Malignant by Vinayak K. Prasad

Author:Vinayak K. Prasad
Language: eng
Format: epub
Publisher: Johns Hopkins University Press
Published: 2020-09-02T16:00:00+00:00

Responses That Go Nowhere

In chapter 13, I make the case that single agent activity, that is, the ability to shrink tumors, should be the general prerequisite for moving forward in drug development. Not producing responses means a drug is unlikely to greatly benefit patients, but merely having responses is no guarantee of a successful drug. Consider the case of two recent drugs.

Brivanib was once a promising drug for liver cancer. In a study of 55 people who received brivanib, four patients (7%) had responses and 24 (44%) had stable disease.21 Stable disease only means that the disease had not progressed. When you give a drug to patients who have been chosen for a clinical trial, who are often exceptionally fit, and you don’t have a group of patients to compare them against, stable disease is the most useless thing in the world. You have no idea whether stable disease is because the drug slows tumor growth or because you just picked people who are progressing slowly. Regardless, a 7% response rate, although low, was better than some successful drugs in this space. Sorafenib had a 2% response rate and ended up getting approved.22

At least four phase 3 trials of brigatinib were attempted, further bolstering the point that drug companies have huge incentive to pursue drugs. The first trial randomized over a thousand patients to either the drug or sorafenib (the current standard of care). In that trial, overall survival was not non-inferior (pardon the double negative).23 That double negative essentially means overall survival was worse with brivanib, which means do not pass go, do not collect $200, and back to the drawing board. The second trial tested the drug against placebo, among patients whose tumors had progressed on sorafenib. It was also a negative trial, finding no survival benefit.23 The third trial was like the second trial but in Asian patients, and it was stopped by the company.24 The fourth trial tested brivanib after local treatment for liver cancer, which ended early after the first three negative trials. The results at that time showed no benefit.25

Unlike brivanib, which never made it to the US market, atezolizumab (Tecentriq, Genentech) did receive accelerated approval in May 2016 for second-line bladder cancer. Atezolizumab is one of those new, sexy checkpoint inhibitor drugs that you may have seen a TV commercial about. Atezolizumab got approved based on response rate in a small trial with no control arm. The response rate was modest, just 14.8%,26 but it was something, and frankly we did not have a lot of options to treat bladder cancer after it progressed on initial therapy.

However, it wasn’t long before more sobering results came forward. Proving a drug has a response is proving it has activity against cancer. It is not the same as proving it benefits patients. To prove that a drug benefits patients, you have to show it improves survival or quality of life beyond the best available therapies. To test atezolizumab, a randomized trial was performed. That trial randomized patients to atezolizumab or an older chemotherapy drug picked by the doctor.

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