Novel HPK1 Inhibitor NDI-101150 Shows Early Activity in RCC

Anita Scheuber, MD, PhD

The highly selective, small molecule HPK1 inhibitor NDI-101150 showed signals of early efficacy in patients with solid tumors, particularly in those with renal cell carcinoma (RCC), and the agent will also be evaluated in combination with pembrolizumab (Keytruda), according to Anita Scheuber, MD, PhD.

Findings from a phase 1/2 trial (NCT05128487) revealed that 16.7% of response-evaluable patients treated with NDI-101150 monotherapy (n = 30) experienced clinical benefit. Additionally, 6 of the 8 patients with RCC who received NDI-101150 achieved a best overall response of stable disease or better. As of March 18, 2024, 44 patients had received treatment in the dose escalation cohort and 15 patients received the agent in expansion cohorts.1 Further findings including efficacy data in patients with RCC will be presented at the 39th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) occurring November 6 to 10, 2024, in Houston, Texas.2

“[This is] a drug in the immuno-oncology [IO] space that has single-agent activity,” Scheuber said in an interview with OncLive®. “For RCC in general, despite the tremendous advancements in this space including the use of neoadjuvant pembrolizumab and then first- [and] second-line treatments, once patients relapse on those standards of care [SOC], they have no options. [Therefore], it is encouraging to see [activity with NDI-101150].”

In the interview, Scheuber detailed the rationale for combining NDI-101150 with a checkpoint inhibitor, early data seen with the monotherapy, and how HPK1 could be an attractive target. Scheuber is senior vice president and therapeutic area head of oncology at Nimbus Therapeutics.

OncLive: What is the mechanism of action of NDI-101150?

Scheuber: NDI-101150 is a novel, oral, highly selective, small molecule inhibitor of HPK1. HPK1 stands for hematopoietic progenitor kinase 1 and belongs to the MAP4K kinase family. It’s a kinase that can negatively regulate T cells, B cells, and dendritic cells.

NDI-101150 is an immune engaging agent that is not a checkpoint inhibitor, and in preclinical studies it has demonstrated an increase in CD8-[positive] T cells. That is saying that there is a change in the immune system, and there is also an increase in cytokine secretion [and] anti-tumor immune responses. That led us to believe that HPK1 is a very attractive high-priority target for a novel IO agent, particularly in patients who have previously been treated with checkpoint inhibitors.

What patients were included in the phase 1/2 trial evaluating NDI-101150? How was the trial designed?

We are still currently enrolling patients into that dose escalation/expansion trial. For the dose escalation [portion], we enrolled patients with advanced solid tumors. It was a basket trial agnostic of indication [for] whoever needed a clinical trial—if they met inclusion/exclusion criteria they were able to enroll into our study. We then developed the maximum-tolerated dose [MTD] and exceeded the MTD.

Then, based on a very early clinical efficacy signal that we saw during dose escalation, including a complete response at our lowest dose, we focused on [certain] patients a bit more in our expansion cohort. We currently have 3 expansion cohorts open in RCC, non–small cell lung cancer, and gastric/gastroesophageal junction indications. Those are 3 active dose expansions that are open and only in RCC—that’s where we picked up on the early signal—do we have 2 different doses that we are currently testing.

At the same time, we also have a combination [portion of the trial] open for patients with solid tumors that is in the dose escalation [phase combining NDI-101150] with pembrolizumab [Keytruda] 200 mg every 3 weeks. We have tested 2 doses—50 mg of NDI-101150 and 100 mg of NDI-101150 and now, as we clear this cohort, we will consider going to the next higher dose of 150 mg.

What makes it attractive to combineNDI-101150 with pembrolizumab?

There are multiple reasons to combine NDI-101150 with pembrolizumab or any other checkpoint inhibitor. We wanted to generate safety data at this point in time, and picked pembrolizumab as it’s broadly used, but it could have been any other checkpoint inhibitor and also other combination partners depending on the tumor type you’re [treating]; in RCC it could [have been combined with] other SOC therapies that are not IO assets or in other tumor types, such as lung or gastric, it could have been combined with chemotherapy.

It’s not necessarily the one and only combination that you would want to pursue, but it makes sense to combine [NDI-101150] with a checkpoint inhibitor [because] HPK1 inhibition increases PD-1 expression on T cells, which primes those cells to be more receptive for a PD-1 inhibitor to work even better. We would anticipate that there is synergy in combining NDI-101150 with a checkpoint inhibitor.

What data have been seen so far in the trial regarding anti-tumor activity?

It’s mostly in RCC that we are seeing [activity], all the other cohorts are a bit early to report on, including the combination cohorts. At this point in time, there’s not much that I can report on. We had KOL interactions [on] this, and I can report that they are excited about the monotherapy data that they have been seeing. That is encouraging. We did see some tumor shrinkage in other tumor types as well. The patients did notachieve a partial or complete response with NDI-101150 at that point in time, but clearly had tumor shrinkage.

[Data on the other cohorts] probably will not come out anytime soon because we have been focusing a bit more on the RCC cohort lately, but we will be presenting a poster at SITC with a clinical update on [efficacy in patients with] RCC and the safety update on the combination with the checkpoint inhibitor pembrolizumab.

What data were seen regarding safety with NDI-101150?

We escalated the dose from 50 mg to 200 mg, and did observe dose-limiting toxicities at 200 mg, although when talking to KOLs who have extensive experience with checkpoint inhibitors, they were not too impressed with what we have been seeing at 200 mg. We declared [200 mg] exceeded the MTD [and] because we had seen responses at 50 mg and at 100 mg, we felt we may not even need to use a 200 mg dose.

However, at lower doses we can offer a much better safety profile. Taking into account that NDI-101150 is an oral drug, we are mostly seeing [toxicities] from the gastrointestinal space where we have seen the most common any-grade treatment-related adverse effect [TRAE] of nausea, vomiting, diarrhea, and fatigue. TRAEs greater than grade 3 were very rare, but they were mostly in the immune-related area such as pneumonitis, colitis, [and] skin reactions which included vitiligo. Vitiligo was interesting for us to observe because it does not affect patients other than changes in pigmentation, but it clearly indicates that there are immune reactions happening, and that is indirect proof of mechanism-based immune-related AEs.

How could HPK1 inhibitors fill an unmet need for patients with solid tumors?

We have not been the first to study [HPK1 inhibitors]. There [has been] great interest from many large and small companies to study HPK1 inhibitors, and it is well recognized and identified as a potential immune cell engager that goes beyond actual T-cell engagement. We are engaging T cells, but also B cells and dendritic cells.

[An HPK1 inhibitor] sees the tumor, and it presents the tumor to other cells, and it can attack the tumor at the same time, including all these other immune cells. There’s definitely huge potential that others have seen. It seems that others were perhaps not as successful as Nimbus has been in getting the inhibition on and releasing the breaks on other kinases that are needed to fully develop the activity of HPK1 inhibitors. We are that specific in inhibiting HPK1 only and now cover other antagonistic kinases which makes [NDI-101150] unique, and I believe perhaps one of the best-in-class molecules for an HPK1 inhibitor.

What would you like your colleagues to take away from this research?

[NDI-101150] is an attractive drug [in] an interesting trial, and investigators are excited that they can offer a potentially active drug to their patients when their last option for clinical treatment is a clinical trial. It’s a good option to have when you’re a treating physician and can give it to a patient as a potential beneficial agent with an acceptable safety profile.

As a class in general, we are watching the field and are seeing where other assets will be emerging. A few of [the HPK1-targeted agents] have been shelved, and I don’t know whether they will be taken off the shelf again, but hopefully we can create excitement with our data so that others see that HPK1 indeed could be an interesting target.

What are next steps with NDI-101150?

There’s clear potential to fill an unmet need either in later lines [of therapy] as we typically [use new agents] in oncology as monotherapy, and then growing the field from the back end or in combination in earlier lines with either checkpoint inhibitors or other suitable combination partners that would make sense to combine NDI-101150 with.

We are currently exploring what our next steps should be [with] how to develop a proof of concept so that this agent can go into RCC, and then beyond RCC into other indications. We are planning out a development map for our lead indication that likely can be RCC and then beyond [that as well].

This is a novel IO agent and one of our investigators said we went under the radar with our trial [in] that NDI-101150 has single-agent activity, which is rare to see these days with an IO agent. Even though we believe that in oncology we make such great progress, whether it’s in breast cancer, lung cancer, or other tumor types, there’s still such a huge unmet need; if you talk to patients, you know how urgently they need new drug solutions.

References

1. Noel MS, Demel KC, Srivastava B, et al. Phase 1/2 trial of the HPK1 inhibitor NDI-101150 as monotherapy and in combination with pembrolizumab: clinical update. J Clin Oncol. 2024;42(suppl 16):3083. doi:10.1200/JCO.2024.42.16_suppl.3083
2. NDI-101150 / Nimbus Therap, Schrodinger – Larvol Delta. Larvol. Accessed October 9, 2024. bit.ly/3BEJ2mi