Guest Column | April 14, 2022

FDA Issues Guidance On Expansion Cohorts In Clinical Trials Of Oncology Drugs

By Marjorie Zettler, Ph.D., MPH, senior director, clinical science, Accutar Biotech

In March, FDA issued the final guidance document for first-in-human trial designs that consist of both dose escalation as well as multiple expansion cohorts to evaluate safety, anti-tumor activity, pharmacokinetics (PK), and other properties of oncology drug products, all within a single protocol.

By following the FDA guidance on dose escalation, sponsors can ensure that the trial design aligns with regulatory expectations and facilitates the evaluation of safety, anti-tumor activity, pharmacokinetics (PK), and other properties of oncology drug products within a single protocol.

The concept is straightforward: Once the recommended Phase 2 dose is determined in the dose escalation part of the trial, expansion cohorts can be opened to investigate different aspects of the oncology drug’s activity.

The objectives for each cohort may include further dose or dose schedule investigation (e.g., once daily vs. twice daily dosing); comparison of safety, tolerability, and anti-tumor effect of monotherapy vs. combination therapy with another oncology drug; or characterization of the safety, tolerability, and anti-tumor effect in different indications, different lines of therapy, or different patient populations (including those with different tumor mutational status). Expansion cohorts may also be used to evaluate food effect, drug-drug interaction, and PK among patients with organ dysfunction.

Key Points In The Guidance

1. Safety is paramount

  • The scientific rationale for including each expansion cohort should be outlined within the protocol and should establish that the potential benefit the patient could derive from the treatment outweighs the potential risks.
  • Sponsors should have plans in place to continually monitor safety data in real time and to rapidly disseminate evolving information to investigators, institutional review boards, and the FDA, to keep them informed of new safety observations throughout the study.
  • An independent monitoring committee should be established to perform both pre-specified and ad hoc assessments of safety and futility for each expansion cohort. The committee should also recommend protocol changes (adding new safety information or modifying the eligibility criteria), updates to the informed consent document to address safety issues as they emerge (including re-consenting patients if needed), or adjusting the dosing schedule or safety monitoring plan as necessary. A change from the draft to the final guidance includes the allowance for the committee to be internal to the sponsor, for studies of limited sample size.

2.  Statistical considerations

  • The statistical analysis plan should justify the sample size based on cohort objectives.
  • It should also pre-specify analyses, as well as stopping rules (for safety or futility).3
  • The protocol should be designed to support the intended analyses. For example, if the intention is to compare the anti-tumor effect in one cohort vs. another (e.g., a combination therapy cohort vs. a monotherapy cohort), patients should be randomized to those cohorts, and the sample size for each cohort should ensure adequate power to detect a difference, if it exists.
  • A change from the draft to the final guidance is the provision that designs other than Simon two-stage may be used to evaluate anti-tumor activity in a non-randomized cohort.2 The use of Bayesian or other alternative statistical designs will aid in limiting the number of patients exposed to an ineffective drug.3

3. Communication with FDA

  • Bearing in mind the complexity of this strategy, sponsors should consider a pre-IND meeting with FDA to discuss trial design and the overall development plan for the oncology drug product. In particular, if the sponsor intends to submit the data from the trial as primary support for a marketing application, they should plan ahead to make certain they understand and are meeting FDA’s expectations in terms of acceptable data standards, independent review of tumor-based endpoints, etc.

Since the draft guidance was first introduced by FDA in 2018, this strategy has been employed for the development and subsequent accelerated approval of multiple cancer drugs based on single first-in-human Phase 1/2 clinical trials. Five recent examples include the approvals of:

  • sotorasib, for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), who have received at least one prior systemic therapy, in 20214
  • mobocertinib and amivantamab, both indicated for the treatment of adult patients with locally advanced or metastatic NSCLC with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, whose disease has progressed on or after platinum-based chemotherapy), in 20215,6
  • pralsetinib and selpercatinib, both indicated for the treatment of adult patients with metastatic RET fusion-positive NSCLC, adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy, and adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory, in 2020.7.8

Advantages Of The Expansion Cohort Trial Design

The expansion cohort strategy confers significant advantages to sponsors. By transitioning directly from the dose escalation phase (which is typically completed as a stand-alone clinical trial) to multiple expansion cohorts, the sponsor can realize substantial time and cost savings, as well as reduced administrative burden.

The ability to assess multiple patient populations and address multiple hypotheses simultaneously can streamline the path to approval. For example, in the Phase 2 part of the ARROW study, pralsetinib was evaluated in nine different cohorts based on mutational status, prior therapy, tumor type, and country.7 The ARROW trial enrolled 589 patients in total, and pralsetinib received accelerated approval for multiple indications in 2020, three years after the trial began.

This expansion cohort approach also provides an opportunity to gain early data in patient populations that are often excluded or an afterthought in the clinical development of oncology drug products, such as older adults, those with concurrent malignancies or brain metastases, or pediatric populations.9-13 In light of the recent implementation of the Research to Accelerate Cures and Equity (RACE) for Children Act, which authorizes the FDA to require pediatric development of cancer drugs with molecular targets relevant to pediatric cancers,14 use of this tactic could represent an option to generate data to support that requirement (though the final guidance document notes that, depending on the age of the pediatric population, a different formulation may be required for the cohort).

Risks Of The Expansion Cohort Trial Design To Consider

While the expansion cohort trial design has clear benefits, it also carries risks. Because of the complexity of enrolling patients to multiple different cohorts concurrently, each with separate objectives and different inclusion/exclusion criteria or doses, dose schedules, or treatment regimens, it may be difficult to accurately interpret safety signals as they arise.

This could potentially expose patients to increased risk. Similarly, gauging anti-tumor effect based on small numbers of patients in a given cohort may result in overestimation of efficacy, potentially resulting in the exposure of patients to a suboptimal dose. Trial logistics may also be complicated, particularly if some cohorts require randomization but others don’t.

To mitigate possible increased safety concerns, sponsors should not employ this design when the investigational drug product has characteristics such as a narrow therapeutic window or high inter-patient PK variability. The indications investigated should also be limited to serious oncologic conditions where there is still an unmet need for safe and effective therapies.

These criteria are met by each of the five recent examples provided above: all are molecular targeted agents (which have dose–toxicity relationships that may be less steep than cytotoxic agents),15 and all are indicated for the treatment of advanced or metastatic cancers that are rare or orphan diseases without satisfactory alternative treatments.

The use of expansion cohorts in first-in-human clinical trials can improve the efficiency of clinical development of oncology drug products, and this strategy has already been successfully executed to support the approval of numerous cancer therapies. Although these trials are complicated and have many moving parts, with appropriate planning and early interaction with FDA, this approach represents a feasible, expedited alternative to traditional separate Phase 1 and 2 trials.


  1. United States Food and Drug Administration. Expansion Cohorts: Use in First-in-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics. Guidance for Industry. March 2022.
  2. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989 Mar;10(1):1-10. doi: 10.1016/0197-2456(89)90015-9.
  3. Berry SM, Broglio KR, Groshen S, Berry DA. Bayesian hierarchical modeling of patient subpopulations: efficient designs of Phase II oncology clinical trials. Clin Trials. 2013 Oct;10(5):720-34. doi: 10.1177/1740774513497539.
  4. A Phase 1/2, Study Evaluating the Safety, Tolerability, PK, and Efficacy of Sotorasib (AMG 510) in Subjects With Solid Tumors With a Specific KRAS Mutation (CodeBreaK 100). Accessed at:
  5. A Study of TAK-788 in Adults With Non-Small Cell Lung Cancer. Accessed at:
  6. Study of Amivantamab, a Human Bispecific EGFR and cMet Antibody, in Participants With Advanced Non-Small Cell Lung Cancer (CHRYSALIS) Accessed at:
  7. Phase 1/2 Study of the Highly-selective RET Inhibitor, Pralsetinib (BLU-667), in Patients With Thyroid Cancer, Non-Small Cell Lung Cancer, and Other Advanced Solid Tumors (ARROW) Accessed at:
  8. A Study of LOXO-292 in Participants With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer (LIBRETTO-001).
  9. United States Food and Drug Administration. Inclusion of Older Adults in Cancer Clinical Trials. Guidance for Industry. March 2022.
  10. United States Food and Drug Administration. Cancer Clinical Trial Eligibility Criteria: Patients with Organ Dysfunction or Prior or Concurrent Malignancies. Guidance for Industry. July 2020.
  11. United States Food and Drug Administration. Cancer Clinical Trial Eligibility Criteria: Brain Metastases. Guidance for Industry. July 2020.
  12. United States Food and Drug Administration. Cancer Clinical Trial Eligibility Criteria: Minimum Age Considerations for Inclusion of Pediatric Patients. Guidance for Industry and IRBs. July 2020.
  13. United States Food and Drug Administration. Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical Trials. Guidance for Industry. March 2019.
  14. Zettler ME. The RACE for children act at one year: progress in pediatric development of molecularly targeted oncology drugs. Expert Rev Anticancer Ther. 2022 Jan 24:1-5.
  15. Le Tourneau C, Stathis A, Vidal L, Moore MJ, Siu LL. Choice of starting dose for molecularly targeted agents evaluated in first-in-human phase I cancer clinical trials. J Clin Oncol. 2010 Mar 10;28(8):1401-7. doi: 10.1200/JCO.2009.25.9606.

About The Author:

Marjorie Zettler, Ph.D., MPH is director of clinical science at Regor Pharmaceuticals, Inc. An industry veteran with nearly two decades’ experience in the pharma and healthcare sector, her work has focused on clinical research, drug development, and regulatory strategy. She has published more than 100 abstracts, manuscripts, and patents.