Immuno-oncology combinations surge as sector seeks the fairy dust

When in November 2015 EP Vantage published its first immuno-oncology analysis we identified 215 studies of anti-PD-1/PD-L1 projects combined with other approaches, and called this an important industry theme. It is a measure of how central combos have become that today, barely 18 months on, that total has been blown out of the water.

No fewer than 765 studies involving combinations of PD-1 or PD-L1 assets are now listed on the Clinicaltrials.gov registry. This is the top-line finding of our report published today, which aims to quantify how many combination trials are ongoing with which assets and in which cancer indications, as well as suggesting reasons why some of the most popular approaches are being pursued (see charts below).

The surge in combo studies over the past 18 months has come across the board, but the biggest increase has been seen with Keytruda. Combinations involving Merck & Co’s anti-PD-1 MAb have spiralled from 70 to 268, and the drug has overtaken Bristol-Myers Squibb’s Opdivo to stand today as the most extensively combined PD-1/PD-L1 agent.

The most prolific combination grouping we found were studies of PD-(L)1-targeting assets combined with other monoclonal antibodies or immuno-oncology agents. Within this, the most popular combinations involve Opdivo plus Yervoy, and Imfinzi plus tremelimumab.

The study of anti-PD-(L)1 assets combined with small molecules is also receiving a lot of interest. However efforts to add checkpoint blockade to traditional chemotherapy or radiotherapy is one of the most important themes to emerge over the past year or so, our report concludes.

There is a clear scientific rationale for this approach, in that chemotherapy can potentiate immune function, as well as releasing cancer cells as the tumour is attacked. This is speculated by some to result in something akin to a vaccine effect, yielding antigens for the immune system to act against.

Indeed a sharp increase over the past 18 months of PD-(L)1 combinations involving cancer vaccines and oncolytic viruses is one of the most striking observations of our research.

Indication-wise, it is perhaps not surprising to see major combination efforts in melanoma and NSCLC. Melanoma is the first and to date most impressive setting for immuno-oncology, and major efforts are under way to expand the reach of novel drugs beyond a subgroup of strongly responding patients.

Given the speed with which immuno-oncology combination studies have proliferated, and the transformational, blockbuster potential of the anti-PD-(L)1 class, there is little to suggest a slowdown in this field.

However, the focus will increasingly turn from throwing everything into a combination and seeing what sticks to generating real data. The Asco meeting starting this weekend will serve as a platform for the IDO plus PD-(L)1 approach, for instance, and this has already featured extensively at scientific meetings such as Esmo last year.

That said, investors and biotech companies are likely to remain most interested in the discovery and development of novel immuno-oncology agents. And it will be vital to generate more evidence to back the idea of synergy; until then the addition of PD-(L)1 to everything will seem like the optimistic sprinkling of fairy dust in the hope of making a mediocre pharmacological approach stronger.

A full version of this report can be downloaded here.

Our reporters will be on the ground at Asco in Chicago this weekend. Follow @JacobPlieth or @ByJonGardner on Twitter to keep up with our coverage.