Richard L. Schilsky, MD, FACP, FSCT, FASCO
In 2013, during the ASCO Annual Meeting, Richard L. Schilsky, MD, FACP, FSCT, FASCO, then ASCO’s Chief Medical Officer, presented a bold clinical trial concept during an educational session on the challenges of delivering precision medicine services in an oncology community care setting. The idea was to design a clinical study that would serve two purposes: match commercially available targeted therapies to the genomic profile of patients’ tumors to determine the activity of the drugs when used off label; and simplify patients’ access to the drugs, providing patients with truly personalized cancer care—and at no cost.
After presenting the concept to ASCO’s Cancer Research Committee, Dr. Schilsky received approval and funding from ASCO to proceed with development of the Targeted Agent and Profiling Utilization Registry (TAPUR) study, a first-of-its kind prospective, nonrandomized clinical trial, which uses modern research methods to address gaps in scientific knowledge by adopting a tumor-agnostic approach to matching patients with drugs based on their tumor’s genomic profile.
With the official launch in 2016, TAPUR has achieved much success over the last decade, including enrolling more than 3,000 patients across 274 sites nationwide, with additional sites opening later this year in Puerto Rico, and generating results that have been cited more than 800 times in scientific journals. Some successes since TAPUR’s launch include:
- The study of 26 different United States Food and Drug Administration (FDA)-approved targeted anticancer agents, as either monotherapies or combination therapies, to learn how they perform outside of their FDA-approved indications;
- The additions earlier this year of the study’s first antibody-drug conjugate, fam-trastuzumab deruxtecan-nxki (T-DXd); and the combination therapy of dabrafenib and trametinib for the treatment of solid tumors with BRAF V600E mutations;
- The contribution of impactful data that have been incorporated into multiple clinical guidelines; and
- The development of similar precision medicine studies outside of the United States, including in Canada, Europe, and Asia.
Transitioning to a New Role
Last fall, ASCO announced that Dr. Schilsky would be transitioning into a new role at TAPUR as Founding Principal Investigator of TAPUR, and in February, the Society named Neal J. Meropol, MD, FASCO, as Principal Investigator of TAPUR.
“Primarily, I will be involved in the frontend of TAPUR and the backend,” explained Dr. Schilsky. “What I mean by that is I plan to continue to be involved in identifying new treatments for the study in discussion with various drug companies about the opportunity to put their treatments onto the TAPUR platform. On the other end, when we produce results, I’ll be involved in writing the study abstracts and manuscripts as I have been doing all these years. Everything in between, including the day-to-day operations of the study, will be Dr. Meropol’s responsibility. He’s an experienced clinical trialist who is deeply committed to improving access to novel treatments by providing patients with an opportunity to participate in clinical trials, and I look forward to working closely with him to advance the objectives of the TAPUR study.”
Dr. Schilsky’s medical career spans nearly 5 decades and includes a roster of extraordinary accomplishments in patient care, research, and mentoring. He has held leadership positions in academia, first at the University of Chicago, where he spent the bulk of his career; and as Chair of the Cancer and Leukemia Group B (CALGB, now part of the Alliance) from 1995-2010. An ASCO member since 1980, Dr. Schilsky has served in a variety of capacities in the Society, both as a volunteer and as a staff executive, including as President from 2008-2009; and as ASCO’s first Chief Medical Officer and Executive Vice President from 2013 until his retirement in 2021.
In this wide-ranging interview with The ASCO Post, Dr. Schilsky discussed how the TAPUR study is turning genomic insights into real-world treatment options for patients who have exhausted their treatment possibilities, the potential future role of artificial intelligence (AI) in the study, and what’s ahead for the TAPUR study.
Measuring Success
Please talk about the results of the TAPUR study concept so far. Has it met your expectations, and what are some scientific advancements as a result of the study’s findings?
When we launched TAPUR in 2016, we had no idea of what to expect in terms of how well it would be accepted in the oncology community. And I recall telling the TAPUR team that we had assembled at ASCO that if this study ran for 3 years and enrolled 1,000 patients, I would be thrilled. Here we are 10 years later, and we’ve enrolled more than 3,000 patients, so the study concept has far exceeded my expectations for acceptance by the oncology community and the number of patients that might potentially participate in the study.
We intended from the start of TAPUR to be very pragmatic. We wanted the study protocol to be simple to operate for both patients and clinicians. We wanted it to be easily accessible for patients in the communities where they were being treated; and we wanted the study to generate high-quality information with a minimum of burden on the research site. I think we have achieved all those things.
In terms of scientific achievements, they are all available to the general public on the ASCO website (www.asco.org/research-data/tapur-study/study-results). I’ll highlight a few of them here.
One important success is our experience of using the PARP inhibitor olaparib to treat tumors with the BRCA1/2 mutations. Olaparib has been a breakthrough FDA-approved drug in the treatment of breast and ovarian cancers, as well as in the treatment of pancreatic and prostate cancers. We have shown in the TAPUR study that, one, the drug is active in other cancer types harboring the BRCA mutations, including biliary tract cancer, lung cancer, and uterine cancer, among others. Two, we’ve expanded the data available from studies sponsored by olaparib’s manufacturer, AstraZeneca. For example, in one study investigating the drug in men with metastatic prostate cancer, about 100 men were randomized to receive olaparib. One patient out of 100 was Black or African American. In our TAPUR study of olaparib in men with advanced prostate cancer with the BRCA mutations, 23% were Black or African American. Now, that’s still not a huge number of individuals because it was a small total number of participants, but it showed that we can reach a population of patients with TAPUR that is much more representative of the United States population. And, we can offer some assurance to Black men with prostate cancer that olaparib can be effective for them, too.
Another example is our study of olaparib in the treatment of patients with advanced pancreatic cancer. Olaparib was FDA approved as a maintenance therapy following chemotherapy, and it clearly has efficacy in that setting. In the TAPUR study, we investigated a group of patients with the disease who had exhausted all their standard chemotherapy options. They all had tumors with BRCA gene mutations and received single agent olaparib. We found that not only did the drug have good activity in these patients, but two patients achieved complete responses, with one of the patients maintaining a complete response on continuing treatment for 250 weeks, which is nearly 5 years.
These results got almost no fanfare compared to the publicity surrounding the new KRAS inhibitor daraxonrasib for the treatment of advanced pancreatic cancer. Although the TAPUR trial wasn’t a large, randomized study that showed a convincing improvement in overall survival, nevertheless, it is clear from our results that olaparib could be useful even in some patients with BRCA-related advanced pancreatic disease, with some even experiencing exceptional clinical benefit.
The last example I’ll give is TAPUR results in patients with ERBB2/ERBB3 (HER2/HER3)–amplified cancers. Amplification of these genes occurs across a variety of cancer types. We have now reported six cohorts of patients with different solid tumor cancers, including colorectal, endometrial, gallbladder, and non-small cell lung cancers, among others, who achieved a clinical benefit with a combination of the monoclonal antibodies pertuzumab and trastuzumab.
This drug combination does not have tumor-agnostic FDA approval. The only FDA tumor-agnostic approval is for the HER2-directed treatment T-DXd. But that approval is based on immunohistochemistry (IHC) 3+ protein overexpression, and not ERBB2/3 amplification.
Our results have been incorporated in a number of clinical practice guidelines and, although there is no broad FDA approval for this treatment in this setting, our data have shown that this is a strategy that can be effective in a whole variety of cancers.
These are the kinds of results we have seen with TAPUR. Of course, we have had many negative results as well. And it’s important to emphasize those findings as well because all of the drugs in the study have FDA approval and are commercially available. But if they are not effective, oncologists need this information, so they don’t subject patients to treatments that are unlikely to be effective.
Finding New Avenues to Treat Patients With Advanced Disease
In April, TAPUR announced the addition of the antibody-drug conjugate T-DXd and the combination therapy of dabrafenib and trametinib. Please talk about how these additions may impact patients with unresectable or metastatic solid tumors that have no satisfactory alternative treatment options.
On April 5, 2024, the FDA granted accelerated approval to T-DXd for patients with any solid HER2-mutated tumors with IHC 3+ overexpression.1 But there are some patients who have lower levels of IHC 3+ expression who would not be eligible to receive this drug under this FDA approval.
In our discussions with AstraZeneca we asked if the company would be interested in learning whether T-DXd has activity in tumors with amplifications of the ERBB2 gene, regardless of the level of protein expression in the tumor, and that’s what we are studying now in TAPUR. If we find drug activity in this setting it would open up a whole new way of qualifying patients to receive T-DXd, potentially for any cancer that carries an ERBB2 gene amplification, as well as tumors with high expression of HER2.
The combination of dabrafenib and trametinib is an interesting story as well. The treatment combination has an FDA tumor-agnostic approval for any solid tumor harboring a BRAF V600E gene mutation. However, the datasets companies submit to FDA for tumor agnostic approval don’t actually include every cancer type, so the FDA gave Novartis, manufacturer of dabrafenib and trametinib, a postmarketing requirement to get additional data on patients with rare cancers harboring the BRAF V600E mutation. Novartis asked if we could help gather this data, which we were happy to do. We were told that the data would be acceptable for submission to the FDA, which is a very important signal to us that we are generating high-quality data.
An important component of the TAPUR study is that the drugs are provided free to patients. So, for patients with no insurance, inadequate insurance, or who cannot afford on-label co-pays for these drugs, TAPUR offers a real opportunity for patients with rare cancers to receive FDA-approved treatment at no cost. Hopefully, that will be a huge benefit for many patients.
Turning Genomic Insights Into Real-World Treatment Options for Patients
Since TAPUR launched a decade ago, more than 3,000 patients with advanced cancers across 274 sites nationwide have been enrolled. Please talk about how the results from TAPUR are turning genomic insights into real-world treatment options for patients who have exhausted their treatment possibilities. Has the trial improved outcomes for patients, providing better disease control and extending survival?
Those are hard questions to answer because TAPUR wasn’t designed to address those outcomes. The trial is designed to seek signals of activity of drugs outside of FDA-approved indications.
There is no question that there are some patients who have realized long-term benefit from being in the trial. We are in the process now of compiling our results on exceptional responders in the study. These are patients who have been on a TAPUR study treatment for 6 months or longer and have achieved disease control. We’ve calculated the percentage to be about 15% of the total study population of 3,000 plus patients. Another fraction of those patients has achieved disease control on treatment for more than a year. And there are a few patients who have experienced disease control on treatment for many years.
We are trying to understand who these patients are; what are the specific tumor mutations they have; what treatments have they received; and what makes them different from similar patients who have not experienced such prolonged benefit. But it is clear that there is a proportion of patients who have been on the study who were told that there were no longer standard treatment options available to them, who are alive for many months and even many years, and continuing to benefit.
Using AI to Interpret the Genomic Profile of a Tumor
What impact might AI have in helping match patients to specific drugs in the TAPUR study?
We are not using AI in TAPUR. It’s a great question, and the answer is complicated. There are many companies that are developing AI-driven software tools to match patients to eligibility criteria in clinical trials, and those tools remain to be proven effective. Our eligibility criteria in TAPUR are already pretty broad and include that patients must have advanced, measurable solid tumors that no longer respond to standard treatments and that a genomic or molecular test has been performed on the tumor. So, I’m not sure AI can help us enroll more patients.
What I’m a little bit more hopeful about with AI may be its ability to interpret the genomic profiling results on these tumors, because it is clear that in many cases it’s not just one gene that needs to be targeted. It may be a whole pathway or it may be a network of genes. We also have examples in TAPUR showing that a treatment against a particular genomic alteration works in some cancer types but not in all. So, there clearly is heterogeneity across different tumor types in terms of the importance of a particular pathway.
That’s what makes me hopeful about AI, because it would be great to be able to feed a genomic report into an AI algorithm and have it select the optimal treatment or the optimal combination of drugs for a particular patient. I know there are companies working on those approaches.
However, again, this technology needs to be further developed and validated before it can be used in routine clinical care.
There is a lot of promise with AI. We are not using this technology in TAPUR now and we don’t have plans to use it any time soon. But if there is an appropriate approach that comes along in the future that looks useful in treatment selection, perhaps TAPUR could be a platform that is used to test the technology.
Learning New Uses for Drugs Outside of Their Approved Indications
What is next for TAPUR?
In terms of our network, we still have sites around the country that are interested in participating in the TAPUR protocol. And our team at ASCO routinely evaluates sites that submit their information and recommends additional sites for activation in the TAPUR study.
Our big focus right now is getting more interesting drugs into the study. Many of the current drugs have run their course and we need to refresh the study with the newer generation of anticancer agents. We are always looking for therapies on the horizon that will soon get FDA approval to see whether they are suitable for TAPUR.
Each year during the ASCO Annual Meeting, we meet with pharma companies to discuss whether their drugs might be appropriate for TAPUR. It’s been a bit of a challenge in recent years, in part because the success of TAPUR has encouraged some companies to conduct similar studies on their own with their own products, with the potential to get a tumor agnostic approval from the FDA.
And that FDA strategy, whereas it’s great for patients, has been problematic for studies like TAPUR because our whole thesis from its launch is that we could learn about new uses for cancer agents outside of their approved indication. But if the FDA is giving tumor-agnostic approvals, there is no such thing as “off-label” use. Although, TAPUR can still be useful to evaluate alternative drug targets outside the approved label as we are doing with T-DXd or in collecting information on treatment efficacy in tumor types not included in the tumor-agnostic approval dataset, as we are doing with dabrafenib plus trametinib.
One example is that when Merck received its tumor-agnostic approval for pembrolizumab for cancers with high tumor mutation burden, the dataset the company submitted to the FDA for approval included patients with small cell lung cancer and various types of gynecological malignancies. But there were no patients with breast cancer.
Meanwhile, we had been studying pembrolizumab in patients with metastatic breast cancer with high tumor mutation burden in the TAPUR study. We published the data in the Journal of Clinical Oncology, in 2021, showing that pembrolizumab monotherapy had antitumor activity in this population of heavily pretreated patients.2
Now, at the time we published this data, the FDA had already granted a tumor-agnostic indication for pembrolizumab, so you might ask, what information did we add to its clinical use? I would say we added actual data to support using this drug in patients with advanced breast cancer with high tumor mutation burden.
So, TAPUR data continues to broaden the knowledge base regarding treatment efficacy of approved drugs, providing alternative treatment options for patients who have exhausted standard-of-care therapies.
DISCLOSURE: Dr. Schilsky holds leadership positions with Clarified Precision Medicine and Leap Therapeutics and has stock and other ownership interests in Leap Therapeutics. He receives honoraria from Toray Industries, Wugen, Inc., and AbbVie. He is a consultant for Cellworks, Zephyr AI, and Sygnomics; and reports research funding from AstraZeneca, Bayer, Bristol-Myers-Squibb, Genentech/Roche, Lilly, Merck, Pfizer, Boehringer Ingelheim, and Taiho Oncology.
REFERENCES
1. United States Food and Drug Administration: FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. Available at www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2. Accessed June 10, 2026.
2. Alva AS, Mangat PK, Garrett-Mayer E, et al: Pembrolizumab in patients with metastatic breast cancer with high tumor mutational burden: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study. J Clin Oncol 39:2443-2451, 2021.
Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO or The ASCO Post.
