Table 2. Summary of Two Targeted Drugs in Combinationa.
| Second drug at 100% dose percentage of FDA-approved dose/RP2D/MTD | Lowest safe dose percentage of second drug if both are of the same class and/or have overlapping targets | Lowest additive dose percentage of the combination | |
|---|---|---|---|
| First drug at 100% dose percentage of FDA-approved dose/RP2D/MTDb | 61% of trials(74/121)(Note: 74 of the 144 total trials (51%) administered each drug at 100% dose) | 25% of FDA/RP2D/MTDc | 125% |
| First drug at 51-99% dose percentage of the FDA-approved dose/RP2D/MTD | Not applicable(13 total trials) | 29% of FDA/RP2D/MTDd | 104%d 143% (for non-overlapping targets and different classes)e |
| First drug at ≤ 50% dose percentage of the FDA-approved dose/RP2D/MTD | Not applicable(5 total trials) | 10% of FDA/RP2D/MTDf | 60% (overlapping targets in each case)f 90% (for non-overlapping targets, but both same class (small molecule inhibitors)g |
The five studies where no safe dose was found or study was aborted early due to unacceptable toxicity were excluded from this table and include: bevacizumab and sorafenib [28, 29], pazopanib and temsirolimus [27], bevacizumab and everolimus [31], and bevacizumab and temsirolimus [32]
First drug had the dose percentage closest to the FDA-approved/RP2D/MTD dose
In these cases, the combinations were same class (small molecule inhibitors) with non-overlapping targets (sorafenib at 100% with everolimus at 25%, and imatinib at 100% with everolimus at 25%) [12–14].
Sunitinib was at 75% and everolimus at 29% [20]
Rapamycin was at 93% and bevacizumab was at 50% [19]
Bevacizumab with vatalinib [26] and bevacizumab with telatinib [25] each included an anti-VEGF antibody and a small molecule VEGFR inhibitor (both at 10% and 50%, respectively)
Sorafenib was at 50% and temsirolimus at 40% [23]; however the combination of pazopanib and temsirolimus was above the FDA-approved/RP2D/MTD at an additive dose percentage of 65% (albeit with no acute or irreversible side effects and with the nonspecific side effect of fatigue as dose limiting in one patient).
Abbreviations: MTD = maximum tolerated dose; RP2D = recommended phase II dose