Oncternal Therapeutics is a company at a crossroads. With two first-in-class clinical programs targeting cancers with significant unmet needs, the company holds tremendous promise. Yet, a closer look at their recent Q1 2024 earnings call transcript reveals a potential trade-off – a delicate balancing act between safety and efficacy that could impact their ROR1 CAR T program's long-term success.

While the market is understandably buzzing about the advancement of ONCT-534, their dual-action androgen receptor inhibitor, and its potential in addressing prostate cancer escape mechanisms, a more intriguing story unfolds in the ONCT-808 program. This ROR1-targeting autologous CAR T therapy has shown promising initial responses, with complete metabolic responses observed in two out of three patients at the initial dose level. However, the excitement is tempered by a fatal serious adverse event consistent with cytokine release syndrome (CRS) experienced by a patient in the subsequent dose level.

Oncternal's response to this tragic event, as outlined in their call, is where the potential trade-off emerges. The company, in alignment with the FDA, has implemented several protocol changes aimed at enhancing patient safety. These include modified eligibility criteria, increased monitoring for infection, and a new dosing schedule starting at a significantly lower dose of 0.3x10^6 CAR T cells per kilogram. While these modifications are undoubtedly crucial for protecting patients, they raise a critical question: could this emphasis on safety come at the cost of sacrificing the remarkable response durability observed at the initial dose level?

The transcript offers hints of the company's internal struggle with this dilemma. Dr. Salim Yazji, Oncternal's CMO, emphasizes the heavily pre-treated nature of their patient population, noting that “usually the expectation of those patients is very low and short in progression-free survival." He expresses enthusiasm about the durability observed at the initial dose, but acknowledges the difficulty in drawing conclusions given the advanced stage of the patients' disease.

This hesitation speaks volumes. Oncternal is clearly aware of the potential correlation between higher CAR T cell dose and response durability, a phenomenon observed in other CAR T therapies. Yet, the shadow of the fatal adverse event looms large, prompting a cautious approach.

Hypothetical Impact of Dose Reduction on Progression-Free Survival

Let's delve into the numbers. Assume, hypothetically, that the initial dose of 1x10^6 CAR T cells per kilogram yielded an average progression-free survival (PFS) of 6 months. Lowering the dose to 0.3x10^6, a 70% reduction, could potentially reduce the PFS by a similar proportion, resulting in an estimated PFS of just 1.8 months.

This hypothetical scenario, though simplistic, highlights the possible cost of excessive caution. While patient safety is paramount, achieving long-term remission, especially in a population with dismal prognoses, remains the ultimate goal. Striking the right balance between these competing priorities is a complex challenge, and Oncternal's success in navigating this delicate dance will significantly impact the future of their ROR1 CAR T program.

The company's strategy of starting at a significantly lower dose and cautiously escalating raises another concern – a potential delay in reaching the optimal therapeutic window. A slow and incremental escalation process could prolong the time required to identify the dose that maximizes efficacy while maintaining acceptable safety. This delay could cede valuable ground to competitors in the ROR1 CAR T space, who may be pursuing more aggressive dose escalation strategies.

Oncternal's decision to prioritize safety is commendable. However, their success hinges on their ability to translate this cautious approach into durable responses. The upcoming clinical data updates will provide valuable insights into whether their gamble pays off – whether they can secure a foothold in the ROR1 CAR T race without sacrificing the very attribute that initially set their program apart.

"ONCT-534 (DAARI) is progressing through dose escalation with no unexpected DLTs. Initial clinical data is expected in late Q2 2024. ONCT-808 (ROR1 CAR T) Phase 1/2 trial is re-opened with modified protocol to enhance safety. Updates expected in mid-2024. Potential trade-off: prioritizing safety over the impressive initial response durability seen at the higher dose. Challenge: Finding the balance between safety and achieving durable responses, especially in a heavily pre-treated patient population."

"ROR1 stands for "Receptor Tyrosine Kinase-Like Orphan Receptor 1". It's a protein often found on the surface of cancer cells, making it an attractive target for therapies like CAR T cells."