Cancer Drugs Approved as Breakthrough Therapies Have Comparable Clinical Benefit to Those Approved Under FDA’s Standard Regulatory Pathway

The following article features coverage from the American Society of Clinical Oncology 2019 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

Cancer drugs approved with a breakthrough therapy designation may be more or equally likely to demonstrate high clinical benefit compared with non-breakthrough therapy drugs, according to research presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.¹

In the study, the authors set out to compare the characteristics and outcomes of clinical trials that support approval of breakthrough- and non-breakthrough cancer drugs. The investigators searched the [email protected] website for the term “cancer drug approvals” appearing between July 2012 and December 2017. The researchers applied the value frameworks and used thresholds of high clinical benefit developed by American Society of Clinical Oncology Value Framework version 2 (ASCO VF-NHB v2; scores ≥45), the ASCO Cancer Research Committee (ASCO CRC; overall survival gains ≥2.5 months, progression-free survival [PFS] gains ≥3 months), the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS v1.1; grade of A or B for trials of curative intent and 4 or 5 for those of noncurative intent), the National Comprehensive Cancer Network (NCCN) Evidence Blocks (scores of 4 and 5), and the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT). The investigators compared trial characteristics and value framework scores using Chi squared or Mann–Whitney tests.

The researchers found 106 pivotal trials that supported the approval of 52 drugs for 96 indications. They also found that 38 of these indications (40%) were awarded breakthrough designations. The authors identified 44 trials for breakthrough drugs and 62 trials for non-breakthrough drugs.

When the researchers compared trials for breakthrough drugs with those for non-breakthrough drugs, they found that median sample size was smaller in trials for breakthrough drugs (median 373 versus 612, P =.03). Moreover, only 57% of trials for breakthrough drugs were randomized compared with 86% of trials for non-breakthrough drugs (P =.001) In addition, the proportion of trials that were open label was greater among trials for breakthrough drugs: 84% of trials for breakthrough drugs were open label, compared with only 53% of trials for non-breakthrough drugs (P =.001).

Finally, 68% of trials for breakthrough drugs demonstrated high clinical benefit compared with 31% of trials for non-breakthrough drugs (P =.002) according to ASCO VF v2 criteria. According to NCCN Evidence Blocks, 86% of trials for breakthrough drugs demonstrated high clinical benefit compared with 56% of trials for non-breakthrough drugs (P =.002).

The other frameworks used in the study suggested that the proportion of trials supporting breakthrough and non-breakthrough drugs demonstrating high clinical benefit was similar; ASCO Cancer Research Committee frameworks suggested that 82% of trials for breakthrough drugs and 68% of trials for non-breakthrough drugs demonstrated high clinical benefit (P =.25). According to ESMO-MCBS frameworks, 35% of trials for breakthrough drugs and 33% of trials for non-breakthrough drugs demonstrated high clinical benefit (P =.87). Under ESCAT, breakthrough cancer drugs had lower odds for substantial clinical benefit.

In addition, the authors found that the median price of breakthrough drugs was $2,531 more per month compared with non-breakthrough drugs. This difference was statistically significant according to a Mann–Whitney  U test with a P value of .001.

The take-home message is that “advances in our understanding of the molecular and genetic cancer lesions have led to new challenges to the design of clinical trials, with many drugs approved based on surrogate endpoints that not always may benefit patients,” said lead study author Consolación Molto, MD, of Hospital de Sant Pau, in Barcelona, Spain. “The desire to provide earlier access to highly effective drugs should be linked to rigorous confirmatory studies, and robust and transparent criteria for breakthrough designations.”

Read more of Cancer Therapy Advisor‘s coverage of ASCO’s annual meeting by visiting the conference page.

Reference

1. Molto C, Hwang TJ, Andres M, et al. Clinical benefit of breakthrough cancer drugs approved by the United States Food and Drug Administration. Presented at 2019 American Society of Clinical Oncology (ASCO) Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 6513.