These results - including toxicity profile, increases in survival, and sustained remissions - show the potential for a dramatic increase in survival for a group of patients that have historically done poorly.
Let us further break down - and define - the characteristics that make up each of these patient groups reported on.
What are the categories of patients covered in the paper?
This includes patients who were diagnosed with neuroblastoma and enrolled on the standard treatment for their disease where they lived. These kids then completed their upfront therapy and were 'done' with treatment. This is normally where kids stop all treatment and hope it works (66% of these kids make it two years without dying or relapsing). Instead? These stratum 1 patients started taking DFMO for two years with the goal of preventing relapse and increasing that 66% figure.
This includes patients who had previously had their cancer come back - or their disease did not respond to the upfront therapy - and then were able to get back into remission. These stratum 2 kids were also given DFMO for up to two years once they were in remission to see if you could keep their disease from coming back.
Historical Survival Curves for kids who are NED for Stratum 1
Before we get to defining the historical percentages of survival, let's first outline what we are measuring to calculate survival. The goal of this study was to see if the 2 year EFS and the 2 year OS could be improved upon.
EFS: Event Free Survival - this tells you the percentage of kids at two years who have not died and who have not relapsed with new disease
OS: Overall Survival - this tells you the percentage of kids at two years who are still alive. This includes kids who are still alive but may be battling a new relapse.
Stratum 1 Historical numbers:
There are numerous upfront therapies that you could enroll on (the European protocol, a protocol out of Sloan in New York, or the current standard in the US which is from a study called ANBL0032). Currently, the best published results ever reported on upfront neuroblastoma survival come out of that ANBL0032 trial - it is the current 'gold standard' in the US.
What is remarkable is out of the 100 kids who enrolled and could be evaluated in Stratum 1 for the DFMO study, 81 of them did so directly after finishing their enrollment in the ANBL0032 study. So what are the survival statistics for the current gold standard?
Prior Best 2 year EFS
2 year EFS - From the start of immunotherapy was:
66% at 2 years
Prior Best OS
2 year OS - From the start of immunotherapy was:
86% at 2 years
So prior to DFMO - in the history of mankind - the best published results for 2 year survival for kids with high risk neuroblastomas (HRNB) showed that 66% of them could get 2 years out from the start of antibody before relapsing or dying - and that 14% of the kids would be dead within 2 years of starting antibody.
At this point - it is critically important to explain the next step in the process. While we have the 2 year EFS/OS numbers for DFMO it is not correct to directly compare them to the numbers above.
It is at this point in the process where we need to explain how you can not - and this paper is not - doing a direct comparison from the numbers above (66% - 86%) to this study. Let me explain why.
The above ‘gold standard’ results looked at 2 year survival from the first dose of antibody given to the kids in the prior study. They were measuring if the addition of an anti-GD2 antibody would improve survival so their start point was the start of immunotherapy.
For this new paper looking at DFMO maintenance therapy lets look at the subset of 81 out of the the 100 patients from Stratum 1 who immediately prior to enrolling on the DFMO study were enrolled in the very 'gold standard' of care study we mentioned above.
These 81 kids were not 'like' those patients - they were actually on that prior trial - and thus provide a remarkable contemporaneous control group. As a result - this subset of 81 patients was used to perform an analysis of patient risk variables that were matched to prior ANBL0032 study kids - including time from diagnosis to enrollment on the study, initial disease stage, MYCN status, age at diagnosis and response to induction therapy.
What does this mean?
What they did was discover that the median time from the start of antibody therapy in the prior study (when they started to measure the EFS/OS that resulted in the 66% and 86% above) to the time that these kids took their first dose of DFMO was 7.2 months.
Sadly, in that 7.2 month period from when they began measuring survival to the time these stratum 1 kids would have gone on DFMO you have some kids dying and some kids relapsing. It would unfairly inflate the results if you excluded that time frame so the statisticians looked at the results that were published from the ‘gold standard’ study to determine the following:
What was the EFS/OS of that study 7.2 months out from the start of immunotherapy?
7.2 months later - after accounting for the relapses/deaths - they are now comparing the DFMO kids to an EFS of 75%
7.2 months later - after accounting for the relapses/deaths - they are now comparing the DFMO kids to an OS of 91%
What does all of this mean?
Since the best survival numbers ever published started measuring survival on the day that kids starting taking antibody - and on this new study the average kid started taking DFMO 7.2 months after their first dose of antibody - you have to account for all of the relapses and deaths of kids that took place in that 7.2 month time period while on antibody. By getting the EFS & OS from their curve at this time point you are able to make a direct comparison.
So let's get to it.
Stratum 1 patients survival DFMO vs. NO-DFMO (81 patients subset)
2 year EFS with DFMO: 86% (vs. 75% for those without DFMO after the 7.2 month adjustment)
2 year OS with DFMO: 97% (vs. 91% for those without DFMO after the 7.2 month adjustment)
As previously mentioned the stratum 2 patients were very different than the patient population in stratum 1 which “... includes patients who had previously had their cancer come back - or their disease never responded to therapy - and then somehow were able to get back into remission. These kids were then given DFMO for up to two years to see if you could keep their disease from coming back.”
Historical Survival for kids who are NED for Stratum 2
Treatment for relapsed or refractory neuroblastoma involves many different therapies and approaches (chemotherapy, radiation, MIBG, antibodies, etc..) offered in a phase I or phase II setting or simply as an off-label use of a drug combination in an effort to find something that is effective. At best these treatments have had modest response rates which are sadly followed by high rates of relapse “generally 80-90% within two years”.*
With so many different and highly toxic therapies having such a low response rate this patient population seemed an ideal place to try and increase survival with a novel and low toxicity approach in light of the heavy pretreatment burden these kids have to endure.
A review of recent studies published in 2017 determined the historical rates of progression free survival (PFS) and overall survival (OS). They are listed below and not surprisingly the outcomes were worse for those kids with MYCN amplification in their tumors.*
*London, W. B. et al. Historical time to disease progression and progression-free survival in patients with recurrent/refractory neuroblastoma treated in the modern era on Children’s Oncology Group early-phase trials. Cancer123, 4914–4923, https://doi.org/10.1002/cncr.30934 (2017)
MYCN amplified PFS
MYCN amplified OS
Stratum 2 Results
There were 39 kids who enrolled in stratum 2 who had received various upfront and relapse therapies. There is a median follow up time of 3.7 years (range of 2.1 - 5.8 years).
First we’ll take a look at the 2 year EFS/OS for all stratum 2 patients and then we’ll dive deeper to compare the refractory to relapsed patients in this group.
EFS for ALL stratum 2 patients
2 year: 54%
OS for ALL stratum 2 patients
2 year: 84%
EFS for RELAPSED stratum 2 patients
2 year: 35%
OS for RELAPSED stratum 2 patients
2 year: 80%
EFS for REFRACTORY stratum 2 patients
2 year: 68%
OS for REFRACTORY stratum 2 patients
2 year: 89%
As you can see the overall EFS/OS numbers are better for all the kids on DFMO at 2 years than the previously reported one year survival figures! Even the relapsed kids EFS/OS is better at two years than historical 1 year survival.
However, the figure that really jumps out at you from this paper is the EFS of 68% and the OS of 89% at two years for the kids with refractory disease.
What does all of this mean? What is next?
With few exceptions the standard of care for neuroblastoma - be it upfront therapy at diagnosis or with salvage therapy post relapse - has not changed dramatically in the last twenty years save for the introduction of an anti-GD2 antibody therapy. And while there was a demonstrated increase in two year EFS and OS with this therapy the cost and toxicity are not to be ignored. More importantly, the latest update provided on the results of the ANBL0032 study that demonstrated this increase in survival is showing that at 4 and 5 years out from the start of antibody the difference seen in EFS/OS for kids who did - and did not - get antibody are becoming no longer statistically significant.
Therefore, it is imperative that something be done to:
Get more kids into remission
Keep more kids there
Work to decrease the toxicity currently used to achieve goals 1 & 2 above
Given those needs and the encouraging results from this study the following steps are underway with the development of DFMO.
After meeting with the FDA another phase II confirmatory trial was opened. The goal was to replicate the results seen in this trial with a shorter time to enrollment along with further stratification of patients (COG, Sloan, Europe,etc…). This trial will be finished enrolling patients in 2018 and with the study endpoints being two year EFS and two year OS the results will be completed by the end of 2020.
In the study that was published - as well as in the confirmatory study mentioned above - DFMO is given after patients are finished with their anti- GD2 antibody. Sadly, about 14% of the patients who take this antibody relapse while taking it. Therefore, a trial was opened three years ago (September of 2015) for kids newly diagnosed with NB that is randomizing kids onto DFMO when they start antibody. Half of these kids will be given DFMO during antibody - the other half will start it at the end of antibody. This study is giving DFMO during antibody in order to see if that 14% relapsed figure could be reduced.
The goal is to see if DFMO can keep more kids in remission while finishing upfront therapy. This would then allow these kids - who would have otherwise relapsed - to continue taking DFMO for the two year maintenance period.