Breast cancer treatment – the next advances

pharmafile | February 7, 2012 | Feature | Business Services, Manufacturing and Production, Medical Communications, Research and Development, Sales and Marketing |  Afinitor, CDF, Lorena Tonarelli, T-DM1, breast cancer, pertuzumab 

When a close member of my family was diagnosed with breast cancer, the doctors didn’t give us much hope. They said there wasn’t anything they could do, and that we just had to “wait for the inevitable to happen”. Which it did.

But that was more than 30 years ago. Thankfully, since then treatment and survival rates have improved considerably, and breast cancer is no longer necessarily a death sentence. There are at least two reasons – firstly regular screening programmes and advanced diagnostic methods mean breast cancer is more likely to be detected in the early stages, when it’s easier to treat successfully.

Secondly, new therapies have been developed which are effective at keeping the disease under control, or preventing its recurrence. As a result, patients can now expect to beat breast cancer or live much longer with it thanks to treatment. Recent statistics show for example that of the 49,700 women who are diagnosed with breast cancer in the UK every year; 85% survive at least 10 years.

Established and new options

In most cases, surgery is the first line of treatment for breast cancer, followed by  chemotherapy and, in some cases, radiotherapy. Those whose breast cancer is oestrogen receptor positive (ER+) are also prescribed hormone therapy, usually with tamoxifen, to lower the levels of oestrogen in the body and, in turn, reduce the risk of the cancer coming back. Additionally, targeted therapy agents can be considered, which vary depending on the type of breast cancer.

For example, patients with high levels of human epidermal growth factor receptor-2 (HER2) on their breast cancer cells are typically given Roche’s established tumour drug Herceptin (trastuzumab), either as monotherapy or in combination with chemotherapy.

HER2, a protein produced by a cancer-causing gene mutation found in about 25% of breast cancer patients – generally those with the most aggressive form of the disease – stimulates tumour cell growth. Herceptin, a monoclonal antibody, works by binding to HER2, thereby blocking its action.

Herceptin is normally delivered via intravenous infusion which can take up to 90 minutes to complete, so Roche are developing an injectable version. This new formulation takes just five minutes to administer and has shown similar efficacy in the HannaH study, a Phase III open-label trial of 596 women with HER2-positive early breast cancer. Roche is expected to submit a marketing application to regulatory authorities in the European Union in 2012. 

An approval would help extend Roche’s market exclusivity for its blockbuster Herceptin, which will otherwise see its patent expire in 2015.

The antibody-drug conjugate approach

Roche is also testing T-DM1 (trastuzumab emtansine), an experimental antibody-drug conjugate enabling the delivery of the chemotherapy directly into the cancer cells of previously untreated HER2-positive patients in the advanced stages of the disease.

Phase II trial data presented at the European Multidisciplinary Cancer Conference (EMCC) held in Stockholm last September, showed that patients treated with T-DM1 had a 41% improvement in the time lived without their disease worsening, compared to patients on standard treatment (e.g., docetaxel chemotherapy plus Herceptin). On average, T-DM1 patients lived five months longer without the disease getting worse than standard treatment patients (14.2 months versus 9.2 months). 

“T-DM1 had a significantly better outcome,” says Dr Carlo Palmieri, a Cancer Research UK clinician scientist, and a senior lecturer and consultant in medical oncology at Imperial College, London. “If confirmed in Phase III trials, these results suggest that patients will only need one drug intravenously instead of chemotherapy and Herceptin.”

This will not only make the treatment more convenient for patients to receive, researchers say it will also eliminate some of the side effects of chemotherapy, such as alopecia and neutropenia. What’s more, if approved, T-DM1 could bring the company annual peak sales of more than CHF1 billion ($1.1 billion). Hal Barron, Roche’s chief medical officer, said: “We have been studying the HER2 pathway for 30 years to bring personalised medicines to people with HER2-positive breast cancer.

“These results show we may soon improve on the current standard of care, Herceptin plus chemotherapy,” he added. 

Another new Roche breast cancer drug in Phase III is pertuzumab. The drug is the first in a new class of targeted agents known as HER2 dimerisation inhibitors (HDIs), and is designed to block the dimerisation of HER2 with other HER proteins, a molecular process which is thought to be involved in promoting tumour growth. Pertuzumab and Herceptin are thought to work well together because they both bind to different regions of HER2, meaning they could block HER signalling pathways more comprehensively.

Success and failure

Another pipeline breast cancer drug that has made news at the EMCC is Novartis’ Afinitor (everolimus). Already approved for the treatment of advanced renal cell carcinoma (RCC), Afinitor may well now extend its presence into breast cancer treatment.

Data from BOLERO-2, a Phase III study of postmenopausal women with oestrogen-receptor positive (ER+) advanced breast cancer who tested negative for HER2, found that Afinitor plus exemestane, a hormonal therapy, more than doubled the time women lived without cancer growth compared to exemestane alone (6.9 versus 2.9 months).

Ibrahim El Houssieny, country medical director Oncology at Novartis Pharmaceuticals, UK says the results ‘are very promising’. He adds: “The magnitude of benefit seen in these patients, despite their resistance to previous hormonal therapies, demonstrates that everolimus has the potential to become an important new treatment option.” Submissions to regulatory authorities are planned for the end of this year.

Meanwhile GlaxoSmithKline’s dual kinase inhibitor Tyverb (lapatinib), is in Phase III trials in a head-to-head with Herceptin. Like the latter, Tyverb works only in HER2-positive breast cancer patients.

However, GSK has recently halted the Tyverb alone arm of one of these studies (ALTTO), as it “is unlikely to meet the pre-specified criteria to demonstrate non-inferiority to trastuzumab alone with respect to disease-free survival”, according to GlaxoSmithKline.

Static market

So will these advances in breast cancer treatment change the market significantly in the near future? Not necessarily – in fact, according to analysts Decision Resources, the breast cancer drug market, currently worth $10.2 billion globally, is set to remain more or less static over the next ten years. Although the combined sales of new breast cancer agents will account for over 25% of the global market, the latter will increase by only a modest $0.2 billion by 2019, say the analysts.                                     

This is largely as a result of a decrease in the prescribing of Genentech/Roche’s Avastin (bevacizumab), whose indication for advanced breast cancer has been removed in the US last year, for safety concerns and lack of efficacy.

Europe’s regulator the EMA will continue to allow Avastin’s use in combination with paclitaxel, the most common chemotherapy used in Europe, but the drug can no longer be used with docetaxel. An EMA advisory committee decided that this combination did not provide additional survival benefits compared with docetaxel on its own.

What patients want

Patient access to novel breast cancer drugs is of course a major issue, particularly in the UK, where NICE often refuses to recommend new cancer treatments.

Palmieri says: “Patients want their doctor to be able to make the right decision for them, and use drugs they believe are right for their patients, based on what they, and the wider breast oncology community, think about available safety and efficacy data.”  He adds: “What patients don’t want is that those drugs can’t be used, f­or example, because the government has decided that they are too expensive. This, understandably, upsets patients, especially because they are aware of the fact that they could get them if they lived in Europe or in another part of the country.”

Take for example Eisai’s Halaven (eribulin), an injectable non-taxane, microtubule dynamics inhibitor treatment. Halaven is the first novel chemotherapy agent to show a 2.5-month statistically significant increase in overall survival in patients with advanced breast cancer, but it was rejected by NICE in July last year because it was found not cost effective.

England’s Cancer Drugs Fund

The Cancer Drugs Fund (CDF) was launched in England in April 2011 to help cancer patients receive drugs which have been either rejected by NICE, or are still awaiting appraisal. 

So how is the Fund changing things?

In November, Breast Cancer Campaign  looked at the fund’s success in helping more women gain access to breast cancer treatments. It found that in just over half of England’s Strategic Health Authorities, a total of at least 150 women had applications for drugs not routinely available on the NHS approved between April and June 2011.

Drugs accessed through the Fund to treat breast cancer include GSK’s Tyverb (lapatinib), Roche’s Avastin (bevacizumab) and AstraZeneca’s Faslodex (fulvestrant).   Tyverb was the breast cancer drug most consistently accessed across SHAs.

Where evidence is available, it appears that 98% of all breast cancer applications were successful. However, as Palmieri points out that the CDF has not eliminated regional variations in access.

“There are three main agents patients can access through the fund [Tyverb, Avastin, Faslodex]. Some parts of England have all three of these drugs, others have two. So, access to some of the drugs on the CDF really depends on which part of England you live.”

The late-stage pipeline

Three late-stage breast cancer drugs have captured the headlines in recent months thanks to strong trial results – two of them from Roche and one from Novartis.

Pertuzumab

Roche’s dimerization inhibitor antibody is being developed for use as a first line treatment for HER2+ metastatic breast cancer. Dimerization is the process through which a HER2 protein pairs with another HER2 or other  HER proteins. These dimers initiate signals that stimulate tumour cell growth and survival, thus inhibiting them inhibits the disease in turn. 

CLEOPATRA, the first Phase III study of  pertuzumab compared the combination of pertuzumab, Herceptin and docetaxel chemotherapy to Herceptin and docetaxel alone, in people with previously untreated HER2-positive metastatic breast cancer. Those who received pertuzumab and Herceptin and chemotherapy had a 38% reduction in the risk of their disease worsening or death (progression-free survival, or PFS). The median PFS improved by 6.1 months from 12.4 months for Herceptin and chemotherapy to 18.5 months for pertuzumab, Herceptin and chemotherapy. Overall survival (OS) data are still immature, however, with Roche reporting only a modest trend in favour of the pertuzumab combination.

T-DM1

This antibody-drug conjugate uses new technology in which chemotherapy is attached to an antibody – in this case Herceptin – and selectively delivered to tumour cells – promising not only a more effective regimen, but a simpler one with fewer adverse effects. A Phase II trial compared T-DM1 to standard treatment with Herceptin plus docetaxel. Patients with HER2-positive metastatic breast cancer who received T-DM1, experienced a 41% reduction in the risk of their disease worsening or death, and lived a median of five months longer without their disease worsening (PFS 14.2 months against 9.2 months). In addition, women who received T-DM1 had only half the serious adverse events compared to those on the Herceptin plus chemotherapy arm.

Afinitor

Novartis’ drug Afinitor (everolimus) is also giving new hope for women with advanced breast cancer. The BOLERO-2 Phase III study of patients with advanced breast cancer shows Afinitor plus exemestane more than doubled the time women lived without tumour growth (PFS), and significantly reduced the risk of cancer progression by 57% versus exemestane alone. 

The patient’s perspective

Access to treatment has not been an issue for breast cancer survivor Elaine Kirk, a mum of two young boys living in Fife, Scotland.

“Following surgery, chemotherapy and radiotherapy, I was given Herceptin. At that time, access to this drug depended on a ‘postcode lottery’, meaning that only breast cancer patients in certain catchment areas could get it. But I was one of the lucky ones, and the doctors were able to prescribe it to me. I was given Herceptin for a series of weeks, at the hospital to begin with, and then at home. Now I am on tamoxifen for three years.”

Kirk was diagnosed with breast cancer two years ago and has gone through radical breast cancer surgery and reconstruction. She does a huge amount of fundraising and other work to benefit cancer research locally, and is currently raising funds for a calendar for the Maggie’s Breast Cancer Centre in Fife. 

Kirk is very positive about her experience, and part of the reason for this is that she has been given a lot of information about available treatments from those involved in her care. This has allowed her to make informed decisions, as it always should be in these circumstances.

Information about the potential problems treatments may cause is also important. “My consultant told us about the risks and various side effects you may experience,” says Kirk. “Knowing what to expect when you are on a certain drug, for example, that you may feel tired, ill or have pain, was particularly important to me, because I was able to explain all this to my children beforehand.” 

She thinks, however, that information about experimental drugs is somewhat lacking. “I, for example, am not aware of what is going on in terms of breast cancer drugs under development. And I believe this is true for many other patients.”

Actress Veronica Roberts, known for playing Dorothy Bennett in the BBC drama Tenko, and Laura Elliott in the ITV series Peak Practice, agrees. She too has breast cancer and believes knowledge is key. 

“When I was diagnosed, the Macmillan nurses spoke to me about any concern I had; any explanation I wanted to have again. They were fantastic.” Roberts thinks the organisation is a brilliant interface in helping patients who are sometimes confused about treatments.

“In my experience, some women know that Herceptin is a good drug to prevent recurrence, but they don’t know that it only works if you have HER2-positive breast cancer, like I do. They found I had the HER2 gene, which, together with the fact that my tumour was quite advanced and aggressive – but responded brilliantly to chemotherapy – meant I was a good candidate for the drug. It was explained to me very thoroughly the difference that the treatment would have made. Specifically, that it would have helped prevent the tumour from coming back. And, so far, it’s been successful.” 

Because Roberts had chemotherapy before, the blood vessels in her hands were in a bad state, so she wasn’t given Herceptin with intravenous injections. Instead, she had what is known as a porth-a-cath (or port). This is essentially a valve, implanted into the chest, which goes into a main vessel and can be left in place, weeks, months or even years in some cases. Every three weeks, when Roberts went for her treatment, the oncology team would simply put a needle through the skin into the port, and deliver the drug. 

“This was a terrific advantage,” says Roberts. “It made me able to be completely mobile and keep working as usual.”