Kamran A. Ahmed, MD, an assistant member in the Department of Radiation Oncology and the Department of Immunology at Moffitt Cancer Center and an assistant professor in the Department of Oncologic Sciences at the University of South Florida, discusses remaining questions with the use of tucatinib (Tukysa) in breast cancer–related brain metastases.

demonstrated that tucatinib has a role in metastatic breast cancer, says Ahmed. What is interesting to see from the central nervous system data presented during the 

 is the potential role that systemic therapies, such as tucatinib, have in the management of patients with active brain metastases who have not received previous local therapy.

However, questions remain with regard to the agent’s potential role in the management of patients with small asymptomatic brain metastases. In order to examine the intracranial response rate data in greater detail, the full study will need to be released; however, the available data reported thus far is quite intriguing, concludes Ahmed.

Videos

Kamran A. Ahmed, MD, discusses remaining questions with the use of tucatinib in breast cancer–related brain metastases.

Dr. Ahmed on Remaining Questions With Tucatinib in Breast Cancer Brain Metastases

Muhammad Bilal Abid, MD, MRCP, assistant professor of medicine in the Divisions of Hematology/Oncology and Infectious Diseases at the Medical College of Wisconsin, discusses challenges with CAR-T cell therapy during the coronavirus disease 2019 (COVID-19) pandemic.

COVID-19 has caused many disruptions in the administration of CAR T-cell therapy​, says Abid. As such, several considerations need to be taken into account.

To mitigate the risk of severe cytokine release syndrome, ​CAR T-cell therapy should be brought to a temporary halt​, Abid explains. Doing so will prevent dysfunctional T cells and an elevation of inflammatory cytokines.

After stopping CAR T-cell therapy, it is critical to closely monitor patients, Abid concludes.

Muhammad Bilal Abid, MD, MRCP, discusses challenges with CAR-T cell therapy during the coronavirus disease 2019 pandemic.

Dr. Abid on Challenges With CAR T-Cell Therapy During the COVID-19 Pandemic 

Luciano J. Costa, MD, PhD, an associate professor of medicine in the Blood and Marrow Transplantation and Cell Therapy Program at the University of Alabama's Birmingham School of Medicine, discusses unmet need​s in relapsed/refractory multiple myeloma. 

Despite recent advancements in the multiple myeloma space, several challenges need to be addressed, says Costa. 

Some patients progress after proteasome inhibitors, immunomodulatory drugs​, and monoclonal antibodies​, Costa explains. Moreover, there are limited options that can support patients in these ​scenario​s.

A majority of available or emerging therapies produce low response rate​s of around 30%. ​As such, developing more effective and safer regimens remains an unmet need in this setting, Costa concludes.

Luciano J. Costa, MD, PhD, discusses unmet need​s in relapsed/refractory multiple myeloma. 

  Dr. Costa on Unmet Needs in Relapsed/Refractory Multiple Myeloma 

Gary K. Schwartz, MD, professor of medicine, chief, Division of Hematology​/Oncology, ​deputy director, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, discusses the results from the gastrointestinal stromal tumor (GIST) cohort of the phase 2 Alliance A091401 trial.

In the Alliance A091401 trial, patients with advanced sarcoma were randomized to receive nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy).

In the United States, GIST is a common sarcoma ​subtype, ​and finding new therapies is of critical importance​, says Schwartz.

Until the GIST cohort was added to the trial, it was unknown whether patients with GIST could benefit from immunotherapy, Schwartz explains.

However, no patients in the GIST cohort achieved a partial or complete response with either the single agent or combination regimen, and the trial was stopped ​early due to increased treatment-related adverse effects, Schwartz concludes.

Gary K. Schwartz, MD,  discusses the results from the gastrointestinal stromal tumor cohort of the phase 2 Alliance A091401 trial.

Dr. Schwartz on Results From the GIST Cohort in the Alliance A091401 Trial 

Brian Czerniecki, MD, PhD, chair and senior member of the Department of Breast Oncology at Moffitt Cancer Center, discusses the benefit of tucatinib (Tukysa) in patients with HER2-positive breast cancer and brain metastases. 

 in combination with trastuzumab (Herceptin) and capecitabine (Xeloda) for the treatment of patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including those patients with brain metastases, following at least 1 prior anti–HER2­-based therapy in the metastatic setting. 

The approval is based on findings from the phase 2 HER2CLIMB trial in which the triplet induced a 34% reduction in the risk of death compared with trastuzumab/capecitabine alone in the overall patient population and a 52% reduction in patients with brain metastases at baseline.

Although not all patients will benefit from tucatinib, the drug appears to reduce subclinical brain metastases, as well as prevent the development of symptomatic disease in the brain in some patients, says Czerniecki. Ultimately, the agent can have a significant impact on the treatment of about one-third of patients in this space, Czerniecki concludes.

Brian Czerniecki, MD, PhD, discusses the benefit of tucatinib in patients with HER2-positive breast cancer and brain metastases.  




Dr. Czerniecki on the Benefit of Tucatinib in HER2+ Breast Cancer and Brain Metastases

Eric Jonasch, MD, professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the next steps with the potent, selective, small molecule hypoxia-inducible factor (HIF)-2α inhibitor MK-6482 in Von Hippel-Lindau (VHL) disease–associated renal cell carcinoma (RCC).

MK-6482 demonstrated favorable clinical activity in a phase 2 study (NCT03401788) for this rare patient population.

However, whether the agent will receive an approval based on these findings or whether a randomized trial is required remains unclear, Jonasch says.

Another outstanding question is whether MK-6482 could be used as a preventative treatment for lesions that can develop from VHL disease–associated RCC, explains Jonasch. Additionally, combining the agent with another drug or immunotherapy agent may enhance responses in the metastatic setting. 

For example, Toni Choueiri, MD, of Dana-Farber Cancer Institute is spearheading a study evaluating MK-6482 plus cabozantinib (Cabometyx) in this space, concludes Jonasch.

Eric Jonasch, MD, discusses the next steps with the potent, selective, small molecule hypoxia-inducible factor-2α inhibitor MK-6482 in Von Hippel-Lindau disease–associated renal cell carcinoma.  



Dr. Jonasch on Next Steps With MK-6482 in Von Hippel-Lindau Disease–Associated RCC 

John O. Mascarenhas, MD, associate professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai; director of the Adult Leukemia Program; and leader of Clinical Investigation within the Myeloproliferative Disorders Program at Mount Sinai; and a member of the Tisch Cancer Institute, discusses approved and emerging treatment options in myelofibrosis. 

The field of myelofibrosis is becoming more competitive as alternative treatments for patients who progress on ruxolitinib (Jakafi) enter the pipeline, explains Mascarenhas. 

One agent, fedratinib (Inrebic), received FDA approval for the treatment of patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis, says Mascarenhas.

The JAKARTA-2 study, results of which led to the approval of fedratinib, evaluated the agent in the second-line setting. The agent led to significant reduction in splenomegaly in patients who progressed on ruxolitinib, Mascarenhas explains. Although the agent is associated with some gastrointestinal toxicities, it provides another JAK inhibitor option in this space. 

Other novel agents such as CPI-0610 are being evaluated in combination with ruxolitinib in patients who had a suboptimal response to ruxolitinib, says Mascarenhas. Additionally, the BCL-2 inhibitor navitoclax is being explored in the myelofibrosis space.

Ultimately, the goal of clinical trials is to develop novel therapies to better manage spleen symptoms, improve quality of life, and increase overall survival rates, concludes Mascarenhas. 

John O. Mascarenhas, MD, discusses approved and emerging treatment options in myelofibrosis.  



Dr. Mascarenhas on Approved and Emerging Treatment Options in Myelofibrosis 

Sagar Lonial, MD, FACP, professor and chair, Department of Hematology and Medical Oncology, Emory University School of Medicine, chief medical officer, Winship Cancer Institute of Emory University, discusses the FDA approval of belantamab mafodotin in  patients with relapsed/refractory multiple myeloma who have received 4 prior therapies, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody.

The August 5, 2020 FDA approval is based on data from the phase 2 DREAMM-2 trial, in which belantamab mafodotin elicited an overall response rate of 31% (97.5% CI, 20.8-42.6) in patients with relapsed/refractory multiple myeloma who received the treatment at the recommended 2.5 mg/kg dose.

The BCMA-directed antibody-drug conjugate may offer an option to patients who have progressed on the most active regimens in multiple myeloma and whose performance status could limit their ability to tolerate chemotherapy, says Lonial.

Belantamab mafodotin has a novel mechanism of action that can lead to complete and potentially durable remissions without significant toxicities, concludes Lonial.

Sagar Lonial, MD, FACP, discusses the FDA approval of belantamab mafodotin in patients with relapsed/refractory multiple myeloma. 



Dr. Lonial on the FDA Approval of Belantamab Mafodotin-blmf in Multiple Myeloma

Christina L. Roland, MD, MS, FACS, chief of Sarcoma Surgery and assistant professor in the Department of Surgical Oncology in the Division of Surgery; and associate medical director of the Sarcoma Center at The University of Texas MD Anderson Cancer Center, discusses the safety profile of neoadjuvant checkpoint blockade in patients with undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS).

In the study, investigators examined neoadjuvant nivolumab (Opdivo) monotherapy and the combination of ipilimumab (Yervoy) plus nivolumab with and without radiation in patients with treatment-naïve or locally recurrent DDLPS and UPS.

In general, patients tolerated the regimen relatively well, says Roland. In the DDLPS group that just received nivolumab,essentially no grade 3 toxicities were reported. In all other groups, the most common toxicity reported was colitis, which was not surprising in the groups that received ipilimumab, says Roland. Even in the nivolumab/radiation group, however, it seemed that adding radiation increased toxicity, which was more equivalent to dual checkpoint blockade, explains Roland. Patients in the triplet group experienced the most toxicity.

All patients were able to recover from their toxicity and only 1 surgical delay was reported in the ipilimumab/nivolumab arm because of this, although that patient was later able to undergo surgery. In the 3 arms that did not receive nivolumab, at least 30% of patients were unable to complete the treatment because of toxicity, according to Roland.

Notably, even in patients with UPS who received either nivolumab plus radiation or ipilimumab/nivolumab plus radiation, 40% and 50%, respectively, did not receive all of the therapy but still had a significant response. More correlative analyses need to be done, but it is possible that these patients do not need the 4 total doses and 1 or 2 doses might still be enough to experience a response, concludes Roland.

Christina L. Roland, MD, MS, FACS, discusses the safety profile of neoadjuvant checkpoint blockade in patients with undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma.

Dr. Roland on the Safety of Neoadjuvant Checkpoint Blockade in Sarcoma

Christian U. Blank, MD, PhD, a medical oncologist in the Division of Immunology at the Netherlands Cancer Institute, discusses the future of baseline biomarkers in macroscopic stage 3 melanoma.

In the OpACIN trial, investigators compared neoadjuvant ipilimumab (Yervoy) plus nivolumab (Opdivo) with adjuvant ipilimumab plus nivolumab, while the subsequent OpACIN-neo trial evaluated 3 different dosing schedules of neoadjuvant ipilimumab plus nivolumab only. Updated data from the trials were recently presented during the AACR Virtual Meeting II.

For translational analyses from the trial, baseline biomarkers, such as tumor mutational burden (TMB) and interferon gamma expression, were used to predict which patients would have favorable responses to treatment, says Blank. These were found to be independent biomarkers, but if both of these markers were favorable, patients would also have a favorable response, adds Blank. If only 1 of the markers are favorable, either interferon signature high and TMB low or TMB high and interferon signature low, patients still experienced a relatively high response rate. If both biomarkers are low, then patients have a lower response rate; this is a subgroup of patients that will require extended treatment, either with a triplet or alternative treatment to increase response rates, explains Blank.

That effort is being worked on with the phase 1/2 DONIMI trial (NCT04133948), which will examine a neoadjuvant triplet combination versus monotherapy in patients with either low or high interferon signature; this will also examine de-escalated therapy in the patients who have a very high interferon signature.

It is known that a PD-1 inhibitor given by itself can provide a good response, although the percentage of response is low. Therefore, if the optimal patients for this approach can be identified, they also can achieve benefit, says Blank. This is the future of personalized treatment in patients with melanoma: trials examining RNA signature–driven treatments. Through the use of precision medicine, there will be less patients with stage IV disease, concludes Blank.

Christian U. Blank, MD, PhD, discusses the future of baseline biomarkers in macroscopic stage 3 melanoma.

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