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Lenvatinib plus pembrolizumab led to tumor responses regardless of mismatch repair–proficient status, histology, and prior adjuvant therapy.

Lenvatinib Plus Pembrolizumab Affords Deep and Durable Responses in Endometrial Cancer

Datopotamab deruxtecan shows antitumor activity in patients with advanced/metastatic ovarian and endometrial cancer and progressive disease following platinum chemotherapy.

Dato-DXd Demonstrates Efficacy, Safety in Platinum-Resistant Ovarian and Endometrial Cancers

Ipilimumab given in combination with nivolumab met the primary end point of 12-month OS rate vs SOC in patients with nccRCC in the SUNNIFORECAST trial.

Ipilimumab Plus Nivolumab Increases 12-Month OS Rate vs SOC in nccRCC

Benmelstobart plus anlotinib improved PFS, OS, and ORR vs sunitinib in first-line advanced renal cell carcinoma.

Benmelstobart Plus Anlotinib Demonstrates Efficacy in Frontline Advanced RCC

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Articles

Richard Vile, PhD, explains how CAR-T cell therapy works, including the benefits, risks and realities of treatment.

Understanding CAR T-Cell Therapy for Cancer: Mayo Clinic Expert Explains How It Works

 in November 2021 as a senior editor and became the website's managing editor in October 2023. Before arriving at MJH Life Sciences, he spent nearly a decade covering professional and high school sports—including the New Jersey Devils and the NHL from 2016 to 2021—for The Star-Ledger and NJ.com. Email: chryan@onclive.com

Kyle Doherty joined MJH Life Sciences in 2021 and is the lead editor for 

as well as news and conference updates for OncLive.com. Email: kdoherty@mjhlifesciences.com

The FDA has granted orphan drug designation to the novel oncolytic virotherapy CF33-hNIS for cholangiocarcinoma.

FDA Grants Orphan Drug Designation to CF33-hNIS for Cholangiocarcinoma

ICT01 plus azacitidine and venetoclax has received fast track designation from the FDA in patients with untreated AML unfit for induction chemotherapy.

FDA Grants Fast Track Designation to ICT01 Plus Azacitidine/Venetoclax in Treatment-Naive AML

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Authors

Christina Wu, MD, discusses key targeted therapies under investigation in patients with colorectal cancer. 
 


Dr. Wu on the Current Utility of Targeted Therapy in CRC

Brigatinib in NF2-Related Schwannomatosis with Progressive Tumors

Scott Plotkin, MD, reviews data from a phase II study on brigatinib, a multi tyrosine kinase inhibitor, across various tumor types in patients with NF2-related schwannomatosis.

Long-term Follow-up of Selinexor Maintenance for Patients With TP53wt Advanced or Recurrent Endometrial Cancer: A Prespecified Subgroup Analysis From the Phase 3 ENGOT-EN5/GOG-3055/SIENDO Study

David Miller, MD, reviews a plenary presentation (originally presented at the ASCO 2024 Annual Meeting by Vikky Makker, MD) on the long-term follow-up of the ENGOT-EN5/GOG-3055/SIENDO trial, focusing on selinexor maintenance for patients with TP53 wild-type advanced or recurrent endometrial cancer.

Clinical

Dr Rafiq on Novel Strategies for CAR T-Cell Engineering in Solid Tumors

Sarwish Rafiq, PhD, assistant professor, Department of Hematology and Medical Oncology, Emory University School of Medicine; program leader, CAR T Basic/Translational Research, Winship Center for Cancer Immunology, Winship Cancer Institute of Emory University, discusses how novel methods for engineering metabolically fit, memory rich CAR T-cells may address barriers to CAR T-cell efficacy in solid tumors.

At the Frontiers in Cancer Immunotherapy 2024 Symposium, Rafiq presented and shared 2 novel approaches to CAR T-cell engineering. The first multi-cytokine particle approach is a CAR T-cell extrinsic method, which involves engineering microparticles to enhance the manufacturing process of CAR T cells, Rafiq states. Since CAR T cells are extracted from patients, modified ex vivo, and then reinfused, this approach focuses on improving the quality of the cells during the manufacturing stage, she details. The engineered microparticles help in enriching the cells for memory phenotypes, which are associated with more durable responses in patients, Rafiq explains.

The second approach is a T-cell intrinsic method where CAR T cells are engineered to secrete their own antagonistic peptide against a novel immune checkpoint, Rafiq says. This modification alters the metabolism and activation profile of the CAR T cells, resulting in a more potent product, she describes.

Before these approaches can be used to manufacture CAR T cells for patients, additional GMP grade studies are needed, Rafiq continues. These studies will indicate whether the extrinsic approach can be implemented in a manufacturing facility to produce CAR T cells. For the intrinsic approach involving vasoactive intestinal peptide receptor antagonists, current research is focused on syngeneic mouse models, which involve the use of mouse CAR T cells in mice that have an intact immune system and tumors, Rafiq says. This research aims to determine if an endogenous immune response can be engaged and to assess any potential on-target off-tumor toxicities from antagonizing the receptor, she explains.

Additionally, studies addressing toxicity with the secreting CAR T cells are necessary to ensure their safety for patients, Rafiq notes. These steps are crucial for advancing these innovative CAR T-cell approaches from experimental stages to clinical application, she concludes.

Sarwish Rafiq, PhD, discusses how engineering metabolically fit, memory rich CAR T-cells may address barriers to CAR T-cell efficacy in solid tumors.

Perioperative chemotherapy with docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil (FLOT protocol) led to a significant overall survival (OS) benefit vs neoadjuvant chemoradiation (CROSS protocol) in patients with resectable esophageal cancer

 according to findings from the phase 3 ESOPEC trial (NCT02509286) presented during the 

At a median follow-up of 55 months, patients in the intention-to-treat population who received the FLOT protocol (n = 221) achieved a median OS of 66 months (95% CI, 36-not evaluable [NE]) compared with 37 months (95% CI, 28-43) among those who were treated with the CROSS protocol (n = 217; HR, 0.70; 95% CI, 0.53-0.92; 

 = .012). The 3-year OS rates were 57.4% vs 50.7%, respectively, and the 5-year OS rates were 50.6% vs 38.7%, respectively.

Additionally, the median progression-free survival (PFS) was 38 months (95% CI, 21-NE) in the FLOT arm compared with 16 months (95% CI, 12-22) in the CROSS arm (HR, 0.66; 95% CI, 0.51-0.85; 

 = .001). The 3-year PFS rates were 51.6% vs 35.0%, respectively, and the 5-year PFS rates were 44.4% vs 30.9%, respectively.

“Many patients in the US and Europe are still treated with the CROSS radiochemotherapy protocol. Our study shows that patients with resectable esophageal cancer should have FLOT chemotherapy before and after the operation in order to optimize the chance of curing their tumors in the long term,” Jens Hoeppner, FAChirg, FACS, MD, the director of the Department of Surgery at University Medical Center, University of Bielefeld, in Detmold, Germany, stated in a press release.

ESOPEC was a prospective multicenter study that enrolled patients with esophageal adenocarcinoma across 25 sites in Germany between February 2016 and April 2020. Eligible patients needed to be at least 18 years old, have received no prior abdominal or thoracic radiotherapy, have an ECOG performance status of 2 or less, and have adequate organ function. Patients were also required to have pretreatment stage cT1N+, M0 or cT2-4a, N0/+, M0 disease. The presence of squamous or other non-adenocarcinoma histology, gastric cancer, clinical stage cT1cN0 and cT4b disease, or metastatic disease excluded patients from enrollment.

Patients were randomly assigned 1:1 to receive either the FLOT or CROSS protocol. Those in the FLOT arm received repeated doses of 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel every 2 weeks over 4 neoadjuvant cycles prior to surgery and 4 adjuvant cycles after surgery. In the CROSS arm, patients received neoadjuvant radiation therapy and concurrent chemotherapy with carboplatin and paclitaxel for 5 cycles in 5 weeks prior to surgery. Following neoadjuvant treatment, patients in both arms waited 4 to 6 weeks before proceeding to surgery. 

The primary end point was OS. Secondary end points included PFS, recurrence-free survival, postoperative pathological stage, postoperative complications, and postsurgical quality of life.

At baseline, the mean age of patients in the FLOT and CROSS arms was 63.1 years (standard deviation [SD], 8.6) vs 62.6 years (SD, 9.8), respectively. Most patients in both arms were male (89.1% vs 89.4%), had clinical T-stage cT3-4 disease (79.1% vs 81.9%), and had clinical N-stage cN+ disease (77.8% vs 81.6%). Overall, 191 patients in the FLOT arm underwent surgery compared with 180 patients in the CROSS arm.

Additional findings from ESOPEC showed that the pathological complete remission rates among patients who underwent surgery in the FLOT arm was 16.8% compared with 10.0% in the CROSS arm. In both arms, complete regression (18.3% vs 13.3%) or near complete regression (25.1% vs 39.4%) was observed. Most patients across both arms underwent an R0 resection (94.2% vs 95.0%).

Patients in the predefined protocol population in the FLOT (n = 207) and CROSS (n = 196) arms achieved a median OS of 66 months (95% CI, 38-NE) vs 39 months (95% CI, 29-45), respectively (HR, 0.72; 95% CI, 0.54-0.96; 

 = .023). The 3-year OS rates were 58.1% vs 52.6%, respectively, and the 5-year OS rates were 51.8% vs 40.5%, respectively.

Results from an exploratory subgroup analysis demonstrated that the OS benefit in favor of FLOT vs CROSS was observed in all subgroups examined. The most pronounced benefit was reported in patients aged less than 60 years (HR, 0.57; 95% CI, 0.34-0.95) and those with clinical T-stage T3-4 disease (HR, 0.68; 95% CI, 0.50-0.92).

Most patients in both the FLOT and CROSS arms started neoadjuvant treatment; these patients comprised the predefined protocol population. A majority of patients in both arms completed neoadjuvant treatment (87.3% vs 67.7%) and received neoadjuvant treatment plus surgery (86.0% vs 82.9%). In the FLOT arm, 63.3% of patients received adjuvant treatment and 52.5% completed adjuvant treatment.

In the 90 days post-surgery, 3.2% of patients in the FLOT arm died compared with 5.6% in the CROSS arm. The 30-day postoperative mortality rates were 1.0% vs 1.7%, respectively At the data cutoff, 97 and 121 patients died in these respective arms.

“Perioperative chemotherapy with FLOT plus surgery improves OS compared with neoadjuvant chemoradiation with CROSS plus surgery in patients with locally advanced, resectable esophageal adenocarcinoma. ESOPEC found that perioperative chemotherapy with FLOT should be preferred over neoadjuvant chemoradiation with the CROSS protocol for improving survival in resectable esophageal adenocarcinoma,” Hoeppner concluded in an oral presentation. 

Hoeppner J, Brunner T, Lordick F, et al. Prospective randomized multicenter phase III trial comparing perioperative chemotherapy (FLOT protocol) to neoadjuvant chemoradiation (CROSS protocol) in patients with adenocarcinoma of the esophagus (ESOPEC trial).

. 2024;42(suppl 17):LBA1. doi:10.1200/JCO.2024.42.17_suppl.LBA1

Chemotherapy before and after surgery may be new standard treatment for some patients with esophageal cancer. News Release. ASCO. June 2, 2024. Accessed June 2, 2024. https://society.asco.org/about-asco/press-center/news-releases/chemotherapy-and-after-surgery-may-be-new-standard-treatment

Perioperative chemotherapy compared to neoadjuvant chemoradiation in patients with adenocarcinoma of the esophagus (ESOPEC). ClinicalTrials.gov. Updated May 8, 2024. Accessed June 1, 2024. https://clinicaltrials.gov/study/NCT02509286

 study was published on June 2, 2024, from the press briefing, and was updated on June 4, 2024, with additional information/data from the oral session.

Perioperative chemotherapy using the FLOT protocol demonstrated a significant overall survival benefit over neoadjuvant chemoradiation (CROSS protocol) in patients with resectable esophageal cancer, as evidenced by the phase 3 ESOPEC trial. With a median follow-up of 55 months, the FLOT protocol achieved a median overall survival of 66 months compared to 37 months with the CROSS protocol. The study suggests that FLOT chemotherapy before and after surgery should be considered to optimize long-term tumor cure rates in these patients.

Perioperative chemotherapy with FLOT improved OS vs neoadjuvant chemoradiation with CROSS in resectable esophageal cancer.

Conference

Perioperative Chemotherapy Prolongs OS vs Neoadjuvant Chemoradiation in Esophageal Cancer

Pembrolizumab (Keytruda) continued to demonstrate improved survival benefits compared with ipilimumab (Yervoy) in patients with unresectable stage III or IV melanoma, according to 10-year follow-up data from the phase 3 KEYNOTE-006 study (NCT01866319) presented during the 

The trial, which was launched to compare the safety and efficacy of the immunotherapy agents in this population, concluded on June 3, 2019.2 Eligible patients were able to transition to the open-label phase 3 KEYNOTE-587 extension study (NCT03486873), which was designed to continue collecting long-term efficacy in those with solid tumors who received prior pembrolizumab in a clinical trial. The median time from KEYNOTE-006 entry to KEYNOTE-587 data cutoff was 123.7 months (range, 122.0-127.3).

Patients who received pembrolizumab (n = 159) experienced a median overall survival (OS) of 32.7 months (95% CI, 24.5-41.6) vs 15.9 months (95% CI, 13.3-22.0) with ipilimumab (n = 52; HR, 0.71; 95% CI, 0.60-0.85). The 8- and 10-year OS rates in the pembrolizumab arm were 36.9% and 34.0%; in the ipilimumab arm, these rates were 24.8% and 23.6%. Those in KEYNOTE-006 who did not transition to the extension study were censored at the date last known to be alive or the data cutoff of KEYNOTE-006, which was July 31, 2019; those without an overall survival (OS) event were censored at the date last known to be alive or the data cutoff of KEYNOTE-587, which was May 1, 2024. 

The modified median progression-free survival (PFS) with pembrolizumab was 9.4 months (95% CI, 6.7-11.6) vs 3.8 months (95% CI, 2.9-4.3) with ipilimumab (HR, 0.64; 95% CI, 0.54-0.75). The PFS rates at 8 and 10 years in the pembrolizumab arm were 23.4% and 22.0%; in the ipilimumab arm, these respective rates were 12.8% and 12.8%. As with OS, the patients who did not transition from one trial to the other were censored. The median melanoma-specific survival (MSS) with pembrolizumab was 51.9 months (95% CI, 30.0-114.7) vs 17.2 months (95% CI, 13.9-25.9) with ipilimumab (HR, 0.66; 95% CI, 0.55-0.81). The 8- and 10-year MSS rates in the pembrolizumab arm were 46.5% and 45.2%; these rates were 32.1% and 31.3% in the ipilimumab arm.

“With this 10-year follow-up, we have an OS rate of 34% but a MSS rate of 45.2%. We have a very good outcome for patients who responded or who had the benefit to the first course, and again, it shows that response is actually the best marker for long-term outcome. Unfortunately, we cannot know before [treatment] who is going to respond, but the patients who respond really do very well,” Caroline Robert, MD, PhD, of Gustave Roussy and Paris-Saclay University, in Villejuif, France, and a 2018 Giant of Cancer Care® inductee in melanoma, said in a presentation of the data. “We [also] show that we have an additional activity that is quite significant for patients who are rechallenged if they had the benefit in the first course of pembrolizumab. I also would like to remind you of the safety. We all know that the grade 3 and above adverse effects with a single[-agent] regimen is around 15% to 20%, which is far below what we can see with a combination.”

KEYNOTE-006 enrolled patients with unresectable stage III or IV melanoma not amenable to local therapy who had at least 1 measurable lesion by RECIST 1.1 criteria.2 Patients were at least 18 years of age, had an ECOG performance status of 0 or 1, and known 

 mutational status. They could have received up to 1 prior systemic treatment as long as it was not an anti–CTLA-4, PD-1, PD-L1, or PD-L1 agent. Those with uveal or ocular melanoma or with known central nervous system metastases were excluded. Notably, patients with previously treated, stable brain metastases were permitted. Any patients enrolled in this trial who received study treatment or were in the survival follow-up phase of the research were able to transition to the extension study.

In KEYNOTE-006, participants were randomly assigned 1:1:1 to receive pembrolizumab at 10 mg/kg every 2 weeks up to 2 years, pembrolizumab 10 mg/kg every 3 weeks up to 2 years, or ipilimumab at 3 mg/kg every 3 weeks for 4 cycles.

Those who experienced a complete response (CR), which had been confirmed on 2 scans at least 4 weeks apart, were able to stop treatment, as long as they received pembrolizumab for 6 months or more and had received 2 or more doses of the agent beyond achievement of CR. Patients who experienced stable disease (SD) or better during the first course of treatment with pembrolizumab were able to receive a second course at 200 mg every 3 weeks for up to 1 year or approximately 17 cycles while in either trial if they experienced progressive disease after discontinuing therapy.

In KEYNOTE-006, investigators evaluated tumor response via CT/MRI at week 12; this was subsequently done every 6 weeks through week 48, and every 12 weeks thereafter. Once treatment was stopped, participants were monitored for survival every 12 weeks until the end of the trial. Those who transitioned to KEYNOTE-587 were then followed for long-term survival, progressive disease, and initiation of next anti-cancer treatment. Moreover, those who receive a second course of pembrolizumab in the extension trial were also followed for assessment.

For KEYNOTE-587, the primary end point was OS. Exploratory end points included PFS and PFS on the second course of pembrolizumab. Investigators conducted post-hoc analyses that examined MSS in the overall population, OS in subsets, OS and modified PFS from week 94 in those who received at least 94 weeks of pembrolizumab, and more.

Of those assigned to pembrolizumab treatment in KEYNOTE-006 (n = 556), 228 were eligible to transition to KEYNOTE-587, and 159 were enrolled in the trial. Of the 278 patients assigned to the ipilimumab arm on KEYNOTE-006, 105 were able to enroll in the extension trial and 52 did so.

Pembrolizumab continued to show superiority over ipilimumab with regard to OS outcomes across all subgroups analyzed, including those with elevated lactate dehydrogenase levels (n = 270; HR, 0.60; 95% CI, 0.44-0.80), those with large tumors defined as at least 10 cm (n = 186; HR, 0.64; 95% CI, 0.45-0.91), and those with brain metastases (n = 80; HR, 0.56; 95% CI, 0.32-0.98).

In those who completed at least 94 weeks of treatment with pembrolizumab (n = 103), and with a median follow-up duration of 122.9 months (range, 56.2-127.2), the median OS from week 94 was not reached (NR; 95% CI, NR-NR); the 6- and 8-year OS rates from week 94 were 91.8% and 80.8%, respectively. The median modified PFS in those who completed 94 weeks or more of pembrolizumab was also NR (95% CI, NR-NR); the 6- and 8-year modified PFS rates from week 94 were 73.2% and 64.8%, respectively.

Of the patients who received a second course of pembrolizumab in either trial (n = 16), 5 achieved a CR, 5 experienced a partial response, and 4 had SD, and 2 experienced disease progression. The median modified PFS from the start of the second course of pembrolizumab was 51.8 months (95% CI, 11.0-NR); 4- and 6-year modified PFS rates from the start of the second course were 56.3% and 49.2%, respectively.

Of the overall population (n = 556), 66.2% of those who received pembrolizumab and 65.1% of those given ipilimumab received the agents in the first-line setting. In these patients, the median OS with pembrolizumab or ipilimumab was 38.7 months (95% CI, 27.3-50.9) and 17.2 months (95% CI, 13.8-26.2; HR, 0.68; 95% CI, 0.55-0.86). The respective 8-year OS rates were 40.1% and 27.0%; the 10-year OS rates were 36.9% and 25.0%. The median modified PFS in these patients who received pembrolizumab or ipilimumab as first-line treatment was 12.0 months (95% CI, 8.3-16.6) and 4.1 months (95% CI, 2.9-5.2; HR, 0.62; 95% CI, 0.50-0.76). The 8- and 10-year modified PFS rates were 27.0% and 25.5% with pembrolizumab and 15.1% and 15.1% with ipilimumab.

“These results confirm that pembrolizumab provides long-term benefit in patients with advanced melanoma, supporting it as a standard of care in this setting,” the study authors conclude.

Disclosures: Dr Robert disclosed receipt of consulting fees from Bristol Myers Squibb, Roche, Pierre Fabre, Novartis, Sanofi, Pfizer, MSD, Merck, Sun Pharma, Ultimovacs, Regeneron, Egle, Philogen, MaaT Pharma, and IO Biotech. She received honoraria from Pierre Fabre, Sanofi, BMS, MSD, and Novartis and support for attending meetings and/or travel from Pierre Fabre. She serves on the data safety monitoring board or advisory board for Bristol Myers Squibb, Roche, Pierre Fabre, Novartis, Sanofi, Pfizer, MSD, Merck, Sun Pharma, Ultimovacs, Regeneron, Egle, Philogen, and MaaT Pharma. Study funding was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. Medical writing and/or editing assistance was provided by Jemimah Walker, PhD, and Mehak Aggarwal, PharmD, of ApotheCom and the assistance was funded by Merck Sharp & Dohme LLC.

Robert C, Carlino MS, McNeil C, et al. Pembrolizumab vs ipilimumab for advanced melanoma: 10-year follow-up of the phase 3 KEYNOTE-006 study. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Presentation LBA44.

Long GV, Carolino MS, McNeil C, et al. Pembrolizumab versus ipilimumab for advanced melanoma: 10-year follow-up of the phase 3 KEYNOTE-006 study. 

. Published online September 15, 2024. doi:10.1016/j.annonc.2024.08.2330

Pembrolizumab continued to demonstrate improved survival vs ipilimumab in  unresectable stage III or IV melanoma.

Long-Term KEYNOTE-006 Data Support Pembrolizumab as SOC in Advanced Melanoma

Sameh Gaballa, MD (Associate Member, Division of Malignant Hematology at Moffitt Cancer Center)

Sponsored Content by Ipsen Biopharmaceuticals, Inc.

The following contains case studies reflecting actual patient experiences written by Dr. Gaballa. Patient experiences may vary. Information presented does not encompass all considerations for tazemetostat eligibility. Dr. Gaballa was compensated for his time by Ipsen.

The accelerated approval for tazemetostat is based on an open-label, single-arm, multi-center Phase 2 clinical trial evaluating tazmetostat (800 mg oral twice daily) in 99 patients with histologically confirmed FL whose disease had progressed following at least two prior systemic treatment regimens and was inclusive of EZH2 activating mutations (45 patients) and wild-type EZH2 (54 patients).

Among the EZH2 activating mutation cohort, at the 22 month follow-up, the overall response rate (ORR) was 69% (95% CI; 53%, 82%) with 12% of patients achieving a complete response and 57% achieving a partial response to tazmetostat. The median duration of response (DOR) was 10.9 months.

Among the wild-type EZH2 cohort, at the 36 month follow-up, ORR was 34% (95% CI; 22%, 48%), with 4% of patients achieving a complete response and 30% achieving a partial response to tazmetostat. The median DOR was 13.0 months.

Serious adverse reactions, irrespective of attribution, occurred in 30% of patients receiving tazmetostat. Serious adverse reactions in ≥2% of patients who received TAZVERIK were general physical health deterioration, abdominal pain, pneumonia, sepsis, and anemia.

Eight patients (8%) discontinued due to adverse reaction during the trial. Dosage interruptions due to an adverse reaction occurred in 28% of patients. Dose reduction due to an adverse reaction occurred in 9% of patients.

The most common (≥20%) adverse reactions were fatigue, upper respiratory tract infection, musculoskeletal pain, nausea and abdominal pain.

A male in his 50s without significant past medical history presented to the emergency room with chest pain and shortness of breath. A computed tomography (CT) chest scan with angiography showed bilateral pulmonary embolism and an ultrasound of his lower extremities revealed bilateral extensive DVTs in his legs reaching up to his iliac veins.

At that time, he had no known risk factors for having a hypercoagulable state. He was initiated on anticoagulation, given extensive thrombosis, and underwent a thrombectomy procedure. The workup for hypercoagulable status included CT imaging, which identified bulky lymphadenopathy above and below the diaphragm. A core needle biopsy of a left groin lymph node came back consistent with low grade lymphoma, WHO grade 1-2.

Given his bulky adenopathy and hypercoagulable status, he was initiated on first-line therapy for follicular lymphoma. After 6 cycles of bendamustine-rituximab chemoimmunotherapy, a positron emission tomography (PET) scan showed partial remission (PR) of the lymphoma with residual adenopathy and a standardized uptake value (SUV) of 8 (Deauville score 4). The patient was then started on maintenance rituximab.

A year later, PET imaging showed the disease progressed, and a repeat lymph node biopsy showed low-grade follicular lymphoma with no evidence of transformation to an aggressive lymphoma.

Given he progressed in less than 24 months from initiation of therapy (POD24), which puts him in a high-risk category, the patient was started on obinutuzumab/lenalidomide for 10 cycles, which was complicated by diarrhea and grade 3 neutropenia requiring dose interruptions followed by dose reductions of the IMiD down to 10 mg. While his PET scan restaging initially showed a partial response (PR), by the end of cycle 10 of treatment he developed progressive adenopathy.

At that point, CAR T-cell therapy was offered to the patient given he failed 2 lines of therapy and had high-risk follicular lymphoma. However, due to family events and professional obligations, the patient was not able to commit the time needed for CAR T-cell therapy. EZH2 testing was performed at the time and he had EZH2 wild-type disease. He was started on oral single agent tazemetostat, and continued to have stable disease on imaging for the next 12 months.

After 12 months, the patient experienced progression and subsequently received CAR T-cell therapy with no response. He then received a bispecific antibody on a clinical trial but had refractory disease after 3 cycles and lymph node biopsies continued to show low grade lymphoma without evidence of transformation to an aggressive lymphoma.

Eventually, he received R-CHOP and achieved a complete response followed by consolidation with an allogeneic stem cell transplant and remained in remission.

A male in his 60s with a history of morbid obesity, status post gastric bypass, was incidentally found to have bulky retroperitoneal lymph nodes upon CT imaging done during workup of suspected GI bleeding. A retroperitoneal core needle biopsy came back consistent with follicular lymphoma, grade 3A. Given that he had bulky disease, he received 6 cycles of R-CHOP and achieved a complete remission. About 18 months later, surveillance imaging identified progressive disease with new left inguinal adenopathy and a T4 paraspinal mass, which were 18F-Fluorodeoxyglucose (FDG)-avid on PET imaging with a standardized uptake value (SUV) of 7.8. A biopsy from the inguinal lymph node was consistent with relapsed follicular lymphoma, grade 1-2. He subsequently underwent radiation to the T4 paraspinal mass followed by R2 and achieved complete remission again. However, 13 months afterwards, he complained of left lower extremity pain and was found to have relapsed disease with bulky FDG-avid pelvic adenopathy on PET imaging in addition to other FDG-avid adenopathy above and below the diaphragm. The highest SUV was less than 10 in the pelvic area and a pelvic lymph node biopsy showed follicular lymphoma without evidence of transformation to an aggressive lymphoma. At that point CAR T-cell therapy was discussed, but the patient lived more than 2 hours away from the medical center and did not have a caregiver, which was a prerequisite to getting CAR T-cell therapy. EZH2 testing was performed on a prior lymph node biopsy which was positive for an EZH2 mutation. He was initiated on oral tazemetostat and achieved a partial remission and remained without progression at his last follow up visit 18 months later. 

A female in her early 80s* presented for management of relapsed low grade follicular lymphoma. She had an extensive medical history, including coronary artery disease status post stent placements, cerebrovascular stroke without residual motor or sensory deficits, diabetes, and chronic kidney disease. She initially presented with right inguinal mass and right lower extremity edema. Work-up at the time revealed FDG avid bulky adenopathy in the inguinal, pelvic, retroperitoneal, and bilateral axillary areas. The max SUV was 9 in the pelvic area and a biopsy from a pelvic lymph node was consistent with follicular lymphoma, low grade 1-2. She received therapy with mini-R-CHOP, which she tolerated reasonably well and achieved complete remission. Three years later, she was found to have relapsed disease when she again developed right lower extremity edema and imaging revealed adenopathy in the inguinal and pelvic area. A restaging PET revealed FDG-avid adenopathy in the inguinal and pelvic regions. She received radiation therapy to the pelvic and inguinal lymph nodes and was again in remission which lasted 12 months when she was found to have recurrent adenopathy in the axillary and retroperitoneal regions on surveillance imaging. She remained on active surveillance, but then developed left lower extremity edema and was found to have recurrent left pelvic adenopathy. A repeat lymph node biopsy was done which showed follicular lymphoma grade 1-2 without evidence of transformation and EZH2 testing came back as EZH2-wild type. Given her age, comorbid conditions, and performance status, she was deemed not a good candidate for further chemoimmunotherapy and was started on oral tazemetostat. She achieved a partial remission for the next 14 months. Eventually she developed recurrent disease with FDG-avid adenopathy with SUV 17 and a lymph node biopsy showed transformation to diffuse large B-cell lymphoma. She was subsequently treated with an anti-CD19 monoclonal antibody and achieved a partial remission for 4 months, but then relapsed and received hospice care.

The risk of developing secondary malignancies is increased following treatment with TAZVERIK. Across clinical trials of 758 adults who received TAZVERIK 800 mg twice daily as monotherapy, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), or B-cell acute lymphoblastic leukemia (B-ALL) occurred in 1.7% of patients. One pediatric patient developed T-cell lymphoblastic lymphoma (T-LBL). Monitor patients long-term for the development of secondary malignancies.

Based on findings from animal studies and its mechanism of action, TAZVERIK can cause fetal harm when administered to pregnant women. There are no available data on TAZVERIK use in pregnant women to inform the drug-associated risk. Administration of tazemetostat to pregnant rats and rabbits during organogenesis resulted in dose-dependent increases in skeletal developmental abnormalities in both species beginning at maternal exposures approximately 1.5 times the adult human exposure (area under the plasma concentration time curve [AUC0‑45h]) at the 800 mg twice daily dose.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TAZVERIK and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with TAZVERIK and for 3 months after the final dose.

In 99 clinical study patients with relapsed or refractory follicular lymphoma receiving TAZVERIK 800 mg twice daily: Serious adverse reactions occurred in 30% of patients who received TAZVERIK. Serious adverse reactions occurring in ≥2% were general physical health deterioration, abdominal pain, pneumonia, sepsis, and anemia. The most common (≥20%) adverse reactions were fatigue (36%), upper respiratory tract infection (30%), musculoskeletal pain (22%), nausea (24%), and abdominal pain (20%).

Avoid coadministration of strong or moderate CYP3A inhibitors with TAZVERIK. If coadministration of moderate CYP3A inhibitors cannot be avoided, reduce TAZVERIK dose.

Avoid coadministration of moderate and strong CYP3A inducers with TAZVERIK, which may decrease the efficacy of TAZVERIK.

Coadministration of TAZVERIK with CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and reduced efficacy of CYP3A substrates.

Christina Wu, MD

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