A survey of over 1,000 patients with metastatic breast cancer found that 86.1% reported having experienced at least one significant treatment-related side effect, with 20.3% of those patients ending up in the hospital or emergency room and 43.2% missing at least one treatment.¹ Subsequent dose reductions resulted in relief for 82.6% of patients.¹ This study highlights the burden of toxicity borne by patients when the dosages of cancer therapies are not adequately optimized.

Conventional dose-finding methodology, originally developed decades ago for cytotoxic chemotherapy, is centered on the premise that efficacy and toxicity increase in parallel.² Under this paradigm, the objective of dose-finding studies is to identify the maximum tolerated dose (typically using a 3+3 design trial). Although modern oncology drugs such as targeted therapies have different properties compared to their cytotoxic predecessors, dose-finding practices have largely remained the same: of 67 novel anticancer therapies approved by the FDA between 2018 and 2023, approximately two-thirds employed the 3+3 design in their first-in-human dose escalation studies.³ When outdated or ill-suited methods are utilized for dose selection, the therapy may be approved at a higher-than-necessary dose, leading to safety and tolerability challenges for patients.

Growing evidence from real-world studies of cancer therapies has indicated that alternate dosing strategies can afford an improved safety and tolerability profile, with comparable efficacy. For example, a study comparing weekly cetuximab dosing (the approved regimen) versus an every two weeks regimen among patients with metastatic colorectal cancer between 2013 and 2019 found that overall survival was similar between the two dosing regimens, but time to treatment discontinuation was significantly longer among the every-two-weeks cohort.⁴ In some studies, patients receiving a reduced dose experienced better survival outcomes relative to patients receiving the approved dose: an evaluation of patients with advanced breast cancer who were treated with palbociclib between 2017 and 2020 found that those patients with dose reductions had a significantly longer time to next treatment and median overall survival compared to those patients without dose reductions.⁵ While these studies provide important information, they are typically not conducted until years after a drug’s approval, at which point countless patients have already been treated at suboptimal dosages.

When the FDA’s review prior to approval finds indicators that the optimal dose has not been identified (such as a high incidence of dose modifications or discontinuations), post-marketing requirements or commitments (PMRs/PMCs) for further dose exploration may be issued. Analysis by Friends of Cancer Research found that over half of the novel oncology drugs approved by the FDA between 2012 and 2022 were issued PMRs to collect more data about dosing.⁶ In particular, PMRs requiring the sponsor to evaluate the safety and efficacy of lower doses increased markedly over the decade assessed, from 18.2% of dosing-related PMRs issued during the time period 2012–2015 to 71.4% of dosing-related PMRs issued 2020–2022. ⁶ This increased emphasis on dose exploration coincides with other efforts by the FDA to prioritize dose optimization, including the 2021 launch of Project Optimus and the publication of several scientific articles on the topic.^7-9 Although the issuance of PMRs/PMCs represents one avenue by which the FDA can ensure dosages of cancer therapies are sufficiently investigated, ideally dose optimization would occur in the pre-approval setting.

In January 2023, the FDA issued a draft guidance for industry titled “Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases”.¹⁰ The final guidance document was released in August 2024.¹¹ Overall, the final guidance largely resembles the original draft, with a few noteworthy changes.

Some additions of interest:

• Sponsors are urged to speak with the FDA regarding their plans for dosage optimization early in clinical development. The new Model-Informed Drug Development paired meeting program is introduced as an option in addition to formal meetings. Language also has been added to encourage initiating an evaluation of population pharmacokinetics (PK), dose and exposure-response relationships, studies of the impact of intrinsic factors on PK, pharmacodynamics, and safety, and studies of potential drug-drug interactions with concomitant medications early in the development program.
• The use of modeling, including semi-mechanistic or mechanistic approaches, is suggested as a potential strategy for the identification and support of the dosages to be evaluated in dose optimization trials. These methods could also be used to support dosages for other future indications or usages.
• Greater detail has been provided regarding the design of dose optimization studies. In particular, leveraging data from other therapies within the same or similar class or with the same mechanism of action is proposed as one means to support the dosages for evaluation (in addition to model-informed or model-based approaches, as mentioned previously). Tumor-assessment-based endpoints such as overall response rate or progression-free survival are suggested as relevant measures of activity. The idea of blinding (subjects and investigators) within the study to reduce potential bias is also presented as a feature that may be applied within dose optimization studies. In trials with a crossover design, the FDA recommends pre-specification of how activity and safety will be evaluated post-crossover in the analysis plan. Finally, assessment of dosing strategies (e.g., intra-patient dose escalation/de-escalation) within dose optimization trials is also recommended as appropriate.

One conspicuous omission:

The statement, “Clinical trials should enroll an appropriately broad population to allow assessment of the dosage(s) across relevant subpopulations,” which appeared in the original draft guidance, has been removed from the final guidance. This is a somewhat surprising change given FDA’s commitment to diversity in clinical trials.¹² However, several comments on the draft guidance referenced this statement and expressed doubt that the sample size for the dose optimization trials would be sufficient to draw meaningful conclusions regarding any given subpopulation.¹³

Where further guidance is still needed:

Some common themes among the public comments posted to the docket for the draft guidance included requests for further elaboration on the approach to dose optimization for combination therapies, greater clarity on statistical considerations for dose optimization trials, and a statement on the applicability of the recommendations for novel therapeutics (such as antibody-drug conjugates).¹³ No new information addressing these concerns was included in the finalized document, leaving it up to sponsors to address their specific issues with the agency directly. In this final guidance, the FDA has clearly spelled out its expectation that dose optimization activities for oncology drugs should commence early in clinical development. To further underscore the FDA’s position, the final guidance also states that a protocol evaluating dosages that the FDA does not consider to be adequately supported may be placed on clinical hold. The finalization of this guidance represents an important step toward ensuring dosages of cancer therapies are optimized before registration, which will ultimately result in minimizing avoidable toxicity and allowing patients to remain on therapy for a longer period of time, maximizing the benefit they can derive from treatment.

References:

1. Loeser A, Kim JS, Peppercorn J, Burkard ME, Niemierko A, Juric D, et al. The Right Dose: Results of a Patient Advocate-Led Survey of Individuals With Metastatic Breast Cancer Regarding Treatment-Related Side Effects and Views About Dosage Assessment to Optimize Quality of Life. JCO Oncol Pract. 2024 Jul;20(7):972-983. doi: 10.1200/OP.23.00539..
2. Zettler ME. Dose Optimization of Targeted Therapies for Oncologic Indications. Cancers (Basel). 2024 Jun 9;16(12):2180. doi: 10.3390/cancers16122180.
3. Jiang Z, Sun W, Du R, Yang R. A review of dose escalation for FDA-approved products treating solid tumors and hematological malignancies in first-in-human trials. Clin Transl Oncol. 2024 Sep;26(9):2116-2125. doi: 10.1007/s12094-024-03451-2.
4. Aggarwal H, Han Y, Sheffield KM, Cui ZL. Real-world comparison between weekly versus biweekly dosing of cetuximab for metastatic colorectal cancer. J Comp Eff Res. 2023 Feb;12(2):e220143. doi: 10.2217/cer-2022-0143.
5. Ismail RK, van Breeschoten J, Wouters MWJM, van Dartel M, van der Flier S, et al. Palbociclib dose reductions and the effect on clinical outcomes in patients with advanced breast cancer. Breast. 2021 Dec;60:263-271. doi: 10.1016/j.breast.2021.11.013
6. Collins G, McKelvey B, Andrews HS, Allen JD, Stewart MD. An Analysis of Dosing-Related Postmarketing Requirements for Novel Oncology Drugs Approved by the U.S. Food and Drug Administration, 2012-2022. Clin Cancer Res. 2024 Mar 1;30(5):937-941. doi: 10.1158/1078-0432.CCR-23-2268.
7. FDA. Project Optimus website. Accessed at: https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus
8. Shah M, Rahman A, Theoret MR, Pazdur R. The Drug-Dosing Conundrum in Oncology – When Less Is More. N Engl J Med. 2021 Oct 14;385(16):1445-1447. doi: 10.1056/NEJMp2109826.
9. Fourie Zirkelbach J, Shah M, Vallejo J, Cheng J, Ayyoub A, Liu J, et al. Improving Dose-Optimization Processes Used in Oncology Drug Development to Minimize Toxicity and Maximize Benefit to Patients. J Clin Oncol. 2022 Oct 20;40(30):3489-3500. doi: 10.1200/JCO.22.00371.
10. FDA. Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases. Draft Guidance for Industry. January 2023. Accessed at: https://www.regulations.gov/document/FDA-2022-D-2827-0002
11. FDA. Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases. Guidance for Industry. August 2024. Accessed at: https://www.fda.gov/media/164555/download
12. FDA. Diversity Action Plans to Improve Enrollment of Participants from Underrepresented Populations in Clinical Studies. Draft Guidance for Industry. June 2024. Accessed at: https://www.fda.gov/media/179593/download
13. FDA. Comments on docket for Optimizing the Dosage of Human Prescription Drugs and Biological Products Used in the Treatment of Oncologic Diseases, Draft Guidance for Industry. Posted Jan 18, 2023, closed Mar 20, 2023. Accessed at: https://www.regulations.gov/docket/FDA-2022-D-2827/comments

https://www.clinicalleader.com/doc/fda-finalizes-guidance-on-dose-optimization-for-oncology-therapies-0001