NICE has failed to recommend GSK’s Tyverb (lapatinib) or Roche’s Herceptin (trastuzumab) with aromatase inhibitors as a first line treatment for a particular type of breast cancer in final draft guidance.

The decision is based on uncertainties over the overall survival benefits compared to existing treatments of both medicines and the high cost of the treatments.

Sir Andrew Dillon, Chief Executive of NICE, said that while the two have been shown to reduce the growth and spread of breast cancer the extent of overall survival extension “appears to be small or difficult to quantify”.

Final guidance on the appraisal is now expected in June.

The guidance only advises the use of the drugs alongside aromatase inhibitors as a first line treatment option to delay the growth of advanced breast cancer that has spread and reacts with oestrogen or progesterone and has high levels of HER2.

Alongside the clinical benefits, NICE also raised concerns around the cost effectiveness of both products. GSK estimates that the most plausible incremental cost effectiveness ratio (ICER) for Tyverb is likely to be around £74,400 per QALY gained. Roche estimates the most plausible ICER for Herceptin to be around £51,000 per QALY gained – both far in excess of the £20,000-£30,000 NICE typically deems to be a cost effective use of NHS resources.

Roche intends to submit its new T-DM1 breast cancer drug for EU and US approval this year following its successful phase III trial.

The biotech giant said its ‘armed antibody’ drug candidate, which combines the active agents of Herceptin and a chemotherapy drug, showed better progression-free survival data than a combination of Tyverb and Xeloda.

T-DM1, developed by Roche in partnership with ImmunoGen, is considered a potential successor to Roche’s blockbuster breast cancer drug Herceptin, which faces completion from biosimilars in 2015.

Herceptin has been approved in the EU for treatment of Her2-positive breast cancer, an aggressive type of cancer linked to a particular gene variant.

T-DM1 combines the antibody trastuzumab from Herceptin with the agent DM1from the chemotherapy drug maytansine.

Roche said that according to the EMILIA trial results, Her2-positive breast cancer patients showed longer progression-free survival than a combination of two major existing products: GSK’s Tyverb and Roche’s Xeloda.

In addition, it caused less side-effects (such as hair loss and reduced white blood cell count) than Herceptin alone, as well as offering the convenience of a combined medication.

The overall survival rates from the EMILIA trial are likely to become available by 2014.

Roche anticipates that T-DM1 will successfully rival generic versions of Herceptin and newer branded medications such as Tyverb.

Oral cancer drugs such as Glivec and Tarceva are negatively affected by other medications including steroids and antibiotics, according to a new US study.

The Medco Research Institute (MRI) has claimed that medications taken by as many as 75% of cancer patients interfere with the effects of oral kinase inhibitors, a major class of adjunctive cancer therapy.

The effect of the medication interference is to weaken the effectiveness of the anti-cancer treatment and/or increase its toxicity, the study found.

Oral kinase inhibitors, which suppress tumour cell metabolism, are widely prescribed for their ability to increase the effectiveness (and reduce effective dosage levels) of chemotherapy.

The MRI study, which looked at 4,617 cancer patients, found that 23–74% of them were being prescribed a medication that interfered with their oral cancer drug. Of these, 43% showed a reduction in the efficacy of the cancer drug and 68% showed an increase in its toxicity.

Oral kinase inhibitors include (UK trade names): Glivec (imatinib), Tarceva (erlotinib), Sprycel (dasatinib), Afinitor (everolimus), Tyverb (lapatinib), Tasigna (nilotinib), Votrient (pazopanib), Nexavar (sorafenib) and Sutent (sunitinib).

The medications that interfere with them, according to the study, are calcium channel blockers, antifungal agents, steroids, proton pump inhibitors and some antibiotics.

Dr Steve Bowlin, Senior Director at the MRI and co-author of the study, said: “Since these are drugs launched in the past decade for fairly small patient populations, we are learning more about how they are used in real-world settings as compared to traditional clinical trials that test safety and efficacy in a tightly-controlled environment.

“Oncologists are not always aware of other medications prescribed by other doctors and vice-versa, which can pose a real hazard for their patients on oral cancer therapies.”

The application to extend Tyverb’s (lapatinib) therapeutic indication in Europe has been formally withdrawn by GlaxoSmithKline’s Research and Development division.

GSK applied to extend the marketing authorisation of Tyverb in combination with paclitaxel for the treatment of patients with metastatic breast cancer whose tumours over express HER2 (ErbB2).

However, in its official letter, it stated the decision was based on the CHMP’s assessment that the lack of an active-controlled trial hampers the proper assessment of the benefit-risk balance in the indication.

Tyverb was given conditional approval and was first authorised in the European Union in June 2008. It is currently authorised to treat women with breast cancer in combination with Xeloda (capecitabine) for patients with advanced or metastatic disease with progression following prior therapy, which must have included anthracyclines and taxanes and therapy with Herceptin (trastuzumab) in the metastatic setting. It is also authorised in combination with an aromatase inhibitor for postmenopausal women with hormone receptor positive metastatic disease, not currently intended for chemotherapy.

In April 2011, GSK submitted the application to extend the marketing authorisation of the treatment but patients in the registration study were not previously treated with Herceptin in either the adjuvant or metastatic setting.

Tyverb continues to be authorised in the currently approved indications. The EMA says the withdrawal does not prejudice any future applications.

NICE has failed to recommend GSK’s Tyverb (lapatinib) or Roche’s Herceptin (trastuzumab) with aromatase inhibitors as first-line treatments for women with breast cancer in a second draft guidance.

Questions were again raised about the cost and effectiveness of both treatments when compared against existing options to delay the growth of advanced breast cancer that has already spread to other parts of the body, and for patients whose tumour cells react with oestrogen or progesterone and have high levels of HER2.

Sir Andrew Dillon, Chief Executive of NICE said that independent analyses indicate that both treatments “do not appear to be cost effective for the NHS” due to “uncertain clinical benefits”.

The second draft guidance follows an appeal from Roche against NICE’s independent Appraisal Committee and its initial findings published in July 2011. The Committee concluded that Herceptin did fulfil the small population criterion within NICE’s “end of life criteria”. This decision was subject to appeal, but upheld by an independent panel in November 2011.

Experts estimate that between 50 and 2,000 postmenopausal women are diagnosed with this type and stage of breast cancer each year. It is believed that the majority of these women are likely to be offered Herceptin as a first-line treatment option.

Tyverb and Herceptin would only usually be considered as first-line options alongside aromatase inhibitors when chemotherapy is deemed unsuitable – but it is unclear how many patients this would be relevant to.

“Having reviewed the available evidence, our committee of experts has found that while both lapatinib and trastuzumab can reduce the growth and further spread of metastatic breast cancer tumours when taken alongside the aromatase inhibitors letrozole and anastrozole, the extent that these treatments can improve overall survival appears to be small or undefined,” said Sir Andrew.

The Scottish Medicines Consortium (SMC) also failed to recommend the use of Tyverb or Herceptin for use on the NHS in Scotland for this particular type and stage of breast cancer when it recently published advice.

NICE’s draft guidance has now been issued for consultation. The deadline for comments to be received is Tuesday 6^th March. The independent Appraisal Committee will then meet to review any submissions.

GlaxoSmithKline’s breast cancer drug Tyverb (lapatinib) has failed to show a significant increase in disease-free survival (DFS) when used alone in patients with early-stage HER2-positive breast cancer.

The results of the TEACH phase III clinical trial mean that Tyverb (known as Tykerb in the US) is unlikely to succeed as a monotherapy in this indication, though it will continue to be used in combination therapy.

The TEACH trial established that 13% of patients treated with Tyverb following initial surgery or chemotherapy for breast cancer achieved DFS after four years, compared to 17% on placebo.

The trial did not compare Tyverb with Roche’s breast cancer drug Herceptin (trastuzumab). The two drugs were approved by the FDA for use in combination in 2007, and in that indication earned GSK $360 million in 2010.

However, whereas Herceptin has proved successful as a monotherapy, Tyverb has not. In September, GSK abandoned the monotherapy arm of another trial (ALTTO) after concluding that Tyverb was less effective in treating early-stage breast cancer than Herceptin alone.

The TEACH trial is still expected to support the use of Tyverb in combination with Herceptin.

“We are disappointed that the improvement in disease-free survival with lapatinib monotherapy in TEACH did not reach statistical significance,” said Rafael Amado, Senior VP of Oncology Development at GSK.

“Lapatinib combination therapy remains an important treatment option for patients with metastatic HER2-positive breast cancer whose disease has progressed on treatment with trastuzumab-based regimens.”

GSK has discontinued one part of a four-arm clinical study for its breast cancer drug Tyverb after data indicated it was likely to produce inferior results to Herceptin.

ALTTO, a Phase III study of adjuvant lapatinib (Tyverb), trastuzumab, their sequence and their combination in patients with HER2 positive early stage breast cancer, has randomised over 8,000 patients in 44 countries since 2007.

But patients assigned to the lapatinib alone arm of the trial will discontinue the drug and discuss treatment options with their physician following an independent data review.

The company said that study findings indicated that lapatinib alone was unlikely to meet pre-specified criteria to demonstrate non-inferiority to trastuzumab alone with respect to disease-free survival.

The remaining three arms of the trial will continue without modification.

Tyverb (known in the US as Tykerb) is approved in Europe for advanced, metastatic HER2-positive breast cancer, and also, in combination with an aromatase inhibitor (AI), for the treatment of post-menopausal women with hormone receptor (HR)-positive, HER2 (ErbB2) over-expressing metastatic breast cancer for whom chemotherapy is currently not intended. But GSK had hoped an extension of its indications into the early-stage setting would help accelerate sales.

NICE has been unable to recommend Tyverb (lapatinib) or Herceptin (trastuzumab) as a first-line treatment for a specific type of advanced metastatic breast cancer in draft guidance.

The Institute claims that the clinical and cost effectiveness of the two alongside an aromatase inhibitor to certain postmenopausal women has not been clearly demonstrated.

Sir Andrew Dillon, NICE Chief Executive, says there was a lack of “convincing evidence” on the benefit either drug provided and the price to the NHS was also “significantly uncertain”.

The appraisal focused on the use of GSK’s Tyverb (pictured) or Roche’s Herceptin alongside the use of the hormone therapy called aromatase inhibitor. This combination is used when the breast cells have receptors for the hormone oestrogen and also high levels of protein.

Despite the failure to recommend either product, women already receiving either Tyverb or Herceptin with aromatase inhibitors can continue their treatment until they and their doctors consider it appropriate to stop.

“NICE’s job is to ensure patients have access to the best treatments possible within the NHS’s limited resources,” Sir Andrew Dillon said.

Registered stakeholders have now been invited to appeal against the draft recommendation. If no appeals are received, final guidance is expected on 24^th August 2011.

NICE has failed to recommend Tyverb (lapatinib) and Herceptin (trastuzumab) in combination with an aromatase inhibitor for the treatment of metastatic breast cancer that is both hormone-receptor and HER2-positive in draft guidance.

The Institute questioned the long-term benefits of the two compared with existing treatments currently prescribed.

Sir Andrew Dillon (pictured), NICE Chief Executive, said that evidence did not provide “enough additional value to patients”, although he did say the two “could delay the growth and spread of the disease”.

Nearly 46,000 women are diagnosed with breast cancer every year in the UK.

Evidence presented for Tyverb by GSK compared the drug in combination with an aromatase inhibitor with letrozole monotherapy. Data showed that the median value for progression-free survival was 8.2 months in combination compared with three months with monotherapy. But the overall survival value in combination was on average a month more than monotherapy alone.

Results for Herceptin in combination with another aromatase inhibitor, anastrozole, compared with anastrozole alone were presented by Roche during the appraisal. Data showed that when combined Herceptin could delay the growth and spread of the disease, with the median value for progression-free survival double that of anastrozole alone. The overall survival value also showed a non-statistically significant difference of 4.6 months in favour of Herceptin.

But despite the results, Sir Andrew Dillon said the uncertainties around of the long-term future when using Tyverb and Herceptin influenced the draft guidance decision.

“The evidence suggests that these drug combinations do not offer enough additional value to patients over and above currently available treatment to justify the high cost that the NHS would have to pay for them,” he said.

“Although trial data indicated that these treatment combinations could delay the growth and spread of the disease, an overall survival benefit was less certain. Also, patients who would be likely to receive lapatinib or trastuzumab in combination with an aromatase inhibitor are those in whom chemotherapy is not deemed suitable. However, we cannot say with certainty how many patients this would be.”

The preliminary guidance is now available for public consultation until 19 January 2011. 

The combined sales of seven emerging breast cancer drugs are expected to reach nearly $5bn in seven major markets by 2019, says a new report.

The Pharmacor 2010 findings from the Breast Cancer study predicted sanofi-aventis’s Iniparib as a potential blockbuster in the US, France, Germany, Italy, Spain, UK and Japan, with sales in excess of $1bn predicted.

The increasing uptake of Herceptin (trastuzumab) and Tykerb/Tyverb (lapatinib), plus the approval of three new HER2-targeted therapies, is also expected to raise $2bn.

But Decision Resources, who completed the study, says the future may not be as bright for Avastin (bevacizumab). Despite it already amassing huge sales figures last year, its future is in doubt after the FDA and CHMP recently questioned its benefits and risks.

It was recently recommended by the National Comprehensive Cancer Network, an alliance of 21 of the world’s leading cancer centres, but healthcare analyst Dr Niamh Murphy says its sales will fall in coming years.

“The fact that the National Comprehensive Cancer Network guidelines panel for breast cancer recently affirmed its existing recommendation for Avastin is a positive sign for Roche,” she said.

“However, even in the event that Avastin manages to hang on to a first-line metastatic breast cancer label, its sales – which surpassed $1 billion for breast cancer alone in 2009 in the world’s major markets – will plummet over the next several years.

“By 2019, sales of Avastin in breast cancer will drop to $350 million as a result of oncologists’ diminishing confidence in the agent, increased prescribing and reimbursement restrictions and competition from emerging therapies – most notably, Iniparib and Eli Lilly’s VEGF inhibitor, ramucirumab.”