BOS172738 demonstrates high efficacy/tolerance in RET-modified MTC and other solid tumors

BOS172738 shows promising results in the treatment of RET-altered medullary thyroid cancer and non-small cell lung cancer, according to a phase 1 study.

Results from a Phase 1 study show that BOS172738 has strong anti-tumor activity and a well-tolerated safety profile in the treatment of RET medullary thyroid cancer (MTC) and non-small cell lung cancer (NSCLC).1

BOS172738 is a very potent and selective oral RET inhibitor is used for the treatment of RET mergers and RET mutations in solid tumors and certain hematological malignancies. According to

Patrick Schöffski, MPH, MD, who presented the Phase 1 data at the 2021 Annual Meeting of the American Society of Clinical Oncology; “RET mergers and RET activating point mutations are well-established primary oncogenic drivers. RET gene fusions occur in up to 2% of non-small cell lung cancers, in more than 60% of CMT cases, and in 10% to 20% of other thyroid malignancies. RET alterations have also been identified in a variety of other low-frequency tumor types.

The open-label, multicenter, dose-escalation trial (NCT03780517) evaluated the safety, efficacy, pharmacokinetics, and pharmacodynamics of BOS172738. Participants aged 18 years or older with an advanced solid tumor with RET-genetic alteration, adequate bone marrow, renal, hepatic and cardiac function were eligible for the study.2

The median age of the patient population was 59 years (range, 25-86) and patients were predominantly male (57%). The median number of prior systemic treatments of enrollees was 2, 28% of participants had previously been treated with a multi-kinase inhibitor, 16% had brain metastases at study entry, and had an ECOG performance status of 0-1. The majority of RET the genotypes included in the study were NSCLC (n=34) and MTC (n=21).

Phase 1 included seven dose levels ranging from 10 to 150 mg where all 67 participants received an oral dose once daily during each 28-day cycle. Intra-patient dose escalation was permitted, as was overaccumulation to dose levels deemed safe.

The primary endpoints of the study include safety, tolerability, objective response rate (ORR), pharmacokinetics (PK), and determination of maximum tolerated dose for recommendation.

Significant tumor reduction was demonstrated in 54 patients in the efficacy evaluable cohort. In the entire phase 1 population, the ORR was 31% (including 5 unconfirmed partial responses) and 2% confirmed complete responses. Of the 30 evaluable patients with NSCLC, the ORR was 30% and 44% in the 16 patients with MTC.

Strong anti-tumor activity was observed in both patients RET-modified NSCLC and MTC. ORR of 30% (n=9/30) was shown in RET fusion+ NSCLC and ORR by 44% (n=7/16, including 1 complete response) and one patient with RET fusion+ pancreatic cancer reported a partial response.

At a median exposure duration of 150 days, the safety profile of BOS172738 was promising, with most treatment-emergent adverse events (TEAEs) being grade 2 or lower, reversible, and not drug-related. The most common grade 3 upper TEAE was increased creatinine phosphokinase (60%). Others included dyspnoea (37%), increased aspartate aminotransferase (30%). diarrhea (30%), anemia (28%), fatigue (27%), constipation (22%) and neutropenia (22%). A low incidence of hypertension and liver enzyme elevations compared to other inhibitors have also been reported, and the maximum tolerated dose has not been reached, as well as limited cases of muscle weakness, cough and hypophosphatemia. .

With respect to PK, BOS172738 was measured in plasma and demonstrated a linear pKa profile with steady state concentrations on IC90 achieved at doses greater than 20 mg.

Additionally, dose-dependent exposure, rapid absorption, and an extended half-life of approximately 65 hours maximizing target coverage were also examined. Many patients remain in the study, with the longest being 659 days at the time of data closure.

Part B is currently recruiting and will focus on dose expansion and will investigate BOS172738 at a dose of 75mg using 3 cohorts of 20 patients. These cohorts are defined to include a RET fusion-positive NSCLC cohort, a RET-mutant MTC cohort, and one patient with others RET-altered tumors or NSCLC or MTC patients who have already been exposed to RET-cohort of specific targeted therapies.

1. Patrick Schoffsky. BOS172738, a highly potent and selective RET inhibitor, for the treatment of RET-altered tumors, including RET-fusion + NSCLC and RET-mutant MTC: Phase 1 study results. J Clin Oncol. 2021;39(suppl 15;abstract 3008). doi: 10.1200/JCO.2021.39.15_suppl.3008
2. Safety, efficacy and tolerability of BOS172738 in patients with advanced genetically modified tumors rearranged during transfection (RET). Accessed February 18, 2022.

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