Novel Cancer Vaccine Yields Promising Survival Rates in Pancreatic Cancer

Tara Seery, MD

Updated results of the fully enrolled cohort of the phase 2 QUILT 88 study (NCT03563144) showed a doubling of survival in third-line patients with metastatic pancreatic cancer when treated with the novel combination immunotherapy protocol of low-dose chemoradiation, N-803, and PDL1 t-haNK therapy.

In the multi-center, randomized, phase 2 study, patients with metastatic pancreatic cancer were treated with low dose, chemoradiation nab-paclitaxel at a dose of 100 mg/m² via intravenous (IV) infusion, gemcitabine at 600 mg/m² IV, cyclophosphamide at 50 mg twice daily, and low dose stereotactic body radiation therapy.

Patients enrolled in the study had a median age of 62, males made up 46% of the patients, and 97% had an ECOG performance status of 0-1. The median follow-up for patients was 4.9 months. Six patients are still undergoing treatment (7%), with the longest duration of therapy to date at 17.1 months.

Findings presented at the 2023 American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI) showed that the median overall survival (OS) for patients was 5.7 months (95% CI, 4.9-6.4), and the median PFS was 2.3 months (95% CI, 2.0-3.6). A total of 37% of subjects achieved stable disease at 8 weeks or longer. The median OS in the third-line setting (n = 38) is 6.3 months, and the median OS in fourth-line or greater (n = 40) was 5.0 months.

Looking at safety, 89% of patients reported at least 1 investigational product related adverse event (AE), and 76% of patients had at least 1 AE that was grade 3 or higher. The most common AEs included anemia (41%), neutropenia (20%), thrombocytopenia and (10%). Serious AEs observed because of the investigational agents were in 10% of patients.

In an interview with Targeted Oncology^TM, Tara Seery, MD, Hoag Cancer Center, discussed the rationale and findings from cohort 3 of the QUILT 88 study in metastatic pancreatic cancer.

TARGETED ONCOLOGY: What did you discuss during ASCO GI this year?

Seery: As a gastrointestinal oncologist, I mainly focus on hepatobiliary, so we were happy to present our abstract on a trial that we've been running for the past few years called the QUILT 88 study. We were excited to start giving the information on the third-line patients, which has been eagerly awaited by many people.

What was the rationale behind the study?

This is a complicated study if anybody has ever looked at our abstracts, and what we did is we took a step back, and we realized that we have not really changed anything in pancreatic cancer. Unfortunately, all the results from ASCO GI pretty much showed we're not changing survival at all. Our thought was, let's take a step back and let's look to see how we can kind of help orchestrate the immune system to help fight this cold tumor. Our thought was that we would use chemotherapy in a little bit of a lower volume, we would use radiation, and then we're using immune-based therapy or natural killer [NK] cells and IL-15 to target it.

Now, the thing that gets confusing for some people is that we call it a pancreatic cancer vaccine. It's not a specific 1 shot vaccine. What we're doing is we're trying to train your immune system to go after the tumor itself. That was 1 of the many questions I got from people, but it's a philosophical vaccine. When patients are interested in the trial, what I typically do is walk them through it because it is such a complicated trial. The arm that we presented in our abstract was the third-line arm. These are patients with locally advanced or metastatic pancreatic cancer who have received 2 prior lines of therapy. Anyone who treats pancreatic cancer is aware that there is nothing approved in the third-line, so a lot of times we recycle chemotherapy that patients have had before. There's nothing concrete so we are guessing what the survival is for the third-line. We had to come up with some data because there is [none in the] third-line. We thought it was about 8 weeks as typical survival.

The thought is that we give kind of a lower dose chemotherapy, it's more metronomic dosing. What we're trying to do is start to suppress the suppressor cells with the chemotherapy. Then we introduce the damps, and we expose the PD-L1. Then what we do is activate your own T helper cells and activate your natural killer cells. By doing all this, we're conditioning the tumor microenvironment to the memory T and NK cells. People are starting to think this way that maybe just pure chemotherapy is not enough.

What were the findings from cohort C of the QUILT 88 study?

We ended up enrolling 83 patients, which is a large volume. What we found is in the patients who had a CA19-9 less than 4,120, we noticed a survival of 6.9 months, which is great in our minds and exciting. We still have some patients that are ongoing and still on treatment. I've had a patient for over 20 months now, but it has stopped accruing. Hopefully by ASCO [this year], we will have the final data, but I expect our survival to go further up.

What are the next steps moving forward?

We still have an ongoing second-line trial. When we opened the third line, people from all over the world flocked in. Now that that is full, we want to get the second-line filled. Second-line is for patients who have had only 1 prior line of therapy. We are randomizing patients to either the experimental arm vs what is approved as our standard of care 5-FU and irinotecan liposome injection [Onivyde]. Now, we know that might be an issue with [the irinotecan liposome injection] in the first-line setting, but still 50% of patients receive first-line gemcitabine and paclitaxel. Some people might say they had gemcitabine/paclitaxel, so why would they want to go into this experimental arm that does use gemcitabine/paclitaxel. We have seen people respond even if they've received gemcitabine/paclitaxelbefore, so that's not an issue in our minds.

What unmet needs still exist in this space?

We need everything in pancreatic cancer. Unfortunately, how everything moves in oncology is we kind of work in the metastatic setting, and then we move forward. We're trying to make a change in this advanced setting, and once we see that, then we will go into the adjuvant setting. Then from the adjuvant setting, we go into that kind of screening phase, but it's still a long haul that we have to do.

Are there any other trials or research going on that have caught your eye in this space?

Other things that are fascinating are that the majority of patients with pancreatic cancer, about 90%, have a RAS mutation. We know about the KRAS G12C, granted that's more in lung and colon cancer, but there's some trials up and coming up in G12D. I think that's another target that we're all after. People are still trying to get some vaccines going, and we have some early data. But I think that the KRAS is the other area people are targeting, so it will be interesting to see more of that come out.

For the community oncology audience, what are the key takeaways from this trial?

This is a third-line trial that's showing a survival of 6.9 months, which is kind of unheard of when most patients that survival is less than 2 months in the third-line. We are hitting something, and we encourage patients to enroll in our second-line trial so that we can make a difference. We are getting better, we are improving, and [don’t] give up. It is sad because I still see a handful of patients that their primary care doctor told them not even to get treatment and go straight to hospice. But we are making headway, so I think it's just getting that word out that people are living longer, and some people do amazingly well. We still need to figure out who that person is and why, but we are doing much better overall.

REFERENCES:

Seery TE, Nangia CS, Reid PD, et al. Overall survival in patients with metastatic or locally advanced pancreatic cancer following chemoradiation with novel combination of aldoxorubicin, N-803 IL-15 superagonist, and PDL1- NK cell therapy. J Clin Oncol. 2023;41 (suppl 4):720-720. doi:10.1200/JCO.2023.41.4_suppl.720