New immunotherapies, such as the checkpoint inhibitors, have created a great deal of excitement in the oncology community because of their potential to improve outcomes for some patients.
However, these agents are effective for only for a minority of patients with advanced cancer; many patients have no response or respond only for some time. As a result, questions have been asked about the value of these new drugs.
One way of assessing value is by using a framework such as that devised by the American Society of Clinical Oncology (ASCO), which awards bonus points if substantial durable survival is demonstrated for a given therapy.
But a new analysis found that only 3 of 23 immunotherapy drug indications gained the “bonus points” that the ASCO value framework awards for durable survival benefits.
The authors, led by Omer Ben-Aharon, MBA, MHA, from the Health System Management Program, Bar Ilan University, Ramat Gan, Israel, point out two possible reasons for these results.
“The first is that the public excitement concerning durable survival with immuno-oncology may lack sufficient supporting data,” they write. “The second is that the ASCO value framework may be insufficiently calibrated to reward durable survival benefits.”
The study was published online December 28 in JAMA Oncology.
Awarding of Bonus Points
The revised ASCO framework, which emphasizes achieving improved survival or long-term disease control, awards bonus points if an agent meets certain criteria.
These points are issued if the regimen/drug being studied is able to achieve the following: The study results show a common survival index (overall survival or progression-free survival), the time frame is at twice the median survival index, at least 20% of the control group is alive, and the proportion of patients receiving the test drug who have survived has improved by at least 50%.
The framework will award 20 points if the improvement is overall survival and 16 points if the improvement is progression-free survival.
Three Meet Criteria
In the new analysis, the authors examined which immune-oncology agents fulfilled the criteria of the durable survival threshold as defined in the updated ASCO value framework.
The drugs investigated included ipilimumab (Yervoy, Bristol-Myers Squibb), pembrolizumab (Keytruda, Merck), nivolumab (Opdivo, Bristol-Myers Squibb), atezolizumab (Tecentriq, Genentech), avelumab (Bavencio, Pfizer), and durvalumab (Imfinzi, AstraZeneca).
These drugs had all had received approval from the US Food and Drug Administration (FDA) from March 2011 to August 2017 for a total of 23 metastatic conditions.
This included 10 approvals (43%) based on survival endpoints and 13 (57%) based on objective response rate.
The indications approved were melanoma (six approvals [26%]), non-small cell lung cancer (NSCLC) (six approvals [26%]), urothelial carcinoma (five approvals [22%]), head and neck cancer (two approvals [9%]), microsatellite instability–high cancer (two approvals [9%]), renal carcinoma (one approval [4%]), and Merkel cell carcinoma (one approval [4%]).
Only three drug indications fulfilled the ASCO criteria of a minimum 20% survival rate for the control group: ipilimumab indicated for second-line treatment of melanoma (22%), nivolumab for first-line treatment of melanoma (25%), and nivolumab for second-line treatment of squamous NSCLC (22%).
A very small number of patients (≤10%) survived at twice the median overall survival time point for all indications studied, except for pembrolizumab indicated for first-line treatment of melanoma, in which case 18% survived at twice the median overall survival time point.
Set the Bar Higher
The oncology community should be moving toward setting the bar even higher, comment Lowell E. Schnipper, MD, from Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, and Richard L. Schilsky, MD, senior vice president and chief medical officer at ASCO, writing in an accompanying editorial.
“Concern about whether or not value frameworks account for durable survival is a critically important issue,” they write, adding that of even greater importance “is the need for innovation that results in more patients enjoying long-term survival.”
Dr Schnipper and Dr Schilsky explain that concerns regarding imprecision as a “function of too few patients alive or progression free” at the milestone initially selected by the ASCO Value Framework Task Force helped lead to the decision of setting a bar of 20% for controls groups.
“The task force also wished to ensure that the incremental benefit of the new treatment would be clinically meaningful by setting it at a 50% improvement over the control,” they write.
The editorialists urge the oncology community to set the bar higher. Of all drugs approved by the FDA between 2014 and 2016, only 19% met or exceeded the modest hazard ratio targets having a clinically meaningful benefit, as identified by the ASCO Cancer Research Committee.
“The ASCO value framework is an iterative endeavor,” they conclude. “As clinical science changes, evaluative tools with which to assess comparative clinical efficacy will evolve. The emphasis must be on raising the bar for outcomes as we design clinical trials and assess the net health benefits and value of new treatments.”
The authors and editorialists have disclosed no relevant financial relationships
JAMA Oncol. Published online December 28, 2017. Abstract, Editorial
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