Adding an HPK1 Inhibitor to Immune Checkpoint Inhibition May Be Effective in Solid Tumors

As preclinical investigations have shown that HPK1 inhibition may enhance the antitumor activity of immune checkpoint inhibitors (ICIs), combination strategies are at the forefront, with several HPK1 inhibitors looking to expand on the efficacy of ICIs.^1,2

HPK1, a hematopoiesis-specific serine/threonine kinase and a member of the MAP4K family, has emerged as a promising target because its inhibition can alleviate T-cell exhaustion, enhance T-cell functionality, and improve upon immunotherapy’s efficacy.³ It is an intracellular negative regulator primarily in hematopoietic lineage cells and negatively regulates T cells, B cells, and dendritic cells.^3,4 When HPK1 kinase activity is lost, cytokine secretion becomes exacerbated, T-cell signaling is enhanced, and viral clearance is improved, which investigators have noted increases restraint of tumor growth.

“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,” Anita Scheuber, MD, PhD, senior vice president and therapeutic area head of oncology at Nimbus Therapeutics, said in an interview with OncologyLive.

However, challenges noted with targeting HPK1 encompass limited selectivity, uncertainty on the role of non-kinase scaffold functions of HPK1, and insufficient immune stimulation, according to prior research.³ Agents currently under investigation in phase 1/2 trials include the novel inhibitor NDI-101150, which has demonstrated early efficacy in patients with renal cell carcinoma (RCC) in particular.⁵

“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,” Scheuber said. “That is saying that there is a change in the immune system, and there is also an increase in cytokine secretion [and] antitumor immune responses. That led us to believe that HPK1 is a very attractive high-priority target for a novel immuno-oncology [IO] agent, particularly in patients who have previously been treated with ICIs.”

NDI-101150 Demonstrates Early Efficacy

The oral, highly selective, small molecule HPK1 inhibitor NDI-101150 is currently being evaluated as monotherapy and in combination with pembrolizumab (Keytruda) in a phase 1/2 trial (NCT05128487). The dose-escalation phase evaluated the monotherapy and doublet in patients with advanced solid tumors, and the expansion phase is also evaluating both regimens, but in disease-specific cohorts.^5,6

“Based on a very early clinical efficacy signal that we saw during dose escalation, including a complete response [CR] at our lowest dose, we focused on [certain] patients a bit more in our expansion cohort,” Scheuber said. “We currently have 3 expansion cohorts open in RCC, non–small cell lung cancer [NSCLC], and gastric/gastroesophageal junction indications. Those are 3 active dose expansions that are open and only in RCC—[because] 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 200 mg every 3 weeks.”

Data presented at the 2024 American Society of Clinical Oncology Annual Meeting included results from 44 patients who received treatment in the dose-escalation cohort as of March 18, 2024, and 15 patients who received therapy in the expansion cohorts. Results showed that among response-evaluable patients who received NDI-101150 monotherapy (n = 30), 16.7% experienced clinical benefit. Further, 1 patient with clear cell RCC achieved a CR approximately 15 weeks after receiving the first dose of therapy at 50 mg; disease progression then occurred approximately 40 weeks after receipt of the first dose. One patient with clear cell RCC treated with the 100-mg dose experienced a partial response, which is ongoing.⁵

“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,” Scheuber said. “We did see some tumor shrinkage in other tumor types as well. The patients did not achieve a partial or complete response with NDI-101150 at that point in time, but clearly had tumor shrinkage.”

Of the 8 enrolled patients with RCC, 6 achieved a best overall response of stable disease (SD) or better and 1 patient experienced SD for 21 months. Additionally, SD lasting at least 6 months occurred in 3 patients in the trial—1 patient had RCC, and 1 patient each with pancreatic cancer and endometrial cancer experienced SD. Investigators also observed an increase in activated CD8-positive cells and dendritic cells in the on-treatment biopsy vs the archival biopsy.⁵

Most patients thus far have received the agent as monotherapy, and the combination therapy cohorts with pembrolizumab are ongoing. Scheuber added, “It’s not necessarily the 1 and only combination that [one] 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.”

“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,” Scheuber said.

The Power of an ICI/HPK1 Combination and Safety of HPK1 Inhibitors

In a phase 1 trial (NCT04649385), the addition of BGB-15025 to tislelizumab-jsgr (Tevimbra) showed early efficacy, as patients treated with the doublet (n = 49) experienced an objective response rate of 18.4%; no patients treated with BGB-15025 monotherapy (n = 60) experienced a response. The disease control rate was 57.1% with the combination vs 35.0% with the monotherapy; respective clinical benefit rates were 30.6% and 6.7%.⁷

There were no dose-limiting toxicities (DLTs) observed in patients who received the monotherapy, and 5 DLTs occurred in those treated with the doublet, including grade 3 increased alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels, grade 4 increased ALT/AST levels, grade 3 colitis, grade 3 immune-related hepatitis, and grade 3 increased γ-glutamyl transferase levels. The maximum tolerated dose for the combination regimen was 150 mg once daily for BGB-15025. The most common any-grade treatment-related adverse effects (TRAEs) occurring in the doublet arm were nausea (30.6%), diarrhea (28.6%), fatigue (20.4%), and vomiting (12.2%). Additionally, 3 patients died from TRAEs and 12.2% discontinued treatment because of TRAEs.

Safety findings on the HPK1 inhibitor NDI-101150 revealed that the most common any-grade TRAEs experienced in the safety population (n = 59) were diarrhea (39.0%), nausea (39.0%), vomiting (30.5%), fatigue (23.7%), and anemia (8.5%). Investigators noted the 200-mg dose of the agent was not tolerated.⁵

“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 TRAEs [of] nausea, vomiting, diarrhea, and fatigue,” Scheuber said. “TRAEs greater than grade 3 were very rare, but they were mostly immune related.”

What’s Next for HPK1 Inhibitors?

The combination of BGB-15025 plus tislelizumab is under evaluation in the phase 1b expansion portion of the trial, and a phase 2 international umbrella study (NCT05635708) in patients with NSCLC is also ongoing.⁷ Regarding NDI-101150, new findings, including efficacy data from the patient population with RCC, will be presented at the 2024 Society for Immunotherapy of Cancer Annual Meeting occurring November 6 to 10, in Houston, Texas.⁸

“As a class in general, we are watching the field and are seeing where other assets will be emerging,” Scheuber said. “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 [on NDI-101150] so that others see that HPK1 indeed could be an interesting target.”

Furthermore, the experimental HPK1 inhibitor GRC 54276 is being evaluated in a first-in-human phase 1/2 trial (NCT05878691). In March 2023, the FDA accepted the investigational new drug application from the agent’s manufacturer, Glenmark Pharmaceuticals Ltd, to proceed with the trial in the US for the treatment of patients with advanced solid tumors and lymphomas. The trial is open at 16 locations in India and 2 in the US.^9,10

Another first-in-human phase 1/2 study (NCT04521413) is enrolling patients with advanced solid malignancies to receive the HPK1 inhibitor CFI-402411 as monotherapy and in combination with pembrolizumab11 (Figure).^6,7,9,11

“For RCC in general, despite the tremendous advancements in this space, including the use of [adjuvant] pembrolizumab and first- [and] second-line treatments [in the metastatic setting], once patients relapse on those standards of care, they have no options,” Scheuber said. “[Therefore], it is encouraging to see [activity with NDI-101150]. 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.”

Editor’s note: This interview took place prior to the 2024 Society for Immunotherapy of Cancer Annual Meeting.

References

1. Tellis JC, Wei B, Siu M, et al. Discovery of GNE-6893, a potent, selective, orally bioavailable small molecule inhibitor of HPK1. ACS Med Chem Lett. 2024;15(9):1606-1614. doi:10.1021/acsmedchemlett.4c00319
2. Sommerhalder D, Noel M, Boiko S, et al. Monotherapy results from an ongoing phase 1a dose escalation study of NDI-101150, a highly selective oral hematopoietic progenitor kinase 1 (HPK1) inhibitor. J Immunother Cancer. 2023;11(suppl 1):A1-A1731. doi:10.1136/jitc-2023-SITC2023.0751
3. Xu J, Li Y, Chen X, et al. Opportunities and challenges for targeting HPK1 in cancer immunotherapy. Bioorg Chem. Published online October 4, 2024. doi:10.1016/j.bioorg.2024.107866
4. Chen H, Guan X, He C, Lu T, Lin X, Liao X. Current strategies for targeting HPK1 in cancer and the barriers to preclinical progress. Expert Opin Ther Targets. 2024;28(4):237-250. doi:10.1080/14728222.2024.2344697
5. 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
6. A study of NDI 1150-101 in patients with solid tumors. ClinicalTrials.gov. Updated August 29, 2024. Accessed October 9, 2024. https://clinicaltrials.gov/study/NCT05128487
7. Deva S, Zhou C, Bishnoi SK, et al. A first‑in‑human phase 1a dose‑escalation study of BGB‑15025 (HPK1 inhibitor) as monotherapy and in combination with tislelizumab (TIS; anti‑PD‑1 antibody) in patients (pts) with advanced solid tumors. J Clin Oncol. 2024;42(suppl 16):2585. doi:10.1200/JCO.2024.42.16_suppl.2585
8. NDI-101150 / Nimbus Therap, Schrodinger – Larvol Delta. Larvol. Accessed October 9, 2024. bit.ly/3BEJ2mi
9. A study of GRC 54276 in participants with advanced solid tumors and lymphomas. ClinicalTrials.gov. Updated July 22, 2024. Accessed October 9, 2024. https://clinicaltrials.gov/study/NCT05878691#contacts-and-locations
10. Glenmark receives acceptance from U.S. FDA on its IND application for GRC 54276 to proceed with a phase 1/2, first-in-human clinical study of the molecule for the treatment of patients with advanced solid tumors and lymphomas. News release. Glenmark. Accessed October 9, 2024. prn.to/3Y2UjV0
11. Safety and efficacy study of CFI-402411 in subjects with advanced solid malignancies. ClinicalTrials.gov. Updated September 19, 2024. Accessed October 9, 2024. https://clinicaltrials.gov/study/NCT04521413