Recent Report Highlights Success in FDA Subgroup Approval & Treatment Arm Data

Recent Report Highlights Success in FDA Subgroup Approval & Treatment Arm Data


A recent report published by the American Association for Cancer Research titled Subgroup Analyses in Oncology Trials: Regulatory Considerations and Case Examples offers clinical cancer research perspective into regulatory science and policy. The piece was authored by a team of experts and led by corresponding author Anup Amatya who works in the Office of Biostatistics, Division V at the Center for Drug Evaluation and Research for the U.S. Food and Drug Administration.

In the article the team summarizes key findings related to the benefit-risk assessment of cancer drugs specifically as they relate to subgroup analyses. Case examples for large-scale evaluation and small scale investigation are discussed with examples provided from the FDA Oncology Center of Excellence (OCE). These illustrate the approach that the FDA takes when considering the appropriate patient population for cancer drug approval. Generally, if a subgroup is of interest, the subgroup analysis should be hypothesis-driven with adequate sample size to demonstrate evidence of a treatment effect.

What are Subgroup Analyses?

Subgroup analyses are assessments of treatment effects based on certain patient characteristics within a larger group of data from the total clinical study population. Historically these have been critical for interpretation of pivotal oncology trials. However, the appropriate use of these subgroup analyses and data results in regards to regulatory decision-making and product labeling has historically been a challenging venture.

Generally, cancer drugs that are approved by the FDA are indicated for use in the total patient population that is studied. Recently there have been more examples of positive results standing out from specific subgroups and additional focus being placed on those patients. 

Statistical efficacy considerations for both the total population and any subgroups included are necessary for the labeling and pathophysiology of the disease, mechanistic justification, safety data, and external information available. 

Oncology drug review utilizes the totality of the data as part of the decision-making process that helps to ensure indication is granted and drug labeling appropriate to reflect the necessary scientific evidence that led to approval. Patients must know that for their specific population a drug is both safe and effective.

Importance of Pre-Specified Analyses 

Regulators have designated that it is most helpful to distinguish the intent of subgroup analyses with pre-specific intent as either Inferential, Supportive or Explanatory. This categorization helps guide the statistical analysis plan adding context when the data is interpreted as well as evaluating the credibility of the subgroups found.

  • Inferential Subgroup Analyses
    • These analyses are prespecified with adequate power and alpha control. The intent is to establish efficacy in a subgroup of interest. 
  • Supportive Subgroup Analyses
    • These analyses are prespecified but do not include prospective planning for testing within subgroups. They are aimed at descriptively investigating consistency of the treatment effect across subgroups only after the treatment effect is shown to be significant in the total population.
  • Exploratory Subgroup Analyses
    • These are generally included in the protocol to maximize the utility of the clinical trial data and generate hypotheses. They can also be used to gain further insight into potentially predictive mechanistic elements of treatment and biological characteristics of the disease.

A list of examples illustrate approvals in the intention-to-treat population despite decreased treatment effect in a subgroup. Additional examples illustrate the exception to the typical approach where clinical rationale and mechanistic justification drive interpretation of results for regulatory decision making in subgroups.

FDA Drug Approvals in Intent to Treat (ITT) Populations


The first example cited is CHECKMATE-057 which was a pivotal trial supporting the approval of nivolumab for second-line treatment of patients with metastatic non-squamous non-small cell lung cancer who had experienced disease progression during or after one prior platinum d doublet-based chemotherapy regimen. The CHECKMATE-057 trial demonstrated a statistically significant improvement in OS between the nivolumab arm and docetaxel arm for the ITT population. There was however no strong evidence of OS effect in subgroup of patients with PD-L1 <1%.

CHECKMATE-057 also noted that PD-L1 <1% patients were not harmed citing no safety issues. This study is similar to the recent study from Cel-Sci Corporation where OS was shown to significantly increase in the treatment arm that did not receive chemotherapy, while no treatment arms or any patients encountered safety or efficacy issues. 

On May 15, 2020, the Food and Drug Administration approved the combination of nivolumab (OPDIVO, Bristol-Myers Squibb Co.) for first-line mNSCLC (PD-L1 tumor expression ≥1%). Specific details regarding the trial subgroups were included in product labeling to help assist patients and providers both with the treatment decisions.


The second example of approvals in ITT subgroup populations highlights the approval of pembrolizumab for first-line treatment for advanced non-small-cell lung cancer and the KEYNOTE-042 trial. In the trial a 4.6 month improvement in estimated median OS  for patients on single agent pembrolizumab was shown compared to patients on carboplatin-based chemotherapy. 

The results of the exploratory subgroup raised uncertainty regarding the benefit within the subgroup, it  was not possible  to draw definitive consolutsion as the trial was not powered for subgroup analysis. KEYNOTE-042 was an active control with no apparent detrimental effect on OS in the subpopulation of patients randomized to pembrolizumab compared to chemotherapy.

On March 22, 2021, the FDA approved pembrolizumab (brand name Keytruda) in combination with platinum and fluoropyrimidine-based chemotherapy for patients with metastatic or locally advanced esophageal or gastroesophageal carcinoma, with tumor epicenter 1 to 5 centimeters above the gastroesophageal junction.

Keytruda has become a foundational cancer treatment with activity across 25 different cancer types. The drug has also been projected to generate $22.5 billion in revenue by 2025, according to an analysis by GlobalData, a data and analytics company.

TUKYSA FDA Approval 

The final study cited for ITT subgroup population approval outlined the approval of margetuximab in combination with chemotherapy for the later line treatment of metastatic HER2-positive breast cancer based on the SOPHIA trial. The trial met its primary PFS analysis endpoint in the ITT population. An exploratory subgroup analysis by CD16A allotypes however indicated possible differential effects of margetuximab. 

Patients carrying the CD16A low-affinity F allele (F/F or F/V) appeared to have a greater benefit from margetuximab vs. trastuzumab (HERCEPTIN), PFS showed a trend in favor of the HERCEPTIN over TUKYSA in the subgroup of patients with CD16A V/V genotype.

Despite this data, the FDA granted approval for the entire study population because there was no clear mechanistic basis for the heterogeneity of results by the CD16A allotypes.

On December 16, the U.S. Food and Drug Administration (FDA) approved margetuximab-cmkb (Margenza) in combination with chemotherapy for the treatment of adult patients with metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease.

Further reports from clinical trials correlating CD16A F158V genotypes with trial efficacy endpoints will be submitted in the future as part of post marketing commitment to further characterize the clinical benefit that may inform product labeling.

FDA Drug Approvals in Subgroups


The PAOLA-1 pivotal trial supported the approval of olaparib in combination with bevacizumab (MVASI) for first-line maintenance treatment of adult patients with advanced epithelial ovarian cancer whose cancer is associated with  homologous recombination deficiency (HRD)-positive status. The study demonstrated a statistically significant improvement in the primary endpoint of PFS  in the ITT population however  during the review based on subgroup analysis it was concluded that the treatment effect in the ITT population was in fact driven by  the HRD-positive subgroup.

For the HRD-negative subgroup (33%) in the PAOLA-1 trial no treatment effect was observed for PFS, and OS numerically favored placebo + bevacizumab treatment arm. Though it was based on an exploratory subgroup analysis, the differential efficacy between HRD-positive and HRD-negative populations was plausible.

On May 19, 2020, the Food and Drug Administration approved olaparib (LYNPARZA, AstraZeneca Pharmaceuticals, LP) for adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).


Study 309 enrolled patients with advanced liposarcoma (32%) or leiomyosarcoma (68%). This study led to the approval of eribulin (HALAVEN). Study 309 demonstrated a statistically significant improvement in the  primary endpoint of OS in the ITT population. A prespecified exploratory subgroup analysis based on histologic subtype discovered that the overall OS results appeared to be strongly driven by a large treatment effect in the smaller group of patients with liposarcoma, less than ⅓ of the population. 

The differential treatment effects observed among secondary endpoints and biological differences between the two sarcomas concluded that substantial evidence of effectiveness was only limited to the liposarcoma subgroup.

On January 28, 2016 the U.S. Food and Drug Administration approved Halaven (eribulin mesylate), a type of chemotherapy, for the treatment of liposarcoma (a specific type of soft tissue sarcoma) that cannot be removed by surgery (unresectable) or is advanced (metastatic). This treatment is approved for patients who received prior chemotherapy that contained an anthracycline drug.


IMpassion130 study results led to accelerated FDA approval for atezolizumab in combination with paclitaxel protein-bound (Taxol) for treatment of adult patients with unresectable locally advanced or metastatic Triple-Negative Breast Cancer whose tumors express PD-L1. The recommendation for approval was based on the efficacy and safety data from IMpassion130.

This study was designed to formally test the treatment effect in the ITT population and PD-L1+ subgroup by splitting alpha between two populations. While PFS results were statistically significant for the ITT  population, the magnitude of difference in media PFS was relatively short suggesting uncertainty in the clinical benefit of adding atezolizumab to paclitaxel protein-bound for the entire study population. The indication for approval was limited to PD-L1+ population in which PFS benefit was greater with a favorable trend in OS benefit.

On May 18, 2020, the Food and Drug Administration approved atezolizumab (TECENTRIQ®, Genentech Inc.) for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression (PD-L1 stained ≥ 50% of tumor cells [TC ≥ 50%] or PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 10% of the tumor area [IC ≥ 10%]), with no EGFR or ALK genomic tumor aberrations.

Conclusion Discussion & Potential Impact on Upcoming Trials

While it is understood that the population to include in a new drug indication is challenging, little is known about how the determination is made. The report makes a strong claim that an effective therapy should be made available to all patients who derive benefit from it while noting that broad use therapy may not be appropriate when benefit-risk assessment  is not favorable in important subgroups.

For studies where risks were minimal or non-existent and the primary endpoint not yet met, hope could still remain for FDA approval and sweeping change. Cel-Sci Corporation is planning to submit for approval their drug, Multikine, which showed positive results in a treatment arm but missed primary endpoints. With no risks of safety or efficacy concerns and potential benefit demonstrated, access should be granted and medication provided to patients in need.

Rigorous statistical analysis continues to be crucial in determining drug indications though this remains challenging in late stage clinical trial data because the subgroups have a limited ability to inform identification of the appropriate patient population for the approved indication.

Challenges & Concerns of Onologic Subgroup Review

Interpreting subgroup analyses during oncologic drug review is heightened due to the increased nature of life-threatening cancer with regulatory decisions based on multiple endpoints in a single pivotal trial such as Progression-Free Survival (PFS) and Overall Survival (OS) for example. Multiple endpoints exacerbate the multiplicity problem that occurs in subgroup analysis. Furthermore, single pivotal trials do not allow opportunity to replicate or establish analytical credibility of subgroup findings, particularly when such finding is not anticipated prior. 

When strong treatment effects are anticipated in a subgroup, a trial should be pre-specified to formally evaluate this subgroup and powered to detect such an effect. Interpretation of the study finding in the total population should also then consider the adequacy of data in the complementary subgroup in context of the disease setting. 

Ultimately, Anup Amatya of the FDA recommends that incorporation of results of subgroup analyses should take into account multiple factors as part of the regulatory decision-making process including:

  • Pathophysiological rationale
  • Non-Clinical and Pharmacological Support
  • Clinical Experience with Similar Agents
  • Other Supportive Endpoint Results
  • Benefit-Risk Evaluation
  • Medical Need in Therapy
  • Additional Considerations

If needed, post-marketing commitments or requirements can be requested to better define the  full extent of a drug’s effect. These decisions are guided by a goal to ensure promising and safe therapeutic options are available to all patients who benefit from treatment and to provide useful information in regards t o clinically important  and scientifically supported observed differences in treatment  effects promoting optimal decision making among patients with cancer and their healthcare providers. For these patients, access is key.

Leave a Reply

Your email address will not be published. Required fields are marked *

You May Also Like