimes utilized for the treatment of CML, similar to its use for the treatment of the acute leukemias, but it’s now used less frequently for CML, basically  because these patients are often elderly, and in part due to the introduction of Gleevec® (imatinib mesylate, Novartis).

The Gleevec launch has change the treatment guidelines for CML. While originally indicated for use in advanced patients, it has moved forward to treat patients in earlier disease stage. Gleevec, a specific inhibitor of the BCR-ABL tyrosine kinase, is the primary chemotherapy agent used to treat CML.

Usually, chemotherapy has not been proven to increase survival in CML, but it does significantly improve the life quality. The complete remission is not appropriate for CML treatment with chemotherapy, because the chromosome abnormalities persist or only transiently disappear during therapy. The goal of therapy has primarily been to relieve symptoms and to control disease.


Stem Cell Transplantation

Allogeneic SCT (allo SCT), which used a donor, as opposed to autologous SCT (auto SCT), which uses the patient’s own stem cells following chemotherapy, results in the lowest incidence of leukemic relapse. This finding has led to the concept of an immunologic graft-versus-leukemia effect similar to graft-versus-host disease (GVHD).

Interferon alfa (IFNα) and hydroxyurea are standard treatments used to stabilize patients prior to SCT. Two retrospective series following allo SCT from a human leukocyte antigen (HLA)-matched unrelated donor showed a five-year relapse rate of 3% to 10% and a five-year overall survival rate of 31% to 57% (most deaths were treatment-related). Cyclosporine and methotrexate are used to prevent GVHD, and the relapse incidence at five years ranges from 20% to 30%. However, if T-cell depletion is used to minimize GVHD, relapse increases to 60% to 70%.


Tyrosine Kinase Inhibitors


Gleevec has revolutionized the treatment of CML patients. The drug targets the abnormal BCR-ABL kinase chromosomal translocation. Patients with this translocation, the Ph chromosome, are said to be Ph+. Gleevec does not cure CML, but effectively suppresses it and prolongs the lives of these patients. It inhibits proliferation and induces apoptosis of BCR-ABL-positive cells. Besides Gleevec, these patients can be treated with regimens containing IFNα, cytarabine, and/or hydroxyurea if they are eligible for transplantation. The prognosis of accelerated and blast- phase patients has been improved by Gleevec based on historical controls.



Sprycel® (dasatinib, Bristol-Myers Squibb) is a tyrosine kinase inhibitor, like Gleevec, that targets BCR-ABL.

Sprycel interact with forms of the enzyme that do not respond to Gleevec, such as those with mutations. Until 2006, once patients no longer responded to Gleevec, they had a poor prognosis with few remaining options. Long-term follow-up of the pivotal Gleevec trial showed that 3.3% of chronic-phase patients become refractory or insensitive to Gleevec in the first year of therapy, 7.5% become refractory/insensitive in the second year, 4.8% in the third year, 1.5% in the fourth year, and 0.9% in the fifth year. Of patients who receive Gleevec as second-line therapy after first-line interferon therapy, 25% experience progressive disease at 48 months. Of newly diagnosed patients in accelerated and blast phases treated with Gleevec, 24% and 66%, respectively, do not reach hematologic remission. This revealed unmet patients need in who do not respond or lose response to Gleevec. Sprycel was approved in 2006 for use in these patients, and was recently approved by the FDA for newly diagnosed patients.



Tasigna® (nilotinib, Novartis) is another tyrosine kinase inhibitor of BCR-ABL approved for the treatment of Gleevec-resistant/-intolerant patients. It was designed by Novartis to have a higher affinity for BCR-ABL than Gleevec, thereby earning itself the nickname “Super Gleevec.”



CML Drug Development Opportunities

As dasatinib (Bristol-Myers Squibb/Otsuka’s Sprycel) and nilotinib (Novartis’s Tasigna) start to be used more frequently in the first-line setting for chronic myeloid leukemia (CML), following their 2010 FDA approval in this setting, some experts raise concerns that fewer treatment choices will be available for patients who become refractory to up-front treatment. Although imatinib (Novartis’s Gleevec/Glivec) has been used for the past decade as first-line treatment for patients with CML, U.S. and European approvals of the second-generation tyrosine kinase inhibitors (TKIs) (i.e., dasatinib

and nilotinib) in 2010 as first-line therapies for CML patients will alter the CML treatment landscape.

Robust molecular responses, in comparison with imatinib, were observed for nilotinib in the ENESTnd trial and for dasatinib in DASISION trial (Kantarjian H, 2011; Larson RA, 2011). US and European KOL indicates that they will continue to prescribe imatinib over the second-generation TKIs because more long-term data are available for imatinib as a first-line therapy than for the second-generation TKIs and because reimbursement may be an issue with the second-generation TKIs in this setting.

Interviewed oncologists, KOL, and experts think that intermediate and high-risk patients as well as patients with primary resistance to imatinib in particular might benefit the most from a more potent second-generation TKI as up-front treatment. Using a potent second generation TKI as first-line therapy typically means that the less potent imatinib will never be used during a patient’s course of treatment so a line of therapy is lost with use of up-front dasatinib or nilotinib. In addition, many unanswered questions remain regarding the long-term use of second generation TKIs—in particular, some experts are concerned about an increasing incidence of hard-to treat BCR-ABL mutations (e.g., T315I). In addition to the T315I mutation, other BCR-ABL mutations arise in the course of TKI treatment, and switching to another non-treatment-resistant TKI is typically the best solution. However, patients may be limited by which TKIs they receive based on risk factors, mutational status, and/or comorbidities. Therefore, it remains necessary to develop additional treatments that not only improve outcomes for CML patients who have become refractory to initial treatment with a TKI but also for a wide variety of patients with different health characteristics. Several therapies are in development for treatment refractory CML, some of which address the therapeutic needs of patients with the T315I mutation.

Although they will target a subset of patients in an indication that has low incidence, treatments fulfilling these unmet needs will be commercially compelling because they will be able to command premium pricing and are treatments that patients take for many years. Although dasatinib and nilotinib are both frequently used to treat patients who become refractory to initial treatment with a TKI, we selected dasatinib as the comparator for our target product profile study. In the United States, these treatments are both widely prescribed for CML.


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