There is a new class of anti-cancer drugs which stop the cancer "hiding" from the body's immune system which are showing considerable promise in clinical trials. Over the past week, the results of two of these trials were presented to a conference of oncologists. One trial used a combination of two to treat patients with advanced melanoma with 60% showing shrinkage of their tumors. In trials using one of the drugs on patients with lung cancer who had already been failed by other treatment, there was an average extension of life of around 3 months (from 9.4 to 12.2 months) although some survived for up to 19.4 months. The current costs however are presenting a challenge for both insurance companies and "single payer" systems.
Both trials involve the use of drugs from Bristol-Myers Squibb although other drug companies are developing drugs which also engage the patient's own immune system to fight the cancers. Nivolumab, marketed as Opdivo, was approved by the FDA as a "breakthrough therapy" in December 2014 for the treatment of melanoma. The trial results in the treatment of lung cancer showed the significant results above. Like many drugs, the dosage has to be calculated according to the patient's body mass. For a 70Kg person, the wholesale cost of the drug is between $130,000 and $157,000 a year. It should also be emphasized that the trials involved patients who had already received conventional chemotherapy and that the progress of the disease, although considerably slowed, had resulted only in life extension rather than cure.
The second trial looked at the additional use of another Bristol-Myers Squibb drug, Ipilimumab, which has approval in the UK, to treat advanced melanoma. In 58% of the cases, the tumors had stopped spreading for nearly a year.
An international trial on 945 people showed that taking both drugs led to tumours shrinking by at least a third in 58% of patients - with the tumours stable or shrinking for an average of 11.5 months.
The figures, published simultaneously in the New England Journal of Medicine, for ipilimumab on its own were 19% and 2.5 months.
Dr James Larkin, a consultant at the Royal Marsden Hospital and one of the UK's lead investigators, told BBC News: "By giving these drugs together you are effectively taking two brakes off the immune system rather than one so the immune system is able to recognise tumours it wasn't previously recognising and react to that and destroy them.
"For immunotherapies, we've never seen tumour shrinkage rates over 50% so that's very significant to see.
For patients, the big downside is that the incidence of side-effects increased, roughly doubling so around 50% experienced some form. These include fatigue, a rash or diarrhoea. The positive results are however so significant that they are the lead story on BBC News today. Ipilimumab is also very expensive and was only approved for use in NHS in England "only if the manufacturer provides ipilimumab with the discount agreed in the patient access scheme". The dosage also varies with the weight of the patient (
.pdf):
Ipilimumab costs £3750 for 50 mg and £15,000 for 200mg (excluding VAT, British national formulary, September 2012). Assuming an average body weight of 70kg, each dose of ipilimumab would need a 200mg vial and a 50mg vial costing £18,750. A 4-dose course would therefore cost £75,000, not including administration costs. Costs may vary in different settings because of negotiated procurement discounts.
The manufacturer of ipilimumab has agreed a patient access scheme with the Department of Health, in which a discount on the list price of ipilimumab is offered. The size of the discount is commercial in confidence
That cost equates to about US$120,000. The combination therapy would therefore be something like $250,000 in the first year with a continuing $120,000 p.a. for as long as the nivolumab is tolerated,
if the patient is 70Kg (around 155 lbs). A
2012 survey showed that was roughly the average for American women whereas for men the average was 196 lbs. There is a
patient access scheme in the USA run by Bristol-Myers Squibb which could reduce the cost to the patient.
Things to note are that the high cost may well reduce, certainly for "single payer" national schemes like the English NHS, there may well be opportunities to negotiate significant reductions until the price reduces anyway. The main caveat is that both trials were conducted with patients with stage III or IV cancers so, although life extensions can be demonstrated, along with side-effects; the efficacy at earlier stages difficult to assess, although quite likely will be positive. There are other developments that also look promising. Cardiff University in Wales has a research unit which has just licensed a potential discovery for development:
Researchers have identified a compound which targets aggressive tumour cells found in breast, pancreas, colon and prostate cancers.
The discovery has now been licensed to biotech investors Tiziana Life Sciences.
It is hoped the compound can eventually be developed for clinical trials.
The research was conducted by Cardiff University's European Cancer Stem Cell Research Institute (ECSCRI) and the School of Pharmacy and Pharmaceutical Sciences.
Scientists revealed details of the compound - called OH14 - on Thursday morning when the deal with Tiziana was made public on the London Stock Exchange
Another drug discovered by Cardiff University is at the
final stages of clinical trials:
Acelarin is designed to stop patients becoming resistant to common therapies in treating cancer of the lung, ovary, breast, colon and pancreas.
Two phases of clinical trials show half of 78 patients responded to treatment.
The treatment was invented at Cardiff University and Prof Chris McGuigan said the drug's success was "remarkable".
It was tested on patients who had exhausted all other forms of treatment at London's Hammersmith Hospital.
"These were terminal cancer patients, all of whom had solid tumours that were growing," explained Prof Chris McGuigan from Cardiff University.
"Seventy-eight patients were given Acelarin - and remarkably half had their disease brought under control; the tumour growth was stopped, and in some cases reversed."
As with the immunology drugs, long term effects are still unknown. The question however becomes whether an insurer, whether that be a private company or national scheme like NHS England will be able to afford such drugs (let alone the patient if they have to make a co-pay based on a percentage costs). The National Institute for Health and Care Excellence (abbreviated for historical reason to NICE) assesses the cost of a QALY or "
quality adjusted life year" to decide whether to recommend a novel treatment is cost-effective for NHS England to provide. If lower than between £20k and £30k (the exact amount is confidential to avoid drug makers pitching a price), a new drug or procedure is very likely to be approved for general use. In England there is a special additional fund for these new and very expensive cancer drugs but the scheme is subject to individual patient reference and is not available in the other three constituent countries in the UK. Clearly at the moment these two new drugs from BMS have only been shown to extend lives by several months in later stage cases. They will therefore have a very high cost per QALY and are unlikely to be approved for general use.
I presume similar decisions will be made by US insurance companies (and the nationalized services like Medicare, Medicaid and VA). On the more hopeful side, drug prices tend to reduce dramatically from the initial launch price. Further trials are obviously needed to see if they have any advantage over conventional treatment by surgery, radiation and chemotherapy at much earlier stages.
Although I have emphasized the early development stages of these treatments, it does look like we may be within sight of a time when most cancers are conditions that a patient lives with rather than dies of. In the meantime, I think it right that we acknowledge those patients who took part in the clinical trials who had very little hope apart from the knowledge that their contribution would help others.