In recent months, 7 new drugs against cancer(1) have received an unfavorable opinion from the Haute Autorité de Santé with a view to their reimbursement by health insurance. These therapies, targeting rare mutations and often indicated for patients in dead end of treatment, had however delighted the oncologists during the presentation of their results in the international congresses.
Many learned societies and patient associations have protested against HAS’s position, pointing the finger at an assessment methodology that is not suitable for these innovative treatments. The Ministry of Health had also summoned the health authority to revise its copy. Almost a year and a half later, she finally publishes this new “doctrine” that Pr Pascal Pujol, head of the clinical oncogenetics department at the Montpellier University Hospital and president of the Sfrench society for predictive and personalized medicinecomment for us.
Seven anti-cancer drugs recently received an unfavorable opinion from the HAS. What treatments are these?
Pujol: These are targeted therapies and immunotherapies indicated in the treatment of cancers at a metastatic stage. They concern a small percentage of patients with a rare marker. It can either be a mutation in a gene, such as RET in lung or thyroid cancers. Or a so-called “agnostic” marker, that is to say predictive of a good response to an anti-cancer treatment, whatever the location of the cancer. In this case, to immunotherapy. This is the case of microsatellite instabilities (MSI) in endometrial or colorectal cancer.
The HAS has classified these treatments in ASMR5 (see insert). For what ?
The HAS considered that we did not have reliable data to demonstrate that these innovative treatments perform better than current treatments, in this case chemotherapy. She is waiting for the results of phase III clinical trials, that is to say a study in which the 2 treatments are compared on a large number of patients.
“Waiting for a phase III clinical trial would simply not be ethical. »
And according to you, it is an aberration…
With these treatments, response rates are obtained between 40 and 80%, where chemotherapy only gives 10%. In other words, patients who were dying see their tumors regress or even disappear after a few weeks. These results are sufficiently spectacular for us not to expect any more!
Conducting phase III clinical trials for these treatments would therefore be a waste of time in your opinion?
Beyond that, it is simply impossible! These treatments target rare mutations. They therefore only concern a very small percentage of patients. For therapies targeting RET mutations in lung cancer, for example, hospitals around the world had to be mobilized to enroll 300 patients in a phase II trial, and that was laborious. Asking to do a phase III on a larger number of patients is absurd! And you are going to compare the effectiveness of these treatments to what? To chemotherapy that does not work in the vast majority of cases? It just wouldn’t be ethical.
The HAS has just published a document in which it adapts its evaluation method to these new issues. Does it meet your expectations?
French experts had been waiting for a year and a half for this new “doctrine”: since the referral to the executive on October 5, 2021 in the face of “difficulties in accessing certain treatments and the rise of new research methodologies with requests access to the market solicited at ever earlier stages”.
Unfortunately, we are still not there. The HAS still puts forward the usual randomized controlled trials. It does accept certain alternatives to speed up access to treatment, such as so-called “virtual” arms (2), but the specifications to be complied with are so heavy that it is a challenge to comply with them! As for the so-called “sneaker” trials(3), which are the only ones that can be set up in the context of rare mutations or agnostic markers, they are quite simply not part of it. Nor does the doctrine mention other criteria to account for the clinical effect of targeted therapies, such as the response rate or the duration of the response.
Should the HAS therefore go further in its evaluation criteria for these innovative treatments?
Absolutely. This is what the European Medicines Agency did. Today, the EMA grants authorizations to drugs on the basis of a phase II if the response rates are strong. Moreover, 28% of the drugs it has authorized in oncology have not been evaluated by a phase III trial and 23% have not been the subject of a comparative arm. At the SFMPP, we regret that the HAS does not appropriate these new evaluation criteria for these particular cases. Especially since these treatments are neither a fad nor special cases: all the progress made in oncology over the past 20 years concerns targeted therapies or immunotherapies. This is the future of cancer treatments.
France would therefore be out of step?
Yes and it’s a shame. France has an incredible healthcare system. We have all the tools to carry out personalized medicine thanks in particular to the France genomics plan and the molecular analysis platforms set up by INCa. The early access reform is also a success. We only have one weak link: the expertise to evaluate innovative drugs targeting rare mutations on the basis of modern criteria.
” It was too late. My patient had entered palliative care. »
These innovative treatments, for which the HAS has given an unfavorable opinion, have therefore been authorized in Europe by the EMA?
Yes. They have also entered European and international repositories. As a result, we arrive at a total disconnection between the opinions of the HAS and the recommendations for the practice of oncology. And we find ourselves at odds with our patients.
Today, do you sometimes have the impression of not being able to offer the best care to your patients?
Yes, and I have a concrete case in mind. I received a woman with endometrial cancer with Lynch syndrome. This genetic disease is associated with MSI so I knew she would most likely respond to immunotherapy with dostarlimab. This treatment had been presented at the ASCO in colorectal cancer. I still remember it, it was extraordinary: 100% response in 100% of patients. You just couldn’t see the tumor anymore! And in endometrial cancer, the response rate is around 50%.
The problem is that dostarlimab is one of the treatments rejected by the HAS. So I didn’t have access to it. So, I asked for the treatment at the laboratory on a compassionate basis. I didn’t have it. I contacted Prof. Ray-Coquard, who is conducting clinical trials on this molecule, to try to get my patient into a clinical trial. It took 2 months for her to tell me that she had found a possibility for her. But it was too late. My patient had entered palliative care.
Well, this is real life. We cannot help being affected by it.
What is the role of HAS?
The HAS is an independent public authority whose role is to evaluate medicines on the basis of scientific data. It is on the basis of its opinions that the DGS decides whether a drug will be covered by health insurance and, if necessary, to negotiate its price.
HAS assesses the “benefit rendered” of medicinal products in comparison with existing medicinal products (if any) and thus defines the Improvement of the Actual Medical Benefit:
- ASMR I, majeure,
- ASMR II, important
- ASMR III, moderate,
- ASMR IV, mineure,
- ASMR V, non-existent, means “lack of therapeutic progress”.
Source : HAS
Interview by Emilie Groyer
1. selpercatinib, prasetinib, capmatinib, larotrectinib, entrectinis, pembrolizumab, dostarlimab
2. The “virtual” arm simulates a group of control patients (having received the reference drug or a placebo) thanks to mathematical models designed from real-life data. It serves as a comparator for the arm made up of patients “actually” treated with the innovative drug.
3. “Basketball” trials consist of putting patients with the same marker (a rare mutation, for example) in the same basket and treating them with a drug targeting this marker, regardless of the location of their cancer .
