Although combination treatments that include immune checkpoint inhibitors (ICIs) often demonstrate efficacy in clinical trials, that effect may be due to independent drug action rather than synergistic or additive effects, according to a study published in Clinical Cancer Research.

The study showed no evidence of drug synergy or an additive effect in 12 of 13 phase 3 trials testing ICI combination therapies in various cancers. 

“Combination therapy dominates the treatment landscape for cancer,” said study author Peter Sorger, PhD, of Harvard Medical School in Boston. “There is enormous interest in understanding why combination therapies work or don’t work for patients, and in understanding how we can better design new combinations.”

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With this goal in mind, Dr Sorger and colleagues analyzed data from 13 trials testing ICI combination therapies in patients with lung, breast, gastric, kidney, or head and neck cancers as well as melanoma.

Using a probability model, the researchers calculated the expected progression-free-survival (PFS) if the combination therapies worked through independent drug action.

In all but 1 study, this modelling corresponded well to the actual trial results. This suggests that, in many cases, benefits to patients likely came from independent drug action, not synergy or additivity.

The only trial with a PFS suggesting synergy or additivity was the phase 3 IMpower150 trial ( Identifier: NCT02366143). This study was designed to compare chemotherapy plus bevacizumab with atezolizumab plus chemotherapy, with or without bevacizumab, in previously untreated patients with stage IV non-small cell lung cancer. 

Implications and Future Directions

The researchers emphasized that their findings do not mean ICI combination therapies are useless. The team noted that even if a patient only derives benefit from part of a combination, there may be an advantage over monotherapy simply by increasing the chance that the patient will be given a drug that elicits a response. The researchers called this “bet hedging.”

“There are a lot of cases where meaningful improvements for populations have been achieved by a drug being helpful for a small fraction of patients,” said study author Adam Palmer, PhD, of the University of North Carolina at Chapel Hill.

“But if a standard of care therapy has a 50% response rate, and you add a drug to it, and it goes up to a 60% response rate, that doesn’t mean that new drug was beneficial for 60% of patients,” Dr Palmer explained.

The “bet hedging” strategy does come with drawbacks as well, the researchers acknowledged. If patients are only benefiting from part of a combination treatment, they may be enduring toxicities of therapies that don’t benefit them.

The researchers suggested that administering drugs sequentially in some cases — rather than together — might be a way of reducing toxicities without reducing clinical efficacy. However, with aggressive and quickly progressing cancers, the researchers agreed that combination therapies provide the greatest chance of controlling the disease.

“Ideally, we need to much more precisely understand how an individual patient — not a population of patients — can benefit from multiple drugs given at once,” Dr Sorger said. “The long-term vision is more biomarkers and much more personalization.”

“Genomics is going to have a big impact, but there’s a whole series of other things that should be done too, and one of the most important is pharmacokinetics, as well as immune profiling and tissue profiling,” he added. “Since we often biopsy patients, particularly in more advanced cancer centers, we ought to measure whether those patients are responding individually to the drugs and the combination.”

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Palmer AC, Izar B, Hwangbo H, Sorger PK. Predictable clinical benefits without synergy in trials of combination therapies with immune checkpoint inhibitors. Clin Cancer Res. 2022;28(2):368-377. doi:10.1158/1078-0432.CCR-21-2275

This article originally appeared on Cancer Therapy Advisor