BOS172738 Demonstrates Strong Efficacy/Tolerability in RET-Altered MTC and Other Solid Tumors

Results from a phase 1 study show BOS172738 to have strong anti-tumor activity and a well-tolerated safety profile in the treatment of RET gene altered medullary thyroid cancer (MTC) and non–small cell lung cancer (NSCLC).¹

BOS172738 is a highly potent and selective oral RET inhibitor is used for the treatment of RET fusions and RET mutations in solid tumors and some hematologic maligancies. According to

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

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 any RET-gene alteration, adequate bone marrow, renal, hepatic, and cardiac function were eligible for the study.²

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

Phase 1 included seven dose levels ranging from 10-150 mg where the 67 participants received an oral dose once a day in each 28-day cycle. Intra-patient dose escalation was allowed as was over-accrual to dose levels deemed to be safe.

Primary end points of the study include safety, tolerability, objective response rate (ORR), pharmacokinetics (PK), and to determine the maximum tolerated dose for recommendation.

Significant tumor reduction was demonstrated across 54 patients in the efficacy-evaluable cohort. Across the entirety of the phase 1 population, ORR was reported to be 31% (including 5 unconfirmed partial responses) and 2% confirmed complete responses. Of the 30 evaluable patients with NSCLC, ORR was 30% and 44% in the 16 patients with MTC.

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

At a median duration of exposure of 150 days, the safety profile of BOS172738 was promising with most treatment-emergent adverse events (TEAEs) to be grade 2 or lower, reversible, and not related to the drug. The most common grade 3 higher TEAE was creatinine phosphokinase increase (60%). Others included dyspnea (37%), aspartate aminotransferase increase (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 was also reported, and the maximum tolerated dose was not reached along with limited cases of muscle weakness, cough, and hypophosphatemia.

In regard to PK, BOS172738 was measured in plasma and demonstrated a linear pKa profile with steady-state concentrations over IC₉₀ achieved at doses above 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 on study, including the longest being 659 days at the time of the data cutoff.

Part B is currently enrolling and will focus on dose expansion and examine BOS172738 at a dose of 75 mg using 3 cohorts with 20 patients. These cohorts are set to include a fully enrolled RET fusion-positive NSCLC cohort, a RET-mutant MTC cohort, and a patient with other RET-altered tumors or NSCLC or MTC patients with prior exposure to RET-specific targeted therapies cohort.

REFERENCES:

1. Patrick Schöffski. 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;abstr 3008). doi: 10.1200/JCO.2021.39.15_suppl.3008

2. Safety, Efficacy, and Tolerability of BOS172738 in Patients With Advanced Rearranged During Transfection (RET) Gene-Altered Tumors. ClinicalTrials.gov. Accessed February 18, 2022. https://bit.ly/34JT6dS