When, for the first time in decades, a trial last year showed an improvement in survival in patients with stage III inoperable non–small cell lung cancer (NSCLC), the results swiftly led to approval of the immunotherapy that had demonstrated this benefit — durvalumab (Imfinzi, AstraZeneca).
However, unlike regulatory authorities elsewhere in the world, the European Medicines Agency (EMA) decided to restrict use of this drug to patients whose tumors were positive for programmed death ligand 1 (PD-L1).
Now, this decision has been condemned by lung cancer experts as depriving patients of potentially curative treatment.
An editorial criticizing the decision was published online in the Annals of Oncologyon January 8.
The authors describe the EMA's decision as "surprising" and "a major cause for concern among the thoracic oncology community."
"At a time when the therapeutic options are improving for lung cancer, a lethal disease for the vast majority of the patients, we worry that the present EMA decision could result in a lost therapeutic opportunity in the curative setting for a sizeable subset of patients," they write.
Solange Peters, MD, PhD, the lead author of the editorial, is head of medical oncology and chair of thoracic malignancies in the Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. Her coauthors include 21 experts in lung cancer from across Europe, as well as experts from Australia and the United States.
Improved Survival Demonstrated
The approval application for this indication was based on the results from the PACIFIC trial, presented recently at the 19th World Conference on Lung Cancer and published simultaneously in the New England Journal of Medicine. Those results show that treatment with durvalumab after chemotherapy was associated with significantly longer overall survival compared with placebo.
As reported at the time by Medscape Medical News, this study demonstrated, for the first time in decades, an improvement in overall survival for patients with locally advanced stage III unresectable NSCLC.
A secondary endpoint analysis of patient-reported outcomes also indicated that durvalumab was well tolerated and did not affect quality of life. Some symptoms, such as dysphagia and alopecia, even improved.
These results led to the approval by the US Food and Drug Administration (FDA) in February 2018 of durvalumab as consolidation therapy after chemoradiotherapy in unselected patients with unresectable stage III NSCLC.
Similar approval was granted by regulatory agencies in Canada, Japan, Australia, Switzerland, Malaysia, Singapore, India, and the United Arab Emirates, despite concerns over its cost-effectiveness.
The EMA, however, chose in July 2018 to limit the use of durvalumab to those patients with tumors that had high levels of expression of PD-L1.
That decision was based on a post hoc, unplanned analysis in which it could not be unequivocally demonstrated that durvalumab yielded a survival benefit in patients with low expression of PD-L1 (a subgroup of 150 patients from the 700 trial participants).
In their editorial, Peters and colleagues argue that basing the decision on a post hoc subgroup analysis "is against the integrity of the clinical trial rules on which the principles of evidence-based medicine are based.
"It could create an unprecedented situation unique to Europe with regards to management of stage III NSCLC compared to other countries, and set worrying precedents with respect to analysis of future clinical trial data," they write.
The authors worry about the consequences of that decision and say that "European patients belonging to a group of high unmet need will not have access to durvalumab."
This EMA decision "will have a negative social impact, creating unacceptable disparities across countries, with differential access to treatments," they write.
The result will be that "some patients will pay for the treatment, some patients with private insurance shall get access and some might decide to get treatment abroad, where the drug is available."
Trouble With Testing
In an interview with Medscape Medical News, Peters pointed out that for approximately 20% of lung cancer patients, not enough tissue is available for testing PD-L1 status, and up to 30% of the remaining patients are found to be PD-L1 negative.
Because the EMA decision restricts use of durvalumab to patients who are PD-L1 positive, between 40% and 60% of patients with stage III NSCLC in Europe might not be able to receive the drug.
Peters said that, with the EMA being at odds with so many other regulatory agencies, including the FDA, the decision "is about opinion, because all the agencies have obviously been exposed to the same data."
She thinks that this difference of opinion may have resulted from the EMA trying to be "extremely accurate in the way it looks at the new large immunotherapy dataset," as well as the EMA having concerns over the potential economic burden of any decision.
"We know it's not the role of the EMA but of the HTAs [health technology assessment agencies] to think about this, but at the same time, the sustainability of our healthcare systems is a concern for all," she said.
Peters also feels that the EMA has a strong desire to move more into the realm of personalized medicine, and she said it is "quite frustrating" that no biomarker has been defined for durvalumab, either in PACIFIC or, more generally, in the wider setting of NSCLC.
"We would really like to be able to be sure that we can identify the patients who benefit," she commented.
"The only problem is you shouldn't do it by using statistical shortcuts, and you shouldn't do this by trying to interpret a little bit too far in a retrospective subgroup analysis," she said.
She added: "Unfortunately, PACIFIC is not a trial aimed at giving personalized oncology results; it's just aimed at improving the currently dismal survival of all stage III NSCLC."
The next step would therefore be to conduct a trial to determine who benefits from durvalumab and who does not, "but it is not this trial with which we will have the answer."
Questioning the EMA Decision
In their editorial, Peters and colleagues set out a number of reasons why they disagree with the EMA's decision.
First, they note that the conclusion was not based on the primary analysis of the intention-to-treat (ITT) population, "as is customary and appropriate," and that the cutoff the agency requested for its post hoc analysis was not prespecified in the protocol.
Moreover, they point out that expression of PD-L1 "can be dynamic and heterogeneous," inasmuch as it is influenced both by tumor biology and the quality and quantity of biopsy samples.
Other factors at play include the type of antibody used for the analysis, as well as the scoring system and the cutoff used to assess PD-L1 status.
They also highlight that, in the PACIFIC study, PD-L1 expression was examined only with pretreatment samples, not post-chemoradiotherapy samples, meaning that "the predictive capacities of baseline PD-L1 expression cannot be accurately assessed.Furthermore, tissue collection was not mandatory, and there was no stratification by PD-L1 expression.
Consequently, the baseline characteristics of the various PD-L1 subgroups may not be balanced, and it is not possible to fully take into account the potential confounding effects of other prognostic factors.
The authors also write that the control arm in the PD-L1-negative subgroup overperformed in comparison with the ITT placebo arm, and there is a "high probability of false negative results."
"Not surprisingly, based on the above caveats, the OS [overall survival] result is inconclusive in the PD-L1 negative subgroup, with the additional observation that it does not indicate harm in these patients," they say.
Peters said that the decision by the EMA is all the more difficult to understand, given the fact that the agency "is extremely scientific, and...I would say they really do an excellent job.
"The reason why we wrote this text is our incapacity to understand this specific decision, as it does not seem to follow the principles of primary interpretation of clinical trial data, and it does not consider the rules of statistics," she said.
"We would expect, based on the way the EMA usually analyzes clinical trial results, that this decision would have been different, that it would have been the same as the FDA and all the 15 other regulatory bodies that have decided about this trial," she added.
The authors therefore await additional explanations as to why the EMA would make this decision. In the meantime, there is the risk that "patients in a curative setting are deprived of a curative treatment."
Peters pointed out that "we all expect new data, but the question is what to do in the interval. Deprive the patients? Or allow them to get access and potentially try, if you can, to better define the subset of patients who benefit?
"As a doctor looking after patients, I would prefer the second solution," she commented.
She continued: "All authors of the editorial are fully dedicated and have spent part of their professional life to define the new paradigms of precision oncology. That discussion is the one we would like to have."
She revealed that some national HTAs in Europe are taking the unusual step of asking themselves whether the EMA decision has to be followed and whether they can instead adopt a broader definition of registration of durvalumab.
Peters said: "I don't remember having seen it so much before, so that's something which is also interesting to observe."
The authors' relevant financial relationships as listed in the original article.
Ann Oncol. Published online January 8, 2019. Abstract
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