Contributed Commentary By Stephen Gately

October 25, 2018 | You’d be hard-pressed to peruse the NIH’s clinical trial database without finding a combination clinical trial that includes an immunotherapeutic agent. Last December, Nature reported that more than 400 combination trials launched in the first half of 2017—with a thousand more ongoing.

You can’t blame researchers for jumping on the “combination bandwagon.” The market is ripe for such opportunities. Immunotherapies (especially checkpoint inhibitors) have shown great promise for patients, and consequently, have become common knowledge even to those outside the medical field.

The growing evidence of clinical activity for immunotherapies makes them an attractive combination choice for companies with new cancer medicines who may also be seeking capital investments. Perhaps standing on the shoulders of the giants is one way to get noticed?

Not quite. The problem with that view is that drugs can’t ride the coattails of immunomodulation without a good amount of scientific consideration.

Combination strategies can work; pembrolizumab with chemotherapy earned approval in May 2017 for patients with non-small-cell lung cancer. But such pairings have to be thoroughly vetted to make sure the combinations make sense in the clinic—not just perception in the market.

To find out for yourself, ask a series of questions to tease out the goals, opportunities, and challenges of combination-based research:

1. In addition to killing cancer, does your drug also kill immune cells?

If it does, it’s not going to work with an immunotherapy drug. That’s just basic science and a simple experimental check that sadly gets lost in all the enthusiasm around combination therapy. You’d be surprised at how many people progress compounds without asking this fundamental question.

If you add your drug into a petri dish and human immune cells like cytotoxic T-cells are killed, there’s no way your drug will work when combined with an immune checkpoint inhibitor. It’s just a costly and counterproductive avenue that won’t benefit patients.

2. How will the combination impact toxicity?

Most people think that checkpoint inhibitors are easier to take than cytotoxic therapies, but that’s not always the case—especially given potential side effects, such as an activated immune system that may also attack normal tissue.

Murine studies alone have not been predictive in determining additive toxicity. Left unchecked, that risk carries through to the clinic—where you may have increased anticancer activity from the combination, but you’ve made the side effect profile worse for patients.

That’s what happened with the FDA-approved combination of two checkpoints, nivolumab with ipilimumab, which showed extended survival at the price of higher toxicity—nearly 6 in 10 patients had serious side effects, which was at least twice as many as each drug caused alone.

It’s a double-edged sword, but you have to do due diligence through nonclinical and clinical research to evaluate for unacceptable toxicity risks when adding a new medicine with an immune checkpoint inhibitor—instead of just assuming there won’t be any.

3. How will the combination impact scheduling of drug administration?

You can’t alter the dose or frequency of an FDA-approved checkpoint inhibitor—but you can (and should) evaluate how that schedule of administration fits into the combination with your drug. It is important to test the combination using a regimen that offers the greatest opportunity to demonstrate clinical benefit for the new medicine. 

A common problem is that researchers alter the schedule of the new medicine to that of the immune checkpoint inhibitor at the expense of giving their own drug the best opportunity to succeed. Don’t compromise the activity of your drug to fit within an existing regimen. If you have to give it daily, give it daily. But consider how the schedule impacts each drug’s dose, frequency, and activity.

4. Are you doing the right clinical trial?

For a well-grounded combination study poised for success, you have to run a randomized, controlled study of the combination versus the single agent approved drug. Too often, researchers conduct open-label studies of the combination and compare that result with historical performance for the checkpoint inhibitor alone. This can lead to overestimating the combination’s benefit which could be markedly diminished in subsequent randomized, larger, and more expensive trials. Do the right clinical trial first before discovering the combination is no better than the single agent alone.

5. What’s the end game?

Before moving forward with a combination therapy, consider the finish line. What does the approval trial look like for the combination? Researchers need to be thoughtful about what exactly they plan to do (and can do) for an approval—from the feasibility of enrollment to the costs of running a trial at the size and scope the circumstances require. 

Combine Cautiously

Everyone wants to be part of immunotherapy’s success story—as well they should: It’s a compelling one, and multipronged attacks are important. But to get there, researchers must ground their efforts with strategy and science—rather than just taking every drug hopeful and pairing it with a checkpoint inhibitor.

You need a good scientific story, but even more than that, you need to check your enthusiasm at the door and go with what the research tells you, rather than the market. By all means combine, but combine with caution.

Dr. Stephen Gately is president and Chief Executive Officer at TD2, an oncology-focused drug development organization. He obtained his Ph.D. from McGill University in the Department of Neurology and Neurosurgery at the Montreal Neurological Institute and Hospital. He can be reached at sgately@td2inc.com.