By Jonathan Montagu, CEO of HotSpot Therapeutics, as part of the From The Trenches feature of LifeSciVC
HotSpot’s trip to Barcelona for the recent European Society of Medical Oncology (ESMO) Annual Meeting was no ‘European Vacation,’ but it was certainly teeming with excitement. At the congress, we were thrilled to share some of the clinical data emerging from our Phase 1 program, an ongoing study evaluating our potent and selective investigational CBL-B inhibitor, HST-1011, in patients with advanced solid tumors. This presentation marked the most significant clinical disclosure of any CBL-B inhibitor to date, an important moment not only for industry, but for us at HotSpot.
Of note, ESMO also provided a unique opportunity to learn about important progress happening across the oncology landscape, including some intriguing new datasets for other I-O agents that have been in the clinic far longer than HST-1011.
Second-Generation I-O Agents Beginning to Show Positive Data in Phase 2 Combo Studies
The power of leveraging the body’s own immune system to target cancer has been well-established by first-generation I-O therapeutics, but the biopharma community has struggled to find success stories beyond the anti-PD-(L)1 class. Despite significant time and capital deployment since first-generation anti-PD-(L)1 inhibitors opened an I-O supernova a decade ago, improving such a paradigm-shifting therapeutic approach has been difficult. That said, two presentations at ESMO in non-small cell lung cancer (NSCLC) were perhaps “green shoots” for the field.
The first presentation of interest was the Phase 2 data set for belrestotug, an inhibitor of the immune checkpoint receptor TIGIT, in front-line NSCLC patients with PD-L1 expression of greater than 50%. Anti-TIGIT antibodies have been clinically evaluated since 2016, and an absence of single-agent data has left a void in the scientific community’s understanding of the mechanism. However, the data presented at ESMO 2024 showed that the combination of belrestotug with a PD-1 inhibitor led to an encouraging 30% improvement in ORR compared with anti-PD-1 alone.
The second presentation of note was the Phase 2 data for relatlimab, an inhibitor of LAG3, another checkpoint receptor, in patients with NSCLC. Relatlimab has been in the clinic since late 2013, where similar questions have existed about the mechanism due to an absence of disclosures of single-agent pharmacodynamic and efficacy data. Despite achieving approval in melanoma when combined with anti-PD-1, relatlimab faced persisting doubts because of clinical setbacks in other indications. At ESMO 2024, the combination of relatlimab with anti-PD-1 and chemotherapy showed a promising benefit in NSCLC patients compared to anti-PD-1 and chemotherapy alone, most notably, in the subgroup of patients with PD-L1 levels in the 1-49% range.
In spite of somewhat arduous clinical development pathways, these data sets are now providing some cautious optimism for each mechanism’s potential to drive benefits for NSCLC patients.
Phase 1 CBL-B Inhibitor Data Set Builds Early Confidence Ahead of Phase 2
As we look to HST-1011, we’re aiming to differentiate from these other more advanced programs to help guide our own development program.
One of the reasons for the length of time it takes to understand novel I-O mechanisms is the challenge of interpreting early clinical data. This is due to a myriad of reasons – the advanced nature of Phase 1 patient populations (very progressed disease, multiple prior lines of therapy), the broad heterogeneity of the patients enrolled (across tumor type, state), and the typical rapid advancement into combination studies, which can make it difficult to distill the individual behavior of the novel agent itself.
At HotSpot, we designed an early clinical development program for HST-1011 focused on establishing critical linkages among exposure, upstream and downstream pharmacology, and trends toward clinical activity to enable an early understanding of the mechanism.
To that end, our Phase 1 monotherapy data hit the mark and showed early evidence of precisely what we were looking for:
- A dose-dependent pharmacokinetic profile that achieved target exposures at dose levels that were well-tolerated by patients.
- Changes in both proximal measures of CBL-B inhibition and downstream measures of its ability to activate the immune system.
- Clear early signals of clinical activity in heavily pre-treated patients who have failed to respond or are no longer responding to any other treatment.
These Phase 1 data have provided critical insights into CBL-B inhibition as a mechanism, offering a strong foundation upon which we plan to advance HST-1011 through the clinic. While the TIGIT and LAG3 examples highlighted at ESMO 2024 have offered glimmers of hope in the I-O world, with our Phase 1 data now in-hand, we believe we are optimally positioned to drive forward the development of HST-1011 to ensure we can fully exploit the potential substantial value that exists. Moreover, rich biomarker datasets, including those recently highlighted, underscore the substantial potential that exists to enrich patient populations in future clinical studies, particularly in this era of AI and machine learning. With our novel mechanism and a purposeful clinical development program, we believe we have a unique opportunity to advance HST-1011 and aim to ultimately bring the power of I-O to more patients.
