Innovations in oncology

How will we treat cancer tomorrow

Galina Galkovskaya, "Weekly Pharmacy" www.apteka.ua No. 33-2013

Oncological pathology is a heterogeneous group of diseases that can develop in any part of the body. Malignant neoplasms are one of the main causes of death in the world. In 2008 they caused 7.6 million deaths (13% of total mortality; WHO, 2012). According to WHO forecasts, morbidity and mortality will increase, and in 2030 pathology will claim more than 13 million lives.

Despite the progress that exists today in understanding the causes of cancer and an integrated approach to their treatment, there is no need to talk about a real solution to these problems. And although the main goals of the treatment of nosologies, according to WHO, are to cure or significantly prolong the life of patients while improving the quality of life, the question of whether this is actually feasible remains, unfortunately, rhetorical. Especially when it comes to healthcare in developing countries, where many patients do not have access to modern expensive drugs. In addition, in the world of oncology, the terms "average life expectancy", "median time before the development of metastases" are still used, and the very concept of "cure" for many types of diseases is rarely used.

At the same time, it is not worth sprinkling ashes on your head. The scientific community and the largest pharmaceutical companies are actively working towards finding ways to improve the effectiveness of antitumor therapy, which implies the improvement of existing and the development of innovative drugs. And this work does not remain fruitless: the effectiveness of therapy increases.

In order to bring a new drug to the US or EU market, it must successfully pass all the necessary studies, during which its effectiveness will be proven, as well as the safety profile studied. This path requires a lot of material costs and time. Thus, according to the Association of Researchers and Manufacturers of Pharmaceutical Products of the USA (Pharmaceutical Research and Manufacturers of America – PhRMA), the period from the beginning of drug development to its introduction to the market is 9.5-15 years.

However, in cases where the presented results of the early phases of clinical trials indicate the high effectiveness of a candidate for drugs, this period may be shortened. This is due to the fact that in the treatment of oncological diseases, the use of effective therapy cannot be postponed in time, because for many patients this drug may be the only chance for life.

This publication is dedicated to candidates for drugs that are at the stage of clinical trials. The US Food and Drug Administration (FDA) has given these agents the status of "Breakthrough Therapy", and it remains to be hoped that at the final stages of clinical trials their effectiveness will be confirmed and the drugs will soon be approved for use (table).

Candidate drugs for the treatment of oncological diseases,
being at various stages of clinical trialsTitle

Ibrutinib ("Pharmacyclics" and "Johnson&Johnson")Ibrutinib is a selective inhibitor of Bruton tyrosine kinase, which plays an important role in the maturation and functioning of B lymphocytes and other blood cells.

This signaling molecule is overexpressed in many types of B-cell lymphoma and prevents the implementation of programmed cell death.

The results of phase II clinical trials have demonstrated the high efficacy of the drug candidate. Currently, Pharmacyclics and Johnson & Johnson, whose cooperation began in December 2011, are conducting 5 Phase III clinical trials. The published interim research results indicate its effectiveness and a favorable safety profile. With the use of this agent, the progression of the disease was suspended in 96% of newly treated patients and in 75% of patients at risk of tumor progression. The data were obtained 26 months after the start of the use of the drug candidate.

If it is approved for the treatment of chronic lymphocytic leukemia, according to the forecast of analysts of the company "FierceBiotech", the annual volume of its sales may amount to 5 billion US dollars. Of course, the prospect that ibrutinib could become a blockbuster had a positive impact on the market value of the Pharmacyclics company – today it is estimated at $ 6.5 billion.

Currently, the FDA has given ibrutinib the status of a "revolutionary therapy". This drug candidate may be approved by the FDA for use in chronic lymphocytic leukemia and mantle zone lymphoma by the end of this year.

Nivolumab ("Bristol-Myers Squibb" and "Ono Pharmaceutical")Nivolumab is a monoclonal antibody that blocks the ligand–activated pathway of programmed cell death 1 (Programmed cell death 1 pathway – PD-1).

It is one of the most promising candidates for drugs for use as immunotherapy for oncological diseases.

Normally, T-killers eliminate tumor cells, but when the PD-1 signaling pathway is disrupted due to the disease, this does not happen. The development companies have relied on the creation of a therapy that directly affects the development of an immune response that allows them to support the fight against tumor cells.

Currently, Bristol-Myers Squibb is conducting 6 late-stage clinical trials, which study the effectiveness of this therapy in the treatment of a number of solid tumors. After the publication of the results of early-stage clinical trials of nivolumab, the FDA announced that it was granted the possibility of approval for an accelerated procedure.

If the data on the effectiveness of this agent in the treatment of lung cancer are confirmed at the final stages of clinical trials, it can be expected that its sales volume will exceed the same indicator of such a megablockbuster as Avastin (bevacizumab) "Roche".

Bristol-Myers Squibb, Merck & Co. and Roche are developing similar drugs, the action of which will mediate the development of an immune reaction in the patient's body, leading to the death of tumor cells. Despite this, Bristol-Myers Squibb has certain advantages. Thus, the company is also studying the effectiveness of its PD-1 inhibitor in combination with the marketed immunotherapy drug – Yervoy (ipilimumab) "Bristol-Myers Squibb" for the treatment of late-stage melanoma.

Palbociclib (Pfizer)Palbociclib is a selective inhibitor of cyclin-dependent kinases (cyclin–dependent kinases - CDK)

CDK 4/6, oral release form. Currently, the results of clinical studies indicate its high effectiveness in the treatment of metastatic breast cancer. Currently, the drug candidate is in the late stages of clinical trials. In April of this year, the FDA awarded it the status of a "revolutionary therapy".

Breast cancer is a heterogeneous group of nosologies, which is the main cause of death in the structure of oncological diseases in women (WHO, 2013). Currently, information has been obtained indicating the effectiveness of palbociclib in the treatment of homron+, Her2-breast cancer in postmenopausal patients. This subspecies of pathology accumulates about half of all cases of breast cancer.

In December 2012, interim results of Phase II studies were presented. According to them, in patients receiving palbociclib in combination with the standard hormone therapy Femara® / Femara® (letrozole) Novartis, the period before the disease progression was 18 months longer compared to patients taking hormone therapy in a single mode. At the same time, today there is still no reliable data on the overall survival of patients when using a drug candidate, although this indicator should be the main argument in favor of granting the status of "revolutionary therapy".

Currently, the company is conducting a number of clinical studies that study the effectiveness of palbociclib in the treatment of ovarian cancer, myeloma, as well as acute lymphoblastic leukemia.

According to FierceBiotech's forecast, if data on its effectiveness are confirmed in late-stage clinical trials, it can be expected that the annual sales volume of the drug will amount to $ 5 billion.

Obinutuzumab ("Roche Glycart")Obinutuzumab is a glycosylated monoclonal antibody that has a double antitumor effect.

Thus, the drug candidate is an immunomodulator that promotes the development of an immune response in the patient's body that eliminates tumor cells, and, in addition, an independent cytotoxic agent that directly interacts with the CD20 marker on the surface of the tumor cell, which leads to its death.

Currently, the results of late–stage clinical trials are expected to be published, which will demonstrate the survival rate of patients with leukemia, as well as provide information on the effectiveness of the drug candidate in comparison with its predecessor, rituximab, in the treatment of hematoblastosis.

The company has already applied for approval of obinutuzumab in the USA and the EU for use in chronic lymphocytic leukemia. In May of this year, preliminary results of the first stage of phase III clinical trials were published, in which the effectiveness of a candidate for drugs for the treatment of patients with chronic lymphocytic leukemia was studied. In this research paper, the effectiveness of treatment regimens including a targeted agent and a chemotherapy drug was compared: obinutuzumab+ chlorambucil compared with chlorabmucil, and rituximab +chlorambucil compared with chlorambucil. Preliminary results indicate that among patients treated with obinutuzumab+ chlorambucil, the average life expectancy before the disease progressed was 23 months. In addition, there was an 86% reduction in the risk of disease progression or death compared with chlorabucil in monotherapy mode. The results of phase II clinical trials of phase III were published on June 24, 2013, their preliminary assessment indicates confirmation of the previously obtained data.

The efficacy of obitunuzumab and rituximab in non-Hodgkin's lymphomas and diffuse B-large cell lymphoma is also being studied.

One of the most important aspects in the treatment of oncological diseases is the safety profile of a drug candidate. According to the data obtained during the studies, the use of obitunuzumab is associated with the development of fewer complications associated with infusion therapy than with the administration of rituximab or chemotherapy.

Based on the currently available data on the effectiveness of the drug candidate, the FDA has given it the status of a "revolutionary therapy".

Lambrolizumab (Merck&Co.)In the fall of 2012, Merck &Co. attracted the attention of the cancer society with impressive interim results obtained during the Ib phase of clinical trials of a drug candidate – lambrolizumab (PD-1 inhibitor) for the treatment of metastatic melanoma.

After studying the 12-week results, the researchers concluded that with the use of lambrolizumab, a general response to therapy develops in 51% of patients, and a complete response – in 9%.

The FDA has also given this drug candidate the prestigious status of a "revolutionary therapy", and if the data on its effectiveness are confirmed at the final stages of clinical trials, it can be admitted to the market under the rapid approval procedure.

Currently, the company is awaiting the preliminary results of phase II clinical trials, in which the effectiveness of lambrolizumab for the treatment of pretreated patients was studied.

LDK378 («Novartis»)Novartis is currently one of the main players in the development of next–generation anaplastic lymphoma kinase (ALK) selective kinase inhibitors, which are used for the treatment of non-small cell lung cancer.

Based on the results of phase I clinical trials in which this therapy was used in 88 patients, the drug candidate received the status of a "revolutionary therapy" from the FDA. The company plans to obtain approval for the use of the drug in 2014, an application for approval will be submitted after the completion of phase II clinical trials, which study the effectiveness of LDK378 in the treatment of patients with this pathology.

Non-small cell lung cancer occupies one of the leading positions in the structure of oncological diseases in terms of the number of deaths to which it leads. At the same time, only 3-8% of patients with non-small cell lung cancer are diagnosed with an ALK-positive tumor. Previously, the drug Xalkori (krizotinib) from Pfizer was approved for the treatment of this disease. The use of LDK378 drug candidate demonstrated the development of a clinical response in 80% of patients with relapse after Xalkori therapy.

Today, companies such as Novartis, Ariad Pharmaceuticals, Tesaro and Chugai are developing next-generation ALK inhibitors for patients with non-small cell lung cancer. Phase II clinical trials are currently being conducted, the results of which will soon be made public.

Despite the expected high effectiveness of the drug candidate, it will be used in a limited market segment, and for this reason, it may not become a blockbuster.

Talimogen laherparepvek (OncoVex) ("Amgen")This drug candidate is an injectable oncolytic immunotherapeutic agent, it is designed for selective replication in tumor tissues.

After injection into the body, the agent replicates (multiplies) in tumor cells until the membrane is destroyed, "killing" pathological cells. After that, the constructed virus is released from the cell together with granulocyte-macrophage colony-stimulating factor (Granulocyte-macrophage colony–stimulating factor - GM-CSF), which the virus is designed to express. This, in turn, activates the body's systemic immune response aimed at eliminating tumor cells.

At the annual meeting of the American Society of Clinical Oncology (American Society of Clinical Oncology – ASCO) in 2013, preliminary results of phase III clinical trials were presented, in which the effectiveness of a candidate for drugs for the treatment of patients with inoperable melanoma of stage III, III and IV was studied. Patients in the control group took GM-CSF. The preliminary endpoint of the study was the frequency of reliable responses (the sum of complete and partial responses, the observation time was 6 months).

According to published data, the development of the response rate when using this agent compared to the control group is significantly different – 16 and 2%, respectively. The overall response rate when using the drug candidate was 26%, and the control agent was 6%. There was also a trend associated with an increase in overall survival in patients of the control group.

Johnson&Johnson/Janssen, Genmab (Daratumumab)In preclinical studies, the drug candidate led to the death of multiple myeloma cells, as well as increased the effectiveness of other drugs used in the treatment of this pathology.

The company published preliminary results of Phase I/II clinical trials in June 2012, indicating the effectiveness of the agent in the treatment of patients with recurrent multiple myeloma. After that, the FDA granted the drug candidate the status of a "revolutionary therapy" and the possibility of quick approval. The most recent research results were presented in December 2012, and they confirm the information received earlier, according to which daratumumab can be used in mono mode.

The mechanism of action of this molecule is the effect on the CD38 marker expressed on the surface of multiple myeloma cells. This drug candidate has a number of properties that determine a wide range of its effects on these pathological cells. Thus, it exhibits complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, leads to the development of antibody-dependent cellular phagocytosis, apotosis, and also modulates the enzymatic activity of CD38.

Daratumumab may be effective in the treatment of other hemoblastoses in which cells express CD38, including diffuse B-large cell lymphoma, chronic lymphocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, follicular lymphoma, and mantle cell lymphoma.

Multiple myeloma is a tumor disease in which plasma cell malignancy occurs. In the structure of hematological tumor processes in the USA, it occupies the 2nd place, giving way to the sad primacy of non-Hodgkin's lymphomas, and accounts for about 1% of all oncological nosologies (according to the National Comprehensive Cancer Network). With standard therapy, the average life expectancy of patients is 3-4 years, but new "breakthrough" drugs such as Velcade (bortezomib) from Takeda and Johnson & Johnson, as well as Revlimid (lenalidomide) from Celgene Corporation have allowed to increase the average life expectancy of patients to 5 years.

Idelalisib (Gilead Sciences)Targeted oral inhibitor of inositol triphosphokinase delta for the treatment of refractory to rituximab and therapy including alkylating agents, indole non-Hodgkin's lymphomas.

The urgency of creating such a drug is due to the fact that there was no effective therapy for this category of patients before.

The results of phase II clinical trials were presented at the 12th International Conference On Malignant Lymphoma in Lugano, Switzerland (12th International Conference On Malignant Lymphoma). The use of the agent in mono mode allowed to achieve a general response in 53.6% of cases, the median response duration in this preliminary analysis was 11.9 months. In addition, the majority of patients (89%) showed a certain decrease in lymph nodes.

Earlier, the company published the results of phase II clinical trials, which studied the effectiveness of therapy in the treatment of patients with chronic lymphocytic leukemia. The achievement of a general response was noted in 97% of cases, and a complete response – in 19% of cases. Survival without disease progression was 24 months in 93% of patients. A significant decrease in lymph nodes was detected in more than half of the patients (54%), on average, the progression of the disease was delayed by 17 months.

According to Gilles A. Salles, Professor of Medicine, Department of Hematology, Cloud Bernard University, Lyon San Hospital Center, Pierre-Benit (France), despite the progress made in the treatment of oncological diseases in recent years, most patients with indolent non-Hodgkin lymphomas with the progression of pathology are in the group resistant to currently used therapy. Therefore, today there is an urgent need to create effective therapy for this category of patients. The information provided, according to the specialist, can allow for a long time to monitor the course of the disease in patients for whom almost all methods of therapy have been tried.

MPDL320A («Genentech/Roche»)Another targeted drug candidate is a PD-1 inhibitor on our list.

At the meeting of the American Association for Cancer Research (AACR), encouraging results of phase I clinical trials were presented, which may indicate the prospects of this drug candidate.

Unlike other PD-1 inhibitors mentioned above, this agent has a different mechanism of action that causes the development of an immune attack of tumor cells. This immunotherapy affects the PD-L1 ligand of tumor cells, which use it to block attacks by immune cells expressing PD-1. The Bristol-Myers Squibb and Merck &Co. programs are in the later stages of clinical trials, but their drug candidates directly affect PD-1 expressed on immune cells. The developers of Genentech suggested that targeting PD-L1 may have a more favorable safety profile, since drugs acting on PD-1 can also affect healthy cells expressing PD-L2, which can lead to the development of inflammatory processes in the lungs.

The AACR provides information on the antitumor activity of MPDL320A against kidney, lung, colon and stomach cancers. The company has registered clinical trials that will study the effectiveness of this immunotherapy in combination with the currently marketed drugs Zelboraf/Zelboraf (vemurafenib) from Roche for the treatment of melanoma and Avastin™/Avastin (bevacizumab) for the treatment of primary multiple cancer.

The head of the study, who presented the results at the AACR, noted the favorable safety profile of the drug candidate and the absence of dose-dependent toxicity. In addition, despite the fact that this study included a small number of patients, the results obtained can be called promising: some patients whose disease was in the late stages remain alive a year after the start of the use of the agent.

BIND-014 («Bind Therapeutics»)This agent is a targeted polymer nanoparticle (TNP) containing the chemotherapeutic agent docetaxel (docetaxel – DTXL) for the treatment of patients with solid tumors.

DTXL-TNP specifically affects prostate-specific membrane antigen expressed on tumor cells in prostate cancer and neovascular cells of most solid tumors.

The presented results of phase I clinical trials on AACR are quite promising in terms of treatment for solid tumors. Thus, in 9 out of 28 patients who had previously received a number of different drugs, the agent caused a decrease in tumor volume, including the development of a complete response in cervical cancer, as well as a partial response in patients with non-small cell lung cancer. During the phase II clinical trials, its effectiveness in the treatment of other tumor diseases will be studied.

Currently, there are no reliable forecasts regarding the future fate of this drug candidate. He still has a considerable and difficult way to prove the effectiveness in the treatment of oncological pathology. At the same time, it is possible that nanotechnology will turn out to be a tool that will effectively combat oncological diseases that are currently difficult to treat.

In conclusionThe drugs being developed, which have high hopes for bringing qualitative changes to the very concept of "cancer treatment", are created at the junction of such modern sciences as molecular biology, biotechnology, etc.

At the same time, we are all well aware that these trends are developing faster than ever today and what a few years ago seemed like an excerpt from a futuristic story is already quite feasible today.

In other words, if over the past few years the effectiveness of the therapy of certain tumor diseases has increased significantly, we can expect that even more innovative and effective drugs will appear in the near future.

Portal "Eternal youth" http://vechnayamolodost.ru26.08.2013