Jared Kaltwasser

When patients with locally advanced or metastatic soft tissue sarcoma (STS) do not respond to standard chemotherapy, they face a difficult situation.

“There are very few FDA-approved treatments for patients with soft tissue sarcoma,” Scott Michael Schuetze, MD, PhD, a clinical professor for the University of Michigan Health at Michigan Medicine, said.

Doxorubicin (Lipodox) is generally the first chemotherapy offered. Other drugs, such as trabectedin (Yondelis) and eribulin mesylate (Halaven), are also approved for certain patients, but such therapies come with significant risk of adverse effects. Although it’s a short list, it may soon grow.

“Over the past 10 to 20 years, researchers have identified molecular abnormalities in sarcomas that may be vulnerable to disruption by drugs targeting specific growth pathways, and pharmaceutical companies have done a remarkable job in developing pharmaceuticals to target these pathways,” Schuetze explained.

Of course, developing such drugs is one thing, getting them to patients who need them can be quite another.

TAPUR Design First launched in 2016, TAPUR (NCT02693535) is a phase 2, open-label, basket study sponsored by the American Society of Clinical Oncology (ASCO) that allows investigators to evaluate how small cohorts of patients with tumors having the same or similar genetic variations will respond to targeted therapies already approved for other indications. The study uses next- generation sequencing (NGS) to match patients with potentially actionable mutations to promising therapies and study cohorts. Cohorts begin with up to 10 patients who have the same cancer type, genomic alteration, and study drug. If 2 or more patients appear to respond to the therapy, the cohort can be expanded to 28 enrollees.

Currently, TAPUR is enrolling patients at 141 sites, and 19 drugs are accessible through partnerships with drug developers (

One of those drugs is palbociclib (Ibrance), a therapy approved for the treatment of hormone receptor–positive, HER2-negative breast cancer. At 2021 ASCO Annual Meeting, Schuetze and colleagues reported on the use of palbociclib in patients with STS and CDK4 amplification.

 Each of the patients in the study had either not responded to or progressed following treatment.

“Most of the patients treated in this cohort had a life expectancy of less than a year, and identification of more effective and better-tolerated treatments for these patients is a priority,” Schuetze said.

Earlier work has identified CDK4 and MDM2 as overexpressed and pathologically important for the tumor type, Schuetze said. TAPUR gave investigators the ability to determine responses in a small group of patients with STS.

In their TAPUR study, 1 patient had a partial response and 12 patients had stable disease at 16-plus weeks (SD16+). That translated to a disease control rate (DCR) of 48% (95% CI, 31%-62%) and an objective response rate (ORR) of 3.7% (95% CI, 0.1%-19%). Schuetze and colleagues said 9 of the 13 patients with disease control continued on treatment for more than 32 weeks.

“Most of the patients who enrolled in the study had dedifferentiated liposarcoma, and the results in this group were in line with expectations and results from prior studies, although it was disappointing that we did not see objective tumor responses in this sarcoma subtype,” Schuetze said. “The objective response in a patient with soft tissue sarcoma that was not a dedifferentiated liposarcoma was a bit of a pleasant surprise.”

Further, adverse events (AEs) were consistent with previous studies, he said.

Ajjai Alva, MBBS, another TAPUR investigator from Michigan Medicine, noted that TAPUR is not the first time a trial has attempted to use NGS sequencing to identify patients for quick entry into trials. The National Cancer Institute (NCI) launched the NCI-MATCH trial (NCT02465060) in 2015 using a similar model of matching patients via genetic mutations. However, Alva said that study had some limitations that TAPUR does not. For instance, in NCIMATCH, the sequencing was done at a single center to ensure uniformity in the sequencing.

“They really placed an importance on the stringency of the sequencing, which is good for science,” he said. However, it also resulted in procedural bottlenecks. “So logistically, it was very difficult.” TAPUR offers more flexibility in terms of where sequencing is done and which platforms are used. That makes the process of enrolling patients and beginning therapy significantly faster, something that is key for patients who often face progressing disease.

Schuetze’s study was not the only news to come out of the ASCO meeting. As TAPUR reached its 5-year anniversary, a number of new results were presented, including reports on head and neck cancer and uterine cancer.

In another palbociclib study, Evan Pisick, MD, of Cancer Treatment Centers of America, and colleagues evaluated the drug in a cohort of patients with head and neck cancer and CDKN2A mutation (8 patients) or loss (20 patients).

 Like the patients in Schuetze’s study, these patients had no standard treatment options and advanced disease.

 loss achieved SD16+, and 1 patient with a 

 mutation achieved the same. The DCR was 37% (95% CI, 21%-50%).

Half the patients (14) experienced at least one grade 3 to 5 AE or serious AE, the most common of which was low white blood cells/platelets. One patient experienced grade 5 respiratory failure, which investigators said was most likely due to extensive lung metastases and aspiration, although they noted that palbociclib-related pneumonitis could not be ruled out.

Additionally, Hussein Moustapha Ali- Ahmad, MD, of the Michigan Cancer Research Consortium, reported on a cohort of patients with uterine cancer who had 

 amplification, overexpression, or mutations.4 The 28 patients all had measurable disease and no standard treatment options. Most of the patients (21) had 

 amplification. They were treated with pertuzumab (Perjeta) and trastuzumab (Herceptin).

 amplification had partial responses, and 7 achieved SD16+. One patient with 

 8421 mutation but without amplification also achieved SD16+. That translated to a DCR of 37% (95% CI, 21%50%) and an ORR of 7.1% (95% CI, 0.8%-24%). Just 1 patient experienced a grade 3 AE (muscle weakness), which investigators said was possibly related to the therapy.

The combination of pertuzumab and trastuzumab was also the subject of research presented last year at the ASCO Gastrointestinal Cancers Symposium. That report evaluated the combination therapy’s ability to treat patients with colorectal cancer and 

 One patient in the study also had a mutation of the gene. The results of the trial produced better DCR (50%) and ORR (25%) versus Ali-Ahmad’s and colleagues’ new uterine cancer study.

Other 2020 results included promising outcomes for patients with prostate cancer and 

/2 inactivating mutations who were treated with olaparib (Lynparza).

 That study found 68% of patients achieved disease control and 36% of patients had an objective response.

However, olaparib did not perform as well in patients with pancreatic cancer and

1/2 inactivating mutations. In that study, 31% and 4% of patients achieved disease control and objective response, respectively.

Alva’s research involved looking at pembrolizumab (Keytruda) in patients with metastatic breast cancer who had high tumor mutational burden (TMB). The study found TMB was a meaningful biomarker predictive of response to pembrolizumab, leading to a DCR of 37% and ORR of 21%.

 Median progression-free survival was 10.6 weeks, and median overall survival was 30.6 weeks.

Alva said that before TMB was identified, the protein PD-L1 was used as a biomarker, but it was imprecise.

“A lot of patients in every cancer type do not express or do not have detectable PD-L1 and still respond,” he said. “And the other way around also is true: Sometimes there is high PD-L1 expression, and those tumors also do not respond.”

The TAPUR study showed TMB, although not a perfect biomarker, could help identify a cohort of patients in whom a significant proportion would respond to the therapy.

A similar study of pembrolizumab found DCR and ORR of 28% and 4%, respectively, in patients with metastatic colorectal cancer and high TMB.

Shortly after those studies were released, the FDA approved pembrolizumab for patients across cancer types if they have high TMB, progressed despite treatment, and have no other available treatment options.

The expanded approval was based on the KEYNOTE-158 trial.

 Alva noted that the TAPUR studies are not designed to lead to FDA action—with just 28 patients they generally are too small—but they can quickly generate data sufficient to trigger larger studies.

“The study was never designed to back FDA regulatory approval,” he said. “It was merely to find signals, quick signal checking—does TMB hold promise?”

Schuetze added that TAPUR allows for the investigation of therapies for cancer types that might otherwise be too rare to be the subject of a major study.

“These cancers studied in TAPUR are, for the large part, too rare for study in larger randomized phase 2 or phase 3 trials, and TAPUR is an innovative mechanism to collect treatment data from patients with very rare cancer subtypes,” he noted.

Schuetze said because the trials are not randomized makes it difficult to determine the impact of what the TAPUR study will be, but he added that it is already serving a meaningful opportunity “to gain knowledge about new treatment options and further medical care for patients with rare cancers.”

As for what it all means long term, Alva said he is a big believer in NGS as a tool that will play a major role in the future of cancer care.

“Biology wise, it gives us a lot of clues about prognostic markers, for example, that some things are going to work, some things are more likely to work, and some things are never going to work,” Alva said. “Those kinds of information—the more information, the better for us.”

1. News & updates. ASCO TAPUR. Updated April 26, 2021. Accessed July 1, 2021. https://bit.ly/2VfDolw 

2. Schuetze S, Rothe M, Mangat PK, et al. Palbociclib (P) in patients (pts) with soft tissue sarcoma (STS) with CDK4 amplification: results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study. 

Clin Oncol. 2021;39(suppl 15):11565. doi:10.1200/JCO.2021.39.15_suppl.11565

3. Pisick EP, Rothe M, Mangat PK, et al. Palbociclib (P) in patients (pts) with head and neck cancer (HNC) with CDKN2A loss or mutation: results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study. 

l. 2021;39(suppl 15):6043. doi:10.1200/jco.2021.39.15_suppl.6043 

4. Ali-Ahmad HM, Rothe M, Mangat PK, et al. Pertuzumab plus trastuzumab (P+T) in patients (Pts) with uterine cancer (UC) with ERBB2 or ERBB3 amplification, overexpression or mutation: results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.

. 2021;39(sup-pl 15):5508. doi:10.1200/jco.2021.39.15_suppl.5508

5. Gupta R, Garrett-Mayer E, Halabi S, et al. Pertuzumab plus trastuzum-ab (P+T) in patients (Pts) with colorectal cancer (CRC) with ERBB2 am-plification or overexpression: results from the TAPUR study. 

 2020;38(suppl 4):132. doi:10.1200/jco.2020.38.4_suppl.132 

6. Pisick EP, Garrett-Mayer E, Halabi S, et al. Olaparib (O) in patients (pts) with prostate cancer with BRCA1/2 inactivating mutations: results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study. 

. 2020;38(suppl 15):5567. doi:10.1200/jco.2020.38.15_sup-pl.5567

Articles

When patients with locally advanced or metastatic soft tissue sarcoma do not respond to standard chemotherapy, they face a difficult situation.

TAPUR Results Roll Out, Bringing Potential New paradigms Into Focus

When historians look back at this era of cancer care, it is quite possible that the development of immune checkpoint inhibitors (ICIs) will be seen as the beginning of a crucial new treatment paradigm. T-cell–targeted immunomodulators burst onto the scene a decade ago, and investigators turned their focus to immune checkpoints such as CTLA-4, PD-1, and PD-L1 to develop new cancer-fighting strategies.

As Caroline Robert, MD, PhD, head of the Dermatology Unit at Gustave Roussy institute and codirector of the Melanoma Research Unit at INSERM 981 Paris-Sud University near Paris, France, noted in a 2020 article in Nature Communications, the introduction of the CTLA-4–targeted ipilimumab (Yervoy) in 2011 sparked a race to develop more ICIs.

By the end of 2020, more than 3000 active clinical trials were evaluating T-cell modulators, comprising two-thirds of all oncology trials.

Another 6 ICIs, all targeting the PD-1/PD-L1 signaling pathway, had been approved by the FDA as of December 2020. The approved indications range across 19 cancer types and 2 tissue-agnostic signatures.

Scott M. Lippman, MD, professor of medicine, senior associate dean and associate vice chancellor for cancer research and care, and director of Moores Cancer Center at the University of California (UC) San Diego Health in California, said ICIs have been transformative because in many cases, patients who previously had very grim prospects were suddenly cured.

“There are 2 major things that are different from any other kind of systemic therapy we’ve had,” Lippman, who also holds the Chugai Pharmaceutical Chair in Cancer at UC San Diego Health, told Targeted Therapies in Oncology. “One is the broad spectrum of activity—lung, head and neck, all of them, and unselected patients. And 2 is the tail on the curve.”

However, if the tail on the curve—the limited number of patients whose survival is substantially improved by ICI therapy—is an indication of the tremendous possibilities with ICIs, it is also a sign of the current limitations of these therapies.

Jiuwei Cui, MD, of the First Hospital of Jilin University in Changchun, China, addressed the problem in a 2020 review article.

“Although the clinical development of immune checkpoint inhibitor therapy has ushered in a new era of antitumor therapy, with sustained responses and significant survival advantages observed in multiple tumors, most patients do not benefit,” Cui and colleagues wrote.

Investigators know ICIs can work wonders; they just do not know which patients are most likely to benefit from these therapies.

Lippman specializes in head and neck cancer, and he has seen anti–PD-1 checkpoint inhibitors lead to dramatic results. However, they work in only approximately 20% of patients. Measuring PD-L1 protein expression on tumor cells can help identify patients that are likely to do well, but according to Lippman it is essentially a crude tool, and one that applies only to treatment with PD-1/PD-L1 inhibitors.

“PD-L1 is out there. It’s not great, as it applies to the PD-1 axis only,” he said. “So the question is, can we come up with better predictors of response and survival? And it’s these predictive genomics that will take [ICIs] into the era of precision therapy.”

First Wave of Biomarkers As Cui and colleagues noted, multiplex immunohistochemistry, high-throughput sequencing, and microarray technology have aided the ongoing development of a variety of biomarker strategies. The identification of single biomarkers or combinations of predictive markers helps enable oncologists to choose the most effective treatments for patients.3 The search for biomarkers has been wide ranging, though this research is very much in the early stages.

In a 2019 review article, Michael J. Duffy, PhD, and John Crown, PhD, of St Vincent’s University Hospital in Dublin, Ireland, outlined some of the key predictive biomarkers associated with response to ICIs. The authors also described several emerging biomarkers that are still undergoing validation but may provide valuable assistance with clinical decision-making in the future (TABLE).4 In addition to PD-L1 expression, microsatellite instability/defective mismatch repair (MSI/dMMR) and tumor mutational burden (TMB) were among the first ICI biomarkers to show promise.

A high level of MSI/dMMR is thought to be a pan-cancer biomarker that can be predictive of response to a specific ICI, such as pembrolizumab (Keytruda).

“MSI/dMMR is approved for clinical use irrespective of the tumor type, whereas PD-L1 is approved only for use in certain cancer types,” Duffy and Crown wrote.

At the time they were writing, in 2019, TMB had not yet been approved for clinical use as a biomarker. That changed in 2020, when the FDA approved pembrolizumab to treat metastatic or unresectable solid tumors with high TMB.

In a March 2021 review article, the FDA’s Julianne D. Twomey, PhD, and Baolin Zhang, PhD, explained that TMB, a broad assessment of the rate of mutations present in a tumor, appeared to be associated with ICI efficacy.

“The higher mutational burden within a tumor is expected to correspond to a higher level of immunogenic neopeptides that would drive T-cell–mediated antitumor immunity,”they wrote.

Unfortunately, the logic of higher TMB corresponding to higher immunogenicity does not always hold. Naiyer A. Rizvi, MD, then of Columbia University, and colleagues discussed this problem in the 

American Society of Clinical Oncology Educational Book

“TMB is not a useful marker in all cancer types,” they wrote. “In some histologies, substantial responses to ICIs are observed despite a low TMB.”

For instance, they noted, in renal cell carcinoma,there does not appear to be a clear correlation between TMB and response to ICIs.

Additional Potential BiomarkersIn addition to PD-L1, MSI/dMMR, and TMB, a number of other potential biomarkers have been proposed. Serine/threonine kinase 11 (STK11) inactivation has been linked with a worse prognosis and resistance to ICIs in patients with KRAS-mutant lung cancers, Rizvi and colleagues reported

In addition to PD-L1, MSI/dMMR, and TMB, a number of other potential biomarkers have been proposed. Serine/threonine kinase 11 (STK11) inactivation has been linked with a worse prognosis and resistance to ICIs in patients with KRAS-mutant lung cancers, Rizvi and colleagues reported.

Mutations in Kelch-like ECH-associated protein 1 (KEAP1), which commonly co-occur with STK11 mutations, appear to correlate with poor clinical outcomes, according to results of a pan-cancer analysis published in 2020 in Annals of Translational Medicine.7 In a cohort of 1661 patients who received ICI therapy, the 99 patients with 

 mutations had an over-all survival of just 10 months vs 20 months in the 

Yet it is not clear whether these mutations can predict ICI-specific outcomes. For instance, results of a 2020 analysis of more than 2000 patients in a real-world non–small cell lung cancer (NSCLC) cohort suggested that the presence of 

 mutations conferred a worse prognosis regardless of the type of frontline therapy the patient received.

“Mutations in STK11 or KEAP1 were associated with poor outcomes across multiple therapeutic classes and were not specifically associated with poor outcomes in [immune checkpoint blockade] cohorts,” wrote corresponding author Alice M. Walsh, PhD, of Bristol Myers Squibb.

Data from the KEYNOTE-042 study (NCT02220894) showed similar efficacy of pembrolizumab in patients with advanced PD-L1–positive NSCLC regardless of 

The tumor suppressor PTEN has also been identified as a potential biomarker. Rizvi and colleagues noted that genetic aberrations in 

 appear to be most common in endometrial cancer (66% of cases) but have also been found in 10% to 15% of cases in several other cancer types. A lack of 

 expression is believed to impair T-cell–mediated antitumor activity, and research is ongoing to find out whether, and how, loss of PTEN protein affects ICI response.

Upregulated WNT/β-catenin signaling and β2-microglobulin (

) mutation are 2 other possible biomarkers of ICI resistance, though research is in its early stages. As a part of the WNT signaling pathway, β-catenin is involved in cell differentiation and migration, whereas B2M plays a critical role in antigen presentation to cytotoxic T cells.

“Given its multitude of functions, dysregulation of the [WNT/β-catenin] pathway is frequently involved in tumorigenesis and cancer metastasis,” Rizvi and colleagues wrote. Similarly, they noted that B2M loss is a mechanism of immune evasion, and B2M mutations have been linked with resistance to anti–PD-1 therapy in several cancer types.

What is notable about the list of biomarkers under investigation is not so much that it is long but, rather, that it has the potential to become much longer.

Lippman’s excitement about ICI biomarkers is heightened in part because of a discovery he and his colleagues made in a study whose results were published earlier this year.10 While researching links between genetic abnormalities and invasive head and neck cancers, they zeroed in on gene copy number imbalances that seemed to be involved in tumor development. However, they soon realized that the abnormalities they had discovered were also related to ICI susceptibility.

Lippman and colleagues found that loss of chromosome 9p and JAK2–PD-L1 codeletion were linked with ICI resistance

 Lippman said the identification of a potential biomarker came as a welcome surprise.

“This 9p story was not our hypothesis going into [this study]; it just fell out of it,” he said.

Lippman said that in earlier research, his team had found evidence suggesting chromosome 3p loss and chromosome 9p loss played important roles in the development of human papillomavirus–negative head and neck cancers. For many years, 3p received most of the attention. That is, until Lippman’s new data came out. When the new data suggested 9p was the more important of the 2 types of deletion, Lippman and col-leagues knew the clinical implications, so they verified their findings using real-world post-ICI patient survival data from Caris Life Sciences. The association between chromosome 9p loss and ICI resistance held firm.

“The 9p observation was…a year and a half before we submitted the paper,” Lippman said. “It was so striking that we just wanted to make sure that we were 100% confident in that finding because it changed everything.”

Though the FDA has taken initial steps to pair approval of tools such as biomarker tests with therapeutic approvals, the type of routine testing and therapy selection envisioned by Lippman and others cannot yet happen on a wide scale due to the absence of 2 key factors: standardization and approved diagnostic platforms.

In their analysis of biomarkers, Duffy and Crown noted that although TMB, PD-L1, and MSI/dMMR have become important metrics, the utility of those biomarkers remains limited by the absence of clearly standardized assays. They added that uncertainties about appropriate cutoff values for biomarker positivity remain largely unresolved.

“Despite being widely investigated, assays for MSI/dMMR, PD-L1, and TMB lack standardization and are still evolving,” Duffy and Crown wrote. “An urgent focus of future research should be the optimization and standardization of methods for determining these biomarkers.”

Lippman commented on the need for several additional measures, including FDA approval of more diagnostic assays to guide the use of ICI treatments. Still, he thinks our current path could lead to more advanced precision immunotherapy and the kind of world where next-generation sequencing informs therapeutic choices with very high rates of success. Such a future is in sight, he said, but there is still a long way to go.

“I really do think we’re going to eliminate cancer as we know it today,” Lippman said. “It’s not suddenly going to go away, but it’s not going to be the scary thing that it was before.”

1. Robert C. A decade of immune-checkpoint inhibitors in cancer therapy. 

. 2020;11(1):3801. doi:10.1038/s41467-020-17670-y

2. Twomey JD, Zhang B. Cancer immunotherapy update: FDA-approved checkpoint inhibitors and companion diagnostics. 

. 2021;23(2):39. doi:10.1208/s12248-021-00574-0

3. Bai R, Lv Z, Xu D, Cui J. Predictive biomarkers for cancer immunotherapy with immune checkpoint inhibitors. 

. 2020;8:34. doi:10.1186/s40364-020-00209-0

4. Duff y MJ, Crown J. Biomarkers for predicting response to immunother-apy with immune checkpoint inhibitors in cancer patients.

. 2019;65(10):1228-1238. doi:10.1373/clinchem.2019.303644

5. FDA approves pembrolizumab for adults and children with TMB-H solid tumors. FDA. Updated June 17, 2020. Accessed June 4, 2021. https://bit.ly/3ph7ekx 

6. Lagos GG, Izar B, Rizvi NA. Beyond tumor PD-L1: emerging genomic bio-markers for checkpoint inhibitor immunotherapy. 

7. Chen X, Su C, Ren S, Zhou C, Jiang T. Pan-cancer analysis of KEAP1mutations as biomarkers for immunotherapy outcomes. 

. 2020;8(4):141. doi:10.21037/atm.2019.11.52

8. Papillon-Cavanagh S, Doshi P, Dobrin R, Szustakowski J, Walsh AM. STK11 and KEAP1 mutations as prognostic biomarkers in an observational real-world lung adenocarcinoma cohort. 

 2020;5(2):e000706. doi:10.1136/esmoopen-2020-000706

9. Cho BC, Lopes G, Kowalski DM, et al. Relationship between STK11 and KEAP1 mutational status and effi cacy in KEYNOTE-042: pembrolizumab monotherapy versus platinum-based chemotherapy as first-line therapy for PD-L1-positive advanced NSCLC.

. 2020;80(suppl 16):CT084. doi:10.1158/1538-7445.AM2020-CT084

10. William Jr WN, Zhao X, Bianchi JJ, et al. Immune evasion in HPV–head and neck precancer–cancer transition is driven by an aneuploid switch involving chromosome 9p loss. 

. 2021;118(19):e2022655118. doi:10.1073/pnas.2022655118

T-cell–targeted immunomodulators burst onto the scene a decade ago, and investigators turned their focus to immune checkpoints such as CTLA-4, PD-1, and PD-L1 to develop new cancer-fighting strategies.

Quest for Immune Checkpoint Inhibitor Biomarkers–a Long but Exciting Road

Most of the time, evidence of a cancer therapy’s success in clinical trials is reassuring. This time, it was not.

Narjust Duma, MD, was treating a patient at the Mayo Clinic, in Rochester, Minnesota, where she was a hematology–medical oncology fellow. The patient asked the usual questions, and she responded with the usual answers: data describing the therapy’s overall odds of success and the odds of the cancer returning following therapy.

Unfazed, Duma explained that the data she was quoting were based on cancer stage and thus represented a reasonable expectation of a patient’s odds with that stage of cancer.

The patient, however, was not satisfied. He kept asking, over and over again, “What about me?”

“And when I finally stopped and I asked, ‘What do you mean?’” she said, “he [answered], “What about me? What about Black men like me?’

She did not know how to answer his question, Duma realized. “And I remember, my stomach was hollow for, like, 2 days,” she said.

The patient knew that as a Black man, his life expectancy was already shorter than that of his White peers. He wanted to know what the trial data showed about the success of the therapy in Black men, not just White men.

Duma tried to find out, but when she examined the study data, she found that of the thousands of patients recruited, just 5 were Black men—not nearlyenough to draw reasonable conclusions about the safety and efficacy of the therapy in Black men such as her patient.

. “I went back,” Duma said, “and I told my patient, ‘I don’t know.’ ”

Underrepresentation Is a Widespread, Long-Term Problem

The clinical trial process has birthed a revolution in cancer care, allowing a host of cutting-edge therapies to make it from the laboratory to the clinic. However, the success of the modern drug development pipeline obscures one important fact: The trials that are meant to prove the safety and efficacy of potential therapies consistently overrepresent White patients and often underrepresent racial and ethnic minorities, women, and individuals of lower socioeconomic status.

The problem connects to issues of health care access and equity, but it also underscores an uncomfortable truth: In many cases, the trial data available for minority populations are much less robust than the data available for members of majorities.

The problem is evident from the data. The FDA’s 2018 Drug Trials Snapshots, for instance, showed that of the more than 5000 patients that year who participated in oncology trials that led to approvals, just 4% were Black and 4% were Hispanic, despite the fact that 13.4% of the US population was Black and 18.1% was Hispanic.

 Women were also under-represented: They made up 38% of the trial population

 At the same time, Asian patients were overrepresented, making up 15% of the trial population but just 5.8% of the US population.

The problem is not new. In 1993, Congress passed the National Institutes of Health Revitalization Act, which directed the agency to develop guidelines to boost inclusion of women and minorities in clinical trials. Those guidelines were published the following year. However, in a landmark 2004 study, future US Surgeon General Vivek H. Murthy, MD, MBA, and colleagues reported that patients who were female, older, or Black or Hispanic were still considerably less likely than male, younger, and White patients to enroll in cooperative group cancer trials. They also found that Black participation in such trials had been decreasing, not increasing, in recent years.

The problem exists not just in a macro sense but also within specific cancer types. For instance, Black patients have 2 to 3 times the risk of being diagnosed with multiple myeloma (MM) compared with White patients, and Black patients also tend to be diagnosed with MM at a younger age than White patients. However, a survey of MM pivotal trials supporting FDA applications between 2003 and 2017 found that just 4.5% of patients in clinical trials were Black.

In a 2020 examination of racial disparities in MM risk and outcomes, corresponding author Timothy R. Rebbeck, PhD, of the Dana-Farber/Harvard Cancer Center in Boston, and colleagues said the lack of Black enrollment led to significant limitations in the conclusions that could be drawn from MM studies.

“The small numbers of Black [patients] enrolled in clinical trials not only limit the confidence in the reported results, but they raise questions as to whether the trends observed in the Black patients who did enroll are generalizable to broader patient populations,” Rebbeck and colleagues wrote.

or Duma, now an assistant professor at the University of Wisconsin School of Medicine and Public Health in Madison, the interaction with the patient was a call to action. She had seen the results of Murthy’s 2004 study, but she also knew that the study was based on National Cancer Institute (NCI)–funded trials, and since then, industry-funded trials had become more common.

“So I was wondering, are we doing better now that the whole drug development platform has changed?” she said.

Duma and colleagues decided to search the ClinicalTrials.gov database for US-based oncology clinical trials completed between 2003 and 2016. Of the 1012 trials involving the 7 most common cancers, 31% reported ethnicity, for a total of 55,689 patients. They found that Black and Hispanic patients were still significantly less likely than White patients to be enrolled in clinical trials.

When they compared their results with the historical data from 1996 to 2002 reported by Murthy,

 they found that enrollment had actually dropped for both Black (from 9.2% to 6.0%) and Hispanic patients (from 3.1% to 2.6%). Duma and colleagues also found that women were disproportionately under-enrolled in studies focusing on melanoma, lung cancer, and pancreatic cancer.

“Your race and your background will affect you if you are included in a trial and ultimately will affect the long-term outcome [of your disease],” Duma said.

That is one reason real-world evidence (RWE)—data collected outside of clinical trials—has grown in importance, according to a 2019 paper coauthored by Atul Batra, MBBS, MD, DM, and Winson Cheung, MD, MPH, both of the University of Calgary, in Alberta, Canada. Looking specifically at colorectal cancer, they wrote that RWE is an important complement to data from randomized controlled trials (RCTs) because it gives insights into the actual patient population, instead of just the potentially unrepresentative population included in the trials.

“Although RCTs remain the ‘gold standard’ for evaluating the efficacy of novel interventions in cancer, there is general acceptance that RCTs alone might not offer all the answers to relevant clinical or research questions,” Batra and Cheung wrote.

For community oncologists, the primary clinical questions revolve around safety, efficacy, and dosage. Duma said it is impossible to confidently answer such questions when treating patients whose demographic groups were not adequately represented in the associated trials.

“Safety is always the No. 1 rule in anything with medicine,” Duma said. “You need to be safe for your patients, but it’s unsafe to give a drug after it’s approved, but was [not tested] in the group [to which your patient belongs.]”

According to Batra and Cheung’s research, one issue that leads to disparities between trial populations and the general population is the use of stringent eligibility criteria in clinical trials. “Real-world” patients may have comorbidities and other traits that can lead to their exclusion from cancer trials that are designed for maximum clarity of data.

Lori J. Pierce, MD, professor and vice provost for Academic and Faculty Affairs at University Hospital, University of Michigan, Ann Arbor, and president of the American Society of Clinical Oncology (ASCO), has made increasing diversity in trials a focal point of her tenure at the organization. She and ASCO have worked with the NCI and FDA on efforts to expand trial eligibility criteria, hoping that broadening the potential pool of enrollees would help diversify trials without sacrificing the integrity of the results.

“They found out that by changing just 3 common eligibility criteria—renal function measures, the presence of brain metastases, and having a history of a prior cancer—the eligibility for clinical trials increased by almost 2-fold,” Pierce said during an interview with Targeted Therapies in Oncology.

Those results, noted Pierce, show that using more relaxed exclusion criteria can make a major difference in trial populations.

Another limiting factor that has seen progress is insurance coverage. Private insurers in the United States are required to cover costs associated with clinical trials, such as costs for blood tests and x-rays. However, the requirement does not extend to Medicaid. Although 15 states have long directed their state Medicaid programs to cover the costs, there was no federal coverage mandate.

That was a problem, Pierce noted, because underrepresented minorities tend to rely on Medicaid at disproportionately high rates.

ASCO has been pushing for Congress to extend the coverage mandate to Medicaid for a number of years. The effort finally paid off in December 2020, when Congress included the Clinical Treatment Act in its year-end coronavirus disease 2019 relief bill.

“We were popping the cork—I personally was popping the champagne cork—when this [legislation] was passed, because I really think that it will make a big difference,” Pierce said.

Duma agreed that the lack of Medicaid coverage has been a significant part of the problem, but she noted that individuals on the economic margins will still face significant cost burdens. For instance, an analysis conducted in 2019 found parking fees at NCI-designated cancer treatment centers can be very expensive. Such treatment centers tend to be located in the downtown areas of major cities, where parking can cost as much as $40 per day, although some cancer centers provide free parking.

 Duma said that trial sponsors should help cover parking and other transportation costs to make participation more feasible for all patients.

Although some hurdles can be overcome with straightforward policy adjustments, others require broader changes. One problem, Pierce noted, is that many clinicians do not have the time or the infrastructure in place to participate in trials, or to get their patients involved in trials. She suggested that better training of community oncologists to help them understand how to become involved in trials would help. So, too, would cultural awareness training and translation services to facilitate better communication with potential enrollees who do not speak English. However, she declared that success will require involvement by more than just physicians.

“Not everything needs to rest on the shoulders of the physician,” Pierce said. “It takes a village, right?”

In this case, the “village” means patient navigators, physician’s assistants, nurse practitioners, and others who can spend time getting to know patients, figuring out which patients would be a good fit for trials, and helping to walk those patients through fears and past barriers.

Building Trust in Marginalized Communities

At the same time, such interventions will work only if patients trust the health care system.

“Sometimes that lack of trust in the health care system is seen as though it doesn’t have a basis [in fact],” pointed out Duma. “It does have a basis.”

Duma noted, for instance, a 2020 whistleblower complaint in which a nurse working at an immigration detention center alleged that mostly Spanish-speaking women detained by US Immigration and Customs Enforcement were undergoing hysterectomies at alarming rates, raising questions about whether medical professionals there had consistently obtained informed consent.

One way to build up trust is by explaining and offering options to patients. This is good practice in general; it also helps those with distrust of the system to feel that they are in control of their own health care decisions.

Pierce said there is ample evidence that one way to boost diversity in clinical trials is simply to do a better job of informing patients about the option to participate. She pointed to a study by Joseph M. Unger, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, and colleagues. They analyzed 35 cancer studies published between 2000 and 2020, comprising almost 10,000 patients.

They found that 55% of patients who were asked to participate in a trial agreed to do so, a figure that held firm for both treatment and cancer control trials. Notably, Black patients were just as likely as White patients (58% vs 55%) to say “yes” when asked (

Pierce said the Unger study should serve to contradict concerns that minority patients are reluctant to enroll in trials; the data show that they are not unwilling, when given ample opportunity and information. Although it is important to acknowledge the roots of mistrust, physicians can succeed in enrolling a diverse patient population if they take the time to explain studies and the safeguards.

“From a scientific point of view, to be able to prove the safety and prove the efficacy, and from a trust point of view...to be able to say, yes, members of various ethnic and racial groups were represented on this trial, I think are all very important,” Pierce said.

Last year, ASCO and the Association of Community Cancer Centers (ACCC) announced a partnership to develop solutions to the problem of underrepresentation of minorities in clinical trials.

 The partnership’s steering committee, which is cochaired by Pierce, is currently at work on a 3-pronged process to try to address the issue (

Their plan will join reports by the Enhancing Minority Participation in Clinical Trials (EMPaCT) consortium, which has published a number of papers and training tools for health care workers. Also finding success are other local efforts, such as a program by Andrea Silber, MD, to recruit more women in the New Haven, Connecticut, area into trials.

Pierce said the ASCO-ACCC initiative expects to unveil its plan, currently under development, in early 2022, adding that she hopes such efforts can make meaningful strides in addressing what has proven to be a durable problem. However, Pierce said that in the end, success may come not from overhauling systems, but from taking the current strategies that work and making them the norm.

“I [am not convinced] that we’ve got to come up with some brand-new idea that never has been thought of before,” she said. “Practical solutions that are consistently applied may be the solution here. So, I’m very optimistic.”



1. Nazha B, Mishra M, Pentz R, Owonikoko TK. Enrollment of racial minorities in clinical trials: old problem assumes new urgency in the age of immunotherapy. 

2. Kaiser Family Foundation. State health facts: population distribution by sex: timeframe 2018. Published October 23, 2020. Accessed February 6, 2021. 

3. Murthy VH, Krumholz HM, Gross CP. Participation in cancer clinical trials: race-, sex-, and age-based disparities. 

. 2004;291(22):2720–2726. doi:10.1001/jama.291.22.2720

4. Bhatnagar V, Gormley N, Kazandjian D, et al. FDA analysis of racial demographics in multiple myeloma trials. 

. 2017;130(Suppl 1):4352. doi:10.1182/BLOOD.V130.SUPPL_1.4352.4352

5. Marinac CR, Ghobrial IM, Birmann BM, Soiffer J, Rebbeck TR. Dissecting racial disparities in multiple myeloma. 

. 2020;10(2):19. doi:10.1038/s41408-020-0284-7

6. Duma N, Vera Aguilera J, Paludo J, et al. Representation of minorities and women in oncology clinical trials: review of the past 14 years. 

. 2018;14(1):e1-e10. doi:10.1200/JOP.2017.025288

7. Batra A, Cheung WY. Role of real-world evidence in informing cancer care: lessons from colorectal cancer. 

. 2019;26(Suppl 1):S53-S56. doi:10.3747/co.26.5625

Jared Kaltwasser | Authors

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