“New ‘smart’ breast cancer drug gives an extra six months of life and stops loss of hair,” states the headline in the Daily Mail.
The news is based on the publication of the results of a new trial for treatment of a type of breast cancer known as HER2-positive breast cancer, which accounts for around one in five cases. HER2 is a protein found on the surface of normal breast cells, which helps cells grow and divide. It is found at abnormally high levels on some breast cancer cells, triggering abnormal cell growth and division.
The current treatment of choice for this type of cancer combines traditional chemotherapy with a medication called Herceptin (trastuzumab), which blocks the harmful effects of the HER2 protein.
Not all women respond to this treatment, which means that the cancer can spread out of the breast into other parts of the body (advanced breast cancer).
In this study researchers looked at a new type of drug called T-DM1. This is a ‘combination drug’ consisting of trastuzumab and a toxic agent called DM1. DM1 is toxic not just to cancerous cells but also to healthy cells, so it can cause a wide range of unpleasant side effects. By joining DM1 to trastuzumab the drug can be targeted to cancerous cells, reducing the amount and severity of side effects. This is in addition to the HER2-blocking activity of trastuzumab.
The new drug T-DM1 was found to increase the survival of patients and reduce side effects, when compared with standard treatment.
This exciting study has shown the efficacy and safety of T-DM1 for patients with advanced breast cancer. However, it should be remembered that this treatment is only suitable for HER2-positive cancers. This treatment will now proceed to licensing and regulatory approval.
Where did the story come from?
The study was carried out by an international team of researchers and was funded by F. Hoffmann-La Roche/Genentech – the manufacturer of this drug.
It was published in the peer-reviewed journal, the New England Journal of Medicine.
The research was reported on in The Daily Telegraph, the Daily Mail, the Daily Mirror and Channel 4 News.
The coverage was broadly accurate, although there were several puzzling reports that the new drug would reduce the hair loss traditionally associated with cancer treatment.
Although the study found that patients taking T-DM1 experienced fewer side effects compared with standard treatment, hair loss was not looked at specifically.
What kind of research was this?
This was a randomised controlled trial. It aimed to compare the efficacy and safety of a new drug (T-DM1) for HER2-positive advanced breast cancer with the current standard treatment used as a second choice after trastuzumab has failed. This current standard second-line treatment is lapatinib plus capecitabine. This is the ideal trial design to address this question.
What did the research involve?
The researchers recruited 991 patients with locally advanced or metastatic HER2-positive breast cancer. These patients:
- could not be treated with surgery (usually this is because the cancer has spread out of the breast so surgery would not provide an effective cure) and
- failed to respond to the standard drug treatment of trastuzumab (Herceptin) and a taxene (a chemotherapeutic agent).
They were randomly assigned to receive either:
- lapatinib (Tyverb) with capecitabine (Xeloda, a chemotherapeutic drug), which is standard treatment for unresponsive advanced breast cancer, or
- the new drug T-DM1.
If the patients experienced side effects the treatments could be postponed, the dose could be reduced or the treatment discontinued.
The researchers compared a number of factors, including:
- progression-free survival – the length of time until patients experienced disease progression or death from any cause
- overall survival – the amount of time until death from any cause
- the response rate – whether there was an improvement in the overall state of the disease, such as a slowing in the growth of the tumour or tumours
- time until symptom progression – the amount of time before symptoms of advanced breast cancer, such as bone pain, appeared
- safety and the number and severity of side effects that patients receiving the two different treatments experienced
What were the basic results?
After a median follow-up of 13 months, the researchers found that:
- Median progression-free survival was significantly better with T-DM1. It was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine. The risk of disease progression was reduced by 35% in patients treated with T-DM1 (hazard ratio for progression or death from any cause 0.65; 95% confidence interval CI 0.55 to 0.77).
- The response rate was significantly higher with T-DM1 (43.6% versus 30.8%), and the median length of time that this response was maintained for was increased (12.6 months versus 6.5 months).
- The time until symptom progression was also significantly longer for patients treated with T-DM1 (7.1 months versus 4.6 months).
Overall survival was assessed after a median of 19 months’ follow-up. Median overall survival was estimated at 30.9 months with T-DM1 compared with 25.1 months with lapatinib plus capecitabine, an extension of life approaching six months, which was statistically significant.
The risk of death from any cause was reduced by 32% (hazard ratio for death from any cause 0.68; 95% CI 0.55 to 0.85). Estimated one-year survival rates were 85.2% in the T-DM1 group and 78.4% in the lapatinib–capecitabine group. Rates at two years were 64.7% and 51.8%, respectively.
Among patients that received at least one dose of medication, serious adverse events (such as severe anaemia) were experienced by 15.5% of those taking T-DM1 compared with 18% of those taking lapatinib–capecitabine.
The adverse events were ranked using a pre-determined and widely used scale (Common Terminology Criteria For Adverse Events) consisting of five grades:
- grade 1: mild adverse event
- grade 2: moderate adverse event
- grade 3: severe and undesirable adverse event
- grade 4: life-threatening or disabling adverse event
- grade 5: death related to adverse event
The incidence rates of adverse events of grade 3 or 4 were higher in the lapatinib–capecitabine group than the T-DM1 group (57% versus 40.8%).
There were four deaths in the lapatinib–capecitabine group and one death in the T-DM1 group that were attributed to adverse events due to study medication.
How did the researchers interpret the results?
The researchers conclude that the new drug T-DM1 “has therapeutic potential … for the treatment of advanced HER2-positive breast cancer that has progressed during or after treatment with trastuzumab and a taxene”. This effect was seen in a wide variety of patients.
This exciting study has shown the efficacy and safety of a new drug, T-DM1, for patients with advanced HER2-positive breast cancer.
However, there are several issues to consider:
- Only about 20% of breast cancers overexpress the HER2-protein and are designated HER2-positive, so the drug will not be suitable for everyone.
- The patients in this trial had HER2-positive breast cancer that had progressed during treatment with a combination of trastuzumab (Herceptin) and a taxene (a chemotherapeutic agent). This is a first-line treatment combination, so it is likely that other drugs will be tried before the new T-DM1 drug.
- This is what is known as a phase III trial, which is the last trial a drug undergoes before it can come to market. Since this study suggests that T-DM1 appears to be both safer and more effective than lapatinib–capecitabine, there is no reason to doubt that it will receive licensing and regulatory approval. But how long this will take is still unclear.
- The cost of the drug is as yet unknown, so even if it does come to market it is unclear whether it will be made available free of charge on the NHS. A decision about this will be made by the National Institute for health and Clinical Excellence (NICE). Drugs of this kind can be extremely expensive so NICE will need to decide whether T-DM1 offers value for money.