PYX-201 generates responses and contributes to the growing ADC use in solid tumors

Treatment with PYX-201 produced responses and was tolerable in a phase 1 study (NCT05720117) in patients with heavily pretreated head and neck squamous cell carcinoma (HNSCC), according to Glenn J. Hanna, MD, who added, that this active ingredient leads to a positive effect in the growing arsenal of antibody drug conjugate treatments (ADC).¹

The Phase 1 study evaluated PYX-201 in patients with advanced solid tumors. In the HNSCC population (n = 6) Patients treated with the novel agent experienced a confirmed overall response rate of 50% according to RECIST 1.1 criteria. This consisted of a complete answer and two partial answers.

“It is really encouraging to observe a strong rate of regression or shrinkage in a small group of head and neck cancer (cancer) patients who have been heavily pretreated (and have a heterogeneous clinical profile),” Hanna explained.

In an interview with OncLive®, Hanna examined the efficacy and safety data generated with PYX-201 and predicted its potential utility in the HNSCC armamentarium.

Hanna is Director of the Center for Cancer Therapeutic Innovation (Early Drug Development Program) and Director of the Center for Salivary and Rare Head and Neck Cancers at the Dana-Farber Cancer Institute, as well as an Associate Professor of Medicine at Harvard Medical School, both in Boston, Massachusetts.

OncLive: What is the mechanism of action of PYX-201 and how does it differ from other investigational drugs and approved ADCs?

Hannah: PYX-201 is a very interesting compound. What makes it unique as an ADC is that it is a stroma-targeted ADC with a conjugated payload, or in this case a statin. The idea is that many ADCs target a specific receptor on cancer cells and, once bound, enter the cancer cell (where) the payload is then cleaved, released, and the cell is killed.

In this case, the stroma is the surrounding extracellular matrix, vasculature and fibroblastic environment that makes up a tumor around the tumor cells. This drug targets the extradomain B splice variant of fibronectin. This protein is expressed in the supporting cells that are located around the tumor cells. The idea is that it binds to this supporting cell target, then cleaves and releases the active ingredient in that environment. (Due to) a bystander effect (this would) allow the tumor to be killed. Although the molecule itself is constructed similarly to many others, the idea of ​​targeting the extracellular domain with an ADC makes PYX-201 a unique molecule.

What is the significance of the preliminary safety and efficacy data for PYX-201 in head and neck cancer?

What’s interesting about the PYX-201 data for head and neck cancer patients is that they were heavily pretreated. These were patients who had previously received multiple lines of therapy, including immunotherapies and platinum-based chemotherapy agents. When we see single-agent activity in this population for something like a novel ADC like PYX-201, it attracts the attention of those of us involved in drug development, particularly as head and neck cancer experts.

Although this was a small number of patients, we can learn a lot from the composition of the patients alone. There were a number of patients with different subtypes of head and neck cancer, including human papillomavirus (HPV)-associated and HPV-unrelated (HNSCC). Seeing a signal in potentially more heterogeneous patient groups is also very interesting in head and neck cancer, suggesting that the drug could have broader applicability, even if it is still early.

Considering that we are seeing a decline in cancer due to these reactions, it will be interesting to see whether these reactions end up being permanent. (We would like to see responses that) last over a long period of time so that the antitumor effect is maintained and the drug leads to the delay and progression of cancer and an improvement in survival.

What did you think of the side effect (AE) profile of the active ingredient?

The AE profile was pretty much what we would expect based on the fact that an auristatin payload was bound to the antibody targeting the additional domain B splice variant. If you look at some of the AE rates that you would expect from different ADCs with similar payloads, that’s encouraging for the entire study – not just for the head and neck cancer patients, but for the 60 or 70 or so patients who have dose had been administered – we saw neither a high level of concern nor the frequency of the feared or unwanted side effects associated with ADCs that we hear about. These include, but are not limited to, peripheral neuropathy and numbness or tingling in the hands and feet, which may develop with some of these exposures, and ocular toxicities, which may be disabling.

Additionally, with each of these cytotoxic exposures, we are concerned with the idea that low blood values ​​or cell counts may lead to a risk of infection, bleeding, or fatigue in the event of anemia. Although we have seen some of these things, including rash, which is usually manageable, we have not seen many serious grade 3 or higher toxicity issues. Regarding the auristatin drug level, there was, at least preliminary, no evidence that there were a greater or higher number of limiting AEs associated with the chemotherapy drug level. All of this was pretty encouraging given the early data.

What are the next steps for this Phase 1 study?

The story of PYX-201 deserves quite a bit of attention due to the novelty of the ADC protein, but also its new safety profile and the fact that it shows activity in head and neck cancer and some other tumors with high unmet needs. The next step is for the team to finalize this dose optimization plan and establish a schedule and dose. I think (they’re currently in the process of) figuring out how far they can increase the dose without increasing the risk of toxicity, while also making sure that they feel like they’re having the greatest possible effectiveness. The trial will then move into a pre-specified expansion where different tumor types are identified as likely to be followed up successfully and they will take their selected dose and schedule and treat a range of patients from these tumor types. One of these is likely to be head and neck cancer.

The company also plans to initiate a combinatorial study of PYX-202, which would combine the single-agent ADC with PD-1 inhibition; in this case, pembrolizumab (Keytruda). The company announced that it has been approved to collaborate with Merck to provide pembrolizumab. As you can imagine, it is very interesting to think about an ADC that targets the microenvironment or the stromal environment and then triggers potential interactions with the immune system. The addition of a PD-1 inhibitor could be of interest here.

I know that (the company) is launching a first-in-human study in early 2025 combining pembrolizumab with the (investigational) drug. That is the future for the development of this molecule as it currently stands, and I know that the company is also considering other novel ways to advance the molecule. I had even mentioned to them that there are other tumor types with high unmet needs, but also things like radiosensitization. Could some of these ADCs work with radiation to enhance the effects of radiation? This is just one example of how they might think about developments in the future.

What do you hope your colleagues gain from this conversation?

For the general oncology audience, a few things stand out. I would say the first is to keep an eye on early drug development. Oncology is moving very quickly and there is a lot of excitement as the pace is very fast. There is quite a bit of competition and there are many molecules of interest. If I were speaking to the general audience, I would say: keep an eye on ADCs broadly. As we move forward, I think they have a great opportunity to impact the broader field of oncology. The future will focus on figuring out which targets we should prioritize in different types of cancer.

Many of these medications appear to be effective, but it depends on which medication we should tailor to the individual patient. Maybe, similar to the molecular era where we use targeted therapies based on gene changes and protein changes, we will profile patients for differential expression of targets across ADCs and use them that way and (determine) whether to sequence them by switching can highlight the payload of strong interest.

reference

1. Pyxis Oncology Announces Positive Interim Phase 1 Part 1 Clinical Data for PYX-201. Press release. Pyxis Oncology. November 20, 2024. Accessed December 4, 2024. https://ir.pyxisoncology.com/news-releases/news-release-details/pyxis-oncology-announces-favorable-preliminary-pyx-201-clinical