Missing the target in cancer therapy

Abstract

The deployment of molecular biomarkers that are indicative of sensitivity to tumor-targeted or immune-targeted cancer therapies improves the outcome of individual patients and increases the chances of successful drug approval. However, for many lethal malignancies, the majority of clinical trials are conducted with patients who do not have biomarkers and hence they miss the target.

Fig. 1 |. Example of responders versus non-responders among hypothetical patients with cancer of unknown primary and lung metastases.

a, A patient with cancer and mutations in the gene encoding B who is enrolled in a clinical trial of a B inhibitor that required an alteration in the gene encoding B for trial entry. The patient would be expected to respond to the B inhibitor. b, A patient with cancer and mutations in genes encoding A, B and C who is enrolled in a clinical trial of a B inhibitor that required an alteration in the gene encoding B for trial entry. The patient may respond or may show primary or secondary resistance to the B inhibitor because of the concomitant presence of mutations in the genes encoding A and C. c, A patient with cancer with mutations in genes encoding X and Z who is enrolled in a clinical trial of a B inhibitor (because the trial has no biomarker selection criteria). It would be expected that the tumor would be resistant.