Tucatinib Produces Potent Preclinical Antitumor Activity, CNS Penetrance in HER2+ Breast Cancer | OncLive

Tucatinib Produces Potent Preclinical Antitumor Activity, CNS Penetrance in HER2+ Breast Cancer

June 23, 2020

The HER2-selective TKI tucatinib (Tukysa) demonstrated potent antitumor activity alone and in combination with ado-trastuzumab emtansine (T-DM1; Kadcyla) in HER2-overexpressing breast cancer cell lines and xenograft models.

The HER2-selective TKI tucatinib (Tukysa) demonstrated potent antitumor activity alone and in combination with ado-trastuzumab emtansine (T-DM1; Kadcyla) in HER2-overexpressing breast cancer cell lines and xenograft models, according to findings presented in a poster during the AACR Virtual Annual Meeting II.1

In vitro assays showed that tucatinib suppressed HER2-mediated signaling pathways, such as HER2 (P = .00015), HER3, AKT (P <.0001), and ERK (P =.0008) phosphorylation. Additionally, tucatinib inhibited the growth of HER2-positive breast cancer cell lines in vitro with single-digit nanomolar potencies, although the agent was inactive in inhibiting cell lines that lacked amplified HER2.

Ex vivo tucatinib-treated xenografts demonstrated similar suppression of signal transduction pathways, mirroring data showing the clinical activity of tucatinib in patients with metastatic HER2-positive breast cancer with brain metastases.

“These results, taken together with early clinical data demonstrating preliminary safety and activity of tucatinib in combination with T-DM1, support the continued assessment of [the combination] in patients with HER2-positive metastatic breast cancer, including those with brain metastases,” said Devra Olson, lead study author and staff scientist at Seattle Genetics during a poster presentation of the findings.

On April 17, 2020, the FDA approved tucatinib for use in combination with trastuzumab (Herceptin) and capecitabine for the treatment of patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including patients with brain metastases, following at least 1 prior anti–HER2-based regimen in the metastatic setting.

The approval is based on initial findings from the phase 2 HER2CLIMB trial, which showed a 34% reduction in the risk of death with tucatinib versus trastuzumab and capecitabine alone in this patient population. The primary analysis also showed that patients with brain metastases experienced a 52% reduction in the risk of progression or death with tucatinib.2

At the 2020 ASCO Virtual Scientific Program, updated findings showed that the tucatinib triplet led to 68% reduction in the risk of central nervous system (CNS) progression or death and a 42% reduction in the risk of death among patients with brain metastases.3

In 2018, results from a phase 1b trial (NCT01983501)4 showed preliminary safety and efficacy with tucatinib in combination with T-DM1. The study enrolled 57 women with metastatic HER2-positive breast cancer with or without stable brain metastases who had previously received trastuzumab and a taxane. Patients received 300 mg or 350 mg of oral tucatinib twice daily plus 3.6 mg/kg of intravenous T-DM1 once every 21 days.

Among the 50 patients treated with the maximum-tolerated dose (MTD) of 300 mg, the median progression-free survival (PFS) was 8.2 months (95% CI, 4.8-10.3). Patients who had previously received trastuzumab and pertuzumab (Perjeta) had a median PFS of 6.5 months (95% CI, 4.1-9.2).

The objective response rate (ORR) in 34 evaluable patients with measurable disease was 47%, which included 1 complete response and 15 partial responses. Among 48 evaluable patients, the clinical benefit rate was 58%. The median duration of response (DOR) with the combination was 6.9 months (95% CI, 2.8-19.8).

Patients with brain metastases who received the MTD (n = 30) had a median PFS of 6.7 months (95% CI, 4.1-10.2) and a DOR of 6.9 months (95% CI, 1.45-19.48). The brain-specific ORR was 36% in patients with measurable brain metastases (n = 14).

For the analysis presented during AACR, investigators set out to quantify the antitumor activity of tucatinib and T-DM1 in vitro. To this end, both drugs were screened in a panel of breast cancer cell lines spanning a range of HER2 overexpression levels. Tucatinib was titrated from 0.01 to 25,000 nM and T-DM1 was titrated from 0.01 to 25,000 ng/ml in CellTiter-Glo (CTG) cytotoxicity assays. The values of the concentration of tucatinib that led to a half-maximal response (EC50) in CTG assays were comparable to that of T-DM1 in high HER2-expressing cell lines, at approximately 50 nM or ng/ml, respectively.

To assess the cytotoxic activity of the combination in vitro in HER2-positive cell lines, investigators performed an isobologram analysis of 96-hour CTG cytotoxicity assays with drug concentrations spanning from 0.01 nM to 25 uM for tucatinib and .01 ng/ml to 25 ug/ml for T-DM1. The combination showed the most synergy in high HER2-expressing cell lines, most notably the BT-747 cell line, which had a HER2 overexpression level of 864,064.

The activity of the combination was then assessed in 4 xenograft models: BT-474 (estrogen receptor (ER)–positive/HER2 3+ tumor-derived cell line), CTG-0717 (ER-negative/progesterone receptor (PR)–negative/HER2 3+ primary breast cancer that progressed on neoadjuvant trastuzumab and pertuzumab), CTG-0708 (ER/PR-negative/HER2 3+ breast cancer with lung metastases that progressed on neoadjuvant trastuzumab/pertuzumab), and CTG-0807 (ER/PR-negative/HER2 3+ breast cancer with lung metastases that progressed on neoadjuvant trastuzumab/pertuzumab).

Investigators demonstrated a significant reduction in the mean tumor volume over time after each model was dosed with 50 mg/kg of tucatinib twice daily and 10 mg/kg of T-DM1, with P values of =.002, =.48, =.0029, and .016 in the BT-474, CTG-0717, CTG-0708, and CTG-0807 models, respectively.

To classify the activity and drug penetration of tucatinib in HER2-positive CNS tumors, investigators developed and characterized a red-shifted luciferase-expressing BT-474 breast cancer cell line. The cell line was stereotaxically implanted into the brain.

In vivo bioluminescence imaging was used to evaluate the efficacy of tucatinib as a single agent in CNS tumors. The results showed a significant difference in antitumor activity and survival with tucatinib in treated versus untreated CNS tumors, with P values of =.014 and =.0001, respectively.

Histological assessment of treated tumors confirmed that tucatinib penetrated the blood–brain barrier to suppress HER2 signaling. As part of the drug penetration study of CNS-implanted BT-474 tumors, quantitative autoradiography analysis showed that 14C-labeled tucatinib penetrated the CNS tumor mass with drug concentration levels that surpassed measurements in normal brain regions.

The investigators concluded that tucatinib is a uniquely selective and highly potent inhibitor of HER2 signaling, in breast cancer cell lines as well as in vivo in breast cancer xenograft models. The agent’s cytotoxic activity is most often synergistic when used in combination with T-DM1, showing enhanced antitumor activity in vivo in most HER2-positive metastatic breast cancer xenograft models. Additionally, in CNS-implanted tumors, tucatinib was found to inhibit growth and suppress downstream signaling.

Taken collectively with the results from the phase 1b trial, investigators have launched the phase 3 HER2CLIMB-02 trial (NCT03975647), in which patients with previously treated metastatic HER2-positive breast cancer with or without brain metastases will be randomized to receive either tucatinib/T-DM1 or placebo/T-DM1.

References

  1. Olson D, Kulukian A, Taylor J, et al. Preclinical characterization of tucatinib in HER2-amplified xenograft and CNS implanted tumors. Presented at: 2020 AACR Virtual Annual Meeting II; June 22-24, 2020; Virtual. Abstract 1962.
  2. Seattle Genetics announces US FDA approval of Tukysa (tucatinib) for people with advanced unresectable or metastatic her2-positive breast cancer. News release. Seattle Genetics, Inc. April 17, 2020. Accessed June 23, 2020. bit.ly/2xtQeBe
  3. Lin NU, Murthy RK, Anders CK, et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB). J Clin Oncol. 2020;38(suppl 15):1005. doi:10.1200/JCO.2020.38.15_suppl.1005
  4. Borges VF, Ferrario C, Aucoin N, et al. Tucatinib combined with ado-trastuzumab emtansine in advanced ERBB2/HER2-positive metastatic breast cancer: a phase 1b clinical trial. JAMA Oncol. 2018;4(9):1214-1220. doi:10.1001/jamaoncol.2018.1812

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