Paul E. Oberstein, MD, discusses data for an autogene cevumeran–based regimen in pancreatic ductal adenocarcinoma.
Long-term remissions remain a major focus and challenge for the pancreatic cancer field, and immune system stimulation via a novel mRNA vaccine–based regimen with autogene cevumeran (BNT122; RO7198457) may help more patients with pancreatic ductal adenocarcinoma (PDAC) achieve long-term disease control, according to data from a phase 1 study (NCT04161755).1
“This is a really exciting time for pancreatic cancer, [and] one of the exciting developments is the possibility of having a cancer vaccine that would prevent recurrence of pancreatic cancer. The rationale behind cancer vaccines in general is that there are patients who are found to have [natural] long-term disease control, but that's a small number of people with pancreatic cancer,” Paul E. Oberstein, MD, said in an exclusive interview with OncLive® “There are differences about the immune system in those patients who activate the immune system to fight or prevent the cancer from coming back. The pursuit of a vaccine is [to see if] we get more of that. Can we stimulate the immune system to recognize the cancer cells as being foreign and therefore prevent them from growing to prolong survival?”
During the phase 1 study, responses to autogene cevumeran were defined as high-magnitude T-cell responses to the vaccine neoantigens.2 Data showed that at a median follow-up of 3.2 years (range, 2.3-4.0), responders (n = 8) who received autogene cevumeran, mFOLFIRINOX (irinotecan, oxaliplatin, leucovorin, and fluorouracil [5-FU]), and atezolizumab (Tecentriq) achieved a median recurrence-free survival (RFS) that was not reached (NR) compared with 13.4 months in those who were non-responders (n = 8; HR, 0.14; 95% CI, 0.03-0.59; P = .007).1,2
Oberstein is an associate professor in the Department of Medicine, service chief of the Gastrointestinal Medical Oncology Program, and assistant director of the Pancreatic Cancer Center at NYU Langone Health in New York, New York.
“One of the challenges of vaccines in general is that it's quite difficult, [both] in cancer and many areas, to convince the body's immune system that something is different that needs to be targeted. If it's a cancer, the cancer came from normal cells,” Oberstein said. “Part of what has been done in some of the work that led to this vaccine was identifying specific neoantigens, which are antigens that are tumor-specific, that the body's immune system can recognize and target. What [we do with this] vaccine is take a person's individual tumor, sequence and [analyze] the tumor, and identify specific areas in the tumor that might make the body's immune system very effective in killing that cancer cell. [This mechanism] is really important and a huge discovery. It's tremendous computational and other science. Then, you take that information, and you put it into a vaccine.”
Specifically regarding autogene cevumeran, Oberstein underscored the speed at which the vaccine can be produced.
“The other innovative part of [autogene cevumeran] is that it can be designed very quickly. Since [autogene cevumeran] is customized based on the individual's tumor, you can't make an off-the-shelf vaccine and give it to everyone,” he added. “It has to be done for [an individual] person, and the technology to do that didn't exist a decade or two ago. It's new technology that's being refined and implemented in this vaccine to go from taking a person's tumor, analyzing it, and several weeks later, having a vaccine that you're ready to give to that person.”
The single-center study conducted at Memorial Sloan Kettering Cancer Center in New York, New York, enrolled patients at least 18 years of age with surgically resectable PDAC and an ECOG performance status of 1 or less.2,3 If patients had metastatic, borderline, or locally unresectable PDAC or received prior neoadjuvant therapy, they were not included in the trial.3
After undergoing surgery, patients first received a single dose of atezolizumab at week 6, followed by 8 intravenous priming doses of autogene cevumeran during weeks 9 through 17, followed by 12 cycles of mFOLFIRINOX from weeks 21 to 43.1 A booster vaccine dose was given at week 46.
Safety was the primary end point of the study, whereas secondary end points were RFS and overall survival (OS).
Findings also showed that at a median follow-up of 4.2 years, patients who were identified as responders achieved a median OS that was NR, with 7 of 8 patients alive at data cutoff. Non-responders experienced a median OS of 3.4 years, with 2 of 8 patients alive at data cutoff (HR, 0.15; 95% CI, 0.03-0.70; P = .015).1
Oberstein underscored the improved OS for patients who responded, but he also noted that the OS outcomes for the overall population compare favorably with historical outcomes for this patient population.
“The T-cell responses are quite robust, at least in those who respond to the vaccine. [They] develop these cells that are memory cells that can be rechallenged, come back, and be present in the tumor microenvironment,” he said. “There were isolated cases where a tumor grew, and then it seemed like there was a response again in the tumor. There are strong signals that the immune system is stimulated by this vaccine and that it's done in a way that persists for many years.”
The autogene cevumeran–based regimen is being evaluated in the ongoing, open-label, multicenter, randomized phase 2 IMCODE003 study (NCT05968326), in which patients with resected PDAC are being randomly assigned to receive autogene cevumeran plus atezolizumab and mFOLFIRINOX or mFOLFIRINOX alone.4
On top of expanding evidence for autogene cevumeran by treating a larger population of patients, IMCODE003 could also provide further data on treatment with or without the vaccine, Oberstein said.
“[IMCODE003] is an important trial and will answer a lot of questions about whether the vaccine is helpful for everyone or for certain people, how to predict who will benefit from the vaccine, and how to make the vaccine better so that we can keep using it for more people with more benefit,” Oberstein pointed out.
Ultimately, Oberstein concluded by emphasizing the field’s excitement and shedding light on important remaining unanswered questions.
“[These data] excite people to look at vaccines again and more closely [in PDAC]. The challenge always with vaccines is being able to predict who it's going to benefit. There are certainly hints that vaccines help specific individuals by getting an immune response and preventing tumor recurrence,” he said. “Whether that's broad enough to give to everyone is something that we don't quite know yet… We're all excited to see what [IMCODE003] is going to show.”
References
