ASCO 2014, Melanoma|May 31, 2014 9:27 am

Thoughts on combination therapies

Good morning it’s Day 1 of ASCO 2014 and it’s already a mad house.

The combo Phase 1 study of ipilimumab, dabrafenib (BRAF inhib) and trametinib (MEK inhib) has been presented. Interestingly, the doublet combination (Ipi plus Dab) did not show any significant, dose limiting toxicity (DLT), unlike the combo tested last year of Ipi and Vemurafenib. They are moving forward with an expanded cohort, ie more patients.

in contrast, the triplet combo of Ipi, Dab and Tram was NOT well tolerated, with 2/7 patients with life threatening colitis. This combo is therefore discarded.

Also, with the small numbers of patients, there are no conclusions that can be drawn about efficacy or tumor response.

However, this brings up a very interesting opportunity: the potential “combination” of drugs in sequence instead of concurrently or at the same time.

Classically, cancer treatment has evolved with combination therapies being very important. These are almost always concurrently given, adjusting the doses as needed for toxicity. I call this “more is better”.

But perhaps this trial will show that a more rational approach may be what I term “sequence and timing”, combining agents over time, in a predefined sequence without necessarily waiting for progression or response before changing therapies. This makes particular sense to me when you are talking about radically different mechanisms, such as immunotherapy and targeted therapy.

Also, as pointed out by the discussant, we don’t really know how these two types of drugs interact, by affecting either the target (immunogenicity of targeted therapy affected melanoma cells) or the immune system itself, particularly when combining immunotherapy with cytotoxic chemotherapy.

More to come, it’s not even lunch time.

Eric Whitman, MD

Senior Editor



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