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Preclinical InVivo Data Integrated in a Modeling Network Informs a Refined Clinical Strategy for a CD3 T-Cell Bispecific in Combination with Anti-PD-L1
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- Sánchez, Javier (author)
- Uppsala universitet,Institutionen för farmaci,F Hoffmann La Roche Ltd, Roche Innovat Ctr Basel, Roche Pharma Res & Early Dev, Grenzacherstr 124, CH-4070 Basel, Switzerland.
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- Nicolini, Valeria (author)
- Roche Innovat Ctr Zurich, Roche Pharma Res & Early Dev, Schlieren, Switzerland.
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- Fahrni, Linda (author)
- Roche Innovat Ctr Zurich, Roche Pharma Res & Early Dev, Schlieren, Switzerland.
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- (creator_code:org_t)
- 2022-10-07
- 2022
- English.
- In: AAPS Journal. - : Springer Nature. - 1550-7416. ; 24
- Journal article (peer-reviewed)
Abstract
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- TYRP1-TCB is a CD3 T-cell bispecific (CD3-TCB) antibody for the treatment of advanced melanoma. A tumor growth inhibition (TGI) model was developed using mouse xenograft data with TYRP1-TCB monotherapy or TYRP1-TCB plus anti-PD-Ll combination. The model was translated to humans to inform a refined clinical strategy. From xenograft mouse data, we estimated an EC50 of 0.345 mg/L for TYRP1-TCB, close to what was observed in vitro using the same tumor cell line. The model showed that, though increasing the dose of TYRP1-TCB in monotherapy delays the time to tumor regrowth and promotes higher tumor cell killing, it also induces a faster rate of tumor regrowth. Combination with anti-PD-L1 extended the time to tumor regrowth by 25% while also decreasing the tumor regrowth rate by 69% compared to the same dose of TYRP1-TCB alone. The model translation to humans predicts that if patients' tumors were scanned every 6 weeks, only 46% of the monotherapy responders would be detected even at a TYRP1-TCB dose resulting in exposures above the EC90. However, combination of TYRP1-TCB and anti-PD-L1 in the clinic is predicted to more than double the overall response rate (ORR), duration of response (DoR) and progression-free survival (PFS) compared to TYRP1-TCB monotherapy. As a result, it is highly recommended to consider development of CD3-TCBs as part of a combination therapy from the outset, without the need to escalate the CD3-TCB up to the Maximum Tolerated Dose (MTD) in monotherapy and without gating the combination only on RECIST-derived efficacy metrics.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- CD3-bispecifics
- Checkpoint inhibitors
- Combination
- PKPD modeling
Publication and Content Type
- ref (subject category)
- art (subject category)
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- Waldhauer, Inja
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- Jamois, Candice
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- Fowler, Stephen
- Simon, Silke
- Klein, Christian
- Umana, Pablo
- Friberg, Lena
- Frances, Nicolas
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