Metastatic cancers harbor complex genomic alterations. Thus, monotherapies are often suboptimal. Individualized combinations are needed in order to attenuate resistance. To help inform selection of safe starting doses for novel, two-agent, targeted drug combinations, we identified clinical trials in adult oncology patients who received targeted drug doublets (PubMed, January 1, 2010 through December 31, 2013). The dose percentage was calculated for each drug: (safe dose in combination divided by single agent full dose) X 100. Additive dose percentage represented the sum of the dose percentage for each drug. A total of 144 studies (N = 8568 patients; 95 combinations) were analyzed. In 51% of trials, each of the two drugs could be administered at 100% of their full dose. The lowest safe additive dose percentage was 60% if targets and/or class of drugs overlapped, or in the presence of mTor inhibitors, which sometimes compromised the combination dose. If neither class nor target overlapped and if mTor inhibitors were absent, the lowest safe additive dose percentage was 143%. The current observations contribute to the knowledge base that informs safe starting doses for new combinations of targeted drugs in the context of clinical trials or practice, hence facilitating customized combination therapies.

Combining agents has the potential to attenuate resistance in metastatic cancer. However, knowledge of appropriate starting doses for novel drug combinations in clinical trials and practice is lacking. Analysis of 372 published studies was used to ascertain safe starting doses for doublets involving a cytotoxic and targeted agent. Phase I-III adult oncology clinical trial publications (January 1, 2010 to December 31, 2013) were identified (PubMed). The dose of drug used in each combination was compared to the single agent recommended dose [FDA-approved/recommended phase 2 dose (RP2D)/maximum tolerated dose (MTD)]. Dose percentages were calculated as: (safe dose of drug in combination/dose of drug as single agent at FDA/RP2D/MTD) × 100. Additive dose percentages were the sum of the dose percentage for each drug. A total of 24,326 patients (248 drug combinations) were analyzed. In 38% of studies, both drugs could be administered at 100% of their FDA-approved/RP2D/MTD dose. The lowest safe additive dose percentage was 41% with poly-ADP ribose polymerase (PARP) or histone deacetylase inhibitors as the targeted agents; 82%, in the absence of these agents; and 97%, with an antibody in the combination. If one drug was administered at 100% of the single agent dose, the lowest safe dose percentage for the second drug was 17% (cytotoxic at 100%) or 36% (targeted at 100%) of the FDA-approved/RP2D/MTD dose. The current findings can help inform safe starting doses for novel two-drug combinations (cytotoxic and targeted agents) in the context of clinical trials and practice.

The development of new HER2-directed therapies has resulted in a significant prolongation of survival for women with metastatic HER2-positive breast cancer. Discoveries in the laboratory inform clinical trials which are the basis for improving the standard of care and are also the backbone for quality improvement. Clinical trials can be completed more rapidly by expanding trial enrollment to community sites. In this article we review some of the challenges in treating metastatic breast cancer with HER2-directed therapies and our strategies for incorporating our community partners into the research network.