Combinatorial Therapies: Bringing in Biologics
A 2014 forecast would not be complete without considering new combinatorial therapies for cancer. The year began with an accelerated approval for treating certain metastatic melanomas with a combination of two molecules (trametinib and dabrafenib) that target the MEK and BRAF kinases.
However, unlike most kinase inhibitors, many of today’s drugs are large molecule- or cell-based biotherapeutics such as monoclonal antibodies (mAbs), cancer vaccines, and adoptive immunotherapies, and combining these drugs poses unique regulatory and therapeutic challenges. In the following months, we may see reports from more trials currently underway for biotherapeutic combinations: nivolumab plus ipilimumab (dual blockade of two immune system checkpoints), nivolumab plus an anti-LAG3 antibody, bevacizumab plus ipilimumab (angiogenesis inhibition with immunomodulation), and vemurafenib plus ipilimumab (BRAF kinase inhibition plus immunomodulation).
Regulatory agencies do recognize that combining biotherapeutics holds enormous potential for treating even the most heterogeneous and refractory of cancers. In 2013, the FDA approved the combination of pertuzumab and trastuzumab, two HER2-specific mAbs, for treating breast cancer in combination with chemotherapy. However, challenges to combining biotherapeutics include differential dosing and effects on immunogenicity, toxicity, and pharmacokinetics/pharmacodyamics, not to mention the challenges of regulating co-manufacture and co-packaging. Furthermore, traditional endpoints used to measure efficacy may not be sufficient to determine whether combinations of biotherapeutics, especially immunotherapies, are efficacious.
Ke Liu of the U.S. FDA, in a panel discussion at October’s Molecular Targets and Cancer Therapeutics conference, proposed applying the guidance regarding combinations of small molecule drugs to combinations of biologics and working with drug developers to establish better biomarkers for toxicity, PK/PD, and immunotherapeutic efficacy. We hope that 2014 brings progress toward some of these goals, bringing new combinatorial biotherapeutics closer to widespread clinical use.