This is a company announcement of the results of a phase 3 trial of its new chemotherapy drug Vyxeos (cytarabine: daunorubicin) Liposome for Injection (also known as CPX-351) compared to the standard therapy (cytarabine and daunorubicin, or 7+3) in patients with high risk acute myeloid leukemia (AML). The study results have not yet been published.
Despite the use of some exaggerated language over the implications of this study, and the lack of a cost reference, the news release delivered plenty of data about the benefits in the treatment group versus the comparator group. The release appears thorough in summarizing the study, although we can’t be sure since the results haven’t been made available for independent assessment.
AML is a cancer of the myeloid line of blood cells, where abnormal white blood cells grow rapidly and accumulate in the bone marrow, interfering with the production of normal blood cells. Any chemotherapy advance that can extend the lives of patients with high risk AML without adverse drug effects is highly welcomed. It is possible that the liposome formulation of these two previously used chemotherapies will help patients survive longer than other therapies and be an advance in a disease where there are very few options and low survival rates.
It’s important to assess this release now since the manufacturer indicated it plans to seek U.S. and European regulatory approval for the drug this year. It should be pointed out that the Vyxeos injection appears to combine the same drugs used in the standard therapy, but with a nano particle liposomal membrane package delivery system.
There was no discussion of the costs of the treatment.
The news release gave extensive data on median overall survival (9.56 months compared to 5.95 months for patients receiving 7+3, the standard treatment) and the “percentage of patients alive 24 months after randomization” (31.1% in the treatment arm compared to 12.3% on the 7+3 arm).
It also, helpfully, added the “sixty-day all-cause mortality” as 13.7% versus 21.2%, in favor of patients treated with the intervention drug. The release notes that the treatment gives a Number Needed to Treat (NNT) of about 7, which is very good. (NNT is a measurement of the impact of a therapy by estimating the number of patients that need to be treated in order to have an impact on one person.) The median survival doesn’t look as good. In about half of the patients, there is a four month or less increased survival. This implies that there is a group that has much longer survival. To see that there is a clinically important survival benefit (14% absolute increase) does make a difference.
The release noted that serious harms from the drug were comparable to the standard therapy and listed the adverse events including infections, febrile neutropenia, bleeding, cardiac, gastrointestinal, general systems, metabolic disorders, musculoskeletal, nervous system, respiratory, skin and renal.
One word of caution about the harms. The study was not blinded (according to its listing on ClinicalTrials.gov) and these adverse effects may have been subjectively found, potentially biasing the results. We are not given enough information about this in the news release.
The release gives us a solid overview of the study design with this statement: “The randomized, controlled, Phase 3 trial (Protocol NCT01696084), enrolled 309 patients at 39 sites in the United States and Canada, and compared VYXEOS to the conventional cytarabine and daunorubicin treatment regimen (commonly referred to as 7+3) as first-line therapy in older (60-75 years of age) patients with high-risk (secondary) AML.”
What would have helped is knowing the numbers of patients in each arm (this information was not conveyed) and the extent to which there were dropouts or others who didn’t complete the study. The trial notes that it employed an Intention-to-Treat analysis which can involve missing data because sometimes patients withdraw due to the adverse effects of the intervention. If that happens you don’t know how those patients fared. Are we sure these results reported complete outcome data for all randomized trial participants? No, we’re not, and that omission can reduce the quality of the evidence. What we don’t know about the intention to treat analysis is whether they had the outcome event of survival or death recorded for each patient. Patients lost to follow up in whom no outcome was measured would be left out of this type of analysis. We do know that the study is not blinded and we can’t make any decision on potential for bias if we don’t know how and by whom the measurements were made.
This is a serious disease and there was no evidence of disease mongering. We do learn that in patients over 60 with this disease, “the 5 year survival rate is less than 10%. In high-risk (secondary) AML, overall survival is lower…”
We aren’t told anything about the relationship between the study’s principal investigator, Dr. Jeffrey E. Lancet, and Dr. Gail Roboz and Celator, the company whose drug they are discussing. If there is or isn’t a financial conflict of interest, that needed to be spelled out in the news release. We do know that Scott Jackson, chief executive officer of Celator Pharmaceuticals, has obvious financial ties to the company whose drug he is praising.
The release gets a satisfactory rating for devoting plenty of space to describing the new drug’s advantages in terms of survival advantage over the comparator, or current standard of care. Are there other treatments that are useful in treating high risk AML? We never get that information. This would have been much stronger if a statement about the studies of the non-liposomal formulation of the drug was given.
We learn that the company hasn’t yet sought regulatory and marketing approval for the new drug but will be doing so soon.
The news release makes a few different claims to novelty. For example:
“First therapy to demonstrate statistically significant improvement in overall survival….”
“VYXEOS represents a novel approach to developing combinations of drugs in which molar ratios of two drugs with synergistic anti-tumor activity are encapsulated in a nano-scale liposome in order to maintain the desired ratio following administration.” While that statement may not be precisely true — a review of the literature finds that there are at least a dozen liposomal drugs in development — it does, however, appear to be the first drug to use a fixed molar ratio in the liposomal packets to deliver the drug to the cancer.
Some exaggerated language was used by those describing the implications of the study, including a prediction that the drug will become “a new standard of care” even prior to regulatory approval, and calling the findings “a major step forward,” “an important advance,” and a “major milestone,” for the company making it.