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The dual HER2-targeting combination of lapatinib (Tykerb) and trastuzumab (Herceptin) plus an aromatase inhibitor (AI) was a safe and effective chemotherapy-sparing regimen for postmenopausal women with HER2-positive/HR-positive metastatic breast cancer who had received prior endocrine therapy and prior neo(adjuvant)/first-line trastuzumab plus chemotherapy, researchers reported.

William Gradishar, MD, of Robert H. Lurie Comprehensive Cancer Center at Northwestern University in Chicago, and colleagues recently reported results of the ALTERNATIVE trial in the The results were originally published in 2017, but the new version corrected some statistical errors.

The ALTERNATIVE trial randomized patients to one of three arms: lapatinib+trastuzumab+AI, trastuzumab+AI, and lapatinib+AI.

The study met its primary endpoint in that superior progression-free survival (PFS) was observed with lapatinib+trastuzumab+AI versus trastuzumab+AI (median PFS 11 months vs 5.6 months; HR 0.62, 95% CI 0.45-0.88, P=0.0063). The benefit was seen across predefined subgroups.

"Not all patients with HER2-positive/HR-positive metastatic breast cancer may need or tolerate chemotherapy, and these patients could be candidates for anti-HER2 therapies plus endocrine therapy," the researchers wrote.

In the following interview, Gradishar, who is chief of hematology and oncology and holder of the Betsy Bramsen Professorship of Breast Oncology, discussed the details of the trial.

How was the ALTERNATIVE trial unique?

Gradishar: It was a non-chemotherapy approach for ER+/HER2+ metastatic breast cancer reaffirming that a dual HER2-targeting approach (lapatinib/trastuzumab) with endocrine therapy was superior to monotherapy HER2-targeting along with endocrine.

Progression-free survival was superior for the dual targeting group compared with either lapatinib or trastuzumab combined with an aromatase inhibitor, with the primary comparison between AI plus trastuzumab/lapatinib vs AI/trastuzumab.

You also observed benefits in secondary endpoints. Can you tell us about this?

Gradishar: Response rate, duration of response, and clinical benefit rates were all numerically greater and clinically relevant for the dual HER2-targeting treatment arm.

What did the study find for patients in the third arm, those who received lapatinib+AI?

Gradishar: AI plus TKI (lapatinib) was the least effective as measured by any of the above endpoints, suggesting that a [monoclonal antibody] approach is superior to monotherapy with a TKI combined with endocrine therapy.

Since the initial publication of the results, has this chemo-sparing therapeutic option become more widely used?

Gradishar: The use of this regimen has not changed since publication, largely because of other agents that are used in preference to lapatinib.

In select patients chemotherapy can be avoided where there is concern with tolerance, but the survival advantage seen with the regimen containing chemotherapy and dual HER2-targeting with trastuzumab and pertuzumab remains a standard of care.

Read the study here and expert commentary about the clinical implications here.