Hidalgo Medina, MD, PhD, Discusses the Use of Motixafortide/Pembrolizumab and FOLFIRI in PDAC

Data from the phase 2 COMBAT/KEYNOTE 202 trial (NCT02826486), which assessed the use of motixafortide (previously, BL-8040/BKT140) and pembrolizumab (Keytruda) plus nanoliposomal irinotecan, fluorouracil, and folinic acid in patients with pancreatic ductal adenocarcinoma, highlighted the importance of targeting the CXCR4/CXCL12 pathway, according to Manuel Hidalgo Medina, MD, PhD.

Of the 43 patients who enrolled on the study, investigators reported an overall response rate (ORR) of 21.1% by RECIST 1.1 criteria, as well as a confirmed ORR of 13.2%. Additionally, patients experienced a disease control rate of 63.2%, with a median duration of clinical benefit lasting 5.7 months. The intent-to-treat population experienced a median progression-free survival of 3.8 months and a median overall survival of 6.6 months.

“The other question is [now], can we block additional pathways? Or can we target the pathway from different perspectives? For example, we are doing work with a fibroblast-activating protein antibody-drug conjugates. That will eliminate the source of the tumor—the source of the cytokines—which are the fibroblasts. Will this therapy synergize? Well, that's another question. That's where the will research lead us. The most exciting thing is that there is a relatively consistent parallelism between the mouse model and the clinical results.”

In an interview with CancerNetwork® during Pancretic Cancer Awareness month, Hidalgo Medina, chief of the Division of Hematology and Medical Oncology at Weill Cornell Medicine/NewYork-Presbyterian Hospital, discussed how the development of new molecules against the CXCR4 pathway and assessing combination strategies will be important research points in pancreatic cancer for the future.

CancerNetwork®: What previous research led to the KEYNOTE-202 trial?

Medina: The rationale is based on very nice preclinical work and observations [that were] conducted and published by Douglas T. Fearon, MD, who is a cancer researcher at Cold Spring Harbor [Laboratories] and Weill Cornell, who showed that one of the problems in pancreatic cancer immunotherapy is that T cells don't get into the tumor. The mechanism by which the tumor is able to push these T cells out is because of the fibroblasts that are associated with the cancer produce cytokines, that bind to receptors in the T cells that push them out. The idea was that blocking the CXCR4 pathway would allow cells to get into the tumor and then if you use a checkpoint inhibitor, you will elicit an anti-tumor efficacy that was shown in the preclinical studies.

[The trial's connection to the] phase 3 NAPOLI-1 trial (NCT01494506) came afterwards. We first did the proof of concept of the dual targeted combinations of CXCR4 inhibition with BL-8040 and PD-1, motixafortide and pembrolizumab. We proved that in vivo, the cells get in and we saw some activity [with] the 2 biologics alone. Then we decided to add chemotherapy. The standard of care chemotherapy in the second-line is the NAPOLI [regimen]; we built upon that.

What were some of the key findings to read out of the KEYNOTE-202 trial?

The most important thing to me is that we proved in paired tumor biopsies and because of clinical efficacy, that there is merit in attacking this pathway. However, we have a long way to go until we can make this a transforming treatment for patients. It has to do with basically 2 directions: One is, are we inhibiting the pathway completely and permanently by just the BL-8040, or are there any other molecular entities we can use to achieve that? [This is] because one of the important observations is that you need a very profound and lengthy inhibition. That's 1 thing. We need to work on higher dosages, rules of administration, and other chemical compounds to address that.

How do you feel this research will help to shape future studies?

There are going to be 2 areas [of focus]. One is a little bit early—the development of new molecules against the pathway. There's [also] interest in [examining] other antibodies or small molecules. The other big thing is going to be adding more therapy. When we start adding [more therapies], we run into toxicities, right? [What will be] very important is understanding the sequence. If the hypothesis is that you need to get the T cells into the tumor, maybe that's what we need to do first—get the T cells into the tumor. Then you want to activate these T cells while giving the PD-1 [inhibitor], but not doing it all at the same time. That may be too much. That's something that we need to do additional work on in the mouse models.

Were there any safety concerns with this regimen?

In general, it was well tolerated. We know what the baseline toxicity is for the NAPOLI regimen. Adding PD-1 blockade to chemotherapy is quite standard and well accepted these days. It does not substantially increase toxicity. The BL-8040 because it is administered subcutaneously, causes pain in some patients in the injection site. There were some patients who had rash, but other than that, it was good. Safety is not an issue here.

Are there any other emerging pieces of research or studies in the pancreatic cancer space that you feel has the potential to impact clinical outcomes for these patients?

Right now, one of the frustrations is that pancreatic cancer continues to be the immunotherapy-resistant cancer. Last week, we heard the good news that chemotherapy plus durvalumab [Imfinzi] is more effective than chemotherapy in cholangiocarcinoma and bile duct cancer. [However], we have not achieved that in pancreatic cancer yet. There's a lot of interest in understanding why and combining pathways with checkpoint inhibitors that may overcome that. CXCR4 is one of them, but there are others [such as] CD40, TGFβ, and many others that, by different mechanistic properties, will hopefully create an immune-sensitive tumor microenvironment.

Are there any other ongoing clinical trials that have been of interest to you?

My lab and clinical group continue to work actively in pancreatic cancer, on projects in 2 major areas. One is precision medicine and trying to get treatments for patients with certain molecular genetic abnormalities. We're working on [research] in the BRCA mutation group. The other big field is immunotherapy. [We're] mostly [working on] making PD-1–resistant tumors sensitive. We're working with this pathway, the FAP, and others. We also have an interest in trying to develop cell therapies for pancreas cancer.

What do your hope your colleagues take away from our conversation regarding the importance of early clinical research?

By conducting rigorous preclinical studies and understanding mechanisms of resistance, we can build clinical trials that help us to validate and understand those mechanisms. The field has been wrong in jumping very rapidly to very large clinical trials with very little supporting documented preclinical and early clinical evidence, and then investing a lot of resources and patients' time, lives, and their family’s time and then findings that the results are not good as we wanted. We need to do more fundamental developmental work, so that we understand what works, why [it works], and get very broad signals and then advance to later stage, registration trials.

Reference

Bockorny B, Macarulla T, Semenisty V, et al. Motixafortide and pembrolizumab combined to nanoliposomal irinotecan, fluorouracil, and folinic acid in metastatic pancreatic cancer: the COMBAT/KEYNOTE-202 Trial. Clin Cancer Res. 2021;27(18):5020-5027. doi:10.1158/1078-0432.CCR-21-0929

For additional interviews with leaders in the treatment of pancreatic cancer, see other CancerNetwork® interviews conducted for pancreatic cancer awareness month:

Using Genetic Predispositions to Determine the Likelihood of Being Diagnosed With Pancreatic Cancer

Andrew Hendifar, MD, on Developing Targeted Approaches in Pancreatic Cancers