Nichole Tucker, MA, is the Web Editor for Targeted Oncology. Tucker received her Bachelor of Arts in Mass Communications from Virginia State University and her Master of Arts in Media & International Conflict from University College Dublin.

Nichole Tucker

Consolidation with autologous hematopoietic cell transplantation (AHCT) was less often given to patients with mantle cell lymphoma (MCL) from certain social and educational backgrounds, ultimately contributing to an increased mortality rate, according to a real-world study conducted in Sweden.

“A surprisingly high proportion of younger (<65 years) MCL patients (40%) were not treated with AHCT as part of their primary treatment. Factors associated with a lower likelihood of being selected to an AHCT included higher age, being never married or divorced, having any comorbidity, and lower socioeconomic status. We also noted survival disadvantages for non–AHCT-treated patients, implying that these selection mechanisms may have prognostic implications,” wrote the study authors led by Ingrid Glimelius, MD, PhD, of Uppsala University.

The trends of AHCT and its correlation with mortality have been studied in the United States (NCT03267433) as well.

 In a large cohort of younger patients with MCL who have undergone AHCT, the study showed that AHCT after induction therapy was associated with prolonged progression-free survival (PFS), and the investigators, therefore, recommended consolidation with AHCT for the subgroup. Later, in a study conducted by the Nordic Lymphoma Group, a significant improvement in PFS and modest improvement in overall survival (OS) was observed in older patients who underwent autologous stem cell transplant after rituximab (Rituxan) in combination with ibrutinib (Imbruvica), and cytarabine-containing induction.

Based on the modest OS improvement in patients with MCL following AHCT, little is known about how AHCT impacts survival, warranting new research like the registry study conducted in Sweden.

Patients included in the study we identified through the Longitudinal Integrated Database for Health Insurance and Labor Market Studies in Sweden. The patients were characterized by education of ≤9 years to >12 years and civil status of married, never married, divorced, or widowed. The group of 413 patients enrolled were diagnosed with MCL between January 2000 and June 2014 and were all between the ages of 18 and 65 years old. A total of 44 patients were excluded from the analysis, leaving 369 patients in the final cohort. Of the patients evaluated, 221 had undergone AHCT within 18 months and 148 had not.

Prediction of the probability of death in the patients enrolled was categorized as either alive without AHCT, alive with AHCT, dead before AHCT, or dead after AHCT. Patients were evaluated according to the time scale of time since MCL diagnosis.

In the group of patients who had AHCT, the majority were married (63.8%), but 17.7% had never been married, 16.7% were divorced, and 1.8% were widowed. The bulk of the AHCT cohort had 10 to 12 years of education, while 15.8% had up to 9 years, and 30.8% attended 12 years of school or more. Education data were unavailable for 2.7% of the AHCT cohort.

Among the patients who did not undergo AHCT within 18 months, 50.7% were married, 19.6% were never married, 24.3% were divorced, and 5.4% were widowed. This non-transplanted cohort had 42.6% of patients with 10 to 12 years of education, 30.4% with up to 9 years of education, and 23.7% with 12 years of education or more. Information about education was missing for 3.4% of this group.

The results showed that a total of 5 patients out of 221 who underwent AHCT died within 100 days, which showed that transplant-related mortality was low. During follow-up, another 145 patients with MCL died. Seventy-eight percent of the deaths during follow-up were lymphoma related. Overall, undergoing AHCT was associated with reduction in all-cause mortality compared with no AHCT (HR, 0.58; 95% CI, 0.40-0.85), according to the multivariate Cox analysis.

Notably, the mortality reduction was consistent regardless of age for patients who received AHCT versus those who did not (

 > .05). Use of cytarabine in the induction setting did not significantly impact all-cause mortality in patients who underwent AHCT compared with the no-AHCT group (HR, 1.01; 95% CI, 0.56-1.80). The difference in mortality in patients who underwent AHCT versus those who did not after being treated with chlorambucil, watch and wait, or radiotherapy alone was reduced by 52% (HR, 0.48; 95% CI, 0.32-0.71). Taken together, these findings showed that receipt of AHCT improved the prognosis in comparison to non-AHCT treatment regimens.

Further, an analysis of OS in the study looked into the number of patients who died following AHCT in each age group. The 10-year OS rate was 57% for patients aged 49 or younger, 52% for those aged 50 to 59, and 32% for the 60 to 65 group. Patients in the youngest age group were notably more likely to undergo AHCT and remain alive.

In the older group of patients (age 66-70), there were no deaths in the first 100 days after AHCT, similar to what was observed in the younger group. Receipt of AHCT in the older patients reduced the mortality rate compared with not having AHCT.

Survival was impacted by social status and education level. Overall, being a widower increased all-cause mortality compared with being married (HR, 2.76; 

 = .01), and having a lower education level increased morality compared with a higher education level (HR, 1.57; 

 = .018). Looking at those who received AHCT and were widowers compared with the married population, there was still an increased mortality rate for widowers, however, it was not significant (HR, 2.76; 

 = .43). For those with lower education who underwent AHCT versus those with higher education who underwent AHCT, the HR for the difference was 1.16 (

“This calls for the need of a more informed decision making in relation to not only the patients’ health prior to AHCT but also their sociodemographic situation. In case an AHCT is deemed impossible, integration of novel treatment concepts instead or in combination with standard treatment is needed,” wrote Glimelius et al.

1. Glimeius I, Smeby KE, Albertson-Lindbald A, et al. Unmarried or less-educated patients with mantle cell lymphoma are less likely to undergo a transplant, leading to lower survival. 

2. Gerson JN, Handorf E, Villa D, et al. Survival outcomes of younger patients with mantle cell lymphoma treated in the rituximab era. 

3. Abrahamsson A, Albertsson-Linbald A, Brown PN, et al. Real world data on primary treatment for mantle cell lymphoma: a Nordic Lymphoma Group observational study. 

Articles

According to a new study, marital status and education level may impact treatment and overall outcomes for patients with mantle cell lymphoma. 

Social Factors May Interfere With Transplant, Decreasing Survival in MCL

Bemarituzumab, a novel anti-fibroblast growth factor receptor 2b (FGFR2b)–targeted antibody, was granted breakthrough therapy designation by the FDA for the frontline treatment of patients with FGFR2b-overexpressing and HER2-negative metastatic and locally advanced gastric and gastroesophageal (GEJ) adenocarcinoma in combination with the modified FOLFOX6 regimen (fluoropyrimidine, leucovorin, and oxaliplatin; mFOLFOX6), based on an FDA-approved assay showing at least 10% of tumor cells overexpressing FGFR2b.

The use of bemarituzumab was investigated in the phase 2 FIGHT trial (NCT03694522), announced Amgen, in a press release. The study showed that the addition of bemarituzumab to mFOLFOX6 achieved clinically meaningful and statistically significant improvements in progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Most notably, bemarituzumab plus FOLFOX6 induced a 56% reduction in the risk of disease progression or death compared with placebo.

"The FIGHT trial is the first study to evaluate targeting the overexpression of FGFR2b in cancer. Bemarituzumab demonstrated clinically meaningful outcomes in key endpoints for patients with advanced gastric or gastroesophageal cancer as frontline therapy," said David M. Reese, MD, executive vice president of Research and Development at Amgen, in a statement. "Amgen looks forward to further investigating the role of FGFR2b and will continue to work with regulatory agencies on next steps to bring this potential first-in-class, frontline therapy to patients."

Patients included in the double-blind, placebo-controlled FIGHT study were randomized 1:1 to receive bemarituzumab with mFOLFOX6 or placebo/mFOLFOX6, every 2 weeks. The bemarituzumab arm includes 77 patients, and the placebo arm included 76 patients. The primary end point was investigator-assessed PFS, OS, and ORR were explored as secondary end points.

Findings from the study presented during the 2021 Gastrointestinal Cancers Symposium were for 155 patients in the intent-to-treat (ITT) population. In this population, the median PFS was 9.5 months for the combination arm versus 7.4 months for the placebo arm (HR, 0.68; 95% CI, 0.44-1.04; 

 = .0727). The 1-year PFS rate in the combination arm was 52.5% compared with 33.8% in the placebo arm.

There were 96 patients in the study with FGFR2b overexpression by immunohistochemistry (IHC) 2+/3+ at 10% or more of the sample, and the median PFS for this subgroups of patients was 14.1 months with bemarituzumab plus mFOLFOX6 compared with 7.3 months in the placebo arm (HR, 0.44; 95% CI, 0.25-0.77). The 1-year PFS rate observed with the combination was 57.0% and the rate for the placebo arm was 26.4%.

One-hundred eighteen patients in the study showed FGFR2b overexpression by IHC 2+/3+ in at least 5% of the sample, and in this population, the median PFS was 10.2 months with the combination versus 7.3 months with placebo (HR, 0.54; 95% CI, 0.33-0.87). The 1-year PFS rates were 56.3% and 28.6%, respectively.

In terms of OS in the ITT population, the median was not reached in the bemarituzumab arm versus 12.9 months in the placebo arm (HR, 0.58; 95% CI, 0.35-0.95; 

 = .0268). At 1 year, the OS rates were 65.3% and 56.9%, respectively. Among patients with the IHC 2+/3+ in at least 5% of the sample, the median OS was also not reached with bemarituzumab compared with 12.5 months with the placebo arm (HR, 0.52; 95% CI, 0.30-0.91). At 1 year, the OS rate was 67.9% in the combination arm versus 55.5% in the placebo arm.

Finally, in the group of patients with IHC 2+/3+ in at least 10%, the median OS was once again not reached with bemarituzumab plus FOLFOX6 versus 11.1 months with placebo (HR, 0.41; 95% CI, 0.22-0.79).

Response data showed that a 47% ORR in the combination arm compared with a 33% ORR in the placebo arm. The median time to response was 1.84 months versus 1.67 months, respectively, and the median duration of response was 12.2 months and 7.1 months, respectively.

In the bemarituzumab/mFOLFOX6 treatment arm, 82.9% of patients experienced grade 3 or higher adverse events compared with 74.0% of the placebo arm. In both groups, stomatitis in 9.2% vs 1.3% and dry eye in 2.6% vs 0%, respectively, were the most commonly observed grade 3 or higher AEs. Additionally, grade 5 AEs were observed in 5 patients who received the combination and 4 who received placebo. Notably, serious AEs occurred in 31.6% of the bemarituzumab-containing arm versus 36.4% of the placebo arm.

In 46.1% of the combination arm, AEs led to death compared with 36.4% in the placebo arm.

The study investigators also noted occurrences of corneal-related toxicities, which are commonly observed with FGFR inhibitors like bemarituzumab. In the FIGHT study, corneal-related AEs of any grade were observed in 67.1% of the combination arm versus 10.4%, with a median time to onset being 16.1 weeks for the bemarituzumab/FOLFOX6 arm versus 11.6 weeks in the placebo arm.

Eligible patients for the FIGHT study were those who had not received prior therapy, presented with measurable disease per RECIST v1.1, harbored FGFR2b overexpression by IHC and/or 

 amplification by circulating tumor DNA (ctDNA), an ECOG performance status of 0 or 1, did not show HER2-positive disease, and did not receive 1 dose of mFOLFOX6. In the study, patients meeting these characteristics were stratified by geographic region, a single dose of mFOLFOX6 during screening, and prior adjuvant or neoadjuvant chemotherapy.

Baseline characteristics showed that the cohort was well balanced. The median age of the study population was 59.7 years, and these patients were predominantly male. The study also had a large Asian population of 45 patients in each treatment arm. In terms of geographic region, 42.6% of patients were from the United States or European Union, 17.4% were from China, the remaining 40.0% were from other Asian countries. Screening found 

overexpression or amplification in 94.8% and 15.6% of those randomized to receive the bemarituzumab doublet, respectively. 

overexpression or amplification was also found in the placebo arm in 97.4% and 17.9% of patients, respectively. More than 83% of patients were IHC positive and ctDNA negative at baseline, whereas12.9% were IHC positive and ctDNA positive, and 3.9% were IHC negative and ctDNA positive.

According to Amgen, bemarituzumab is under clinical development in gastric and GEJ cancer as a targeted therapy for tumors that overexpress FGFR2b. The company is also exploring its use in other disease.

1. Amgen's Investigational targeted treatment bemarituzumab granted breakthrough therapy designation. New release. April 19, 2021. Accessed April 20, 201. 

2. Wainberg ZA, Enzinge P, Kang Y, et al. A double-blind randomized study of bemarituzumab (bema) plus mFOLFOX6 versus placebo plus mFOLFOX6 as first-line treatment for advanced gastric/gastroesophageal junction cancer (FIGHT). 

The FDA has granted breakthrough therapy designation to bemarituzumab for the first-line treatment of patients with HER2-negative metastatic and locally advanced gastric and gastroesophageal adenocarcinoma who harbor FGFR2b overexpression or amplification.

FDA Grants Breakthrough Therapy Designation to Bemarituzumab for Select FGFR2b+/HER2- Advanced Gastric and GEJ Cancers

The FDA has granted an orphan drug designation to CA-4948, a first-in-class, small-molecule inhibitor of IRAK4, for the treatment of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), announced Curis, Inc., in a press release.

The novel agent is under investigation as treatment of both AML and MDS in a phase 1 clinical trial (NCT04278768).

"We are pleased to take this important next step in unlocking the potential of CA-4948 to offer a safe and transformative, disease-modifying alternative treatment for patients on the AML/MDS spectrum," said James Dentzer, chief executive officer of Curis, in a statement. "Receiving orphan drug designation for CA-4948 in AML and MDS represents a significant milestone in our mission of slowing or preventing the progression of disease in patients with these rare hematological malignancies.”

In the study, investigators are exploring the maximum tolerated dose (MTD) and recommended phase 2 dose of CA-4948 as co-primary end points. As secondary end points, the study will explore several pharmacokinetic and pharmacodynamic parameters. 

Patients enrolled will receive CA-4948 in tablet form starting at a dose of 200 mg twice daily for up to 28 days. At the start of the study, 3 patients with either AML or MDS will be dosed with the agent and will continue treatment at the next dose level if no dose-limiting toxicities (DLTs) are observed. In the event that 2 or 3 patients experience a DLT at that level, the DLT rate will be considered above 33%, which is above the MTD of the agent, and the dose will be lowered.

To be eligible for enrollment, patients must be 18 years or older, with a life expectancy of at least 3 months, and an ECOG performance status of 2 or lower. Patients with AML are required to have relapsed or refractory disease, and those with MDS are required to have high or very high risk relapsed/refractory disease following at least 6 cycles of therapy with hypomethylating agents or evidence of early progression. At the time of screening in the study, patients must have adequate organ function, a negative serum pregnancy test if they are a female of childbearing age, and be able to undergo serial bone marrow sampling and peripheral blood sampling.

The study excludes patients with acute promyelocytic leukemia, blast phase of chronic myeloid leukemia, active central nervous system leukemia, acute or chronic toxicity resulting from prior anti-cancer therapy, human immunodeficiency virus, hepatitis B or C virus, severe cardiovascular disease, as well as a history of other invasive malignancy, gastrointestinal disease or disorder, other invasive malignancy, uncontrolled fungal, bacterial, viral, or other infection or allergy or hypersensitivity to any component of the formulation of CA-4948.

In terms of prior therapy, patients are not considered eligible for treatment with CA-4948 in the study if they had an allogeneic hematopoietic stem cell transplant within 60 days of the first dose of CA-4948, systemic anti-cancer treatment such as chemotherapy or immunomodulatory drug therapy within 14 days of CA-4948 dosing, or an investigational agent within 28 days of the start of CA-4948 in the study.

Currently, patients with AML and MDS are being recruited throughout the United States at Moffitt Cancer Center, Dana-Farber Cancer Institute, Oncology Hematology West, PC dba Nebraska Cancer Specialists, Albert Einstein Medical College, Novant Health Hematology – Forsyth, and the University of Texas MD Anderson Cancer Center.

IRAK4 kinase plays a roll in the Toll-like receptor and interleukin-1 receptor signaling pathways, both of which are often dysregulated in AML, MDS, and non-Hodgkin lymphomas. The agent is also being explored in combination with ibrutinib (Imbruvica) as treatment of patients with non-Hodgkin lymphoma.

Curis receives FDA orphan drug designation for CA-4948 for the Treatment of AML and MDS. News release. Curis Inc. April 19, 2021. Accessed April 19, 2021. 

The FDA has granted an orphan drug designation to CA-4948, a first-in-class, small-molecule inhibitor of IRAK4, for the treatment of patients with acute myeloid leukemia and myelodysplastic syndrome.

FDA Grants Orphan Drug Status to Novel IRAK4 Inhibitor in AML and MDS

The FDA has lifted a partial clinical hold on a phase 1 clinical trial of SBP-101 (NCT0341279) in combination with the standard-of-care agents gemcitabine and nab-paclitaxel (Abraxane) as treatment of patients with metastatic pancreatic ductal adenocarcinoma (PDAC).

In an effort to get the clinical trial reopened, the developer of SBP-101, Panbela Therapeutics, agreed to exclude patients with a history of retinopathy or who are at risk of retinal detachment from all future studies. The company also agreed to schedule ophthalmologic monitoring for all patients. Screening for retinal toxicity will also be included in future dose-finding studies.

SBP-101 is a polyamine analogue that has demonstrated signals of tumor growth inhibition in clinical trials throughout the United States and Australia. Data supporting the agent suggests that it may compliment an FDA-approved standard-of-care therapy intended for the treatment of patients with metastatic pancreatic cancer. In addition, safety data along with the Pain Management Index profile of SBP-101, as seen in the phase 1 clinical trial, warrant the drug’s continued evaluation.

Earlier in the year, Panbela announced that an independent data safety monitoring board had recommended that administration of the drug be held pending further investigation of visual disturbance toxicities in the phase 1 trial. Complaints of visual changes from participants were reported in the combination phase 1 study that were not seen in the earlier phase 1 monotherapy study.

An estimated 24 patients will be included in the ongoing phase 1a/1b dose-escalation and expansion study of SBP-101 combined with gemcitabine and nab-paclitaxel for the treatment of patients with previously untreated metastatic PDAC. The study is exploring the recommended phase 2 dose of SBP-101. The secondary end points include safety/tolerability—as determined by the number of patients with adverse events, tumor response, area under the plasma concentration versus time curve, and peak plasma concentration.

To be eligible, patients must have histologically or cytologically confirmed metastatic PDAC that was previously untreated, measurable disease on CT or MRI scan by RECIST version 1.1 criteria; ECOG performance status 0 or 1; age ≥ 18 years; adequate bone marrow, hepatic, renal and coagulation function; a life expectancy of at least 3 months; and QTc interval ≤ 470 msec at baseline.

Original exclusion criteria for the study include severe or uncontrolled systemic disease or any concurrent condition that may interfere with treatment, as well as radical or psychiatric conditions, symptomatic central nervous system malignancy or metastasis, deep vein thrombosis, pulmonary embolism or other thromboembolic event, a known active bacterial, fungal, or viral infection requiring systemic therapy, active infection with human immunodeficiency virus, hepatitis B or C virus, or other conditions that may interfere with SBP-101 or chemotherapy.

In a prior phase 1 study (NCT02657330), SBP-101 showed promise as monotherapy in patients with metastatic PDAC.

 A total of 28 patients were enrolled and treated according to a modified 3 x 3 dose-escalation scheme. The doses of SBP-101 administered were 0.05 mg/kg in cohort 1, 0.1 mg/kg in cohort 2, 0.2 mg/kg in cohort 3, 0.4 mg/kg in cohort 4, and 0.8 mg/kg in cohort 5 given for week days for 3 weeks, followed by 5 weeks of observation. The study evaluated the maximum-tolerated dose of the agent.

Treatment with SBP-101 led to stable disease (SD) in 4 patients, 2 of whom were from cohort 3 and 2 from cohort 4. Four patents from cohort 5 also achieved SD. In cohort 3, the median survival observed was 5.9 months.

According to the safety analysis, the most common adverse events (AEs) were abdominal pain, constipation, decreased appetite, dehydration, diarrhea, fatigue, nausea and vomiting. The majority of AEs were grade 1 or 2 in severity and not likely related to the experimental drug. Notably, no patients in the study had drug-related bone marrow suppression or peripheral neuropathy on any dose of SBP-101, and there were no dose-limiting toxicities (DLTs) in cohorts 1 through 4. DLTs of bacterial sepsis with metabolic acidosis, hepatic and renal failure with elevated lipase, and superior mesenteric vein thrombosis with metabolic acidosis were observed in cohort 5 in 1 patient each.

These data showed SBP-101 to be a safe and tolerable agent for the treatment of metastatic PDAC.

SBP-101 was previously granted a fast track designation by the FDA for the treatment of patients with metastatic PDAC in combination with gemcitabine and nab-paclitaxel. At the time the fast track designation was announced, Suzanne Gagnon, MD, chief medical officer of Sun BioPharma, the name of which was later changed to Panbela, stated: “Fast Track Designation is important for Sun BioPharma because it enhances our ability to develop SBP-101 as efficiently as possible.”

1. Panbela announces partial clinical hold lifted on phase i polyamine metabolic inhibitor study in pancreatic cancer. News release. Panbela Therapeutics. April 16, 2021. Accessed April 16, 2021. 

https://panbela.com/wp-content/uploads/2021/04/PBLA-PR-Lifted.pdf

2. Panbela Provides Update on Current Clinical Trial: Decision to Hold Administration of SBP-101. News release. Panbela Therapeutics. February 10, 2021. Accessed April 16, 2021. 

https://panbela.com/wp-content/uploads/2021/02/PBLA-PR-Hold.pdf

3. Tebbutt NC, Kotasek D, Borad MJ, et al. A phase 1 safety study of SBP-101, a polyamine metabolic inhibitor, for pancreatic ductal adenocarcinoma (PDA). 

 2018;36(suppl 15):e16231. doi:10.1200/JCO.2018.36.15_suppl.e16231

The FDA has lifted a partial clinical hold on a phase 1 clinical trial of SBP-101 in combination with the standard-of-care agents gemcitabine and nab-paclitaxel as treatment of patients with metastatic pancreatic ductal adenocarcinoma.

Nichole Tucker | Authors

Articles

Social Factors May Interfere With Transplant, Decreasing Survival in MCL

FDA Grants Breakthrough Therapy Designation to Bemarituzumab for Select FGFR2b+/HER2- Advanced Gastric and GEJ Cancers

FDA Grants Orphan Drug Status to Novel IRAK4 Inhibitor in AML and MDS

FDA Lifts Partial Clinical Hold from Study of SBP-101 in Pancreatic Cancer