Precision Medicines Dominate Oncology Pipelines of Pharmaceutical Majors

Precision or targeted therapies are an increasingly important part of the global oncology market, and the pharmaceutical majors provide an update on their most promising candidates.

Drug companies, researchers, and analysts gathered in Madrid this past weekend and this week for the European Society for Medical Oncology (ESMO) 2014 Congress, the European equivalent to the annual meeting of the American Society of Clinical Oncology (ASCO), which was held earlier this year in late May and early June in Chicago. As with the annual meeting of ASCO, the ESMO Congress is an important venue for drug companies to report on their latest advances in oncology, the largest therapeutic sector in developed markets. The theme of this year’s ESMO Congress was on precision medicines in cancer care, and Bristol-Myers Squibb, Roche, AstraZeneca, GlaxoSmithKline (GSK), and Merck & Co. were among the companies offering updates of their most promising cancer drugs. So what the key market takeaways? DCAT Value Chain Insights examines the highlights.

Global oncology market
The global market for oncology drugs, including supportive care, reached $91 billion in 2013, as measured at ex-manufacturer prices and not reflecting off-invoice discounts and rebates, according to data from the IMS Institute of Healthcare Informatics (1). Although this is up from $71 billion in 2008, it represents a a modest compound annual growth rate of 5.4%. The modest rate reflects a lack of breakthrough therapies for very large patient populations, patent expiries, reductions in the use of supportive care medicines, and stronger payer management, according to IMS. This rate of growth is significantly lower than was seen during the 2003-2008 period when growth each year exceeded 15%, driven by a small number of breakthrough therapies (1). Differences in incidence rates, access to medicines and treatment protocols are substantial between countries, but cancer is still a leading area of healthcare spend. While the US and top five European markets (Germany, France, Italy, Spain, and the United Kingdom) have declined in their share of the global oncology market, they still dominate it with 65% of total sales (1). The US has maintained the largest share of these sales since 2008, most recently tallied at $37.2 billion in 2013. By 2017, IMS projects the oncology drug market in developed markets will reach between $74 billion and $84 billion, making it the number one therapeutic sector in developed markets. For emerging markets, the oncology drug market is projected to reach between $17 billion and $20 billion by 2017, making it the fourth largest therapeutic sector in emerging markets behind drugs for pain (the number one sector), other central nervous system drugs, and antibiotics (1).

“The global oncology drug market reached $91 billion in 2013 with CAGR of 5.4% from 2008 to 2013.”

-Innovation in Cancer Care and Implications for Health Systems: Global Oncology Trend Report (IMS Institute for Healthcare Informatics)

A key change over the past decade and reflected in the pipelines of the pharmaceutical majors is the rise of targeted therapies, which have increased their share of the global oncology market, now accounting for 46% of total sales, up from 11% a decade ago. In 2013, targeted therapies represented 46% of the global oncology market, supportive care products 24%, cytotoxics 20%, and hormonal therapies 10%. In the top seven countries (France, Germany, Italy, Japan, Spain, the UK, the US), the oncology market was valued at $68 billion in 2013. Targeted therapies accounted for 48%, supportive care products 24%, cytotoxics 19%, and hormonal therapies 9% (1). This emphasis on more targeted therapies is evident in the pipelines of the pharmaceutical majors, several of which provided an update at the ESMO Congress

Roche targets Perjeta, immunotherapies, and combination therapies
Perhaps in one of the most noteworthy developments reported at the ESMO Congress, Roche provided Phase III results that showed adding its drug, Perjeta (pertuzumab), to a regimen of Herceptin (trastuzumab) and docetaxel chemotherapy extended the overall survival of people with previously untreated HER2-positive metastatic breast cancer by 15.7 months compared to Herceptin and chemotherapy  alone. 

“Adding Perjeta to treatment with Herceptin and chemotherapy resulted in the longest survival observed to date in a clinical study of people with HER2-positive metastatic breast cancer,” said Sandra Horning, M.D., Roche’s chief medical officer and head of global product development, in a company press release. “The median survival of nearly five years for people who received the Perjeta regimen is 15.7 months longer than for people who received Herceptin and chemotherapy alone, a magnitude of improvement we rarely see in clinical trials in advanced cancer.”

Perjeta targets the HER2 receptor, a protein found on the outside of many normal cells and in high quantities on the outside of cancer cells in HER2-positive cancers. Perjeta is designed specifically to prevent the HER2 receptor from pairing with other HER receptors (EGFR/HER1, HER3 and HER4) on the surface of cells, a process that is believed to play a role in tumor growth and survival. Binding of Perjeta to HER2 may also signal the body’s immune system to destroy the cancer cells. The mechanisms of action of Perjeta and Herceptin are believed to complement each other as both bind to the HER2 receptor, but to different places. The combination of Perjeta and Herceptin is thought to provide a more comprehensive blockade of HER signalling pathways.

Oncology is Roche’s most important therapeutic sector from a revenue perspective. In 2013, sales of oncology products accounted for CHF 22.55 billion ($23.70 billion), or 62% of Roche’s total pharmaceutical sales. Herceptin is one of Roche’s top-selling drugs with 2013 revenues of CHF 6.079 billion ($6.390 billion). Perjeta was approved by the FDA in 2012, in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Perjeta posted 2013 revenues of CHF 326 million ($343 million) and first-half 2014 sales of CHF 388 million ($408 million).

Perjeta in combination with Herceptin and docetaxel chemotherapy is approved in the United States and the European Union for people with previously untreated HER2-positive metastatic breast cancer. The Perjeta regimen has also been granted accelerated approval as a neoadjuvant treatment (use before surgery) for HER2-positive early-stage breast cancer by the US Food and Drug Administration (FDA). An application to update the marketing authorization to include this indication has also recently been submitted by Roche to the European Medicines Agency (EMA).

Roche also reported on clinical progress for its investigational cancer immunotherapy, MPDL3280A (anti-PDL1 or anti programmed death ligand-1) in patients with advanced bladder cancer. Immunotherapy agents, PD-1 modulators and anti-PD-L1 therapies, represent the next phase of targeted agents in oncology and are an area of focus of several companies. Anti-PD-1 inhibitors and anti-PD-L1 inhibitors are immune checkpoint inhibitors. The immune system has checkpoints to keep itself from attacking other normal cells in the body. Cancer cells sometimes take advantage of these checkpoints to avoid being attacked by the immune system. An important checkpoint molecule is the PD-1 protein found on T cells, especially those in tumors and the nearby environment. Cancer cells sometimes have large amounts of the corresponding PD-L1 protein on them, which allow them to escape immune system attack. Drugs that target PD-1 or PDL-1 boost the immune system (1). Anti-PD-1 inhibitors target a receptor protein known as PD-1 on the surface of activated T cells; anti-PDL-1 inhibitors target a binding partner (ligand) of PD-1, called PD-L1, which is expressed at higher than normal levels on many tumors and on cells in the tumor microenvironment.

Roche reported Phase I results for its anti-PD1 inhibitor, MPDL3280A, which showed that the drug shrank tumors in 52% of people who were mostly pretreated for advanced bladder cancer and whose tumors were characterized as PD-L1 positive by a test being developed by Roche. The drug has received Breakthrough Therapy Designation by the FDA. This designation is intended to expedite the development and review of medicines intended to treat serious diseases and to help ensure patients have access to them through FDA approval as soon as possible. 

Roche also reported on results of a combination therapy of MPDL3280A with its cancer drug Avastin (bevacizumab) for treating metastatic renal cell carcinoma (RCC). Results from the Phase Ib study showed that the combination of MPDL3280A and Avastin was well tolerated and shrank tumors in 40% of patients. Avastin is Roche’s top-selling cancer drug with 2013 revenues of CHF 6.254 ($6.572 billion).

“Targeted therapies have increased their share of the global oncology market, now accounting for 46% of total sales, up from 11% a decade ago.”

Innovation in Cancer Care and Implications for Health Systems: Global Oncology Trend Report (IMS Institute for Healthcare Informatics)

Roche also reported positive Phase III results for people with previously untreated BRAF V600 mutation-positive, advanced melanoma who received the MEK inhibitor cobimetinib plus Zelboraf (vemurafenib). Cobimetinib was discovered by Exelixis Inc. and is being developed by Roche in collaboration with Exelixis. Cobimetinib is also being investigated in combination with several investigational medicines, including an immunotherapy, in several tumor types such as non-small cell lung cancer (NSCLC) and colorectal cancer. 

Cobimetinib is designed to selectively block the activity of MEK, one of a series of proteins inside cells that make up a signalling pathway that helps regulate cell division and survival. Cobimetinib binds to MEK while Zelboraf binds to mutant BRAF, another protein on the pathway, to interrupt abnormal signaling that can cause tumors to grow. Zelboraf was co-developed under a 2006 license and collaboration agreement between Roche and Plexxikon, now a member of the Daiichi Sankyo Group. It is approved now in 80 countries to treat unresectable or metastatic melanoma with BRAF V600 mutation as detected by a validated test, such as Roche’s cobas 4800 BRAF Mutation Test. Zelboraf posted 2013 revenues of CHF 354 million ($372 million).

Bristol-Myers Squibb Advances its immunotherapy nivolumab
Bristol-Myers Squibb reported positive Phase III results for Opdivo (nivolumab), the company’s investigational PD-1 immune checkpoint inhibitor versus investigator’s choice chemotherapy in patients with advanced melanoma who were previously treated with Yervoy (ipilimumab), the company’s drug to treat advanced melanoma. 

Like other drug companies, Bristol-Myers Squibb has high hopes for its PD-1 immune checkpoint inhibitor Opdivo. Yervoy was the first checkpoint molecule inhibitor approved by the FDA; it targets a different checkpoint molecule, CTLA-4, on the surface of activated T cells. Yervoy posted 2013 revenues of $960 million.

Bristol-Myers Squibb recently reported on multiple regulatory milestones for Opdivo in the US and European Union (EU) In the US, the FDA accepted for priority review the company’s biologics license application for Opdivo for previously treated advanced melanoma with a Prescription Drug User Fee Act (PDUFA) goal date for a decision of March 30, 2015. The FDA also granted Opdivo Breakthrough Therapy status for this indication. In the EU, the EMA has validated for review the company’s marketing authorization application (MAA) in advanced melanoma. The application was granted accelerated assessment by the EMA’s Committee for Medicinal Products for Human Use. The EMA also validated for review the MAA for nivolumab in NSCLC.  

Bristol-Myers Squibb has a broad, global development program to study Opdivo in multiple tumor types, which consists of more than 35 trials, as monotherapy or in combination with other therapies, in which more than 7,000 patients have been enrolled worldwide. Among these are several potentially registrational trials for NSCLC, melanoma, RCC, head and neck cancer, glioblastoma, and non-Hodgkin lymphoma.

In 2013, the FDA granted Fast Track designation for Opdivo in NSCLC, melanoma, and RCC. In April 2014, the company initiated a rolling submission with the FDA for Opdivo in third-line pre-treated squamous cell NSCLC and expects to complete the submission by the end of this year. The FDA granted its first Breakthrough Therapy Designation for Opdivo in May 2014 for the treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant and brentuximab. On July 4, 2014, Ono Pharmaceutical Co. announced that Opdivo received manufacturing and marketing approval in Japan for the treatment of patients with unresectable melanoma, making it the first PD-1 immune checkpoint inhibitor therapy to be approved globally. In 2011, through a collaboration agreement with Ono Pharmaceutical, Bristol-Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally except in Japan, South Korea, and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Bristol-Myers Squibb and Ono Pharmaceutical further expanded the companies’ strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies, as single agents and combination regimens, for patients with cancer in Japan, South Korea, and Taiwan.

Merck & Co. advances anti-PD-1 therapy Keytruda
A key strategy in oncology overall and for immunotherapies is to advance the drug for multiple cancer indications. In early September 2014, Merck & Co. received FDA approval for Keytruda (pembrolizumab) for treating advanced or unresectable melanoma, making it, the first anti-PD-1 therapy approved in the United States. At the ESMO Congress, the company provided updates on the drug for treating advanced bladder cancer and gastric cancer. The company reported positive Phase Ib results for Keytruda in treating advanced bladder cancer, and the company plans to initiate a Phase III study later this year. The company also reported on promising Phase Ib results for treating advanced gastric cancer. 

Keytruda is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, Keytruda releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. 

AstraZeneca advances its anti-PD-L1 therapy and select small molecules
AstraZeneca is advancing its anti-PD-L1 immune checkpoint inhibitor, MEDI-4736, and reported on some key early-stage results at the ESMO Congress. It reported on preliminary results in the ongoing Phase I trials of MEDI4736 and tremelimumab, the company’s investigational anti-CTLA4 monoclonal antibody in a combination study in patients with NSCLC who have already received prior cancer treatments. 

“We are pleased with the results from MEDI4736 in combination with tremelimumab,” said Edward Bradley, senior vice president, R&D and oncology iMED Head, MedImmune, the biologics arm of AstraZeneca, in a company release. “While it is still early with a limited data set, the tolerability profile is encouraging. We have also seen some evidence of clinical activity in patients who have failed prior lines of therapy and whose tumor does not express PD-L1. This supports our strategy to explore this combination more broadly, particularly in the PD-L1 negative population. This trial will identify the optimal dose to take into our Phase III clinical program.”

MedImmune has initiated additional Phase I immunotherapy combination trials, including MEDI4736 and MEDI0680, an anti-PD-1 monoclonal antibody from AstraZeneca as well as a study for MEDI4736  and MEDI6469 (OX40),  an in-licensed asset from Agonox. AgonOx is a spin-off company from the Providence Cancer Center in Portland, Oregon. It licensed the rights to use OX40 agonists in cancer from Providence Health & Services-Oregon.  AgonOx is developing OX40 agonists and other immune system activators for use in cancer therapy. 

X40 is a protein transiently expressed on the surface of effector T-cells, but only after activation of the T-cells by immune-stimulating antigens, including tumor antigens. Binding OX40 with either anti-OX40 antibodies or OX40 ligand compositions has been shown to inhibit apoptosis in such T-cells, causing T-cell proliferation, immune attack on tumors, and sometimes very distinct tumor-specific therapeutic responses. AgonOx is focused on the development of immune system modulators in combination with other therapies, such as cytotoxic agents, other immunologic modifiers, and tumor-ablation techniques and devices

In May 2014, AstraZeneca initiated a Phase III clinical trial for MEDI-4736 to evaluate the drug to treat locally advanced, unresectable NSCLC. In May 2014, Incyte formed a clinical collaboration with Medimmune for a Phase I/II oncology study to evaluate the efficacy and safety of MEDI-4736, in combination with Incyte’s INCB24360. In addition to evaluating MEDI-4736 in combination with tremelimumab, AstraZeneca is also evaluating  MEDI-4736 in combination with GSK’s BRAF inhibitor dabrafenib and GSK’s MEK inhibitor trametinib. At the ESMO Congress, AstraZeneca also provided updated data from a Phase I monotherapy study of MEDI4736 in patients with metastatic squamous cell carcinoma of the head and neck. AstraZeneca also is evaluating MEDI-0680 (AMP-514), an anti-PD-1 monoclonal antibody in Phase I/II development.

On the small-molecule side, AstraZeneca provided updates on key assets in its small-molecule portfolio, including the investigational NSCLC medicine AZD9291, a highly selective, irreversible inhibitor of both the activating sensitizing EGFR mutation (EGFRm) and the resistance mutation T790M, Iressa (gefitinib), and the PARP inhibitor olaparib. The company provided data for a Phase I/II study on the the activity and safety of AZD9291 in patients with EGFRm T790M+ advanced NSCLC whose disease had progressed following treatment with an EGFR tyrosine kinase inhibitor. AstraZeneca has initiated both Phase II and Phase III studies in this patient population. In addition, a Phase III study evaluating AZD9291 in first line EGFRm advanced NSCLC is scheduled to start later this year. AstraZeneca is also currently investigating combinations of AZD9291 with MEDI4736, and with other investigational drugs selumetinib (small-molecule MEK inhibitor) and AZD6094 (small-molecule MET inhibitor) in NSCLC. AstraZeneca also presented data on the impact of olaparib on the quality of life of patients with BRCA-mutated platinum-sensitive relapsed ovarian cancer. EMA’s Committee for Medicinal Products for Human Use is expected to provide its opinion on olaparib in the EU on October 23, 2014, and the US PDUFA action date is set for January 3, 2015.

GSK reports on Tafinlar
GSK reported results for Tafinlar (dabrafenib) in patients with BRAF V600E mutant metastatic melanoma. These results, which includes new survival data, showed 45% of patients treated with dabrafenib were still alive at two years. Dabrafenib targets BRAF, a key component of the MAPK (mitogen-activated protein kinase) pathway. In many types of melanoma, a mutated BRAF protein on the MAPK pathway disrupts normal cellular regulation and promotes increased cell production. Dabrafenib binds to the mutated BRAF protein, which may lead to an inhibition of oncogenic signaling, thus inhibiting the proliferation of tumour cells. Dabrafenib is a licensed monotherapy in the EU for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation as detected by a validated test. Dabrafenib is also approved in the US, Canada, and Australia.

1. Innovation in Cancer Care and Implications for Health Systems: Global Oncology Trend Report (IMS Institute for Healthcare Informatics, May 2014).

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