Independent drug action responsible for greater clinical efficacy of combination cancer therapies

According to the results of a retrospective analysis, the independent action of the drugs, and not synergy or additivity, explains the clinical effectiveness of almost all the therapeutic combinations examined involving immune checkpoint inhibitors in clinical trials.

Clinical cancer research, a journal of the American Association for Cancer Research (AACR).

The lead and corresponding author is Peter Sorger, PhD, professor of systems biology at Harvard Medical School. The first author is Adam Palmer, PhD.

Although immune checkpoint inhibition, a form of cancer immunotherapy, has significantly improved outcomes for some patients, most patients still do not benefit from this treatment. Combining immune checkpoint inhibitors with each other or with other cancer therapies has improved responses in many cases, leading to the approval of various combinations by the US Food and Drug Administration. United. However, the underlying reason for the greater clinical efficacy of combination therapies compared to single-agent immune checkpoint inhibition remains understudied.

Combination therapy dominates the cancer treatment landscape. So there’s huge interest in understanding why combination therapies work or don’t work for patients, and understanding how we can better design new combinations. »

Peter Sorger, Senior and Corresponding Author, PhD, Professor, Systems Biology, Harvard Medical School

In this study, Sorger, Palmer and their colleagues sought to determine whether the benefits of combination therapies resulted from the synergy of the drugs or were simply due to the independent action of the drugs, which Sorger described as “coverage bets”.

The concept of independent drug action was first introduced by Emil Frei in 1961 and has long been understood to occur in chemotherapy combinations. Sorger, Palmer and their colleagues explained this concept, its historical context and contemporary applications in a recent review article published in Discovery of cancer, another AACR journal.

“While a single drug might not be effective in killing all cancer cells in a heterogeneous tumor, drug combinations have the potential to kill different subsets of cells, improving the likelihood and durability of response. “, they wrote. “The same reasoning also applies to inter-patient heterogeneity: a single therapy will not be effective in all patients, but combination therapies provide patients with multiple opportunities for a clinically meaningful response.” Thus, when a combination acts through an independent drug action, the benefit for an individual patient is attributed to only one of the drugs in the combination; the benefit over monotherapy is due to the increased chance that the combination will include an effective drug for a given patient.

This mode of drug action contrasts with synergism, in which one drug enhances the clinical activity of another drug in the combination, and additivity, in which the clinical benefit is the sum of multiple drugs in the combination.

To determine whether independent drug action underlies the efficacy of combination therapies in oncology, researchers used a predictive model in a retrospective analysis of 13 clinical trials of combination therapies with immune checkpoint inhibitors representing eight different types of cancer.

“For each immunotherapy combination we examined, we used a probability model to calculate the expected progression-free survival distribution that would occur if the combination worked by independent drug action,” Palmer explained. “This expected distribution of independent drug action was then compared to the actual trial result.”

If the actual progression-free survival observed in the clinical trial was no different from the predicted benefit, then the authors concluded that the combination worked through independent drug action; if actual progression-free survival was significantly greater than predicted, then the benefit of the combination was due to synergy or additivity, he added.

Their analyzes revealed that the progression-free survival of patients receiving 12 of the 13 combinations evaluated was similar or shorter than the results predicted for the independent action of the drugs, suggesting that the benefit of these combinations was due to the independent action drugs rather than synergy or additivity. .

In the phase III IMpower150 trial, patients with metastatic non-small cell lung cancer who received first-line treatment with the immune checkpoint inhibitor atezolizumab plus chemotherapy and bevacizumab had a longer progression-free survival than would be expected with independent drug action, suggesting that this drug combination may have a synergistic or additive effect on clinical outcomes in this setting.

“Our study found that the efficacy of all but one of the combination therapies we analyzed occurred through independent drug action, not synergy or additivity,” Palmer summarized.

“To be clear, we are not suggesting that these combinations are ineffective. We agree that the combinations are clinically effective; what we are proposing is that their effectiveness is through a different mechanism than previously thought,” Sorger said. “These findings have important implications for preclinical and clinical research.”

Sorger suggested that instead of focusing on achieving drug synergy through interaction mechanisms, researchers should instead combine drugs known to be effective as a single agent in a given disease setting. “By combining two drugs that are each effective for certain patients with a disease, we can increase the chance that a patient’s cancer will respond to one of the drugs,” he explained.

Sorger added that the study results also indicate the need to better understand the variability of treatment response in patients and to identify biomarkers that could accurately predict a patient’s response to individual medications in a given setting. combination. For combinations working by drug-independent action, greater precision could lead to substantial improvements in clinical outcomes even with existing drugs, a notion supported by preclinical research, he explained.

Furthermore, the propensity for independent drug action in combination therapies suggests that administering drugs sequentially, rather than together, might reduce toxicities without affecting clinical efficacy. However, Palmer adds that in rapidly progressing cancer, it is often best to provide the best chance of tumor control from the outset by using a concurrent combination.