At median follow up of 33.6 months, patients who received the triplet combination of tucatinib, letrozole, and palbociclib, experienced a median progression-free survival of 8.4 months.
A completely oral triplet regimen of tucatinib (Tukysa), letrozole, and palbociclib (Ibrance) was associated with clinically meaningful results in a population of patients with hormone receptor–positive, HER2-positive metastatic breast cancer, according to results from a phase 1b/2 trial (NCT03054363) published in Clinical Cancer Research.
At median follow up of 33.6 months, patients who received the triplet (n = 40) experienced a median progression-free survival (PFS) of 8.4 months (95% CI, 6.6-10.8). The median duration of study treatment was 8.5 months. The median PFS was 10.0 months (95% CI, 7.2-14.9) for those without central nervous system (CNS) metastases (n = 27), who were on the study for a median of 8.7 months compared with 8.2 months (95% CI, 5.4-20.1) for patients with CNS metastases (n = 15), who were on the study for a median of 5.9 months. Additionally, patients with CNS metastases experienced a durable PFS benefit as 26.6% stayed on the study for over a year.
Additionally, patients with measurable lesions (n = 27) achieved a clinical benefit rate of 70.4% after treatment with tucatinib, palbociclib, and letrozole with 44.5% of patients experiencing partial responses and 25.9% had stable disease (SD) for at least 6 months. The overall response rate (ORR) was 44.5% with a median duration of response (DOR) of 13.9 months as 18.5% of patients had SD for less than 6 months and 3 patients had progressive disease (PD).
“Our overall patient cohort did not reach the prespecified median PFS of 9.6 months to achieve a 50% improvement over the historical control median PFS of 6.2 months from the [phase 3] TH3resa trial [NCT01419197] of T-DM1 [ado-trastuzumab emtansine; Kadcyla],” Investigators noted.
At the data cutoff, 4 patients were continuing treatment and considered durable responders; discontinuations occurred because of PD (n = 32) and other reasons (n = 4).
The primary end point in phase 1b was safety and tolerability by National Cancer Institute CTCAE version 4.03, with pharmacokinetics properties serving as a secondary objective. The primary end point in phase 2 was median PFS with secondary objectives including ORR, clinical benefit rate, median DOR, safety, and pharmacokinetics.
In phase 1b, patients were treated on a 28-day cycle and received tucatinib at 300 mg orally twice daily, palbociclib at 125 mg orally daily for 21 days followed by 7 days off, and letrozole at 2.5 mg orally daily. In phase 2, the only change to dosage was regarding palbociclib, which was reduced to 75 mg but given on the same schedule.
The trial enrolled patients at 6 sites in the United States who were at least 18 years old and had received 2 or more HER2-targeted agents in the adjuvant or metastatic setting for hormone receptor-positive HER2-positive breast cancer. Patients also needed to have an ECOG performance score of 0 or 1, an estimated life expectancy of at least 6 months, adequate organ function, and normal left ventricular ejection fraction. Additionally, all premenopausal women received ovarian function suppression.
Treatment with prior EGFR/HER2 TKIs or CDK4/6 inhibitors was not allowed, and patients could not have received 2 or more line of endocrine therapy for metastatic disease or have a significant cardiovascular disease. Those undergoing local treatment for progressing brain metastases were excluded, however, patients with locally treated stable metastases or untreated asymptomatic CNS metastases not requiring immediate therapy were included.
The median patient age at baseline was 52 years (range, 22-81) and women enrolled were predominately White (85.7%), non-Hispanic (73.8%), had an ECOG score of 1 (57.1%), visceral disease (71.4%), and no CNS metastases (64.3%). The mean lines of prior therapy for metastatic disease were 2 (range, 0-5), with patients receiving 0 (2.4%), 1 (42.8%), 2 (26.2%), 3 (7.1%), 4 (16.7%), or 5 (4.8%) prior lines of treatment. All patients previously received the HER2-targeted agents trastuzumab (Herceptin) and pertuzumab (Perjeta), and some received T-DM1 (45.2%), margetuximab-cmkb (Margenza; 2.4%), and fam-trastuzumab deruxtecan-nxki (Enhertu; 2.4%).
Among patients with CNS disease, 2 were continuing treatment at 24 and 32 months and 13 patients came off the study, 11 because of PD. Patients with previously treated metastases (n = 12), achieved a CNS complete response after 4 months of treatment (n = 1), CNS SD for at least 6 months (n = 5), and CNS SD for less than 6 months (n = 6). Among 2 patients who had not received local therapy for CNS, a patient with nonmeasurable dural lesion experienced CNS SD for 5 months and a patient with measurable cerebellar lesion experienced CNS SD for 8 months. Additionally, prior to receiving treatment, 1 patient had surgically resected CNS metastases and did not have CNS disease for 24 months on the study.
An exploratory analysis evaluating median PFS in patients who received the 75-mg fixed dose of palbociclib in phase 2 (n = 22) vs those who received the 125-mg starting dose in phase 1b (n = 20) found that the median PFS was 10.5 months vs. 8.2 months, respectively. Although this was numerically better, it was not statistically significant (log rank test P = .9).
Although the trial was not powered to examine differences in outcomes relating to prior therapies, in the CNS cohort it was observed that 66.7% of patients who were T-DM1 naïve (n = 6/9) stayed on the study for at least 6 months vs 16.7% of patients who received T-DM1 (n = 1/6). The median duration of time on study was 11.1 months vs 5.2 months, respectively. Investigators also noted that this difference was not observed in the non-CNS cohort; however, the data should be interpreted with caution, and this may be the result of the small study size.
In phase 1b, 1 patient (5%) had a tucatinib dose reduction, 9 patients (45%) had a palbociclib reduction due to dose limiting toxicities (DLTs). Two patients (10%) discontinued palbociclib because of neutropenia DLTs but continued treatment with tucatinib and letrozole, and 1 patient discontinued letrozole for toxicity and continued tucatinib and palbociclib.
When phase 2 began, 13 patients had reduced their palbociclib dose to 75 mg and 22 patients were enrolled at 75 mg; 5 patients (14%) had dose reduction of tucatinib, 6 (17%) discontinued palbociclib and continued tucatinib and letrozole, and 2 (6%) discontinued letrozole but continued tucatinib and palbociclib. Additionally, 1 patient came off the study due to asymptomatic grade 4 liver function test elevation.
Findings from the final safety analysis showed that the most common treatment-emergent adverse events (TEAEs) patients (n = 42) experienced at any grade were neutropenia (78.6%), diarrhea (76.2%) fatigue (66.7%), and nausea (64.3%). Common grade 3 and 4 TEAEs including diarrhea (19%), fatigue (14%), and thrombocytopenia (9.5%). Grade 3/4 neutropenia occurred at a rate of 64.3% overall and reduced to 50% following the 75-mg palbociclib dose change.
Shagisultanova E, Gradishar W, Brown-Glabberman U, et al. Safety and efficacy of tucatinib, letrozole and palbociclib in patients with previously treated HR+/HER2+ breast cancer. Clin Cancer Res. Published online June 26, 2023. doi:10.1158/1078-0432.CCR-23-0117