Lapatinib/Trastuzumab/AI Triplet Nearly Doubles PFS in HER2+/HR+ Metastatic Breast Cancer

William J. Gradishar MD

The triplet combination of HER2-targeted therapy and an aromatase inhibitor (AI) improved progression-free survival (PFS) by more than 5 months compared with the combination of trastuzumab (Herceptin) and an AI in patients with HER2+/HR+ breast cancer.

In phase III results from the ALTERNATIVE trial presented at the 2017 ASCO Annual Meeting, the median PFS was 11 months (95% CI, 8.3-13.8) for postmenopausal women with HER2+/HR+ metastatic breast cancer assigned to lapatinib (Tykerb) plus trastuzumab plus an AI compared with 5.7 months (95% CI, 5.5-8.4) for patients assigned to trastuzumab plus an AI. Lead study author William J. Gradishar MD, interim chief of hematology and oncology at Northwestern University’s Feinberg School of Medicine, said that represented a 38% reduction in the risk of progression (HR, 0.62; 95% CI, 0.45-0.88; P = .0064).

“Lapatinib and trastuzumab with an aromatase inhibitor showed superior PFS compared to trastuzumab and an aromatase inhibitor in this population,” Gradishar said. “That effect was seen across all subgroups as well as numerically—there was an advantage in the other, secondary, endpoints of response rate and overall survival.

“Dual HER2 blockade with this triplet of lapatinib, trastuzumab and an AI can offer an effective and well-tolerated chemo-sparing option for patients who are not intended or appropriate for chemotherapy.”

In ALTERNATIVE, 355 women were randomly assigned to 1000 mg daily of lapatinib plus trastuzumab and an AI (n = 120), trastuzumab/AI (n = 117), or 1500 mg of daily lapatinib plus an AI (n = 118). Trastuzumab was administered at the standard dose and choice of AI was at the investigator’s discretion. Therapy continued until progression, toxicity, death, withdrawal, or investigator’s choice.

Patients were excluded from enrollment if they were appropriate for chemotherapy per investigator judgment. “Prior treatment with endocrine therapy in the neoadjuvant, adjuvant, and/or first-line metastatic settings was allowed, as was trastuzumab plus chemotherapy in similar settings,” said Gradishar.

Gradishar said investigators were surprised to discover that PFS in the lapatinib/AI group was superior to the trastuzumab/AI group, 8.3 versus 5.7 months (HR, 0.71; 95% CI, 0.51-0.98; P = .0361). He added that PFS favored the lapatinib groups across various patient subgroups, as well.

He also reported that there was no statistical difference in overall survival (OS) between the treatment groups, but there was a numerical trend favoring the lapatinib groups over the trastuzumab/AI group. Median OS was 46.0 months (HR, 0.60; 95% CI, 0.35-1.04; P = .070) in the lapatinib/trastuzumab/AI group, 45.1 months in the lapatinib/AI group (HR, 0.82; 95% CI, 0.49-1.36; P = .440), and 40 months in the trastuzumab/AI group.

Overall response rate (ORR) was 31.7% for the lapatinib/trastuzumab/AI group compared with 18.6% in the lapatinib/AI group and 13.7% in the trastuzumab/AI group.

While the overall incidence of adverse events (AEs) was high—92% in both lapatinib groups and 74% in the trastuzumab/AI group—Gradishar said incidence of AEs leading to discontinuation was low. Only 3% of patients in the lapatinib/trastuzumab/AI group left the study due to AEs, compared with 9% in the lapatinib/AI group, and 6% in the trastuzumab/AI group.

“On a more granular level, if one looks at the most frequent adverse events, diarrhea, rash, paronychia, and nausea were clearly more common in patients receiving lapatinib, either as part of the triplet or lapatinib and an AI compared to trastuzumab and an AI,” Gradishar said. “Grade 3/4 adverse events were notable in both treatment arms more commonly than they were in trastuzumab and an aromatase inhibitor, but these were in keeping with what has been seen in other lapatinib studies and were manageable.”

A total of 12 patients died while on-treatment, 9 due to progression. In the lapatinib/AI group, 1 patient died due to cardiogenic shock and another died of organ failure. One patient in the trastuzumab/AI group died of cardiopulmonary arrest.

Fourteen percent of patients in the lapatinib/trastuzumab/AI group experienced serious AEs, compared with 17% in the lapatinib/AI group and 10% in the trastuzumab/AI group. Those numbers dropped to 5%, 4% and 2%, respectively, for treatment-related serious AEs.

Roughly one-third of patients in the lapatinib groups experienced grade 3/4 AEs compared with 22% in the trastuzumab/AI group.

In the lapatinib/trastuzumab/AI group, 34% of patients experienced grade 3/4 AEs, primarily diarrhea (13%). In the lapatinib/AI group, 32% of patients experienced grade 3/4 AEs, and, again, diarrhea was the most common (6%). Twenty-two percent of patients in the trastuzumab/AI group experienced serious AEs, with ALT and AST increases being the most common (4% each).

Gardishar WJ, Hegg R, Im S, et al. Phase III study of lapatinib (L) plus trastuzumab (T) and aromatase inhibitor (AI) vs T+AI vs L+AI in postmenopausal women (PMW) with HER2+, HR+ metastatic breast cancer (MBC): ALTERNATIVE. J Clin Oncol 35, 2017 (suppl; abstr 1004).