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Do Early Phase Oncology Trials Predict Clinical Efficacy in Subsequent Biomarker-Enriched Phase III Randomized Trials?

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Abstract

Background

Promising early phase trial results of biomarker-targeted therapies have occasionally led to regulatory approval.

Objective

We examined if early phase trials were predictive of efficacy in randomized controlled trials (RCTs) with matching treatment settings.

Patients and Methods

Cancer drug RCTs conducted between January 2006 and March 2021 were identified through Clinicaltrials.gov. Biomarker-enriched RCTs and associated matching early phase trials were included. Trial pairs were compared using objective response rate (ORR) and progression-free survival (PFS). We examined whether early phase trials results were associated with RCT results using logistic regression.

Results

The search yielded 2157 unique RCTs and 27 RCTs pairing with early phase trials were included. Based on average difference of trial pairs, ORR was similar (1.6%; 95% confidence interval (CI) − 2.5 to 5.6, p = 0.50) and median PFS was higher in early phase trials (2.0 months; 95% CI 0.9–3.0, p < 0.05). On an individual pair basis, there was large variability in difference for ORR (range − 23.9 to 20.2%) and median PFS (range − 0.8 to 7.4 months). The probability of the RCT meeting its primary endpoint is 95% (95% prediction interval (PI) 72.8–99.3%) when the early phase trial ORR is 77.7%.

Conclusions

Overall, in early phase trials, ORR has minimal bias and median PFS appears to be slightly overestimated. Substantial variability between trials suggests early phase trial results may be inconsistent with subsequent RCT. Early phase trial results may be associated with RCTs meeting their primary endpoint when ORR is very high; however, caution must be exercised when using early phase trials as representative of RCTs.

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Acknowledgements

The Canadian Centre for Applied Research in Cancer Control is supported by the Canadian Cancer Society (Grant #2020-706936).

Author information

Author notes

  1. Albiruni R. Abdul Razak and Kelvin K. W. Chan contributed equally to the article.

Authors and Affiliations

  1. Sunnybrook Research Institute, Toronto, ON, Canada

    Suji Udayakumar, Sasha Thomson & Kelvin K. W. Chan

  2. Division of Medical Oncology and Hematology, Drug Development Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada

    Albiruni R. Abdul Razak

  3. Department of Medicine, University of Toronto, Toronto, ON, Canada

    Albiruni R. Abdul Razak & Kelvin K. W. Chan

  4. Odette Cancer Centre, Sunnybrook Health Sciences Centre, 2075 Bayview Ave., T2-058, Toronto, ON, M4N 3M5, Canada

    Kelvin K. W. Chan

  5. Canadian Centre for Applied Research in Cancer Control, Toronto, ON, Canada

    Kelvin K. W. Chan

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  1. Suji Udayakumar
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Correspondence to Kelvin K. W. Chan.

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Funding

No external funding was used in the preparation of this article.

Conflict of interest

Suji Udayakumar, Sasha Thomson, and Kelvin K. W. Chan declare that they have no conflicts of interest that might be relevant to the contents of this article. Albiruni R. Abdul Razak declares having received honoraria from Eli Lilly, Boehringer Ingelheim, Merck, Adaptimmune, GSK and having acted a consultant/advisor for Merck, Bristol Myers Squibb, Novartic, Karyophara, Boston Biochemical, Deciphera, Genentech, Roche, Pfizer, Medimmune, Eli-Lilly, Boehringer Ingelheim, Entremed/CASI Pharmaceutical, Amgen, Champions Oncology, Interion, Blueprint.

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Availability of data and material

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Author contributions

Conceptualization: Kelvin K. W. Chan. Methodology: Kelvin K. W. Chan. Formal analysis and investigation: Suji Udayakumar, Sasha Thomson, Kelvin K. W. Chan. Writing—original draft preparation: Suji Udayakumar, Sasha Thomson. Writing—review and editing: Suji Udayakumar, Sasha Thomson, Albiruni R. Abdul Razak, Kelvin K. W. Chan. Supervision: Albiruni R. Abdul Razak, Kelvin K. W. Chan.

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Udayakumar, S., Thomson, S., Razak, A.R.A. et al. Do Early Phase Oncology Trials Predict Clinical Efficacy in Subsequent Biomarker-Enriched Phase III Randomized Trials?. Targ Oncol 17, 665–674 (2022). https://doi.org/10.1007/s11523-022-00920-y

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