Posted on December 12, 2013

By Karuna Jaggar, Executive Director

This year at SABCS we’ve gotten some updates on HER2+ drug trials that have presented in years past, and researchers now have more mature data. HER2+ breast cancers account for 20-30% of breast cancer diagnoses.

The first trial reported on, Neo-ALTTO, looks at whether adding Lapatinib to Trastuzumab (Herceptin) is beneficial to patients. Lapatanib is another HER2 antagonist. The study design asks whether the incremental gain in pathological complete response (pCR) observed with dual HER2 blockade translates into improved event-free survival (EFS) and overall survival (OS).

pCR means that the tumor has completely disappeared from the breast and lymph nodes. pCR is used as a surrogate endpoint after an FDA meta-analysis showed that pCR is linked to longer overall survival. We have to be very careful with this approach, which has not been shown to be true for ER+ cancers.

In the Neo-ALTTO study, presented by Dr. Martine Piccart-Gebhart, patients who achieved pCR had significantly better event-free survival and overall survival, irrespective of the treatment arm they were in. At approximately a four-year median follow-up, dual HER2 blockade appears to provide better pCR, EFS, and OS benefit for patients with HER2+ hormone- tumors. Overall survival was improved for patients experiencing pCR, with a 60% reduction in mortality. HR negative tumors are the greatest responders, but researchers didn’t see the same impact on ER+ with statistical significance. These are slower-growing tumors that can have late recurrences, so it’s possible they’ve not had enough time to see whether there is a similar benefit.

It is always important to balance potential benefit with safety analysis and quality of life for patients. Most common side effects women experienced include diarrhea, liver enzymes, and rash. One in four patients taking lapatinib in the trial experienced severe diarrhea and patients on the trastuzumab experienced significantly fewer side effects compared with the combination and Lapatinib arms. Indeed, only 2/3rds of patients were able to complete treatment of lapatinib in both phases. In contrast, 90% of patients on the trastuzumab completed their treatment in the neoadjuvant phase, with 80% completing the treatment in the adjuvant phase.

The second Her2+ study, TRIO-US B07, was presented by Dr. Sarah Hurvitz, who shared the final analysis of a Phase II three-arm randomized trial. Because this is only a Phase II trial (drugs don’t come to market until Phase III), I will not discuss this study other than to say I am pleased that there will be an analysis of patients who did not get pCR.

The third trial, the BETH trial, presented by Dr. Dennis Slamon, was a negative trial in that it failed to show any benefit to patients from adding Avastin (bevestuzumab) after surgery for HER2+ tumors. The study compared invasive disease-free survival in patients treated with chemo and Herceptin versus chemo and Herceptin with the addition of bevacizumab (Avastin). After 38 months, 92% of patients had disease free survival for both trial arms—somewhat of a surprise that it was so high. The main difference was in cardiac adverse events, including hypertension—so no benefit for patients, just harm in adding Avastin, based on this evidence.