Roman Perez-Soler, MD, professor in the Department of Medicine (Oncology) and Department of Molecular Pharmacology, and chief of the Department of Medicine Division of Oncology, Albert Einstein College of Medicine, discusses how 

 mutations have evolved and impacted the treatment of patients with lung cancer.

Several compounds are now being used to target 

 in patients with lung cancer, says Perez-Soler. It is exciting to have found a mutation in a sizeable subgroup that drives tumor growth. Capmatinib (Tabrecta), in particular, received its approval from the FDA in May 2020 for the treatment of patients with metastatic non–small cell lung cancer who harbor a 

These specific compounds for MET can be used in the frontline setting, which was similarly observed with compounds for other targets. The 

 mutation has a similar story to others, such as the 

 inhibitor that has a number of different compounds targeting EGFR. According to Perez-Soler, new technology can help physicians identify a compound specific to MET for these patients so that they achieve response rates of 60% to 80% and progression-free survival medians around 10 to 12 months.

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Roman Perez-Soler, MD, discusses how MET mutations have evolved and impacted the treatment of patients with lung cancer.

MET Target Excites Treatment Paradigm for Patients With Lung Cancer

Matthew S. Davids, MD, MMSc, an associate director with the Center for Chronic Lymphocytic Leukemia; director of clinical research, Lymphoma Program; and medical oncologist, Dana-Farber Cancer Institute and an assistant professor of medicine with Harvard Medical School, discusses the prognosis expected for patients with mantle cell lymphoma (MCL), as well as chronic lymphocytic leukemia (CLL), in the relapsed/refractory population.

The advent of the BTK inhibitor ibrutinib (Imbruvica) certainly improved the outlook for patients with relapsed/refractory MCL and CLL, Davids says. It is an active drug, but the durability of response is relatively short among those with high-risk disease. In MCL, for example, even though the response rates are high, the progression-free survival is only a little over 1 year with ibrutinib as monotherapy.

This serves as the rationale for the development of combination approaches for this patient population, and there are a number in development now, says Davids. One combination is looking at dual blockade of the B-cell receptor pathway. It is known the CLL cells and MCL cells depend heavily on this pathway, and there is another arm of the pathway that has Pi3K as a key node, so there is interest in going after this other arm of the pathway to potentially prevent resistance to ibrutinib as a monotherapy, Davids concludes.

Matthew Davids, MD, MMSc, discusses the prognosis expected for patients with mantle cell lymphoma, as well as chronic lymphocytic leukemia, in the relapsed/refractory population.

Using Combination Therapy for Patients With Relapsed/Refractory MCL

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, discusses pacritinib for patients with myelofibrosis and thrombocytopenia.

Mascarenhas thinks pacritinib is an important drug and potentially an agent that will be available in the commercial space because it's the only JAK2 inhibitor that appears to have the least amount of myelosuppression, especially with thrombocytopenia, of the many that have been evaluated. There is an unmet need for patients with extreme thrombocytopenia, defined as platelet counts less than 50,000. Physicians can't effectively and safely deliver the currently approved JAK inhibitors, and there are limited therapies for these patients. He says these patients are typified by a myelodepleted phenotype, so they don't always have large spleens, but they usually are characterized by low blood counts and poor outcomes.

The PERSIST-2 study, a randomized phase 3 study, had efficacy with pacritinib at 20 mg twice a day in both spleen and symptom improvement in these patients with low platelet. The PAC203 was a dose-finding phase 2 randomized study looking at 3 different dose levels, 200 mg twice daily, 100 mg twice daily, and 100 mg once daily. The importance of that study was to document and confirm that the drug can be delivered safely, according to Mascarenhas. The 200 mg twice daily was effective in about 17% of patients in achieving spleen volume reduction, without incurring significant thrombocytopenia. The niche for pacritinib is patients with myelofibrosis who have less than 180 days of prior JAK2 inhibitor therapy that have a platelet count below 50,000.

John O. Mascarenhas, MD, discusses pacritinib for patients with myelofibrosis and thrombocytopenia.

Pacritinib Demonstrates Potential to Fill Unmet Need in Myelofibrosis

Ryan C. DeCoste, MD, QEII Health Sciences Centre, Nova Scotia Health Authority, Halifax, Nova Scotia, Canada, discusses how comprehensive genomic profiling can be used to identify rare subsets of patients with Merkel cell carcinoma.

Merkel cell carcinoma is a relatively rare but highly aggressive skin cancer, according to DeCoste. A previous publication identified a subset of these patients, making up approximately 80% of cases, are associated with a viral oncogenic pathogenesis, which incorporates Merkel cell papilloma virus DNA into precursor cells for subsequent tumorigenesis. However, subsequent to this, a smaller subset was thought not to be associated with this virus and more likely due to UV-induced DNA damage.

Based on these observations, Merkel cell carcinoma can be classified in 1 of 2 categories: virus-positive or virus-negative, and these subsets each have distinct mutational profiles, DeCoste notes.

Ryan C. DeCoste, MD, discusses how comprehensive genomic profiling can be used to identify rare subsets of patients with Merkel cell carcinoma.

Using Comprehensive Genomic Profiling to Identify Rare  Subsets of Merkel Cell Carcinoma

Petros Grivas, MD, PhD, physician, Seattle Cancer Care Alliance; associate professor, Department of Medicine, Division of Oncology, and clinical director, Genitourinary Cancers Program, University of Washington School of Medicine; and associate member, Clinical Research Division, Fred Hutchinson Cancer Center, discusses the phase 3 KEYNOTE-045 trial and the association between gene expression signatures and pembrolizumab (Keytruda) in patients with advanced urothelial cancer.

All the patients receiving pembrolizumab on the KEYNOTE-045 trial appeared to benefit in terms of progression-free survival and overall survival, according to Grivas. There are no biomarkers with clinical utility that can guide selection of which patients should get pembrolizumab or not, based on the data presented the 2020 European Society for Medical Oncology. Therefore, these data show no impact on practice when using pembrolizumab to treat patients with platinum-refractory disease.

Grivas says that the utilization of pembrolizumab based on potential biomarkers needs to be researched further to evaluate the clinical advantage of gene expression signatures. At the moment, patients with platinum-refractory advanced urothelial cancer are all treated able to be treated with pembrolizumab.

Petros Grivas, MD, PhD, discusses the phase 3 KEYNOTE-045 trial and the association between gene expression signatures and pembrolizumab in patients with advanced urothelial cancer.

Further Research Required to Find Biomarkers for Urothelial Cancer

Victor Velculescu, MD, PhD, co-director of Cancer Biology and professor of Oncology, Johns Hopkins Medicine, discusses the key takeaways regarding the use of liquid biopsy to detect cancer and a new cfDNA approach to detect cancer at earlier stages.

The major way to reduce the morbidity and mortality that is associated with cancer is early detection, Velculescu says. Many cancer deaths, unfortunately, are avoidable if they are identified earlier, which represents a major area of unmet need in the oncology space.

The existing approaches for early detection that are available still have some limitations, due to the number of molecules they see of DNA or compounded conditions, says Velculescu. This new type of technology, which he introduced during the 2020 Association for Molecular Pathology Annual Meeting, however, allows for detection of cancer with high performance and across many cancer types and tissues of origin. This advance appears promising, and Velculescu looks forward to seeing this approach validated in the future to further improve patient outcomes.

Victor Velculescu, MD, PhD, discusses the key takeaways regarding the use of liquid biopsy to detect cancer and a new cfDNA approach to detect cancer at earlier stages.

New Liquid Biopsy Method May Improve Upon Current Modalities for Early Detection of Cancer

Maria E. Cabanillas, MD, an oncologic endocrinologist, professor, and faculty director in the Department of Endocrine Neoplasia at The University of Texas MD Anderson Cancer Center, discusses the pooled results of 2 larotrectinib (Vitrakvi) trials (NCT02122913 and NCT02576431) for patients with advanced or metastatic 

The overall response rate (ORR) was 75% for the overall cohort, which included 19 patients with papillary thyroid cancer, 7 with anaplastic thyroid cancer, and 2 with follicular. Cabanillas says there were good results in these patients with differentiated thyroid cancers, where the ORR was 90%, including 2 patients with complete response (CR) 17 patients with a partial response (PR), and no patients with progressive disease (PD).

Patients with anaplastic thyroid cancer had an ORR of 29%, which is good for this population, according to Cabanillas. None of these patients had CR, 2 had PR, 1 had stable disease, and 3 patients had PD as their best response.

The analysis showed that the median duration of response in the overall cohort was not reached, which was impressive, Cabanillas says. The median time to response was 1.9 months. Treatment was ongoing in 68% of patients at the time of the data cutoff. For the overall cohort, the median progression-free survival was not met, and the median overall survival was 27.8 months.

Maria E. Cabanillas, MD, discusses the pooled results of 2 larotrectinib trials for patients with advanced or metastatic TRK fusion-positive thyroid cancer.

Larotrectinib Shows Efficacy in TRK Fusion Thyroid Cancer

Nilanjan Ghosh, MD, a hematologist and medical oncologist at the Levine Cancer Institute, Atrium Health, discusses the effect coronavirus disease 2019 (COVID-19) had on using chimeric antigen receptor (CAR) T-cell therapy to treat patients with diffuse large B-cell lymphoma (DLBCL).

Ghosh says that when the pandemic first started, he and other physicians thought it would not only affect CAR T-cell therapy but also stem cell transplants. CAR T-cell treatments for DLBCL include therapies such as axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah). There was a lot of uncertainty around how long the pandemic would last since it started abruptly with many acute cases, which filled intensive care units and hospital beds.

As the months went on, physicians adapted to treating patients during COVID-19, which Ghosh calls the “new normal.” As of October, the pandemic was not affecting the delivery of CAR T-cell therapy for clinical trials and treatment with standard of care in practices. At the beginning of COVID-19, he and his colleagues were doing their best to deliver standard-of-care CAR T therapy, but it did affect CAR T-cell delivery for clinical trials because of regulatory constraints. There were several months where accrual for these trials was limited, but over the past months, many of those constraints have been lifted and the clinical trials have opened back up.

Nilanjan Ghosh, MD, discusses the effect coronavirus disease 2019 had on using chimeric antigen receptor T-cell therapy to treat patients with diffuse large B-cell lymphoma.

Providing CAR T-Cell Therapy for Patients With DLBCL During COVID-19

Hope Rugo, MD, professor, Department of Medicine (Hematology/Oncology); and Director, Breast Oncology and Clinical Trials Education at the University of California San Francisco, discusses her key takeaways in the field of HER2-positive breast cancer.

The most important takeaway at this time, Rugo says, is that physicians can personalize treatment for patients with early-stage HER2-positive breast cancer. The disease-free survival observed in these patients has been excellent, even in those with multiple positive lymph nodes, and there is only a small number of patients have very resistant disease.

Personalization in the neoadjuvant setting to either escalate or de-escalate therapy based on treatment response is an important area of research in this space, as well as the ongoing studies aiming to improve outcomes for that small number of patients with truly resistant disease, according to Rugo. This represents a subset of patient with dismal outcomes, as well as those with upfront resistance or brain metastases.

The current treatment paradigm shows a number of new directions and therapies for the potential treatment of these patients. Antibody-drug conjugates and tyrosine kinase inhibitors are helping to improve outcomes for these patients, as well as those with de novo metastatic breast cancer, Rugo concludes.

Hope Rugo, MD, discusses her key takeaways in the field of HER2-positive breast cancer.

Reviewing Key Takeaways for the Treatment of HER2-Positive Breast Cancer

Brian A. Jonas, MD, discusses the future of treatment for older patients with acute myeloid leukemia (AML), now that the FDA has granted approval to azacitidine plus venetoclax for patients aged 75 years or older.

Jonas states that many oncologists in the academic setting already consider azacitidine plus venetoclax to be the new standard of care for older patients with AML. The results of the phase 3 VIALE-A study, which led to the FDA approval, demonstrated the ability of this combination for the large majority of patients. Jonas explains, however, that there are still some patients who do not benefit or relapse. For these patients, there may be an opportunity to add on another drug to the regimen.

In addition to azacitidine plus venetoclax becoming a backbone for a new regimen, the future may also hold promise for better toxicity management, explain Jonas. Cytopenias occurred often in the study and required specific strategies to improve patient outcomes. Because these toxicities are of concern for older patients, Jonas suggests re-working the combination to limited toxicity.

Brain A. Jonas, MD, discusses the future of treatment for older patients with acute myeloid leukemia, now that the FDA has granted approval to azacitidine plus venetoclax for patients aged 75 years or older.