Published June 4, 2014 By Dr. Susan Love

Usually I come home from the American Society of Clinical Oncology annual meeting mulling over data on new drugs or new treatment combinations that promise better outcomes. And while there are certainly a lot of new drugs in the pipeline as seen in the exhibit hall (see my AACR blog for some examples), I’m also seeing evidence that in some cases less may actually be more. The first example of “less is more” that I saw is in the findings from the ALLTO study, which is looking at whether using two HER2-targeted therapies—a so-called dual blockade—to treat HER2-positive tumors is more effective than using just one. The ALLTO study randomized 8,381 women in 44 countries to receive trastuzumab (Herceptin) and lapatinib (Tykerb), Herceptin followed by Tykerb, Herceptin alone, or Tykerb alone. Depending on the type of chemotherapy used, the HER2 targeted therapies were given along with or following chemotherapy. (In August 2011, the Tykerb alone arm was stopped because it was found to not be as effective as Herceptin.) Before starting the ALLTO trial, the effectiveness of the Tykerb and Herceptin combination was studied by giving it to women before surgery in a trial called NeoALLTO.Treatment given before surgery is referred to as neoadjuvant therapy. Researchers have been using the time before surgery—the neoadjuvant setting—to test new drugs and new drug combinations in women with large tumors because it allows them to study whether the treatment shrinks the tumor or makes it disappear. When it was tested in the neoadjuvant setting, the dual blockade of Herceptin and Tykerb was more effective at shrinking the tumors than either drug alone. But here at ASCO, we learned that in the adjuvant (after surgery) setting this was not the case: Using Tykerb and Herceptin together did not improve disease-free survival or overall survival. The combination was only as effective as using Herceptin alone. This study is important for two reasons.  First, it shows that more is not necessarily better. Second, it brings into question whether the current practice of using neoadjuvant response as a surrogate for large clinical trial results is always predictive.  Watch this space to see if this mismatch where this combination of  drugs  worked in one setting but not the other is the exception or the norm. The second example I saw of less is more was in the OPTIMIZE-2 trial. This study included 403 patients with breast cancer and bone metastases. All of them had already received monthly doses of an IV bisphosphonate for a year or longer. Half of the women received 4 mg infusions of zoledronic acid (Zometa) once every 4 weeks. The other half received 4 mg infusions of Zometa every 12 weeks. The study found that the risk of further bone problems was 23% when the drug was given every 12 weeks and 22% when it was given every 4 weeks.  In other words, there was no difference! This is important because not only is it more convenient for women with metastatic breast cancer to receive an infusion every 12 weeks, but it may also mean they are less likely to develop side effects like osteonecrosis of the jaw.

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