Figure 7. When sensitivity to different drugs varies between patients, independent drug action is expected to confer clinical benefit and pharmacological additivity or synergy may have limited effect. A.

Superior responses to combination therapy versus monotherapy have two possible explanations: two drugs could act together with additivity or synergy to induce stronger responses in individuals; or two drugs could improve the response distribution solely by independent action because some tumors are sensitive to the first drug and some other tumors more sensitive to the second drug. B. Wide variation in drug response, and low correlation in responsiveness to different drugs, predicts that most patients will benefit from combination therapy because of independent drug action. Each circle represents a tumor, with intensity of blue or red color indicating strength of response to each of two drugs. Most tumors primarily respond to one drug or neither. Additivity or synergy, if present, might be evident only in a minority of patients with partial response to each drug (yellow region). C. In situations with high response rates, more patients might experience synergistic benefit from two strong responses. D. In situations where responses to two drugs are highly correlated, as may occur with similar mechanisms of action, benefit may be more dependent on additive or synergistic effect.