Debating the value of targeted lung cancer treatments
US industry group Pharmaceutical Research and Manufacturers of America (PhRMA) has criticised an evidence report by the Institute for Clinical and Economic Review (ICER), which puts a low value on targeted treatments and immunotherapy for non-small cell lung cancer. ICER’s findings fly in the face of the trend towards individualised cancer treatment, but Abi Millar asks who is right in this case.
Non-small cell lung cancer (NSCLC) is one of the most common cancers in the Western world. It is also one of the deadliest. While the prognosis is generally good for patients diagnosed at the earliest stage (with 58%-73% surviving five years after diagnosis), survival rates dip markedly when the cancer is more advanced. Among those with stage 4 NSCLC, only 2%-13% reach the five-year threshold.
All this said, however, treatments have progressed significantly in recent years, both increasing patients’ chances of survival and improving their quality of life. Depending on the stage of the cancer and other factors, treatment options may include surgery, radiation therapy, chemotherapy and palliative care.
A ‘paradigm shift’
Lately, we have also seen a wave of targeted treatments and immunotherapies, which have been described as a ‘paradigm shift’ in the treatment of the disease.
These new therapies are directly tied to advances in translational research. As researchers have learnt more about the underlying mechanisms of NSCLC, which vary considerably between patients, they have paved the way for drugs that target those mechanisms.
The first to be approved, in 2006, was Bevacizumab (Avastin), a monoclonal antibody used to treat advanced NSCLC. This homes in on a particular protein, VEGF, which helps new blood vessels form. Similarly, Ramucirumab (Cyramza) targets a VEGF receptor and disrupts tumour blood supply.
Another class of treatment, known as tyrosine kinase inhibitors (TKIs), blocks a particular enzyme responsible for growth signaling in cells. These TKIs include Boehringer Ingelheim’s Gilotrif, Genentech’s Tarceva and AstraZeneca’s Iressa, all of which have been approved within the last three years.
Then there are immunotherapies targeting the PD-1 receptor or its ligand (PD-L1), such as Genentech’s Tecentriq, Bristol-Myers Squibb’s Opdivo and Merck’s Keytruda. The PD-1 protein is essentially part of a masquerade that prevents cancer cells from being attacked by the immune system. When it is blocked, immune cells can finally ‘see’ the cancer.
Immunotherapy is generating a major buzz, having been named the American Society of Clinical Oncology’s top cancer advance of the year.
“No recent cancer advance has been more transformative than immunotherapy. These new therapies are not only transforming patient lives, they are also opening intriguing avenues for further research,” said ASCO president Julie M Vose in February this year.
It therefore came as some surprise when, in September, the Institute for Clinical and Economic Review (ICER) published an evidence report into NSCLC, which placed a relatively low value on targeted treatments. Having assessed the drugs’ clinical effectiveness and value, ICER returned the rather muted conclusion that TKI treatments “appear to confer clinical benefits” and that their cost-effectiveness “appears to fall within commonly-accepted thresholds”.
For immunotherapies the verdict was even less glowing. “While the cost-effectiveness of PD-1 immunotherapies exceeds these thresholds, there is greater uncertainty in these findings given variability in estimates of overall and progression-free survival,” wrote the authors.
The report was met with some dismay, with various industry commentators questioning ICER’s methodology. As a blog post by the Personalized Medicine Coalition pointed out, its value assessment process has “no mechanism for capturing the value of targeted medicines, since its model is based on population averages”.
The patient group Patient Rising, meanwhile, remarked that ICER had focused too narrowly on cost. “The budget impact assessment appears to be the main focus for ICER, leaving us to wonder how useful this document could possibly be for determining what is best for the patient,” said the group in response to ICER’s scoping document.
According to Lauren Neves, a director of policy at the US industry group Pharmaceutical Research and Manufacturers of America (PhRMA), the oncological community is right to be concerned.
“ICER looked at a really narrow selection of evidence,” she says. “They also looked at treatments that haven’t completed clinical trials yet, so the data they’re using is incomplete. We would encourage ICER to wait till the drugs have been approved.”
She adds that ICER is also predominantly concerned with survival rates, without taking into account other health outcomes that matter to patients.
“For many non-small cell lung cancer patients, yes they care about survival, but they also care about quality of life and side effects and their ability to continue to work,” she says. “These drugs have a significant benefit for patients in terms of the quality of life, which we don’t think ICER is accounting for.”
PhRMA has been a vocal critic of ICER, claiming on its website that “ICER’s reports have historically relied on flawed methods and assumptions, lacked transparency and failed to reflect the complex realities of optimally caring for patients”.
Such accusations are more than mere sniping: ICER’s assessment reports are designed to guide providers’, insurers’ and policymakers’ decisions. As such, they have a very real impact on which medications US patients are likely to receive.
“We don’t know how the non-small cell lung cancer report will affect patients yet, but we can say from past experience that there’s a real concern that ICER’s report will limit their access to appropriate and necessary treatments,” says Neves. “I would cite as an example the report they issued last September into PCSK9 inhibitors for the treatment of high cholesterol. We heard stories from patients again and again about how, as a result of ICER’s recommendations, they couldn’t access these treatments. So this can really hit patients where it hurts.”
Neves says that PhRMA’s objections can be boiled down into four key areas of concern. The first of these is the fact that ICER arrives at a single value-based price benchmark for drugs.
“We think ICER should develop a transparent dynamic rating system that presents information on the components of value separately, and remove the value-based price benchmark from their evidence report. Value is too complex and personal to be able to quantify like that,” she says.
Secondly, ICER places a budget cap on spending on new drugs, without accounting for the savings that may be made elsewhere. PhRMA believes the budget cap should be removed, leaving room for expensive new drugs that nonetheless cut costs overall. Thirdly, the framework includes a cost-effectiveness analysis, which, says Neves, has widely recognised limitations.
“It doesn’t capture the full range of benefits that treatments can provide, so we would encourage ICER to tweak their method of assessing cost-effectiveness,” she explains.
Finally, ICER’s process has suffered from a lack of transparency, as well as a failure to meaningfully engage with industry and patient groups.
“This has been a repeated problem with ICER, and it has been noted in a lot of the comments by patients and clinicians,” says Neves. “ICER should be transparent about the way they’re doing their analyses, but also talk to people who really have skin in the game.”
A heterogeneous disease
The broader issue, of course, is that as we move towards an age of personalised medicine, no single treatment is likely to help the entire patient group. NSCLC is a highly heterogeneous disease and any given targeted therapy may benefit some patients enormously, while doing very little for the rest.
ICER does acknowledge this issue, stating that “PD-1 immunotherapies improve survival overall compared with docetaxel. This improvement reflects prolonged benefits in a minority of patients and no benefit in the majority of patients, making standard descriptive statistics of survival benefit (median survival and hazard ratios) potentially misleading in understanding the overall effects of these therapies.”
However, because its report is concerned primarily with overall effectiveness, such fine divisions are lost in its overall thrust. It remains to be seen what the ramifications will be, and how the evidence as ICER has framed it will be applied to policy and practice. One thing is clear – for the hundreds of thousands of patients in the US who are living with NSCLC, these questions are more than merely academic.
“Often times patients with non-small cell lung cancer don’t have time to deal with concerns and access issues. Our concern is patients’ ability to get the treatment they need,” Neves explains.