Marco Donia: Most combinations in oncology have additive but not synergistic efficacy

Marco Donia, Clinical Research Associate Professor at University of Copenhagen, shared on LinkedIn:

“Most combinations in oncology have additive but not synergistic efficacy. Published in Nature Cancer (free access link at the author’s page)

Haeun (Hannah) Hwangbo et al. showed that most combinations are as effective as expected from the efficacy of individual drugs (measured by increased progression-free survival, PFS).

My take home:
– if A+B (combination) is better than A alone or B alone because of additive efficacy, A–>B (sequencing at progression) may very well be as good as A + B
Very few trials investigated combination vs sequencing!

My main question:
– Is toxicity additive or synergistic?
If synergistic: most patients may be better off with A–>B
If additive: A+B may be a good strategy.

In melanoma, we have an excellent example (Checkmate-067 PFS, additive drug combination nr. 24 in the manuscript):
Nivolumab (A) + Ipilimumab (B) has better PFS, OS, and ORR than A alone (yes, not powered for that, nonetheless better) or B alone in unselected patients.
Toxicities of A+B seem at least additive (A+B= 58% grade 3-4 TRAE, vs A= 24% and B=28%).

This trial could not provide a clear answer to the question of whether A + B is better than A –> B for most patients (of course, it is pretty clear that for selected patients with e.g. CNS metastases, rapidly progressive disease, or high disease burden, A+ B is more effective – and probably also for patients with PD-L1<1%, as outlined by the European Medicines Agency, page 2 and page 41 of EMA’s smPC).

My learning:
In the legitimate search for new and more effective treatments, we should not forget to generate more data to optimize the use of existing drugs.”

For the article click here.
Source: Marco Donia/LinkedIn