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The ALTERNATE study discussed in a by Johnston et al. explores a regimen of lapatinib (LAP), trastuzumab (TRAS), and an aromatase inhibitor (AI) in HER2-positive and hormone receptor (HR)-positive metastatic breast cancer patients.

A similar chemotherapy-free regimen protocol was previously assessed with the PERTAIN trial, which evaluated the efficacy of a different HER2 and AI combination -- namely pertuzumab (PTZ), TRAS, and an AI. The strategy of using dual inhibition of HER2 and HR signaling to achieve tumor control has already been established as a useful strategy. Preclinical studies have shown that there is bidirectional cross talk between HR and HER2 signaling pathways that may lead to resistance if only one of these pathways is inhibited.

Dual HER2 inhibition is therefore valuable, especially in a setting where chemotherapy is being avoided.

The ALTERNATE study compared LAP plus TRAS plus AI, TRAS plus AI, and LAP plus AI. The triplet LAP-TRAS-AI had superior progression-free survival (PFS) compared with TRAS-AI (11 vs 5.6 months; HR 0.62, 95% CI 0.45-0.88, P=0.0063).

The LAP-AI arm was not found to be statistically better than TRAS plus AI with regards to median PFS (8.3 vs 5.6 months, HR 0.85, 95% CI 0.62 -1.17, P=0.3159). The benefit of a triplet regimen was seen across all predefined subgroups.

Adverse effects were mostly grade 1 and 2 across all arms and the LAP-TRAS-AI arm had a 13% reporting of grade 3 diarrhea, which was higher than in the other arms of the study.

The PERTAIN study evaluated HER2-positive HR-positive patients in a first-line metastatic setting randomized to PTZ plus TRAS plus AI or TRAS plus AI.

Median PFS was improved in PTZ-TRAS-AI arm compared with the TRAS-AI arm (18.9 vs 15.8 months, HR 0.65). The rate of grade 3 adverse effects in both arms were 50.4% and 38.5%, respectively. Diarrhea was seen in 55.1% of patients in the PTZ-TRAS-AI arm, and grade 3 diarrhea was seen in 7.1% of patients.

The ALTERNATE trial included patients who had prior TRAS plus chemotherapy in either the neo(adjuvant) setting or in the first-line metastatic setting. Two thirds of the patients had TRAS in the neo(adjuvant) setting and one third of the patients received TRAS plus chemotherapy in the first-line metastatic setting.

This was a difference from patients in the PERTAIN trial, where 77% of patients had not received prior TRAS. Also of note, 55% of patients in PERTAIN received induction chemotherapy.

In conclusion, the ALTERNATE trial regimen LAP-TRAS-AI joins the armamentarium, along with PTZ-TRAS-AI, as a feasible chemotherapy-sparing option for patients. The findings of these two trials provide an alternative to dual-HER2-regimen chemotherapy-based regimens by using hormonal blockade.

This would be a valuable option for patients who are ineligible to receive chemotherapy, as well as patients who would prefer a chemotherapy break. The unanswered question is which regimen has a superior efficacy and less side effects.

This is difficult to determine as the populations evaluated in both studies are different. Furthermore, we would need to tease out the role of LAP-TRAS-AI in the treatment paradigm when newer promising tyrosine kinase inhibitors such as tucatinib are entering the space.

Currently, the question of whether a chemotherapy-free regimen with dual HER2 inhibition and endocrine therapy is inferior to a chemotherapy-based dual HER2 inhibition regimen remains unanswered. Further studies are needed to identify specific patient characteristics that would enable us to pick a chemotherapy-sparing regimen without detriment to the patients -- for example, age, absence of visceral disease, extent of organ involvement, and time to metastatic disease diagnosis from original diagnosis.

This would be valuable information as we would be able to avoid the unnecessary toxicities of upfront chemotherapy in the appropriate patients.

Rosana Gnanajothy, MD, is a hematology-medical oncology attending physician at Columbia University in New York City and part-time assistant professor of medicine at Bassett Medical Center, Mary Imogene Bassett Hospital, in Cooperstown, New York.

Read the study here and an interview about it here.