The Lynx Group

Can FDA Drug Approval Keep Pace with Translational Research?

November 2013, Vol 4, No 9

Amsterdam, The Netherlands—With the development of targeted therapies, there has been a clear evolution in the pathway to the approval of drugs by the US Food and Drug Administration (FDA), and a rapid approval of a drug after phase 1 clinical trials, which show definitive proof of activity and safety, and “breakthrough” designation, are now possible.

“We are ready for a significant acceleration in the pace of drug approvals,” said Bruce A. Chabner, MD, Professor, Department of Medicine, Harvard Medical School, Boston, who described the new FDA approval algorithm at the 2013 European Cancer Congress.

Accelerated FDA Approval

The possibility of faster drug approval started with the targeted drug trastuzumab (Herceptin) around 2000. Because targeted molecular agents are directed at treating the patients who are the most likely to benefit, activity emerges early in the trial process, making it probable that the drug will show benefit in later-phase trials.

Between 2003 and 2010, some 15 targeted agents received accelerated FDA approval, although not all panned out in the long-run: 2 ultimately failed—gefitinib (Iressa) proved ineffective in the third-line treatment of unselected patients with non–small-cell lung cancer (NSCLC) “in a poorly designed trial,” Dr Chabner said, and bevaciz­umab (Avastin) failed in the first-line setting of HER2-negative breast cancer.

Changing the Paradigm: “Breakthrough Therapy” Designation

The value of accelerated drug approval was shown with the “game-changing” drug crizotinib (Xalkori) in patients with EML4 ALK-positive NSCLC. Approximately 4% of patients have the ALK translocation, and crizotinib showed striking results in this subpopulation. “Virtually all patients experienced tumor shrinkage, lasting about 8 months on average,” Dr Chabner said. “This is remarkable in the context of NSCLC.” Accelerated approval was granted within 3 years of development, based on phase 1 and phase 2 trials.

Crizotinib was also effective in patients with the rare ROS1 kinase mutation, which is confined to 1% of patients with NSCLC. In a phase 1 study of 35 ROS1-positive patients, the overall response rate was 60%, and 80% of the patients achieved disease control; these results will likely lead to FDA approval of crizotinib for this subset of patients, Dr Chabner predicted.

Crizotinib is a good example of how the drug approval process must change to meet the needs of ever-smaller patient subpopulations, he said. The ability of crizotinib to show such clear efficacy in phase 1 trials triggered a change and opened the door to drug approvals after phase 1 trials when “the evidence is sufficient,” Dr Chabner said.

In 2012, Congress established the breakthrough therapy designation to expedite access to drugs that show substantial improvement on a clinical end point or improved safety compared with available therapies. The designation creates an early and intensive FDA guidance during the drug development process, a rolling New Drug Application (NDA) process, and an expedited development and review.

Since 2012, the FDA has received 64 breakthrough therapy designation requests; 21 were granted, 22 are under consideration, and 21 were denied.

“Breakthrough” Cancer Drugs in the Pipeline

The list of current cancer drugs designated as “breakthrough therapy” includes 2 “new and better” ALK inhibitors, Dr Chabner said, a Bruton’s tyrosine kinase (BTK) inhibitor for hematologic malignancies, a cyclin-dependent kinase (CDK) 4/5 inhibitor for breast cancer, and a programmed death (PD)-1 inhibitor for solid tumors.

LDK378, the drug most likely to be approved first on this list, is a potent and selective oral ALK inhibitor that provides durable responses in mouse models, including models of crizotinib resistance. In a study of 78 patients, the overall response rate was 60%, with no differences among patients who had received or were naïve to crizotinib therapy. Only 2 patients discontinued the drug, because of adverse events.

“These are quite impressive results,” Dr Chabner noted. “Virtually all patients have tumor regression, both in previously treated and untreated groups.”

An NDA for LDK378 has been submitted, confirmatory phase 2 studies are recruiting, and phase 3 studies are planned with LDK378 versus chemotherapy in previously crizotinib-treated and untreated patients.

“My hope is that patients will not be denied the better drug for the sake of testing it versus chemotherapy,” Dr Chabner commented.

To date, more than 500 patients have received LDK378. Although fewer patients have used AF802, the other ALK inhibitor with a breakthrough therapy designation, this is also a very promising agent that is active in crizotinib-naïve and previously treated patients, Dr Chabner said.

Because most patients with ALK-positive NSCLC develop resistance to crizotinib within 2 years, these new, potent ALK inhibitors will be important. Both drugs are also active in patients with brain metastases, and visual abnormalities are less frequent than with crizotinib.

The BTK inhibitor ibrutinib has been studied in chronic lymphocytic leukemia, Waldenström’s macroglobulinemia, and in non-Hodgkin lymphoma (NHL), with a 90% progression-free survival rate seen in patients with NHL. Palbociclib, the CDK 4/5 inhibitor, is active in metastatic breast cancer, and lambrolizumab, the PD-1 inhibitor, is active in renal and lung cancers and melanoma.

“These are important new compounds that are producing significant responses and clinical benefits in difficult-to-treat situations. They are likely to get accelerated approval,” Dr Chabner predicted.

“Indeed, the pace of FDA approvals in cancer is accelerating,” he said. In 2011, there were 15 approvals, with 2 accelerated approvals, and 8 drugs were new chemical entities. In 2012, there were 23 cancer drug approvals, 5 accelerated approvals, and 12 new chemical entities. The pace has continued in 2013, with several accelerated approvals.

Dr Chabner suggested that accelerated approvals will only increase. “If you do a trial well and have good patient selection, getting rapid approval after phase 1 trials is very likely,” he concluded.

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