Sarah Cannon

Jesus G. Berdeja, MD, the director of Multiple Myeloma Research at Sarah Cannon Research Institute, discusses updated safety results from the ongoing phase 1b/2 CARTITUDE-1 trial (NCT03548207) with the CAR T-cell therapy JNJ-4528 in multiple myeloma.

In the study, neurotoxicity was rare; only 1 patient reported an event that was grade 3 or higher in severity, Berdeja says. Significant cytopenias were also observed with JNJ-4528, including neutropenia and thrombocytopenia, although most events resolved within 60 days, says Berdeja. All-grade upper respiratory tract infections were reported in 31% of the patients, however, none of these infections were unexpected, adds Berdeja.

Additionally, results showed a 100% overall response rate with the product, which included a stringent complete response rate of 86% and very good partial response rate of 97% at a median follow-up of 11.5 months, explains Berdeja.

Finally, 16 patients with a CR achieved minimal residual disease (MRD)–negative disease status. Of those patients, 81% were MRD negative at 10-5 or better and 69% were MRD negative at 10-6. The estimated progression-free survival rate at 9 months was 86%, concludes Berdeja.

Videos

Jesus G. Berdeja, MD, discusses updated safety results from the ongoing phase 1b/2 CARTITUDE-1 trial (NCT03548207) with the CAR T-cell therapy JNJ-4528 in multiple myeloma.

Dr. Berdeja on Updated CARTITUDE-1 Results With JNJ-4258 in Multiple Myeloma

Stephanie L. Graff, MD, director of the Breast Program at the Sarah Cannon Cancer Institute of HCA Midwest Health and associate director of the Breast Cancer Research Program at Sarah Cannon Research Institute, discusses future research with immunotherapy in breast cancer.

Estrogen receptor–positive breast cancer has not been an area where immunotherapy is often considered, says Graff. However, the earlier patients who have other subtypes, such as triple-negative or HER2-positive disease are treated with this approach, the more robust their response will be, adds Graff.

Future trials should examine immunotherapy in carefully selected patients with hormone receptor–positive disease, says Graff. Going forward, efforts should focus on understanding how other genetic and genomic risk profiles impact treatment decisions, and likely other lines of therapy will be moved up into the earlier-phase setting, concludes Graff.

Stephanie L. Graff, MD, discusses future research with immunotherapy in breast cancer.

Dr. Graff on Future Research With Immunotherapy in Breast Cancer

Ian W. Flinn, MD, PhD, director of the Blood Cancer Research Program, Sarah Cannon Research Institute, discusses the role of BTK inhibitors in chronic lymphocytic leukemia (CLL).

BTK inhibitors such as ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa) have been transformative in the treatment of patients with B-cell malignancies such as CLL, mantle cell lymphoma, marginal zone lymphoma, and Waldenström's macroglobulinemia, says Flinn.

In CLL specifically, BTK inhibitors have become a prominent frontline standard of care, adds Flinn.

Though, it is important to acknowledge that the toxicities that are associated with ibrutinib, including arthralgias, atrial fibrillation, and, though rare, significant bleeding, often lead to treatment discontinuation in patients with CLL.

Ian W. Flinn, MD, PhD, discusses the role of BTK inhibitors in chronic lymphocytic leukemia.

Dr. Flinn on the Role of BTK Inhibitors in CLL

 On Air! I’m your host today, Caroline Seymour

, which provides oncology professionals with the resources and information they need to provide the best patient care. In both digital and print formats, 

 covers every angle of oncology practice, from new technology to treatment advances to important regulatory decisions.

Today, we had the pleasure of speaking with Howard A. "Skip" Burris, III, MD, FASCO, FACP, and Stephanie L. Graff, MD, both of Sarah Cannon Research Institute, to discuss the impact of COVID-19 on patients with breast cancer, the transition to telemedicine, the protocols their institution has put into place to reduce potential exposure to the virus, and some of the work HCA Midwest Health has been a part of regarding COVID-19 prevention and management.

Additionally, Dr. Burris and Dr. Graff shared some of the resources released by the American Society of Clinical Oncology (ASCO) for patients during the COVID-19 pandemic, explained how the society has leveraged its platform to help reestablish cancer care and research, and discussed the ultimate decision to make the 2020 ASCO Annual Meeting virtual.

In our exclusive interview, Dr. Burris, chief medical officer and president of Clinical Operations at Sarah Cannon Research Institute, 2019-2020 ASCO president-elect, and a 2014 

 in Drug Development, and Dr. Graff, director of the Breast Program at the Sarah Cannon Cancer Institute of HCA Midwest Health and associate director of the Breast Cancer Research Program at Sarah Cannon Research Institute, discussed how the pandemic has affected cancer care, the collaborative efforts made between Sarah Cannon and HCA to increase access to investigational COVID-19 treatments, and the steps ASCO has taken to ensure its members’ professional education and well-being during this time.

Podcasts

Howard A. "Skip" Burris, III, MD, FASCO, FACP, and Stephanie L. Graff, MD, discuss how the COVID-19 pandemic has affected cancer care, the collaborative efforts made between Sarah Cannon Research Institute and HCA to increase access to investigational COVID-19 treatments, and the steps ASCO has taken to ensure its members’ professional education and well-being during this time.

Dr. Burris and Dr. Graff Talk COVID-19 and Cancer Care, Telemedicine, and ASCO Initiatives

Therapeutic options for pretreated HER2-positive breast cancer now include tucatinib (Tukysa) as part of a triplet regimen with a tolerable safety profile that promises improved quality of life.

On April 17, 2020, the FDA approved tucatinib in combination with trastuzumab (Herceptin) and capecitabine (Xeloda) for adults with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received at least 1 prior anti—HER2-based regimen in the metastatic setting. Tucatinib is a HER2-directed tyrosine kinase inhibitor.

The approval is based on findings from the phase 2 HER2CLIMB study (NCT02614794), which demonstrated the triplet’s capacity to improve survival in patients with and without brain metastases. In the overall population, the median progression-free survival (PFS) with the 3-agent approach was 7.8 months versus 5.6 months with trastuzumab and capecitabine alone. Among those with brain metastases, median PFS was 7.6 months in the tucatinib arm versus 5.4 months in the control group.

, Erika P. Hamilton, MD, director of the Breast Cancer and Gynecologic Research Program at Sarah Cannon Research Institute in Nashville, Tennessee, discussed the regimen’s potential in earlier lines of therapy and how HER2CLIMB’s inclusion of patients with brain metastases has the power to move the needle in clinical investigations of therapies in this subgroup.

What was noteworthy about the efficacy data?

HER2CLIMB had 4 end points looking at progression-free survival, overall survival, overall response rate, and then progression-free survival among patients with brain metastases. The trial met all 4 of these end points, so it was a win across the board.

The activity in the population of patients with brain metastases really stood out. We have a lot of good therapies for breast cancer, but many of them do not cross the blood-brain barrier, so patients with brain metastases comprise a very highrisk patient population that is known to have worse outcomes. To have a drug that not only [meets end points] across the board but also benefits patients with brain metastases is meaningful. There is a statistic from the trial that [shows] the progression-free survival at 1 year among patients with brain metastases was 0% if they were not receiving tucatinib [compared with] a quarter of patients with brain metastases who remained on the trial at 1 year and were [receiving tucatinib].

Why is HER2CLIMB’s inclusion of a broad population of patients with brain metastases important?

In oncology trials, we commonly allow patients with brain metastases only if they have been treated with local therapy, such as resection or radiation and are stable 4 weeks after they finish local treatment. This trial was very different. HER2CLIMB allowed 3 different populations of patients with brain metastases to enroll: this traditional population with stable, pretreated brain metastases; metastases that had never been treated; and metastases that were treated and had progressed after. It was a very high-risk population.

Right now, I think that there is a lot of talk about how important clinical trials are and many patients’ trouble accessing them. We know that the best treatment option for a patient is enrolling on a clinical trial. There is also a lot of talk about how our inclusion criteria are a little too [strict], maybe [stricter] than they need to be, and historically, there has been some fear from drug companies because they do not want to include patients who may be sicker, not have optimal organ function, or in this case, have actively progressing brain metastases and may not do as well on therapy.

I think it was progressive, wise, and brave to allow these patients on the trial, who probably stood to benefit the most. After this trial, because it is the first one to do so, I think there will be many more companies who will follow suit.

How well is the tucatinib triplet regimen tolerated?

We normally give HER2 therapy in conjunction with chemotherapy. Capecitabine is an oral chemotherapy that tends to be pretty well tolerated. It does not cause hair loss, and it also does not cause a patient’s [white blood cell] counts to drop [significantly], so it is a favored chemotherapy partner in breast cancer. Trastuzumab is our most widely used HER2 antibody, and we learned that having a dual HER2 blockade such as trastuzumab with pertuzumab [Perjeta] or in this case, trastuzumab and tucatinib, can [lead to] additive [efficacy]. It is a very good combination, and I think that what is unique about tucatinib is this [agent] does not add a whole lot of toxicity.

The most common adverse events we saw in the trial were diarrhea, hand-foot syndrome, nausea, and fatigue, and those are the most common side events of capecitabine as a single agent. The addition of tucatinib added some liver dysfunction, about a 5% grade 3 elevation in liver function tests that was reversible.

The most important [characteristic] of tucatinib that is unlike other HER2 [agents] that we are familiar with like lapatinib [Tykerb] and neratinib [Nerylnx] is that tucatinib is specific and only blocks HER2, which makes it better tolerated than some of our more traditional options for HER2-positive breast cancer. Lapatinib and neratinib not only block HER2, but they also block HER1, or EGFR, and toxicities of rash and diarrhea come from EGFR [inhibition].

What are the next steps for the use of this regimen?

Can we move tucatinib earlier [in the treatment paradigm]? There is a lot of excitement around the brain metastases data, but I do not see this as a drug that I would only use in patients with brain metastases because it is an active regimen for the 52% of patients on the trial who did not have brain metastases. Because our systemic therapies are effective for HER2-positive breast cancer, these women are living longer and longer. Up to 50% of people with this disease will eventually develop brain metastases, which is quite a bit higher than some other types of cancer, so using a drug like tucatinib, even in the absence of brain metastases—that can get into the brain and work&mdash;may prevent brain metastases. I think an important question to ask moving forward is if we use tucatinib earlier, could we prevent brain metastases?

Figure. Tucatinib in Combination With Trastuzumab and Capecitabine (Click to Enlarge)

I am currently enrolling [patients in] the HER2CLIMB-02 trial [NCT03975647] of tucatinib in combination with T-DM1 [Kadcyla; ado-trastuzumab emtansine] or T-DM1 alone in the second-line setting.

Articles

Tucatinib Approval Adds Impact to HER2+ Breast Cancer Paradigm

Therapeutic options for pretreated HER2-positive breast cancer now include tucatinib (Tukysa) as part of a triplet regimen with a tolerable safety profile that promises improved quality of life.

On April 17, 2020, the FDA approved tucatinib in combination with trastuzumab (Herceptin) and capecitabine (Xeloda) for adults with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received at least 1 prior anti–HER2-based regimen in the metastatic setting. Tucatinib is a HER2-directed tyrosine kinase inhibitor.

The approval is based on findings from the phase 2 HER2CLIMB study (NCT02614794), which demonstrated the triplet’s capacity to improve survival in patients with and without brain metastases. In the overall population, the median progression-free survival (PFS) with the 3-agent approach was 7.8 months versus 5.6 months with trastuzumab and capecitabine alone. Among those with brain metastases, median PFS was 7.6 months in the tucatinib arm versus 5.4 months in the control group.

In an interview with 

®, Erika P. Hamilton, MD, director of the Breast Cancer and Gynecologic Research Program at Sarah Cannon Research Institute in Nashville, Tennessee, discussed the regimen’s potential in earlier lines of therapy and how HER2CLIMB’s inclusion of patients with brain metastases has the power to move the needle in clinical investigations of therapies in this subgroup.



HER2CLIMB had 4 end points looking at progression-free survival, overall survival, overall response rate, and then progression-free survival among patients with brain metastases. The trial met all 4 of these end points, so it was a win across the board.

The activity in the population of patients with brain metastases really stood out. We have a lot of good therapies for breast cancer, but many of them do not cross the blood-brain barrier, so patients with brain metastases comprise a very highrisk patient population that is known to have worse outcomes. To have a drug that not only [meets end points] across the board but also benefits patients with brain metastases is meaningful. There is a statistic from the trial that [shows] the progression-free survival at 1 year among patients with brain metastases was 0% if they were not receiving tucatinib [compared with] a quarter of patients with brain metastases who remained on the trial at 1 year and were [receiving tucatinib].





In oncology trials, we commonly allow patients with brain metastases only if they have been treated with local therapy, such as resection or radiation and are stable 4 weeks after they finish local treatment. This trial was very different. HER2CLIMB allowed 3 different populations of patients with brain metastases to enroll: this traditional population with stable, pretreated brain metastases; metastases that had never been treated; and metastases that were treated and had progressed after. It was a very high-risk population.

Right now, I think that there is a lot of talk about how important clinical trials are and many patients’ trouble accessing them. We know that the best treatment option for a patient is enrolling on a clinical trial. There is also a lot of talk about how our inclusion criteria are a little too [strict], maybe [stricter] than they need to be, and historically, there has been some fear from drug companies because they do not want to include patients who may be sicker, not have optimal organ function, or in this case, have actively progressing brain metastases and may not do as well on therapy.

I think it was progressive, wise, and brave to allow these patients on the trial, who probably stood to benefit the most. After this trial, because it is the first one to do so, I think there will be many more companies who will follow suit.





We normally give HER2 therapy in conjunction with chemotherapy. Capecitabine is an oral chemotherapy that tends to be pretty well tolerated. It does not cause hair loss, and it also does not cause a patient’s [white blood cell] counts to drop [significantly], so it is a favored chemotherapy partner in breast cancer. Trastuzumab is our most widely used HER2 antibody, and we learned that having a dual HER2 blockade such as trastuzumab with pertuzumab [Perjeta] or in this case, trastuzumab and tucatinib, can [lead to] additive [efficacy]. It is a very good combination, and I think that what is unique about tucatinib is this [agent] does not add a whole lot of toxicity.

The most common adverse events we saw in the trial were diarrhea, hand-foot syndrome, nausea, and fatigue, and those are the most common side events of capecitabine as a single agent. The addition of tucatinib added some liver dysfunction, about a 5% grade 3 elevation in liver function tests that was reversible.

The most important [characteristic] of tucatinib that is unlike other HER2 [agents] that we are familiar with like lapatinib [Tykerb] and neratinib [Nerylnx] is that tucatinib is specific and only blocks HER2, which makes it better tolerated than some of our more traditional options for HER2-positive breast cancer. Lapatinib and neratinib not only block HER2, but they also block HER1, or EGFR, and toxicities of rash and diarrhea come from EGFR [inhibition].





Can we move tucatinib earlier [in the treatment paradigm]? There is a lot of excitement around the brain metastases data, but I do not see this as a drug that I would only use in patients with brain metastases because it is an active regimen for the 52% of patients on the trial who did not have brain metastases. Because our systemic therapies are effective for HER2-positive breast cancer, these women are living longer and longer. Up to 50% of people with this disease will eventually develop brain metastases, which is quite a bit higher than some other types of cancer, so using a drug like tucatinib, even in the absence of brain metastases—that can get into the brain and work—may prevent brain metastases. I think an important question to ask moving forward is if we use tucatinib earlier, could we prevent brain metastases?

I am currently enrolling [patients in] the HER2CLIMB-02 trial [NCT03975647] of tucatinib in combination with T-DM1 [Kadcyla; ado-trastuzumab emtansine] or T-DM1 alone in the second-line setting.

Erika P. Hamilton, MD, director of the Breast Cancer and Gynecologic Research Program and principal investigator at Sarah Cannon Research Institute, discusses the evolution of treatment in HER2-positive breast cancer.

Women with early-stage HER2-positive breast cancer respond well to current therapies, evidenced by the fact that half of women with metastatic HER2-positive disease have de novo metastatic disease. This doesn't mean that de novo disease is becoming more common, says Hamilton, but rather that the women who receive neoadjuvant therapy tend not to relapse.

As the paradigm continues to evolve, the field may see more trials with immunotherapy. Immunotherapy has shown success in triple-negative breast cancer, and smaller trials have combined immunotherapy with HER2-directed agents. There is no reason to think that the combination of an immunotherapy drug and a targeted agent couldn’t lead to synergistic benefit in the HER2-positive breast cancer space as well, concludes Hamilton.

Erika P. Hamilton, MD, discusses the evolution of treatment in HER2-positive breast cancer.

Dr. Hamilton on the Evolution of Treatment in HER2+ Breast Cancer

Stephanie L. Graff, MD, director of the Breast Program at the Sarah Cannon Cancer Institute of HCA Midwest Health and associate director of the Breast Cancer Research Program at Sarah Cannon Research Institute, discusses the FDA approval of sacituzumab govitecan-hziy (Trodelvy) in metastatic triple-negative breast cancer (TNBC).

On April 22 2020, the FDA granted an accelerated approval to the antibody-drug conjugate (ADC) sacituzumab govitecan for the treatment of adult patients with metastatic TNBC who have received at least 2 prior therapies for metastatic disease. The approval is based on data from a phase I/II study, in which, at a median follow-up of 9.7 months, the objective response rate (ORR) was 33.3% by local assessment (95% CI, 24.6%-43.1%) with a median duration of response of 7.7 months (95% CI, 4.9-10.8). The clinical benefit rate (ORR plus stable disease) was 45.4%.

In January 2019, the FDA issued a complete response letter to Immunomedics regarding its biologics license application (BLA) for sacituzumab govitecan as a treatment for patients with metastatic TNBC who have received at least 2 prior therapies, citing chemistry, manufacturing, and control matters. Prior to that, the FDA had granted a priority review designation to the BLA for the ADC in July 2018, which was based on phase II results. The data showed that sacituzumab govitecan demonstrated an objective response rate of 34% in this patient population.

Graff explains that Sarah Cannon Research Institute was one of the centers with patients with metastatic TNBC enrolled on the sacituzumab govitecan trial. The long-term outcomes demonstrated with this drug have been “remarkable,” she says. This will now be another tool in the physician’s armamentarium to manage TNBC.

Stephanie L. Graff, MD, director of the Breast Program at the Sarah Cannon Cancer Institute of HCA Midwest Health and associate director of the Breast Cancer Research Program at Sarah Cannon Research Institute, discusses the FDA approval of sacituzumab govitecan in metastatic triple-negative breast cancer (TNBC).

Dr. Graff on the FDA Approval of Sacituzumab Govitecan in TNBC

Erika P. Hamilton, MD, director of the Breast Cancer and Gynecologic Research Program and principal investigator at Sarah Cannon Research Institute, discusses the FDA approval of tucatinib (Tukysa) in HER2-positive breast cancer.

On April 17, 2020, the FDA approved the combination of tucatinib, trastuzumab (Herceptin), and capecitabine (Xeloda) for the treatment of patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including patients with brain metastases, following at least 1 prior therapy.

The approval is based on data from the phase II HER2CLIMB trial which showed a 34% reduction in the risk of death with the triplet versus trastuzumab/capecitabine alone in heavily pretreated patients. The median overall survival was 21.9 months and 17.4 months with the triplet and doublet, respectively (HR, 0.66; 95% CI, 0.50-0.88;&#8239;

&#8239;= .0048). Moreover, overall response rate and progression-free survival in the overall population and in patients with brain metastases at baseline favored the use of tucatinib.

Notably, 48% and 46% of patients had metastases at baseline in the triplet and doublet arms, respectively, representing a high-risk population, says Hamilton. The study is the first randomized trial in HER2-positive metastatic breast cancer to include patients with untreated or previously treated, progressive brain metastases. The regimen is going to be an important addition to the armamentarium for patients with or without brain metastases, concludes Hamilton.

Dr. Hamilton on the FDA Approval of Tucatinib in HER2+ Breast Cancer

Stephanie L. Graff, MD, director of the Breast Program at the Sarah Cannon Cancer Institute of HCA Midwest Health and associate director of the Breast Cancer Research Program at Sarah Cannon Research Institute, discusses genomic risk prediction in patients with hormone receptor (HR)—positive, HER2-negative breast cancer.

The phase III TAILORx study enrolled women with HR-positive, HER2—negative, axillary node–negative breast cancer. Approximately 69% of patients had a midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. Endocrine therapy proved to be noninferior to chemoendocrine therapy in terms of invasive disease-free survival.

This study showed that genomic risk prediction is a stronger tool to utilize than clinical risk, says Graff. Genomic score outperforms tumor size and grade, adds Graff. The role of the clinical predictors is personalizing care for women with intermediate Oncotype recurrence scores between 14 and 20; this is where the benefit of chemotherapy starts to be incrementally larger based on patients’ overall clinical risk profile, concludes Graff.

Stephanie L. Graff, MD, discusses genomic risk prediction in patients with hormone receptor–positive, HER2-negative breast cancer.

Sarah Cannon

Dr. Berdeja on Updated CARTITUDE-1 Results With JNJ-4258 in Multiple Myeloma

Dr. Graff on Future Research With Immunotherapy in Breast Cancer

Dr. Flinn on the Role of BTK Inhibitors in CLL

Dr. Burris and Dr. Graff Talk COVID-19 and Cancer Care, Telemedicine, and ASCO Initiatives

Tucatinib Approval Adds Impact to HER2+ Breast Cancer Paradigm

Tucatinib Approval Adds Impact to HER2+ Breast Cancer Paradigm

Dr. Hamilton on the Evolution of Treatment in HER2+ Breast Cancer

Dr. Graff on the FDA Approval of Sacituzumab Govitecan in TNBC

Dr. Hamilton on the FDA Approval of Tucatinib in HER2+ Breast Cancer

Dr. Graff on Genomic Risk Prediction in HR+/HER2- Breast Cancer