At a 2-year follow-up, lisocabtagene maraleucel (liso-cel; Breyanzi) continued to yield positive outcomes in patients with relapsed/refractory large B-cell lymphomas (LBCL), according to results from the phase 1 TRANSCEND NHL 001 trial (NCT02631044) presented during the 2022 Transplantation & Cellular Therapy Meetings.

Treatment with liso-cel elicited an overall response rate (ORR) of 73% (95% CI, 66.9%-78.1%), including a complete response (CR) rate of 53% (95% CI, 46.6%-59.2%) among 257 efficacy-evaluable patients after a median follow-up of 23.0 months. The median duration of response (DOR) by Lugano 2014 criteria was 23.1 months (95% CI, 8.6–not reached [NR]) and the probability of continued response at 2 years was 49.5% (95% CI, 41.4%-57.0%).

Additionally, the median DOR was 26.1 months (95% CI, 23.1–NR) and 23.1 months (95% CI, 5.6-NR) in those who achieved a CR and partial response (PR), respectively.

“This 2-year follow-up analysis of TRANSCEND demonstrated durable response to liso-cel in patients with high-risk aggressive relapsed/refractory LBCLs,” Jeremy Abramson, MD, director of the Jon and Jo Ann Hagler Center for Lymphoma, Massachusetts General Hospital, and an associate professor of medicine at Harvard Medical School said during the presentation. “Liso-cel treatment was associated with a low incidence of severe cytokine release syndrome [CRS] and neurologic events,” Abramson added.

To be eligible for the study, patients needed to be 18 years or older and have received 2 or more prior lines of therapy. Those who enrolled had diffuse large B-cell lymphoma that was not otherwise specified (DLBCL NOS)—either de novo or transformed from follicular lymphoma, marginal zone lymphoma, or another disease—high-grade B-cell lymphoma (HGBCL), primary mediastinal large B-cell lymphoma (PMLBCL), or follicular lymphoma grade 3B (FL3B). Other inclusion criteria included previous hematopoietic stem cell transplant and an ECOG performance status of 0 or 2. Primary central nervous system lymphoma was also allowed.

Patients received a lymphodepleting regimen of 30 mg/m2 fludarabine and 300 mg/m2 of cyclophosphamide for 3 days followed by liso-cel 2 to 7 days later. The on-study follow up was 24 months.

The study’s primary end points were adverse effects (AE) and ORR by independent review committee (IRC). Secondary end points included CR rate by IRC, DOR, progression-free survival (PFS), overall survival (OS), and pharmacokinetic profile.

Patients who enrolled on the trial were followed for 2 years after the last liso-cel dose, and the study is ongoing as of the cutoff date of January 2021. Two hundred and sixty-eight patients had died or withdrawn 24 months or more after follow-up. Among 120 patients who completed the study, 81 agreed to be part of a long-term follow-up study assessing safety and OS up to 15 years, but no IRC response assessments were performed.

Notably, 1 patient died following an ongoing CR at 26 weeks due to sepsis. No patients relapsed after 23 months in the study.

The median patient age was 63 years and 41% of patients were aged 65 years or older. The majority of patients had DLBCL NOS (51%), and others had transformed follicular lymphoma (22%), other indolent lymphomas (7%), HGBCL (13%), PMBCL (6%), and FL3B (1%). Additionally, most patients were chemotherapy refractory (67%) and underwent treatment with a bridging therapy (59%). The overall median follow up was 19.9 months.

Additional findings from the study indicated that after a median follow-up of 23.9 months, the median PFS was 6.8 months (95% CI, 3.3-12.7) and the probability of PFS at 2 years was 40.6% (95% CI, 34.0%-47.2%). The median PFS in those who had a CR and PR was 27.3 months (95% CI, 24.0-NR) and 6.8 months (95% CI, 3.3-12.7).

After a median follow-up of 29.3 months, the median OS was 27.3 months (95% CI, 16.2-45.6), with a 2-year probability of OS rate of 50.5% (95% CI, 44.1%-56.5%). The median OS in those who had a CR or PR was 48.5 months (95% CI, 45.2-NR) and 9.0 months (95% CI, 6.0-11.4), respectively. In non-responders, the median OS was 5.4 months (95% CI, 2.9-6.5). Three deaths occurred after 45 months. Moreover, CAR T-cell persistence was detected at 48 months in the long-term follow-up study (NCT03435796) in addition to 37% of patients at 24 months in the TRANSCEND study.

In terms of safety, the most common any AEs within 90 days of infusion were neutropenia (63%), anemia (48%), and fatigue (44%), and grade 3 or higher AEs include neutropenia (60%), anemia (37%), and thrombocytopenia (27%). Any grade and grade 3 or higher infections occurred in 12% of patients, and in 41% of patients with any grade AE. From day 91 to the end of study, the most common any grade AEs were neutropenia (8%), anemia (8%), and fatigue (7%), with grade 3 or higher AEs including neutropenia (7%), anemia (6%), and thrombocytopenia (4%). Any grade and grade 3 or higher infections occurred in 5% of patients, and in 10% of patients with any grade AE.

Investigators reported several AEs of special interest. Any grade and grade 3/4 CRS were reported in 42% and 2% of patients, respectively; the median time to onset and resolution of CRS was 5 days, respectively. Any grade and grade 3/4 neurologic events were reported in 30% and 10% of patients, respectively. The median time to onset was 9 days and the median time to resolution was 11 days. Most cases of CRS and neurological events were grade 1/2, with no grade 5 events.

Second primary malignancies (SPM) occurred in 5 and 17 patients during the treatment emergent and post–treatment emergent periods, respectively. The types and incidence of SPMs were expected given the patient population and prior therapies and included diseases such as non-melanoma skin cancer (n = 9), solid tumors (n = 4), myelodysplastic syndrome (n = 8), acute myeloid leukemia (n = 2), and peripheral T-cell lymphoma (PTCL; n = 1). The single case of PTCL was reported on day 30 and did not appear to be in relation to treatment with liso-cel.

Of 270 patients, 9 died 30 days or less following last infusion, 24 died at over 30 days to 90 days or less, and 100 died at over 90 days. The majority of deaths were attributed to disease progression and no deaths were due to COVID-19.

Abramson JS, Palomba ML, Gordon LI, et al. Two-year follow-up of TRANSCEND NHL 001, a multicenter phase 1 study of lisocabtagene maraleucel in relapsed or refractory large B-cell lymphomas. Presented at: 2022 Transplantation & Cellular Therapy Meetings; April 23-26, 2022. Abstract 65.

Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. 

. 2014;32(27):3059-3068. doi:10.1200/JCO.2013.54.8800

Articles

Patients with relapsed/refractory large B-cell lymphoma continued to derive benefit from lisocabtagene maraleucel after 2 years of follow-up.

Liso-cel Exhibits Durable Responses in Relapsed-Refractory Large B-Cell Lymphoma

Patients with relapsed or refectory large B-cell lymphoma (LBCL) who received axicabtagene ciloleucel (axi-cel; Yescarta) continued to elicit a long-term survival overall survival (OS) benefit at 5-year follow-up, according to data from an analysis of the phase 2 ZUMA-1 trial (NCT02348216) presented during the 2022 Tandem Meeting.

“In this updated 5-year analysis, axi-cel induced long-term OS...among treated patients,” according to Caron A. Jacobson, MD, MMSc, medical director of the Immune Effector Cell Therapy Program and senior physician at Dana-Farber Cancer Institute. “Between the 4- and 5-year analysis, the time to next therapy curve remains stable and 92% of patients remained alive without a need for subsequent therapy, which may be suggestive of a cure in these patients,” said Jacobson, who is also an assistant professor of medicine at Harvard Medical School.

Investigators reported a 5-year OS rate of 42.6% (95% CI, 32.8%-51.9%) following treatment with axi-cel (n = 101). In the population of patients who experienced a complete response, the 5-year OS rate was 64.4% (95% CI, 50.8%-75.1%) and the median OS was not reached (95% CI, 63.4–not estimated). Additionally, 63% of complete responders were alive at the 5-year data cut off. At the 4-year data cutoff, 1 patient died at month 63 and one experienced progressive disease at month 54.

To be considered for treatment, patients were required to have LBCL, including diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma. Patients were also required to have not responded to their last chemotherapeutic or have relapsed 12 months or less following autologous stem cell transplant. Treatment with a previous anti-CD20 monoclonal antibody and anthracycline was also necessary.

Those who underwent treatment received a conditioning regimen of cyclophosphamide at 500 mg/m

 of fludarabine for 3 days. This was followed by axi-cel at a dose of 2x106 CAR T-cells/kg. The primary end point was overall response rate with first response assessment 4 weeks following infusion, Key secondary end points included OS, safety, and translational evaluations.

A total of 111 patients were enrolled on the study, 8 of whom did not undergo treatment due to adverse effects (AEs; n = 4), no measurable disease (n = 2), death due to disease progression (n = 1), and manufacturing failure (n =1); this left 103 patients to undergo conditioning. Of these patients 2 were not treated due to AEs and death, respectively. One hundred and three patients underwent infusion. The data cutoff was August 11, 2021 and the median follow-up was 63.1 months.

Additional findings from the trial highlighted a median time to next anticancer therapy of 8.7 months following infusion. A total of 34% of patients were alive at cutoff with no subsequent therapy or retreatment with axi-cel. Two patients who had prior progression underwent new anticancer therapy.

According to results of an exploratory analysis, investigators reported that 1- and 2-year event-free survival (EFS) may potentially have a role as a surrogate end point for long-term OS. The 5-year OS rates among those who had or had not experienced an EFS event at month 12 were 5.3% vs 90.9%, respectively. The median OS was 8.3 months among those who experienced an event and was not reached in those who did not experience an event. Additionally, the 5-year OS rates among those who did or did not have an EFS event at month 24 were 11.3% and 92.3%, respectively. Moreover, the median OS in both respective groups was 9.2 months and not reached.

Investigators also determined that early CAR T-cell expansion was associated with ongoing response at 60 months. The median peak CAR T levels appeared to be numerically higher in those who had an ongoing response at month 60 and lower in those who relapsed or did not respond to treatment. Similarly, another trend was observed in those who experienced CAR T-cell expansion by area under the curve from day 0 to 28.

A total of 58% of patients had died by the cutoff date. No new safety signals had been observed as of the 5-year data cutoff, including serious AEs or secondary malignancies related to treatment. Patients most commonly died due to progressive disease (n = 45), AEs (n = 4), secondary malignancies (n = 1), or other reasons (n = 9).

Jacobson C, Locke FL, Ghobadi A, et al. Long-term (5 year) overall survival in Zuma-1, the pivotal study of axicabtagene ciloleucel (Axi-Cel) in patients with refractory large B-cell lymphoma (LBCL). Presented at: 2022 Tandem Meetins; April 23-26, 2022; Salt Lake City, UT. Abstract 10.

Patients with relapsed or refractory large B-cell lymphoma experienced improved overall survival following treatment with axicabtagene ciloleucel.

 Axi-cel Sustains Long-Term Survival Rates in Relapsed/Refractory Large B-Cell Lymphoma 

Patients with advanced or recurrent endometrial cancer experienced superior progression-free survival (PFS) following treatment with maintenance selinexor (Xpovio) monotherapy, according to findings from the phase 3 SIENDO/ENGOT-EN5/GOG-3055 study (NCT03555422) that were presented during the 2022 SGO Annual Meeting on Womens’ Cancers.

The findings demonstrated that in the intent-to-treat (ITT) population, the median PFS was 5.7 months (95% CI, 3.81-9.20) in the selinexor group vs 3.8 months (95% CI, 3.68-7.39) in the placebo group (HR, 0.705; 95% CI, 0.499-0.996; one-sided 

Furthermore, at 3-month follow-up, the PFS rates in the selinexor and placebo groups, respectively, were 72.4% vs 66.4%. At a 6-month follow-up, PFS rates were 48.2% vs 40.9%; at a 9-month follow-up, rates were 41.7% vs 34.1%, and by 12 months of follow-up, the rates were 35.3% vs 25.8%.

Among patients with endometrioid carcinoma who also had histologic subtype identified in a prespecified exploratory analysis, the median PFS between the selinexor and placebo groups, respectively, were 9.2 months vs 3.8 months (HR, 0.573; 95% CI, 0.348-0.944; one-sided 

Patients with a serous histology achieved a median PFS of 3.8 months vs 3.7 months, respectively (HR, 0.859; 95% CI, 0.481-1.533; 

 = .309), and patients with wild-type p53 endometrial cancer achieved a median PFS of 13.7 months (95% CI, 9.20-not reached) vs 3.7 months (95% CI, 1.87-12.88), respectively (HR, 0.375; 95% CI, 0.210-0.670; one sided 

“Selinexor demonstrated in the audited ITT population a 30% decrease in risk for progression and/or death compared with the placebo, but this was not significant in the non-audited population,” Ignace B. Vergote, MD, PhD, head of the Department of Obstetrics and Gynecology and Gynecologic Oncology, Catholic University of Leuven, Belgium, said in a presentation during the meeting.

Investigators enrolled patients with stage IV disease or who on their first relapse, including those with endometrioid, serous, undifferentiated, or carcinosarcoma histology. Patients needed to have at least 12 weeks of treatment with taxane and carboplatin followed by a partial response (PR) or complete response (CR). Previous surgery, radiotherapy, or hormonal therapy were allowed.

Patients were randomized 2:1 to receive either 80 mg of selinexor weekly until progressive disease (n = 174) or placebo (n = 89). The primary end point of the trial was investigator-assessed PFS and key secondary end points included overall survival, PFS by blinded independent central review, and disease control rate. Predefined exploratory end points included histological subtype and molecular subclassification.

In the selinexor cohort, 33.3% of patients were 70 years or older and most patients had an ECOG performance status of 0 (56.9%) or 1 (40.8%). Most patients had endometrioid (55.2%) and serous (28.2%) histology. At the time of treatment with the combination chemotherapy regimen, most patients had recurrent disease (55.2%) and 44.8% had stage IV disease. Additionally, 59.8% had a PR and 40.2% had a CR following most recent chemotherapy.

Additionally, in the placebo cohort, 31.5% of patients were 70 years or older, all of whom had an ECOG performance status of 0 (60.7%) and 1 (39.3%). Most patients in the cohort had endometrioid (53.9%) and serous (31.5%) histology. Moreover, 51.7% of patients had recurrent disease and 48.3% had stage IV disease at the time of combination chemotherapy. After the most recent chemotherapy treatment, 55.1% of patients had a PR, and 44.9% had a CR.

Notably, investigators stated that stratification factor of CR and PR was incorrect for 7 patients and was corrected before the database's lock and unblinding. The median follow-up was 10.2 months (95% CI, 8.97-13.57).

In terms of safety, the most common any-grade treatment-emergent adverse effects (TEAEs) in the selinexor arm were nausea (84%), vomiting (52%), constipation (37%), and thrombocytopenia (37%) and grade 3/4 TEAEs included nausea (10%), neutropenia (9%), asthenia (6%), fatigue (6%), and thrombocytopenia (6%). For the placebo group, common any-grade TEAEs included constipation (38%), nausea (34%), diarrhea (23%), and asthenia (21%) and grade 3/4 TEAEs included constipation (2%), nausea (1%), vomiting (1%), fatigue (1%), and asthenia (1%).

Moreover, in the selinexor arm, 49.7% of patients required a dose reduction, 51.5% needed a dose interruption, and 10.5% discontinued. For patients treated with placebo, 3.4% needed a dose reduction, 18.2% had a dose interruption, and 1.1% discontinued. No TEAEs led to death in either arm.

In terms of patient-reported quality of life, investigators did not observe any significant differences in global health, physical functioning, or symptoms.

Vergote I, Pérez Fidalgo A, Hamilton E, et al. SIENDO/ENGOT-EN5/GOG-3055: a randomized phase 3 trial of maintenance selinexor versus placebo after combination platinum-based chemotherapy in advanced or recurrent endometrial cancer. Presented at: 2022 SGO Annual Meeting on Women’s Cancer; March 18-21, 2022; Phoenix, Arizona. Abstract 249.

Selinexor demonstrated impressive efficacy in extending progression-free survival among patient with advanced or recurrent endometrial cancer, particularly among patients with wild-type p53 endometrial cancer. 

Maintenance Selinexor Yields Survival Benefit in Advanced or Recurrent Endometrial Cancer

Patients with checkpoint inhibitor–naïve metastatic urothelial cancer experienced promising antitumor responses after receiving a combination of sacituzumab govitecan-hziy (Trodelvy) and pembrolizumab (Keytruda) in the second-line setting, according to the cohort 3 results from the phase 2 TROPHY-U-01 trial (NCT03547973) that were presented during the 2022 Genitourinary Cancers Symposium.

At a median follow-up of 5.8 months, patients treated with the combination experienced an objective response rate (ORR) of 34% (95% CI, 20.1%-50.6%), and an ORR of 38% among evaluable patients. One patient experienced a complete response (CR), 13 had partial responses (PR), and 11 achieved stable disease. Of those who experienced stable disease, 4 had stable disease for 6 months or more.

“These data support further evaluation of antibody-drug conjugate/checkpoint inhibitor combination [therapy] in metastatic urothelial cancer in the platinum-refractory setting and probably in earlier lines of therapy in a different patient population,” according to lead author Petros Grivas, MD, PhD, a physician at Seattle Cancer Care Alliance; clinical director of the Genitourinary Cancers Program and associate professor of the Division of Medical Oncology at the University of Washington School of Medicine; and associate professor of Clinical Research Division at Fred Hutchinson Cancer Research Center. “Additional follow up for survival events and biomarkers are ongoing.”

As treatment options for patients with metastatic urothelial cancer remain limited and outcomes poor, investigators aimed to assess other safe and efficacious options to improve patient responses. Investigators theorized that antibody-drug conjugates and checkpoint inhibitors may be a valuable combination strategy capable of providing benefit to patients with metastatic disease.

In cohort 3 of the registrational, open-label multicohort study, investigators enrolled up to 61 patients who were checkpoint inhibitor-naïve with progressive disease following treatment with platinum-based therapies. The cohort received sacituzumab govitecan at a dose of 10 mg/kg on days 1 and 8 every 21 days and 200 mg of pembrolizumab on day 1 every 21 days. Treatment continued until patients experienced unacceptable toxicity or disease progression. Patients needed to be 18 years or older with an ECOG performance status of 0 or 1. Additionally, a creatinine clearance of 30 mL per minute or higher and adequate hepatic function were required.

The study’s primary end point was ORR by investigator review, with key secondary end points including safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

The majority of patients were male (83%) and the median age was 67 years. Most patients were White (54%) and had an ECOG performance status of 1 (61%). In total, 49% and 27% of patients had a Bellmunt risk factor of 1 and 2, respectfully. Investigators also reported 49% of patients underwent neoadjuvant or adjuvant therapy with a median time from end of most recent prior systemic therapy to screening date of 1.6 months. In terms of best response to prior systemic therapy in the metastatic setting, 1 patient had a previous CR and 2 had a PR.

Additional findings from the study indicated that 63% of patients experienced tumor shrinkage and the clinical benefit rate was 61% (95% CI, 44.5%-75.8%). Patients had a median time to response of 2 months and the median DOR was not reached (95% CI, 2.80–not available). The median PFS was 5.5 months (95% CI, 1.7–not reached) and the median OS was not reached.

When examining ORR by subgroup, investigators reported that patients with or without baseline visceral metastases and liver involvement, had rates of 41.7% (95% CI, 15.17%-72.33%) and 31.0% (95% CI, 15.28%-50.83%), respectively. Additionally, for patients who had a Bellmunt risk factor of 0, 1, and 2, the ORRs were 40.0% (95% CI, 12.16%-73.76%), 35.0% (95% CI, 15.39%-59.22%), and 27.3% (95% CI, 6.02%-60.97%).

The most common any grade adverse effects (AEs) in cohort 3 were diarrhea (76%), nausea (59%), and anemia (56%), with grade 3 or higher AEs including neutropenia (27%), diarrhea (24%), anemia (20%), and leukopenia (20%).

The median duration of treatment was 4 months with sacituzumab govitecan and 3.5 months with pembrolizumab. Sixty-eight percent of patients permanently discontinued treatment and 32% were still being treated at the time of data cutoff. Patients who discontinued did so due to progressive disease (51%), withdrawal of consent (5%), and AEs (3%).

Grade 3/4 treatment-related AEs (TRAEs) occurred in 59% of patients, with 39% of patients discontinuing sacituzumab govitecan treatment because of TRAEs. The most common any grade TRAEs were diarrhea (71%), nausea (54%), and neutropenia (44%). Twenty-five percent of patients required a steroid to combat an immune-related AE, with 15% of patients requiring topical and 10% requiring oral steroids for diarrhea (n = 2), pruritis (n = 1), and maculopapular rash (n = 1). Investigators also reported that 29% of patients required granuloma macrophage colony–stimulating factor.

“[Other] TROPHY-U-01 cohorts are being assessed. We have cohort 2 looking at sacituzumab govitecan as a single agent after checkpoint inhibition and cohorts 4 and 5 evaluating sacituzumab govitecan in combination with cisplatin plus or minus avelumab [Bavencio] as induction therapy followed…avelumab [switch maintenance therapy],” Grivas concluded.

Grivas P, Poussel D, Park CH, et al. TROPHY-U-01 Cohort 3: sacituzumab govitecan (SG) in combination with pembrolizumab (Pembro) in patients (pts) with metastatic urothelial cancer (mUC) who progressed after platinum (PLT)-based regimens. 

. 2022;40(suppl 6):434. doi:10.1200/JCO.2022.40.6_suppl.434

Adding sacituzumab govitecan to second-line pembrolizumab garnered promising antitumor activity among patients with checkpoint inhibitor–naïve metastatic urothelial cancer. 

Pembrolizumab Plus Sacituzumab Govitecan Yields Encouraging Antitumor Activity in Metastatic Urothelial Cancer

pathway activation may drive the development of secondary uterine cancer in patients who have primary breast cancer and receive treatment with tamoxifen, according to findings published during the 2021 San Antonio Breast Cancer Symposium.

To assess the mutational landscape of tamoxifen-associated uterine cancer, investigators performed whole genome sequencing on 21 samples from the TAMARISK trial, which examined the occurrence of secondary disease among those treated with tamoxifen.

 uterine cancers not associated with tamoxifen treatment gathered utilizing The Cancer Genome Atlas. Findings indicated that genomic alterations in tamoxifen-associated uterine cancer and 

 uterine cancers developed at a similar rate.

“We want to make sure people understand that tamoxifen is safe to use, and tamoxifen-associated uterine cancer is infrequent,” study author Rinath Jeselsohn, MD, an assistant professor of medicine and medical oncology at Dana-Farber Cancer Institute and Harvard Medical School, said. “We wanted to understand the mechanisms behind this uncommon event to potentially help patients who are at an increased risk of uterine cancer due to other additional risk factors.”

Investigators noted that patients who developed tamoxifen-associated uterine cancer had significantly decreased mutations in the 

 signaling pathway, which is known to drive the development of uterine cancer. Moreover, 

 mutations were identified in 14% of patients with tamoxifen-associated uterine cancer compared with 48% of those with 

 mutations were observed in 31% of patients with 

 disease compared with no patients with tamoxifen-associated uterine cancer.

Data from the trial were verified utilizing digital droplet polymerase chain reaction (PCR) to assess 

 hotspot mutations utilizing samples taken from the TAMARISK trial (n = 40), which were then compared with a cohort of samples taken from patients with 

 uterine cancers from the American Association for Cancer Research Project GENIE. Similarly, a decreased incidence in identification of 

 mutations was observed, specifically 7.5% in the tamoxifen-associated uterine cancer arm and 21% in the 

To better understand the mechanisms responsible for decreased 

 mutations among those with tamoxifen-associated uterine cancers, tissue taken from mice treated with tamoxifen were examined. Findings from the assessment highlighted an increased Ki-67 expression. RNA sequencing also highlighted notable pathway activation based on stains for phosphorylated proteins in the 

 pathway. The findings highlight a significant rise in 

 pathway activation in mice treated with tamoxifen vs the control group.

“The model for how secondary cancers occur after chemotherapy, for example, is that cells acquire driver mutations that lead to clonal outgrowth,” presenter Kirsten Kübler, MD, PhD, an associate scientist at the Broad Institute of MIT and Harvard, research staff at Massachusetts General Hospital, and an instructor at Harvard Medical School, said in a press release. “Our results extend that view in the sense that a drug could directly activate a signaling pathway instead of creating mutations that activate the pathway.”

To decrease the risk of increased pathway activation due to treatment with tamoxifen, investigators treated mice with alpelisib (Piqray) in combination with tamoxifen. The regimen appeared to be successful in decreasing Ki-67 staining and markers of 

“For women taking tamoxifen for breast cancer, there may be a possibility of using a PI3K inhibitor for those who are at an increased risk of uterine cancer, as a prevention strategy,” Jeselsohn concluded.

Tamoxifen may boost PI3K signaling to increase uterine cancer risk in patients with breast cancer. News cancer. American Association for Cancer Research. December 7, 2021. Accessed December 7, 2021. https://bit.ly/3Ip1UES

Kübler K, et al. Tamoxifen instigates uterine cancer development by activating PI3K signaling and supersedes PIK3CA driver mutations. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS2-09.

PI3K-pathway mutations may predict an increased risk of secondary uterine cancer in patients receiving tamoxifen to treat primary breast cancer. 

Genomic Alterations in Primary Breast Cancer May Increase Risk of Secondary Uterine Cancer in Patients Receiving Tamoxifen 

Treatment with low-dose venetoclax monotherapy may be effective in reducing tumor activity in patients with heavily pretreated multiple myeloma or light chain (AL) amyloidosis harboring t(11;14), according to data recently published in the 

Across the study population (n = 25), 44% of patients (n = 11) experienced a partial response (PR) or higher following treatment with venetoclax. Specifically, 71% of patients with AL amyloidosis and 33% of those with multiple myeloma achieved a PR or greater.

The study was conducted to assess the safety and efficacy of single-agent venetoclax, as well as to determine the importance of molecular markers in predicting treatment response. Additionally, potential resistance mechanisms of patients with multiple myeloma harboring t(11;14) were evaluated.

“We believe this study is a significant step towards multiple myeloma treatment by providing ways for selection of the optimal treatment regimens, prognostic biomarker, [resistance] mechanism, and increased understanding of t(11;14) role in multiple myeloma pathogenesis,” Hareth Nahi, MD, senior physician of Karolinska Institutet in Sweden, and coinvestigators wrote in the paper.

The trial enrolled 18 patients who were diagnosed with relapsed multiple myeloma and 7 with relapsed AL amyloidosis, all of whom harbored t(11;14). All patients who enrolled received a 100-mg dose of daily venetoclax for the first 3 days, with an escalation of 100 mg every third day up to a maximum dose of 400 mg daily.

Of the 25 patients who enrolled, 20 had diagnostic bone marrow biopsies available. Among the patients with available biopsies, 8 relapse bone marrow biopsies were examined. RNA sequencing was performed on 37 samples from patients with newly diagnosed multiple myeloma, 10 of which harbored t(11;14).

“The newly diagnosed multiple myeloma samples were obtained from untreated patients, whereas relapsed/refractory patients received standard multiple myeloma treatments,” the authors wrote.

Three subsets of these samples were selected based on the following criteria: 

 cohort (n = 37; newly diagnosed myeloma), 27 non-t(11;14) vs 10 harboring t(11;14); resistance cohort (n = 12), 8 newly diagnosed myeloma vs 4 relapsed/refractory myeloma and all patients with t[11;14] more than 60%; and synergy cohort (n = 12), 2 hyperdiploidy, 7 harboring t(11;14), and 3 harboring hyperdiploidy and t(11;14).”

Forty percent (n = 10) of the patient population were male and the median age was 57 years old (range, 43-80). Thirty percent (n = 7) of the population had stage III disease. In addition to all patients having t(11;14), all patients with multiple myeloma harbored another aberration.

The median follow-up time from the start of treatment was 9 months. All of these patients were treated with a proteasome inhibitor and 96% were given an immunomodulatory drug prior to receiving venetoclax. The median prior lines of therapy was 3 (range, 1-9).

The median time on treatment was 7.2 months, and those who achieved a PR or better were on venetoclax for at least 15 months, with no median reached, compared with 6 months for those who achieved less than a PR.

Twenty patients received immunohistochemistry from bone marrow from diagnosis and even later relapse in some cases. No significant changes were noted in terms of percentage of CD138-positive multiple myeloma cells expressing anti- and pro-apoptotic proteins from diagnosis to relapse or between patients who achieved greater than or less than a PR. However, it was noted that the frequency of 

-expressing cells across analyzed myeloma samples were notably higher (

 = .031), in patients who achieved greater than and less than a PR having an average ratio of 2.7 and 1.0, respectively, following treatment.

Similar data was seen in newly diagnosed myeloma samples (

 = .028). Similar trends were noted in patients with relapsed/refractory disease.

 ratios can be used to predict the venetoclax response in addition to presence of t(11;14),” the authors wrote.

Moreover, an RNA-sequencing analysis of the resistance cohort (n = 12) uncovered 46 differentially expressed genes between diagnosis and relapse, 26 of which were downregulated and 20 of which were upregulated. In total, 65% of the downregulated genes contained binding motifs for an IRF transcription family member in the promoter region.

IRFs motif enrichments were calculated in the promoter regions of downregulated differentially expressed genes and the enrichments were hierarchically sorted based on the adjusted 

 values. Results showed that that the IRF5 motif enrichment ranked the highest [

< .001]. However, IRF5 was not found among the differentially expressed genes,” the authors wrote.

Additionally, investigators correlated the top 3 hierarchically ordered IRFs—IRF5, IRF8, and IRF9—with the expression of 17 differentially expressed genes containing IRF motif; IRF5 ranked at first place.

Although 80% of the study population experienced all-grade treatment-emergent adverse effects, grade 3/4 TEAEs occurred in 52% of patients; all events were considered manageable and no deaths linked with treatment occurred, according to investigators. The most common non-hematologic AE was nausea (32%) with hematologic AEs including neutropenia (28%) and thrombocytopenia (28%).

"The study shows that selection of low dose venetoclax was critical to reduce the [AEs] of the drug without adventuring the benefit of venetoclax in regard to response rates and survival," first author Hareth Nahi, MD, a senior physician and associate professor in the Department of Medicine at the Center for Hematology and Regenerative Medicine, Huddinge, Karolinska Institutet, concluded in a press release.

Nahi H, Kashif M, Klimkowska M, et al. Low dose venetoclax as a single agent treatment of plasma cell malignancies harboring t(11;14). 

New findings provide hope for treatment of multiple myeloma. News release. Karolinska Institutet. May 19, 2021. Accessed May 27, 2021. https://bit.ly/3yTPCj8

This article was originally published on OncLive as 

“Low-Dose Venetoclax Achieves Promising Results in AL Amyloidosis and Myeloma Subsets”

Overall, 71% of patients with AL amyloidosis and 33% of those with heavily pretreated multiple myeloma achieved a partial response or greater after receiving treatment with low dose venetoclax. 

Low-Dose Venetoclax Induces Antitumor Activity in Subsets of AL Amyloidosis, Myeloma 

A meta-analysis of prostate cancer genome-wide association studies has indicated that germline variation contributes to racial disparities in prostate cancer risk. Individuals of African descent, according to the data, demonstrated a higher mean genetic risk score (GRS) compared to those of European ancestry.

Results showed that the top GRS decile associated with odds ratio was 5.06 for men of European descent (95% CI, 4.84-5.29) and 3.74 for men of African descent (95% CI, 3.36-4.17). When compared with men of European ancestry, men of African ancestry were estimated to have a mean GRS that was 2.18 times higher (95% CI, 2.14-2.22), while men of East Asian ancestry had a mean GRS that was 0.73 times lower (95% CI, 0.71-0.76).

“We not only found new markers of risk, but also demonstrated that, by combining genetic information across populations, we were able to identify a risk profile that can be applied across populations,” said Christopher Haiman, ScD, professor of preventative medicine and AFLAC Chair in Cancer Research at the Keck School of Medicine of USC, and director the USC Center for Genetic Epidemiology.

 “This emphasizes the value of adding multiple racial and ethnic populations into genetic studies.”

Additionally, investigators identified 86 new genetic risk variants, all of which were found to be independently associated with prostate cancer risk, which brings the total known risk variants to 269.

“To understand the aggregate effect of the 269 variants on prostate cancer risk, we constructed a GRS using the multiethnic weights of the risk variants associated with disease,” wrote the study authors. “Compared with men at average genetic risk in the 40% to 60% GRS category, the estimated odds ratio for men in the top 10% of the GRS [90%-100% GRS category] was 5.06 [95% CI, 4.84-5.29] for men of European ancestry, 3.74 [95% CI, 3.36-4.17] for men of African ancestry, 4.47 [95% CI, 3.52-5.68] for men of East Asian ancestry, and 4.15 [95% CI, 3.33-5.17] for Hispanic men. Men in the top 1% of the GRS distribution had higher odds of disease, ranging from 11.65 [95% CI, 10.56-12.85] for men of European ancestry to 5.68 [95% CI, 4.44-7.28] for men of African ancestry.”

Prior research has shown that certain races not only trend towards higher incidences of prostate cancer, but higher rates of disease-related mortality overall. Incidence rates of prostate cancer from 2012 to 2016 indicated that 172.9 non-Hispanic Black men per 100,000 develop prostate cancer compared with 97.2 non-Hispanic White men, 86.8 Hispanic men, 68 American Indian and Alaska Native men, and 52.9 Asian and Pacific Islander men.

Similarly, mortality rates from 2013 to 2017 indicate that 38.7 non-Hispanic Black men per 100,000 died from prostate cancer vs 18.7 American Indian and Alaska Native men, 18 non-Hispanic White men, 15.7 Hispanic men, and 8.6 Asian and Pacific Islander men.

Despite the increased risk of incidence and death seen in Black patients

White patients are often overrepresented in clinical cancer trials

hindering investigators' progress in identifying reasons for these disparities.

This developed the rationale for the meta-analysis, with researchers from the USC Center for Genetic Epidemiology, as well as the Institute for Cancer Research in London, United Kingdom, striving to identify the reasons for these disparities. Investigators compiled data from the majority of global genomic prostate cancer studies, including 234,253 men of different races and ethnicities from the United States, United Kingdom, Sweden, Japan, and Ghana, consisting of 107,247 cases and 127,006 controls.

In what is considered the largest and most diverse genetic prostate cancer analysis, findings point toward genetics playing a role in the disparities seen across different racial groups, which could possibly help physicians apply precision medicine to early prostate cancer detection in the future.

“Our long-term objective is to develop a genetic risk score that can be used to determine a man’s risk of developing prostate cancer,” said Haiman. “Men at higher risk may benefit from earlier and more frequent screening, so the disease can be identified when it’s more treatable.”

Current prostate cancer screening guidelines recommend that men aged 55 years or older with average risk undergo prostate-specific antigen (PSA) testing. Though high PSA levels are indicative of prostate cancer, this method typically detects more indolent tumors, leading to unnecessary treatment, according to investigators.

Additionally, investigators believe that GRS could help to guide more selective PSA testing by helping to identify patients who are at a higher risk for prostate cancer, potentially including high-risk patients younger than 55 years old. A larger clinical trial is needed in order to better translate these findings into improved early prostate cancer detection, investigators noted.

“Most [importantly], unlike previous screening trials, this [study] would need to be more representative of the diversity we see in the world,” Haiman concluded. “No population should get left behind.”

Conti DV, Darst BF, Moss LC, et al. Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction. 

. 2021;53(65-75). doi:10.1038/s41588-020-00748-0

Largest, most diverse prostate cancer study shows genetic role in health disparities. News release. Keck School of Medicine of the University of Southern California. January 2, 2021. Accessed January 5, 2020. 

Prostate at a glance. American Cancer Society Cancer Statistics Center. Accessed January 5, 2021. 

This article was originally published on OncLive as “

African Ancestry Is Linked With Higher Prostate Cancer Risk Vs European Ancestry

Germline variation may cause men of African descent to have a higher risk of prostate than men of European descent. 

African Ancestry Associated With Increased Prostate Cancer Risk

Although a high body mass index (BMI) has been found to improve survival outcomes among patients with non-small cell lung cancer (NSCLC), a high visceral fat index (VFI) has shown to do the opposite. Data published in the 

, has indicated that high VFI was negatively associated with survival in patients with NSCLC.

As a result, the data suggest that the measurement used to define obesity might influence whether obesity is a risk factor for NSCLC.

An elevated VFI was linked with worse overall survival (OS; HR, 1.84; 95% CI, 1.21-2.81) and recurrence-free survival (RFS; HR, 1.82; 95% CI, 1.06-3.11) in patients with early-stage disease who were undergoing resection. Multivariable modeling confirmed these results indicating that a high VFI is associated with a worse RFS (HR, 1.79; 95% CI, 1.04-3.08) in this population.

Visceral obesity was also found to be associated with changes in the tumor immune microenvironment in patients with late-stage disease. Moreover, obesity exacerbated disease progression, altered gene expression in the tumor immune microenvironment, and attenuated anti-cancer immune responses in mice.

"These findings clarify the truly negative relationship that exists between central obesity and lung cancer outcomes, and they present a viable alternative to the use of BMI in retrospective studies of obesity rooted in biology with clear relevance to cancer outcomes," first author Joseph Barbi, PhD, an assistant professor of oncology and assistant member in the Department of Immunology of Roswell Park, said in a press release.

Thus far, 13 cancer types have been linked with excess body weight, and obesity rates continue to rise within the United States.3,4 Although the association between measures of obesity and cancer incidence and outcome is well understood in other tumors like breast, esophageal, and colon cancer, this correlation is more complicated in lung cancer.

Unlike what has been reported in other cancers, obesity has been associated with reduced incidence of lung cancer. For example, 1 study in which investigators examined the National Institutes of Health—American Association of Retired Persons demonstrated that a high BMI was inversely linked with risk for the disease.5 Controlling for smoking was found to increase the link between this obesity measure and incidence. Other studies have indicated that BMI was linked with better long-term outcomes in this disease.

To gain some clarity on the association between survival with adiposity and NSCLC, investigators set out to measure central obesity in a cohort of patients with stage I NSCLC who were undergoing lobectomy and examine its association with outcomes.

The survival analyses in the trial included data on patients with pathologic stage I and II NSCLC who were undergoing a pulmonary lobectomy at the Roswell Park Comprehensive Cancer Center between October 2008 and December 2015. Investigators included relevant information

from the institutional thoracic surgery database, as well as the medical record. Overall, they examined tumor stage, tumor grade, histology, OS, and RFS data. All confounders were treated as categorical variables, with the exception of age.

VFI was first evaluated as a continuous variable in these studies. In model generation, the following covariates were utilized: age, sex, grade, race, histology, diffusion capacity for carbon monoxide (DLCO), American Society of Anesthesiology (ASA) score, and smoking status.

Investigators conducted univariate analyses to examine the link between individual variables and OS and RFS. Only variables linked with OS and RFS on these analyses were included in the model generation by multivariable analyses. Moreover, because of the link between VFI and age and sex, interaction variables were included in model generation. Both univariate and multivariable analyses were utilized to compare the OS and RFS in these patients.

A total of 554 patients with stage I and II disease were selected for the analysis; investigators were able to collect reliable fat area measurements from 513 of these patients, with 97.3% at L3, 0.9% at L2, and 1.8% at L1. A total of 159 patients with advanced-stage disease who had molecular testing and reliable fat area measurements were included, with 91.8% at L3, 6.3% at L2, and 1.9% at L1.

Inter-observer correlation of VFI measurements were noted to be good (n = 53; R2 = 0.95). Moreover, the correlation of measurements between L2 and L3 levels (n=29; R2 = 0.92; slope = 1.05), as well as L1 and L3 levels (n=28; R2 = 0.85; slope = 1.05) were also determined to be good. Notably, L2 and L1 measures were used when L3 measurements were not available. Computed tomography scans were successfully utilized to identify patients with predominant visceral or subcutaneous adipose tissue distribution.

Additional data revealed that VFI was not linked with BMI (Pearson correlation coefficient = -.006; 

 = .9), although it was linked with sex and age. The mean VFI was higher in males than it was in females, at 0.56 vs 0.37, respectively (

 < .01). Moreover, VFI was noted to elevate with increasing age (Pearson’s correlation coefficient = .32; 

Data from univariate analyses indicated that there was a significant link between sex, ASA score, tumor grade, histology, age, DLCO, and VFI with OS. RFS was also linked with sex, tumor grade, tumor stage, ASA score, and VFI. Multivariable analysis led to a final OS model that retained age, sex, DLCO, ASA score, VFI, tumor grade, and the interaction term between VFI and age. A final RFS model was also produced that retained only tumor grade, tumor stage, and VFI as predictive variables.

Forty-one of the 513 patients had an unknown cause of death, leading investigators to examine disease-specific survival (DSS) in 472 patients. VFI tertile was found to be linked with DSS (HR, 2.1; 

 = .025), but VFI was not statistically significant as a continuous variable (

 = .1). Moreover, VFI tertile was associated with worse DSS (HR = 2.25; 95% CI, 1.16-4.37; 

"Our study provides much needed clarity to the relationship between adiposity and survival [for patients with NSCLC], providing firm scientific justification for the targeting of obesity's pro-tumor effects, which include decidedly adverse effects on the antitumor immune response," Sai Yendamuri, MD, chair of the Department of Thoracic Surgery, professor of oncology, attending surgeon of the Department of Thoracic Surgery, and director of the Thoracic Surgery Laboratory at Roswell Park, stated in the press release.

Barbi J, Patnaik SK, Pabla S, et al. Visceral obesity promotes lung cancer progression – towards resolution of the obesity paradox in lung cancer. 

. 2021;16(8):1333-1348. doi:10.1016/j.jtho.2021.04.020

Research suggests BMI may not be best obesity indicator to assess risk for lung cancer. News release. International Association for the Study of Lung Cancer. June 2, 2021. Accessed July 28, 2021. https://bit.ly/3zM5CTI

Lauby-Secretan B, Scoccianti C, Loomis D, et al. Body fatness and cancer—viewpoint of the IARC Working Group.

. 2016;375(8):794-798. doi:10.1056/NEJMsr1606602

Ogden CL, Fakhouri TH, Carroll MD, et al. Prevalence of obesity among adults, by household income and education — United States, 2011–2014. 

. 2017;66(50):1369-1373. doi:10.15585/mmwr.mm6650a1External.

Smith L, Brinton LA, Spitz MR, et al. Body mass index and risk of lung cancer among never, former, and current smokers. 

. 2012;104(10):778-789. doi:10.1093/jnci/djs179

“High Visceral Fat Index Associated With Worse Survival Outcomes in Early-Stage Lung Cancer”

Whether or not obesity should be considered a risk factor for non-small lung cancer might be determined by how it is measured. 

Visceral Fat Index Score Questions Obesity-Survival Connection in Early-Stage Lung Cancer

Patients with favorable-risk prostate cancer were shown to move away from active surveillance following exposure to their Oncotype DX Genomic Prostate Score (GPS), according to data from the ENACT study (NCT02668276) published in the 

These results suggested that patients’ treatment decisions in diverse populations can be influenced through prognostic molecular assessment.

Results regarding treatment choice at the second visit indicated that assignment to the GPS cohort was linked with a marginally lower likelihood of selecting active surveillance compared with immediate therapy (

 = .067). When excluding 10 men who were assigned to GPS and did not receive a test result, the association was found to be slightly stronger (

 = .029). Unadjusted analyses indicated that intervention reduced the relative odds of selecting active surveillance by approximately half.

Moreover, the choice of management approach was found to be closely associated with a change in the urologist's preference of treatment following GPS results. Following the results, preferences changed from active surveillance to treatment 18 times; preference shifted from treatment to active surveillance only 3 times. For controls, urologist preference shifted from active surveillance to treatment only 5 times and only twice from treatment to active surveillance.

Ratings on the Decisional Conflict Scale—which measures a patient's perception of preparedness, support, and uncertainty, ranging from 0 at the lowest and 40 at the highest—did not significantly differ between the control group (mean, 5.56; standard deviation, 7.25) and GPS group (mean, 4.60; standard deviation, 7.17), respectively, (

 = .37). However, differences in scores on the Decision Regret Scale—which ranges from 5 at the lowest and 25 at the highest—were not found to significantly differ between the control group (mean, 7.54; standard deviation, 2.92) and the GPS group (mean, 8.28; standard deviation, 3.38), respectively (

“We completed the first randomized trial, to our knowledge, of a prognostic multigene expression score on initial treatment choice among men with favorable-risk prostate cancer,” lead author Adam B. Murphy, MD, MBA, MSCI, of Feinberg School of Medicine, and his colleagues wrote. “As more biomarkers yielding probability estimates enter the clinic, it is important to understand their impact on cancer treatment choice and decision quality in diverse patient populations.”

Although men with low-risk prostate cancer need to make a choice between receiving immediate therapy or active surveillance with the possibility of deferred treatment, active surveillance is now considered to be a safe alternative for the right population. Although the utilization of active surveillance has increased in the United States over the past several years, its use in Black patients has lagged.

Concerns exist as to whether this strategy is equally safe in this high-risk subset due to differences in biologic aggressiveness of the diseases, reduced compliance due to issues with access to care, and possible undersampling of tumors in the anterior section of the prostate.

After considering these factors, investigators launched a randomized trial in a predominantly Black patient population from 3 public hospitals to assess whether the addition of the Oncotype DX GPS assay to the National Comprehensive Cancer Network (NCCN)–based risk counseling would impact decisionmaking. Investigators theorized that the biomarker would help to improve risk stratification in diverse, high-risk patient populations by detecting aggressive prostate cancer despite reassuring standard clinical measures.

The trial enrolled men with newly diagnosed prostate cancer who were eligible for active surveillance. Additional enrollment criteria included being under the age of 76 years, having an ECOG performance status of 0 to 2, a life expectancy of over 10 years, and a NCCN risk level of favorable intermediate or below.

Based on consensus among participating urologists regarding eligibility for active surveillance, the favorable intermediate definition was slightly modified from NCCN criteria to exclude cases with grade group 2 and over 3 positive cores, and include those with a prostate-specific antigen (PSA) density of 10 ng/mL to 20 ng/mL if PSA density was less than 0.15, 4 unfavorable intermediate cases were included.

Patients with favorable-risk prostate cancer tended to move away from active surveillance to initiating treatment after receiving their Oncotype DX Genomic Prostate Score.
 


Hayley Virgil