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ASCO 2021 | BOS172738 in RET-altered tumors

Patrick Schoffski, MD, MPH, University Hospitals Leuven, Leuven, Belgium shares the outcomes of the Phase I dose-escalation trial (NCT03780517) of BOS172738, a RET inhibitor, for the treatment of RET-altered tumors. 67 patients with advanced solid tumors with RET gene alterations including non-small cell lung cancer (NSCLC) and medullary thyroid cancer (MTC) were enrolled, with an overall response rate (ORR) of 33% and 44% in NSCLC and MTC respectively. Additionally, Prof. Schoffski discusses the pharmacokinetics and safety profile of BOS172738, with BOS172738 shown to have prolonged tolerance and selective potency. This interview took place at the American Society of Clinical Oncology (ASCO) 2021 Virtual Meeting.

Transcript (edited for clarity)

ASCO 2021, it’s my pleasure to present the results of a phase I study that we have done with a highly specific RET inhibitor. The compound is called BOS172738. It’s an oral agent, which we tested in a dose-escalation and dose-expansion phase I study. The dose escalation has been completed. And this is what I’m reporting at ASCO this year.

During the dose-escalation, we included 67 patients with tumors driven by RET abnormalities...

ASCO 2021, it’s my pleasure to present the results of a phase I study that we have done with a highly specific RET inhibitor. The compound is called BOS172738. It’s an oral agent, which we tested in a dose-escalation and dose-expansion phase I study. The dose escalation has been completed. And this is what I’m reporting at ASCO this year.

During the dose-escalation, we included 67 patients with tumors driven by RET abnormalities. So either by RET fusions, as in the case of non-small cell lung cancers, or RET mutations, as in the case of medullary thyroid carcinoma or a number of other malignancies. We did a very conventional dose escalation. We escalated the dose of BOS172738 from 10 mg to 150 mg absolute dose in small cohorts of patients with advanced and highly refractory RET-driven malignancies. We assessed the safety profile, the pharmacokinetics and early signs of anti-tumor activity in this trial.

In terms of safety, the most common adverse events that we saw were increases in creatine phosphokinase, but also dyspnea, facial edema, increases in liver enzymes, but also some anemia, neutropenia, and diarrhea. The drug was not associated with significant arterial hypertension or significant hepatotoxicity, which is an issue with a multi-kinase inhibitors of RET as a target.

The drug showed quite impressive anti-tumor activity. We saw objective responses in a variety of tumor types. The objective response rate according to the assessment by the investigators was 33% in patients with RET fusion non-small cell lung cancer, and 44% in RET-driven medullary thyroid carcinoma. Interestingly, we also saw a complete response in a patient with RET-driven pancreatic adenocarcinoma.

Another interesting finding was that patients with brain involvement, who were allowed to be included in this study, showed activity of the drug in the central nervous system as well. We saw a shrinkage of brain metastasis in individual patients.

Another striking observation was that some patients tolerate this drug for quite prolonged periods of time. One of my patients here in Leuven is still receiving the drug after being entered in this study about 659 days ago. The pharmacokinetic analysis showed that this drug has a extended half-life of about 65 hours, which allows maximum target coverage.

So our conclusion from the current results of the dose-escalation part of this study is that BOS172738 is a highly potent, very selective RET inhibitor that has significant activity in patients with RET fusion non-small cell lung cancer, in patients with medullary thyroid carcinoma, and in other malignancies. The trial is currently ongoing with an expansion cohort in specific tumor types. Here we focused on non-small cell lung cancer with RET fusion and medullary thyroid carcinoma, but we also have an ongoing cohort for patients with RET-driven other malignancies and for patients with NSCLC or MTC who had prior exposure to other specific RET inhibitors.

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Disclosures

Patrick Schoffski, MD, MPH has received honoraria from Deciphera, Blueprint Medicines, and Boehringer Ingelheim as well as consulting or advisory roles at Deciphera, Ellipses Pharma, Blueprint Medicines, Transgene, Exelixis, Boehringer Ingelheim, Medscape, Guided Clairy, and Ysios Capital.