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TAPUR study fulfilling need to better understand targeted therapies, ASCO’s Schilsky says

Richard L. Schilsky, MD, FACP, FASCO, ASCO
Richard L. Schilsky

The Targeted Agent and Profiling Utilization Registry , or TAPUR, study is fulfilling a need in clinical research across the United States for patients with advanced cancers that have actionable genomic variants, according to Richard L. Schilsky, MD, FACP, FASCO, ASCO senior vice president and chief medical officer.

While there certainly is a need to evaluate new drugs and new targets, there is also a great need to better understand how our available drugs can work in patients who have genomic abnormalities in their cancers, and this is what we are trying to learn about with TAPUR,” Schilsky said during an interview with HemOnc Today. “We are excited with the progress that the study has made so far, and we look forward to a lot more results coming out in the next few years.”

There are currently 120 TAPUR study sites across 20 states, and more than 1,500 participants have received study therapy. All seven pharmaceutical companies currently participating in the study have renewed their commitment to support the research and provide study drugs at no cost for an additional 1 to 3 years, according to a press release.

HemOnc Today spoke with Schilsky about the most recent data presented during the American Association for Cancer Research and ASCO annual meetings, as well as continued research efforts underway.

Question: What is the overall aim of TAPUR research?

Answer : The overarching goal of TAPUR is to learn from the off-label prescribing of targeted drugs for patients who have an advanced cancer with a specific genomic alteration that might be an appropriate match for the targeted drug. As genomic profiling becomes more available, more clinicians are recommending that patients have their tumors profiled, particularly when they have exhausted all standard therapies, to see if there is a genomic alteration in the cancer that might be effectively treated by a targeted drug. Often, the drug(s) that might be used are already marketed for another indication, but not for the specific cancer type. This means that the drug typically would have to be prescribed off-label, and that creates difficulties for many patients in terms of accessing the drug and getting it paid for by their insurance. More importantly, there has been no mechanism to learn from their experience of getting that treatment. We set up the TAPUR study, to try to solve both of these issues — the access issue, by having as many companies as are interested donate the drugs to the study, and the learning issue, by systematically recording the outcomes of the patients who are receiving these treatments so that we can learn about whether or not prescribing these therapies in this off-label fashion is worthwhile.

At a scientific level, the primary objective of TAPUR is to detect signals of activity for a marketed targeted drug prescribed outside of the FDA-approved indication in a patient with cancer that has a specific genetic alteration. In our protocol, for each of the drugs or combination treatments that are available, specific criteria determine what genomic alterations are considered a match for the drug. Our statistical plan states that we will enroll 10 patients in a cohort, and if we do not see at least two responses to treatment, then we stop enrolling in that cohort because we think the drug is unlikely to be effective. If we see two or more responses in a cohort, we add patients (up to a total of 28), and if we detect responses in at least seven of the 28 patients, we conclude that the drug is showing sufficient evidence of activity and should be studied further.

Q: What did results suggest from data presented during th is year’s AACR Annual Meeting?

A: One of the abstracts reported on cohorts of patients with breast cancer and non-small cell lung cancer using cetuximab (Erbitux, Bristol-Myers Squibb), which targets the epidermal growth factor receptor. We required that these patients not have any mutations in the genes KRAS, NRAS or BRAF, which are associated with resistance to cetuximab. Despite that, neither of these cohorts satisfied our criteria for demonstrating drug activity. There were 10 patients in each cohort and none had an objective response or stable disease for at least 4 months.

The same basic observation was made in a cohort of patients with advanced colorectal cancer — all of whom had amplification of the gene FLT3, which is a known target for treating acute leukemia. There are at least two FDA-approved antagonists for treating FLT3-mutated acute leukemia. In this case, we looked at FLT3 amplification. We did not have a specific inhibitor, but we were studying the drug sunitinib (Sutent, Pfizer) which has a lot of different targets, including FLT3. Again, unfortunately, no objective responses were observed. Two patients had stable disease at the 16-week evaluation, but both died very shortly after that, so we concluded that the drug did not have sufficient activity to be studied further in this population.

Q: What is the rationale for publishing these negative results?

A: The purpose is to inform the clinical community that they should not prescribe these drugs off-label to these patient populations. Instead, we should direct those patients to other clinical trials that might have a greater benefit for them. For TAPUR, although we think that positive results are going to be exciting and open up new possibilities for treatment, we also think that negative results are extremely important. All of the drugs we are studying are already commercially available, so the physician could use them, but when we have data to suggest that they are not going to be effective in a particular population of patients, we want to get that information out there and discourage that use.

Q: What did results suggest from data presented during this year’s ASCO Annual Meeting?

A: We presented two abstracts at ASCO Annual Meeting. One of them reported on palbociclib (Ibrance, Pfizer) among patients with NSCLC with alterations in the gene CDKN2A. The other study examined pembrolizumab (Keytruda, Merck) among patients with metastatic breast cancer with a high tumor mutational burden. Both of those cohorts met our criteria for being positive. They both enrolled up to 28 patients. Disease control (stable disease plus objective response) was observed among 29% of patients with NSCLC and a CDKN2A alteration treated with palbociclib. The objective response rate was 3.6%. Disease control was observed among 37% of patients with breast cancer and a high tumor mutational burden treated with pembrolizumab, and the objective response rate was 21%. Neither of these drugs currently is FDA approved for use in NSCLC or breast cancer. So, our results, at the very least, suggest these drugs should be studied further in those patient populations.

Q: What can clinicians look forward to regarding TAPUR research?

A: A lot more TAPUR results will be rolling out this year. We intend to present other positive results among patients with colorectal cancer at the Gastrointestinal Cancers Symposium in January. I anticipate that, with more than 1,500 patients treated, the results are going to keep coming as these patient cohorts continue to mature. – by Jennifer Southall

References:

Ahn ER, et al. Abstract 9041. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Alva AS, et al. Abstract 1014. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Alvarez RH, et al. Abstract CT146/12. Presented at: AACR Annual Meeting; March 29-April 3, 2019; Atlanta.

Fisher J, et al. Abstract CT135/1. Presented at: AACR Annual Meeting; March 29-April 3, 2019; Atlanta.

For more information:

Richard L. Schilsky, MD, FACP, FASCO, can be reached at American Society of Clinical Oncology, 2318 Mill Road, Suite 800, Alexandria, VA 22314.

Disclosure: Schilsky reports no relevant financial disclosures.

Richard L. Schilsky, MD, FACP, FASCO, ASCO
Richard L. Schilsky

The Targeted Agent and Profiling Utilization Registry , or TAPUR, study is fulfilling a need in clinical research across the United States for patients with advanced cancers that have actionable genomic variants, according to Richard L. Schilsky, MD, FACP, FASCO, ASCO senior vice president and chief medical officer.

While there certainly is a need to evaluate new drugs and new targets, there is also a great need to better understand how our available drugs can work in patients who have genomic abnormalities in their cancers, and this is what we are trying to learn about with TAPUR,” Schilsky said during an interview with HemOnc Today. “We are excited with the progress that the study has made so far, and we look forward to a lot more results coming out in the next few years.”

There are currently 120 TAPUR study sites across 20 states, and more than 1,500 participants have received study therapy. All seven pharmaceutical companies currently participating in the study have renewed their commitment to support the research and provide study drugs at no cost for an additional 1 to 3 years, according to a press release.

HemOnc Today spoke with Schilsky about the most recent data presented during the American Association for Cancer Research and ASCO annual meetings, as well as continued research efforts underway.

Question: What is the overall aim of TAPUR research?

Answer : The overarching goal of TAPUR is to learn from the off-label prescribing of targeted drugs for patients who have an advanced cancer with a specific genomic alteration that might be an appropriate match for the targeted drug. As genomic profiling becomes more available, more clinicians are recommending that patients have their tumors profiled, particularly when they have exhausted all standard therapies, to see if there is a genomic alteration in the cancer that might be effectively treated by a targeted drug. Often, the drug(s) that might be used are already marketed for another indication, but not for the specific cancer type. This means that the drug typically would have to be prescribed off-label, and that creates difficulties for many patients in terms of accessing the drug and getting it paid for by their insurance. More importantly, there has been no mechanism to learn from their experience of getting that treatment. We set up the TAPUR study, to try to solve both of these issues — the access issue, by having as many companies as are interested donate the drugs to the study, and the learning issue, by systematically recording the outcomes of the patients who are receiving these treatments so that we can learn about whether or not prescribing these therapies in this off-label fashion is worthwhile.

PAGE BREAK

At a scientific level, the primary objective of TAPUR is to detect signals of activity for a marketed targeted drug prescribed outside of the FDA-approved indication in a patient with cancer that has a specific genetic alteration. In our protocol, for each of the drugs or combination treatments that are available, specific criteria determine what genomic alterations are considered a match for the drug. Our statistical plan states that we will enroll 10 patients in a cohort, and if we do not see at least two responses to treatment, then we stop enrolling in that cohort because we think the drug is unlikely to be effective. If we see two or more responses in a cohort, we add patients (up to a total of 28), and if we detect responses in at least seven of the 28 patients, we conclude that the drug is showing sufficient evidence of activity and should be studied further.

Q: What did results suggest from data presented during th is year’s AACR Annual Meeting?

A: One of the abstracts reported on cohorts of patients with breast cancer and non-small cell lung cancer using cetuximab (Erbitux, Bristol-Myers Squibb), which targets the epidermal growth factor receptor. We required that these patients not have any mutations in the genes KRAS, NRAS or BRAF, which are associated with resistance to cetuximab. Despite that, neither of these cohorts satisfied our criteria for demonstrating drug activity. There were 10 patients in each cohort and none had an objective response or stable disease for at least 4 months.

The same basic observation was made in a cohort of patients with advanced colorectal cancer — all of whom had amplification of the gene FLT3, which is a known target for treating acute leukemia. There are at least two FDA-approved antagonists for treating FLT3-mutated acute leukemia. In this case, we looked at FLT3 amplification. We did not have a specific inhibitor, but we were studying the drug sunitinib (Sutent, Pfizer) which has a lot of different targets, including FLT3. Again, unfortunately, no objective responses were observed. Two patients had stable disease at the 16-week evaluation, but both died very shortly after that, so we concluded that the drug did not have sufficient activity to be studied further in this population.

PAGE BREAK

Q: What is the rationale for publishing these negative results?

A: The purpose is to inform the clinical community that they should not prescribe these drugs off-label to these patient populations. Instead, we should direct those patients to other clinical trials that might have a greater benefit for them. For TAPUR, although we think that positive results are going to be exciting and open up new possibilities for treatment, we also think that negative results are extremely important. All of the drugs we are studying are already commercially available, so the physician could use them, but when we have data to suggest that they are not going to be effective in a particular population of patients, we want to get that information out there and discourage that use.

Q: What did results suggest from data presented during this year’s ASCO Annual Meeting?

A: We presented two abstracts at ASCO Annual Meeting. One of them reported on palbociclib (Ibrance, Pfizer) among patients with NSCLC with alterations in the gene CDKN2A. The other study examined pembrolizumab (Keytruda, Merck) among patients with metastatic breast cancer with a high tumor mutational burden. Both of those cohorts met our criteria for being positive. They both enrolled up to 28 patients. Disease control (stable disease plus objective response) was observed among 29% of patients with NSCLC and a CDKN2A alteration treated with palbociclib. The objective response rate was 3.6%. Disease control was observed among 37% of patients with breast cancer and a high tumor mutational burden treated with pembrolizumab, and the objective response rate was 21%. Neither of these drugs currently is FDA approved for use in NSCLC or breast cancer. So, our results, at the very least, suggest these drugs should be studied further in those patient populations.

Q: What can clinicians look forward to regarding TAPUR research?

A: A lot more TAPUR results will be rolling out this year. We intend to present other positive results among patients with colorectal cancer at the Gastrointestinal Cancers Symposium in January. I anticipate that, with more than 1,500 patients treated, the results are going to keep coming as these patient cohorts continue to mature. – by Jennifer Southall

References:

Ahn ER, et al. Abstract 9041. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Alva AS, et al. Abstract 1014. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Alvarez RH, et al. Abstract CT146/12. Presented at: AACR Annual Meeting; March 29-April 3, 2019; Atlanta.

Fisher J, et al. Abstract CT135/1. Presented at: AACR Annual Meeting; March 29-April 3, 2019; Atlanta.

For more information:

Richard L. Schilsky, MD, FACP, FASCO, can be reached at American Society of Clinical Oncology, 2318 Mill Road, Suite 800, Alexandria, VA 22314.

Disclosure: Schilsky reports no relevant financial disclosures.

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