Tom Herzog, MD
The vaccine ADXS11-001 (axalimogene filolisbac) had a 12-month overall survival (OS) rate of 38.5% (n = 10) in 26 patients with persistent or recurrent metastatic cervical cancer who had progressed on at least one prior line of systemic therapy, according to phase II study data recently released by the Gynecologic Oncology Group (GOG) and Advaxis, Inc, the company manufacturing ADXS11-001.
Historically, patients with persistent or recurrent metastatic cervical cancer who have failed at least one line of therapy have an estimated survival of 4 to 7 months and limited treatment options.
In the first stage of the phase II study, ADXS11-001, a live-attenuated listeria monocytogenes cancer vaccine, was given to patients intravenously for more than 30 minutes on their first day of treatment followed by the same course repeated every 28 days until disease progression, unacceptable toxicity, or until 3 doses were administered over 3 months. In the stage II, phase II portion of the study, which is currently enrolling patients, the protocol has been amended by the GOG to allow for continuous cycles of treatment until disease recurrence.
Safety data from stage 1 showed that grade 1 or 2 adverse events occurred in 19 out of 26 patients (73%), with fatigue, chills, and fever being the most common. Four patients (15%) experienced grade 3 adverse events (hypotension and cytokine release syndrome) and one patient (4%) experienced a grade 4 adverse event (lung infection and sepsis).
Advaxis has submitted a Special Protocol Assessment (SPA) request to the FDA for a phase III study evaluating the safety and efficacy of ADXS11-001in high-risk, locally advanced cervical cancer. The SPA review process remains ongoing.
spoke to Tom Herzog, MD, clinical director, University of Cincinnati Cancer Institute, who recently presented the phase II ADXS11-001 data at the American Gynecological & Obstetrical Society Annual Meeting. Herzog explained the impact ADXS11-001 may have on patients with recurrent metastatic cervical cancer who currently have limited effective treatment options.
OncLive: What were the most significant findings from this trial?
: In persistent or recurrent metastatic cervical cancer, there are not a lot of options after frontline therapy. If patients do not have a durable response to frontline therapy, they are probably going to live, on average, between 4 and 7 months. There is an unmet medical need. Immunotherapy offers a possible solution to that need.
This trial involved a two-stage enrollment. They took a group of patients and required them to meet a certain bar to go to the second stage. If you look at the history of the GOG, there are not really any studies that have taken this approach.
There were 26 patients in the first phase and, after a preliminary analysis, it was determined that 38.5% of patients had met the bar of 12-month OS. Based on that, the median survival was 7.7 months, which is pretty good. A large number of these patients are still alive so median survival should increase, as well.
What impact could these findings have on patient outcomes?
To say anything more than “this is a good signal” would be overstating the data because, at this point, we are just looking at stage 1 of a phase II study. However, this data does show great potential. The fact that 38.5% of patients had 12-month OS is encouraging. The bottom line is: this is an interesting agent with a good safety profile, but this is still preliminary data.
Were there any concerning toxicities with this drug?
None of the patients discontinued for treatment-related adverse events. Two patients withdrew by choice and four withdrew due to disease-progression. Most of these patients did experience grade 1 or 2 toxicities, including flu-like symptoms, such as fever and chills, and sometimes hypertension. There were only a few grade 3/4 adverse events, which were hypertension and cytokine-release syndrome.
What are the next steps in this research?
It is important to mention that there was an amendment to this protocol. It was amended to allow continuation of the vaccine every 28 days until disease progression or discontinuation due to toxicity. It is possible that giving more of the drug will produce a greater effect.
There are plans to launch a phase III study. This study will be slightly different than the phase II study, as it will be conducted in patients with high-risk locally advanced cervical cancer. These patients can be anywhere between stage I and stage II and with positive pelvic lymph nodes or stage III and IV with any status of their lymph nodes. These are patients that may be in early stages, but are at high-risk for recurrence. All of the patients will receive cisplatin radiation and get randomized 2:1 for placebo or the ADXS11-001 up to 1 year. The vaccine will be given every 28 days. The primary endpoint on this trial is progression-free survival (PFS) with a secondary endpoint of OS.
This approach has a slightly better chance of working for more patients for two reasons. First, immunotherapy seems to work better on disease that is not large-volume. With large-volume disease, the immune system is so suppressed that it is difficult to activate it in a meaningful way with the technologies we currently have. Allowing longer treatment with the vaccine will also be helpful. I think it is going to be interesting.
What makes this agent different than other similar drugs out there?
They think they have some advantages over other therapies in that they use bioengineered listeria monocytogenes. This is a common food bacteria that is very easily spread from cell to cell. This is what could make it effective. They also use the E7 protein, which should also be effective across a number of the high-risk HPV-associated cervical cancers.
With so many different therapies becoming available, what is needed to gain a better understanding of patient selection?
I think we will get to the point where we will have better biomarkers that will dictate which way we should be going with these immuno-oncology platforms. By performing biopsies on the tumors, as well as the microenvironment, we may be able to get a better understanding as to whether one particular agent or strategy will be more effective. That is a really exciting development that we will see down the line.
How has our understanding of vaccines in cancer treatment evolved?
I have been hearing about vaccines for years, and now we are finally starting to see the fruits of all of the failures we have had. In the past, there have been a lot of phase III trials where we were able to get responses in animals but we could not duplicate it in humans, or we could replicate it in humans but it did not have much of an immune response.
Today, we are starting to have a better understanding of vaccines. We have even started to change our assessment of endpoints based on this understanding. We really should be looking at OS instead of response rate or PFS. A great example of this was the prostate therapy sipuleucel-T (Provenge), in that the drug did not improve PFS, response rates were very modest, and yet it improved OS. We are getting a different understanding of how we look at endpoints in immuno-oncology.