T-DM1/Tucatinib Improves PFS Vs Placebo in HER2+ Metastatic Breast Cancer

“Both preclinical and phase 1 and 2 clinical data have indicated that the combination of T-DM1 with tucatinib has promising clinical activity and antitumor responses, as well as a manageable safety profile [in HER2-positive disease],” according to Sara A. Hurvitz, MD.

Patients with previously treated HER2-positive metastatic breast cancer, including those with brain metastases, experienced a significant improvement in progression-free survival (PFS) with tucatinib (Tukysa) plus ado-trastuzumab emtansine (T-DM1; Kadcyla) compared with placebo plus T-DM1, according to primary analysis data from the phase 3 HER2CLIMB-02 trial (NCT03975647) presented at the 2023 San Antonio Breast Cancer Symposium (SABCS).¹

Data showed that tucatinib plus T-DM1 generated 151 PFS events and a median PFS of 9.5 months (95% CI, 7.4-10.9) vs 182 PFS events and a median PFS of 7.4 months (95% CI, 5.6-8.1) in patients who received T-DM1 plus placebo (hazard ratio, 0.76; 95% CI, 0.61-0.95; P = .0163). Patients with brain metastases who received tucatinib in combination with T-DM1 (n = 99) experienced 70 PFS events and achieved a median PFS of 7.8 months (95% CI, 6.7-10.1). Conversely, those with brain metastases in the placebo arm (n = 105) experienced 85 PFS events and achieved a median PFS of 5.7 months (95% CI, 4.6-7.5 [hazard ratio, 0.64; 95% CI, 0.46-0.89]). Across prespecified subgroups, the PFS hazard ratios were consistent with that of the overall population.

The selective, HER2-directed TKI tucatinib was previously approved by the FDA in 2020 for patients with previously treated, HER2-positive, unresectable locally advanced or metastatic breast cancer, including those with brain metastases, who had received at least 1 prior HER2-directed therapy in the metastatic setting.² This regulatory decision was supported by findings from the phase 2 HER2CLIMB trial (NCT02614794), in which the addition of tucatinib to trastuzumab (Herceptin) and capecitabine led to a 1-year PFS rate of 24.9% in patients with brain metastases.³ In patients with brain metastases enrolled in the placebo arm, the 1-year PFS rate was 0% (hazard ratio, 0.48; 95% CI, 0.34-0.69; P < .001).

“Both preclinical and phase 1 and 2 clinical data have indicated that the combination of T-DM1 with tucatinib has promising clinical activity and antitumor responses, as well as a manageable safety profile [in HER2-positive disease],” lead study author Sara A. Hurvitz, MD, of Fred Hutchinson Cancer Center in Seattle, Washington, stated during a presentation of the data.

HER2CLIMB-02 enrolled patients with HER2-positive locally advanced or metastatic breast cancer whose disease had progressed following treatment with trastuzumab and a taxane in any setting. Patients were required to have an ECOG performance status (PS) of 1 or 0 and have previously treated stable, progressing, or untreated brain metastases that did not require immediate local therapy.

Patients were not eligible for enrollment if they had received prior tucatinib, afatinib (Gilotrif), fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), or any investigational EGFR inhibitors, HER2 inhibitors, or HER2-directed TKIs. Patients who had received prior lapatinib (Tykerb) and neratinib (Nerlynx) were not eligible for enrollment if they received these agents within 12 months of initiating the HER2CLIMB-02 regimen. Patients with prior lapatinib and neratinib exposure were permitted to enroll on the study provided they received the agents for no more than 21 days and discontinued the drugs for reasons other than disease progression or severe toxicity. Patients who had received prior pyrotinib for metastatic or recurrent breast cancer were ineligible.

Patients were stratified by line of treatment for metastatic disease (first line vs other), hormone receptor (HR) status (positive vs negative), presence or history of brain metastases (yes vs no), and ECOG PS (0 vs 1). In total, 460 patients were randomly assigned 1:1 to receive intravenous T-DM1 at 3.6 mg/kg plus either oral tucatinib at 300 mg or placebo administered twice daily.

The primary end point of this trial was investigator-assessed PFS per RECIST v1.1 criteria. Key hierarchical secondary end points included overall survival (OS), PFS in patients with brain metastases, confirmed overall response rate per RECIST v1.1 criteria, and OS in patients with brain metastases.

In the tucatinib arm (n = 228), patients had a median age of 55.0 years (range, 26-83), and 99.1% of patients were female. In total, 46.1%, 23.2%, and 30.7% of patients were from North America, Europe/Israel, and Asia-Pacific regions, respectively. Most patients had HR-positive disease (60.1%) and an ECOG PS of 0 (60.1%). Overall, 43.4% of patients had a presence or history of brain metastases, 21.9% of patients had active metastases, and 21.5% of patients had treated stable metastases. Most patients had stage 0 to III disease at diagnosis (52.6%), and patients had a median of 1 prior line of therapy in the metastatic setting (range, 0-8).

In the placebo arm (n = 235), patients had a median age of 53.0 years (range, 27-82), and all patients were female. In total, 39.6%, 32.8%, and 27.7% of patients were from North America, Europe/Israel, and Asia-Pacific regions, respectively. Most patients had HR-positive disease (59.6%) and an ECOG PS of 0 (60.0%). Overall, 44.7% of patients had a presence or history of brain metastases, 24.3% of patients had active metastases, and 20.4% of patients had treated stable metastases. Most patients had stage 0 to III disease at diagnosis (55.3%), and patients had a median of 1 prior line of therapy in the metastatic setting (range, 0-6).

At a median follow-up of 24.4 months and a data cutoff of June 29, 2023, 53% of the prespecified OS events had been observed. The interim OS data did not meet the prespecified crossing boundary of P less than or equal to .0041. Seventy-one and 63 OS events occurred in the tucatinib and placebo arms, respectively. The median OS was not reached (NR; 95% CI, NR-NR) in the tucatinib arm vs 38.0 months (95% CI, 31.5-NR) in the placebo arm (HR, 1.23; 95% CI, 0.87-1.74). Patients in both arms received comparable subsequent systemic therapies. Approximately 50% and 30% of patients received subsequent T-DXd or tucatinib, respectively.

Of the patients evaluable for safety in the tucatinib arm (n = 231), any-grade treatment-emergent adverse effects (TEAEs) occurred in 99.6%, TEAEs of grade 3 or higher were observed in 68.8%, and serious TEAEs occurred in 30.3%. Furthermore, treatment discontinuation due to TEAEs occurred in 17.3% and 20.3% of patients on tucatinib or T-DM1, respectively. TEAEs led to death in 1.3% of patients. The median duration of treatment was 7.4 months with tucatinib and 7.5 months with T-DM1. Increased alanine aminotransferase (ALT) led to tucatinib discontinuation in 2.6% of patients in this arm.

All patients evaluable for safety in the placebo arm (n = 233) experienced any-grade TEAEs. TEAEs of grade 3 or higher were observed in 41.2% of patients, and serious TEAEs occurred in 22.3%. Furthermore, 6.9% and 11.2% of patients discontinued placebo and T-DM1, respectively, because of TEAEs. TEAEs led to death in 2 patients. The median duration of treatment was 6.2 months for both placebo and T-DM1. No patients in this arm experienced discontinuation of placebo because of increased ALT.

The most common TEAEs leading to T-DM1 discontinuation were increased ALT (tucatinib arm, 2.2%; placebo arm, 0%), thrombocytopenia (2.2% vs 0.0%), and interstitial lung disease (0.0% vs 2.1%).

Overall, the most common TEAEs in the tucatinib arm were nausea (grade 1/2, 61.9%; grade ≥3, 3.5%), diarrhea (51.9%; 4.8%), fatigue (42.8%; 6.1%), vomiting (35.1%; 1.7%), increased aspartate aminotransferase (AST; 19.4%; 16.5%), increased ALT (18.1%; 16.5%), headache (34.6%; 1.3%), epistaxis (33.8%; 0.4%), decreased appetite (32.9%; 0.9%), constipation (25.9%; 0.9%), pyrexia (22.9%; 0.9%), and arthralgia 23.0%; 0.4%).

The most common TEAEs in the placebo arm were nausea (grade 1/2, 47.3%; grade ≥3, 2.1%), diarrhea (25.7%; 0.9%), fatigue (34.3%; 3.0%), vomiting (15.1%; 2.1%), increased AST (16.7%; 2.6%), increased ALT (14.6%; 2.6%), headache (38.2%; 0.9%), epistaxis (19.3%; 0.4%), decreased appetite (21.8%; 0.9%), constipation (32.6%; 0.4%), pyrexia (14.6%; 0.0%), and arthralgia 24.9%; 2.1%).

The most common TEAEs of grade 3 or higher in the tucatinib and placebo arms, respectively, were increased ALT (16.5% vs 2.6%), increased AST (16.5% vs 2.6%), anemia (8.2% vs 4.7%), thrombocytopenia (7.4% vs 2.1%), and fatigue (6.1% vs 3.0%).

“Looking closer at the hepatic TEAEs…increases in grade 3 or higher observed events in the tucatinib arm were driven by transaminase elevations,” Hurvitz noted. “The majority of these hepatic resolved or returned to grade 1, with a median of 22 days to resolution.”

“The types of AEs were consistent with previous reporting, and this is the second randomized study that included patients with brain metastases to demonstrate that a tucatinib-based regimen delays disease progression in this disease setting,” Hurvitz concluded.

Editor’s Note: Hurvitz reports grant/research support from Ambrx, Arvinas, Astra Zeneca, Bayer, Celcuity, Cytomx, Daiichi-Sankyo, Dantari, Dignitana, Genentech/Roche, Gi-Therapeutics, Gilead, Greenwich Life Sciences Inc, GSK, Immunomedics, Eli Lilly, Loxo, Macrogenics, Novartis, OBI Pharma, Orinove, Pfizer, Phoenix Molecular Designs, Ltd., Pieris, PUMA, Radius, Sanofi, Seagen, and Zymeworks; spouse stocks in RomTech; honoraria from Curio/Vaniam and OncLive; and additional financial relationships with DSMB: Alliance Foundation, Atossa, and Quantum Leap (PreI-SPY).

References

1. Hurvitz SA, Loi S, O’Shaughnessy J, et al. HER2CLIMB-02: primary analysis of a randomized, double-blind phase 3 trial of tucatinib and trastuzumab emtansine for previously treated HER2-positive metastatic breast cancer. Presented at: 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, Texas. Abstract GS01-10.
2. FDA approves first new drug under international collaboration, a treatment option for patients with HER2-Positive metastatic breast cancer. FDA. April 17, 2020. Accessed December 6, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-new-drug-under-international-collaboration-treatment-option-patients-her2
3. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382(7):597-609. doi:10.1056/NEJMoa1914609