The US Food and Drug Administration granted acalabrutinib approval as the second Bruton tyrosine kinase (BTK) inhibitor to treat patients with chronic lymphocytic leukemia and small lymphocytic lymphoma as monotherapy or in combination with obinutuzumab. This approval was based on 2 phase 3 trials: ELEVATE-TN and ASCEND. There are several concerns with the design of these trials, including suboptimal treatment of patients in the control arm, expansion of the trial population, and lack of data regarding efficacy or tolerability compared with ibrutinib, a first-in-class drug. The Food and Drug Administration approval of acalabrutinib for patients with chronic lymphocytic leukemia and small lymphocytic lymphoma represents concerning drug approval patterns in the United States and a weakness in evidence generation.

Aim

Drug approvals for genome-informed indications have been increasing in recent years, but it is unknown how many of them have demonstrated an improvement in overall survival (OS). We assessed the frequency of approved genome-informed drugs demonstrating improvements in OS and progression-free survival (PFS) and whether the frequencies differed by cancer type.

Materials and methods

We searched all Food and Drug Administration approvals from 2006 to 2020, and for each drug that was approved for a genomic indication, we then searched on PubMed for randomised studies examining OS or PFS.

Results

We found 53 drugs approved for 92 unique indications from 2006 to 2020. We found that 50 drugs (55%) approved for a genomic indication had a randomised study evaluating OS benefit, and of those, only 22 demonstrated an improvement in OS. Similarly, 52 drugs (57%) evaluated PFS benefit, and 51 of these studies demonstrated an improvement in PFS. Drugs approved for BRAF V600 melanoma demonstrated an improvement in OS more often than drugs approved for ALK non-small cell lung cancer. The median improvement in OS was 4.7 months (range 1.5 months-49.1 months).

Conclusion

Although there is widespread enthusiasm for this class of agents, and many demonstrate impressive response rates, further trials or post-marketing studies are needed to ascertain the impact on survival and quality of life, the magnitude of these gains, and the cost-effectiveness of these agents.

Background

Rank preserving structural failure time (RPSFT) is a statistical method to correct or adjust for crossover in clinical trials, by estimating the counterfactual effect on overall survival (OS) when control arm patients do not receive the interventional drug when their tumor progresses. We sought to examine the strength of correlation between differences in uncorrected and corrected OS hazard ratios and percentage of crossover, and characterize instances of fundamental and sequential efficacy.

Methods

In a cross-sectional analysis (2003-2023), we reviewed oncology randomized trials that used RPSFT analysis to adjust the OS hazard ratio for patients who crossed over to an anti-cancer drug. We calculated the percentage of RPSFT studies evaluating a drug for fundamental efficacy (with or without a standard of care (SOC)) or sequential efficacy and the correlation between the OS hazard ratio difference (unadjusted and adjusted) and the percentage of crossover.

Results

Among 65 studies, the median difference between the uncorrected and corrected OS hazard ratio was -0.1 (quartile 1, quartile 3 : -0.3 to -0.06). The median percentage of crossover was 56% (quartile 1, quartile 3: 37% to 72%). All studies were funded by the industry or had authors who were employees of the industry. Twelve studies (19%) tested a drug's fundamental efficacy when there was no SOC; 34 studies (52%) tested a drug's fundamental efficacy when there was already a SOC; and 19 studies (29%) tested a drug's sequential efficacy. The correlation between the uncorrected and corrected OS hazard ratio difference and the percentage of crossover was 0.44 (95% CI: 0.21 to 0.63).

Conclusions

RPSFT is a common tactic used by the industry to reinterpret trial results. Nineteen percent of RPSFT use is appropriate. We recognize that while crossover can bias OS results, the allowance and handling of crossover in trials should be limited to appropriate circumstances.

Importance

Idelalisib is a first-in-class phosphatidylinositol 3-kinase inhibitor that received US Food and Drug Administration accelerated approval in July 2014 as a single-agent treatment for relapsed follicular lymphoma (FL) and small lymphocytic lymphoma (SLL). Serious adverse effects were reported in 2016 leading to termination of postmarketing registry trials. However, idelalisib remained on the market until 2022 when Gilead voluntarily withdrew the drug for the accelerated approval indication.

Objective

Evaluate the regulatory oversight of the accelerated approval pathway and evidence generation for idelalisib during premarketing (2008-2014), postmarketing (2014-2016), and premarketing withdrawal periods (2016-2022).

Data sources

ClinicalTrials.gov, FDA.gov, PubMed database.

Study selection

Clinical trials investigating the safety and effectiveness of idelalisib.

Data extraction and synthesis

Study characteristics and relative risk (RR) of safety outcomes were abstracted. Data were pooled using random effects meta-analysis. The analysis was performed in October of 2022.

Main outcomes and measures

Trial status, recruitment status, publication status, serious adverse events (SAEs), fatal adverse events (FAEs), and all-cause mortality.

Results

Overall, 31 idelalisib trials met selection criteria. In total, 20 of 30 (65%) included SLL and/or FL; 13 (42%) trials were completed, 13 (42%) had published results, and 7 (23%) were randomized clinical trials (RCTs). Overall, 6 RCTs of idelalisib had publicly available data on safety outcomes. By the initial postmarketing period (2016), the cumulative RR for SAEs was 1.86 (95% CI, 1.63-2.11), for FAEs was 3.30 (95% CI, 1.56-7.00), and for death was 1.35 (95% CI, 0.85-2.12). In the premarketing withdrawal period, only a single phase 3 trial was enrolling patients for FL and was terminated. However, idelalisib was not withdrawn from the market until 2022. Gilead reported cumulative sales revenue of $842 million during market authorization (2014-2022) and annual sales had a steady decline from $168 million to $62 million during the premarketing withdrawal period (2016-2021).

Conclusions and relevance

Findings of this systematic review and meta-analysis show that serious risks of SAE, FAE, and death with idelalisib treatment were evident by 2016. However, idelalisib remained on the market for another 6 years, with minimal evidence generation. It was voluntarily withdrawn for FL and SLL accelerated approval indications coinciding with decreasing revenue generation. Closer attention for safety and effectiveness of drugs reaching market by accelerated approval is needed.

Background

Immune checkpoint inhibitor (ICI) therapies have become increasingly popular treatment options for patients with cancer, even for patients in non-metastatic settings. Survival and responses have been reported for individual tumor types, but little is known about these outcomes, collectively. We sought to provide an overview of overall survival (OS) and progression-free survival (PFS) in ICI drugs tested in registration trials.

Methods

In a cross-sectional analysis of US FDA oncology ICI drug approvals (2011-2023), we searched for supporting ICI registration trials. We characterized these trials, regarding differences in median OS and PFS between patients in intervention and control arm participants in ICI registration trials; percentage of patients who receive ICI crossover; and whether there is correlation between the percentage of crossover and differences in OS or PFS.

Results

Fifty-six (54.4 %) approvals had trials that reported median OS for both intervention and control arms (median difference was 2.8 months; IQR: 2.2 to 5.0 months). Sixty-five (63.1 %) approvals had trials that reported PFS data for both arms (median of 0.9 months; IQR: -0.2 to 3.0 months). Subsequent therapy was common (median=18.9 %) and was significantly correlated with a higher difference in median OS in all studies with reported differences (R2 =0.15; p = 0.001).

Conclusion

ICIs are increasingly used in the treatment of cancer, yet the median OS improvement is modest, and many ICIs have not been tested for OS benefit. OS is the outcome most meaningful for patients, and drug regulation should require better testing and reporting of these data.