Hayley Virgil

Two-year follow-up results from the phase 1 TRANSCEND NHL 001 trial (NCT02631044) show that treatment with lisocabtagene maraleucel (liso-cel; Breyanzi) lead to long-lasting responses in patients with relapsed/refractory large B-cell lymphomas (LBCL), according to a presentation given during the 2022 Transplantation & Cellular Therapy Meetings.

Treatment with liso-cel resulted in 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%) 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. He continued “Liso-cel treatment was associated with a low incidence of severe cytokine release syndrome [CRS] and neurologic events.”

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 in the liso-cel set 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.

1. 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.

2. 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

In patients with relapsed/refractory large B-cell lymphoma, the chimeric antigen receptor T-cell agent,  lisocabtagene maraleucel demonstrated durable responses.

Lisocabtagene Maraleucel Achieves Durable Response in R/R Large B-Cell Lymphoma

In patients with relapsed/refractory large B-cell lymphoma (LBCL), the long-term overall survival (OS) findings of the phase 2 ZUMA-1 trial appears to support the 1- and 2-year event-free survival (EFS) findings of axicabtagene ciloleucel (axi-cel), according to data presented at the 2022 Transplantation & Cellular Therapy Meetings.

“In this updated 5-year analysis, axi-cel induced long-term OS...among treated patients,” according to Caron A. Jacobson, MD, MMSc, the medical director of the Immune Effector Cell Therapy Program and senior physician at Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School. She continued, “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.”

Investigators reported a 5-year OS rate of 42.6% (95% CI, 32.8%-51.9%) following treatment with axi-cel. 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/m2 and 30 mg/m2 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.

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.

According to a long-term analysis of the ZUMA-1 study, the overall survival rate yielded by axicabtagene ciloleucel may support 1- and 2-year event-free survival as a surrogate end point in relapsed/refractory large B-cell lymphoma.

Long-Term OS Data for Axi-Cel Hint Short-Term EFS is a Surrogate End Point for R/R LBCL

Use of MEDI5752 in patients with advanced solid malignancies resulted in an boost in peripheral T-cell proliferation among those with, according to results from a first-in-human study.

In particular, this was observed at dose levels of 500 mg or higher, surpassing pharmacodynamic changes observed with 1 mg/kg to 3 mg/kg of tremelimumab, plus 10 mg/kg of durvalumab (Imfinzi).

“The total number of T-cell clones that expanded exhibits a dose-dependent increase before reaching a plateau from doses of 500 mg and beyond,” according to Ben Tran, MBBS, FRACP, lead genitourinary medical oncologist and associate professor at Peter MacCallum Cancer Centre. With regard to the proportion of newly expanded T-cell clones that weren’t present at baseline, he said, “Once again, there is a dose dependent increase before plateauing at 500 mg onwards. At that plateau, newly expanded clones represent 75% of all T-cell clones.”

MEDI5752 was designed to help boost CTLA-4 blockade on PD-1–positive activated T cells. The therapeutic preferentially binds to CTLA-4 on PD-1–positive T cells vs –negative T cells. MEDI5752 is able to induce comparable PD-1 binding on activated T cells, as well as yielding significantly greater CTLA-4 binding compared with co-administration.

Several doses of MEDI5752 were included in the dose-escalation portion of the trial, including 22.5 mg (n = 3), 75 mg (n = 3), 225 mg (n = 7), 500 mg (n = 3), 750 mg (n = 4), 1500 mg (n = 4), 2000 mg (n = 4), and 2500 mg (n = 7). In the immunotherapy-naïve dose expansion cohort (n = 25), patients received a 2000 mg dose intravenously every 3 weeks. The study’s primary objective was to assess the safety and efficacy of MEDI5752 and determine the maximum tolerated dose. Secondary outcomes included pharmacokinetics, immunogenicity, and preliminary anti-tumor activity.

To enroll on the study, patients were required to have measurable and histologically confirmed solid tumors, as well as disease that was refractory or not amenable to standard therapy. Patients also needed to be 18 years or older with an ECOG performance status of 0 or 1 and adequate organ function. Patients who received current or previous immunosuppressive therapy or who had active or prior autoimmune or inflammatory disorders were excluded from the study.

The median patient age was 60.5 years and the majority of patients were men (75.6%). The most common disease types were renal cell carcinoma (RCC; 22.1%) and non–small cell lung cancer (NSCLC; 16.3%). Most patients (61.6%) had a PD-1 expression of less than 1%.

Additional study findings indicated that MEDI5752 yielded dose proportional pharmacokinetics, with doses of over 225 mg providing sustained peripheral PD-1 receptor occupancy of over 90%.

In terms of safety, any grade and grade 3 or higher adverse events (AEs) related to treatment with MEDI5752 occurred in 85.0% and 38.4% of patients, respectively. Additionally, 31.0% of patients discontinued treatment due to AEs and 3 deaths, although only 1 was related to treatment with MEDI5752. Any grade AEs of special interest included dermatitis/rash (56%), hepatic events (27%), and diarrhea/colitis (11%). Grade 3 or higher AEs of special interest included hepatic events (17%), dermatitis/rash (6%), and diarrhea/ colitis (2%).

Doses of less than 1500 mg appeared to be better tolerated, according to Tran.

“The rate of discontinuation due to any grade AE were lower at 9% compared with 47%,” he explained. “Grade 3 to 4 related AEs were lower at 18% compared with 50%. This is also reflected in the grade 3/4 rates of hepatic events and grade 3/4 dermatitis or rash. The low rates of colitis remain consistent in both groups. One caveat of these data is that the low-dose group only includes 13 patients who received 500 mg and 700 mg MEGI5752. However, even when limiting the analysis to those 13 patients, the rates of discontinuation due to AEs remained lower at 23%—less than half that of the higher-dose group.”

Of the response evaluable patients (n = 86), investigators reported an overall response rate of 19.8% (95% CI, 12.0%-29.8%). One patient achieved a complete response, 16 had partial responses, 29 had stable disease, and 32 had progressive disease. The molecular response rate was 36.5% and the disease control rate was 53.5% (95% CI, 42.4%-64.3%). The median duration of response was 17.5 months.

In particular, robust responses were reported across different immunotherapy-naïve solid malignancies and with different doses, including RCC (multiple doses; n = 7), triple-negative breast cancer (2500 mg; n = 1), NSCLC (2000 mg; n = 2), mesothelioma (2000 mg; n = 1), thymic carcinoma (2000 mg; n = 1), colorectal cancer (1500 mg; n = 1), gastric cancer (500 mg, 2000 mg; n = 2), bladder cancer (500 mg; n = 1), Merkel cell carcinoma (225 mg; n = 1), and cervical cancer (22.5 mg; n = 1).

Tran B, Voskoboynik M, Kim SW, et al. MEDI5752, a novel PD-1/CTLA-4 bispecific checkpoint inhibitor for advanced solid tumors: first-in-human study. Abstract CT016

In a first-in-human study, patients with advanced solid tumors experienced an increase in dose-dependent T-cell proliferation following treatment with MEDI5752.

Achievement of Dose-Dependent Peripheral T-Cell Proliferation Increase With MEDI5752 in Advanced Solid Tumors

In the phase 1/2 GLORY study (NCT04270591), treatment with SCC244 led to robust and long-lasting responses in patients with 

)–mutated non–small cell lung cancer, according to findings presented at the AACR Annual Meeting 2022.

Overall, patients who received SCC244 demonstrated an overall response rate (ORR) of 60.9% (95% CI, 48.4%-72.4%). Those who were treatment-naïve and previously treated experienced ORRs of 66.7% (95% CI, 50.5%-80.4%) and 51.9% (95% CI, 31.9%-71.3%), respectively. The disease control rate (DCR) across all 3 groups was 82.6% (95% CI, 71.6%-90.7%), 88.1% (95% CI, 74.4%-96.0%), and 74.1% (95% CI, 53.7%-88.9%), respectively. The median duration of response (DOR) was not evaluable (NE) (95% CI, NE-NE) in the treatment-naïve arm and was 5.1 months (95% CI, 2.8-8.2) and 8.2 months (95% CI, 4.8-NE) in the previously treated and overall populations, respectively. In the overall population, 71% of tumor responses were ongoing and investigators reported the potential for DOR to expand.

“The GLORY study demonstrated a high [and durable] efficacy for SCC244. Statistical hypothesis was achieved. Preliminary efficacy on brain metastases was [also] observed,” according to lead author Shun Lu, MD, PhD, a professor at Shanghai Chest Hospital, Jiao Tong University, and chief of Shanghai Lung Cancer Center.

SCC244 is a high selective MET inhibitor that can be taken orally. The multicenter, single-arm, open-label study aimed to assess a primary end point of ORR by blinded independent review committee. Secondary end points included investigator-assessed ORR, DOR, DCR, time to response (TTR), progression-free survival (PFS), 6-month PFS rate, and overall survival (OS).

Patients were required to have locally advanced or metastatic disease with a 

 skipping mutation. Moreover, individuals could not have received more than 2 previous systemic therapies or have not received any systemic therapies entirely. SCC244 was administered at a dose of 300 mg until disease progression or intolerance to toxicity or death.

In total, 163 patients were screened, 73 of whom were enrolled on the trial and underwent treatment. Of these patients, 36 stopped treatment due to adverse events (AEs; 11.0%), progressive disease (RECIST, 20.5%; clinical judgement, 1.4%), voluntary withdrawal (12.3%), death (1.2%), or other reasons (2.5%). Treatment is ongoing in 37 patients.

In the overall population, most patients were male (56.2%) with a median age of 69.0 years. Nearly all patients were from China (90.4%), although some were from Japan (9.6%). Most patients were either never smokers (58.9%) or had quit smoking (38.4%), and 94.5% had an ECOG performance status of 1. Notably, 87.7% of patients had locally advanced disease, 74.0% had adenocarcinoma, and 13.7% had brain metastases.

Investigators also reported that 58.9% of patients were untreated, 35.6% had previously received 1 prior line of therapy, 4.1% had 2 prior lines, and 1.4% had 3 prior lines or more. Most patients previously received prior chemotherapy (38.4%), immunotherapy (11.0%), targeted therapy (5.5%), or traditional Chinese medicine (4.1%).

In terms of SCC244’s efficacy for brain metastases, the agent yielded 8 partial responses in 10 patients. Targeted brain metastases were reduced by 30% in 5 patients. The median TTR was 1.4 months.

After a median follow-up of 5.6 months, the median PFS was NE (95% CI, 4.3-NE) in the treatment-naïve arm, 5.7 months (95% CI, 2.8-7.6) in the previously treated arm, and 7.6 months (95% CI, 4.2-NE) in the overall population.

In terms of safety, investigators reported that 97.3% of treatment-emergent AEs (TEAEs) were related to the study drug. Serious TEAEs occurred in 27.4% of patients and 28.8% of TEAEs led to dose interruptions. Additionally, 28.8% and 11.0% of patients required a dose reduction or permanent discontinuation, respectively, due to TEAEs. The most common any grade treatment-related AEs (TRAEs) included oedema peripheral (75.3%), headache (32.9%), and nausea (27.4%), with grade 3 or higher TRAEs including oedema peripheral (19.2%), neutropenia (4.1%) and rash (2.7%).

Lu S, Yu Y, Zhou J, et al. Phase II study of SCC244 in NSCLC patients harboring MET exon 14 skipping (METex14) mutations (GLORY study) Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT034.

In patients with non–small cell lung cancer who harbor a MET exon 14 skipping mutation, treatment with SCC244 appears efficacious.

SCC244 Shows Durable Efficacy in Patients With METex14 Skipping+ NSCLC

In the phase 2 LT-SABR study (NCT03548285), tumor-focused stereotactic radiotherapy achieved promising efficacy and patient-reported outcomes (PROs) in patients with early-stage glottic larynx carcinoma, according to findings presented at the 2022 Multidisciplinary Head and Neck Cancers Symposium.

After a median follow up of 23.3 months (interquartile range, 17.1-31.1), investigators reported 2 cases of local recurrence with 1- and 2-year cumulative incidence of local recurrence of 4% and 8.8%, respectively. Another patient experienced in-field recurrence 13 months following completion of radiotherapy at 5 fractions and was salvaged with vertical partial hemilaryngectomy; the patient had no evidence of disease at 14 months. Another patient, who was treated with 16 fractions of radiotherapy, had persistent disease including synchronous regional and distant metastases 4 months following completion of treatment.

“…Both this LT-SABR phase 2 and the phase 1 CK study have shown that stereotactic-level treatments—though done very carefully—are feasible and efficacious,” David Sher, MD, chief of head and neck radiation oncology service at Harold C. Simmons Comprehensive Cancer Center, explained. “More work needs to be done but I am hopeful it can become another tool in the toolbox to successfully treat these cancers while maximizing quality of life.”

Eligibility criteria required that patients have pathologically proven squamous cell carcinoma including 

, and any variant. Patients were required to have stage 0 to II disease with no extension beyond the vocal process of the arytenoid. Exclusion criteria included previous curative intent surgical treatment and smoking more than 1 pack per day.

The study's primary end point was 2-year risk of local failure anywhere in the larynx. Secondary end points included PROs, grade 3 or higher toxicity, and cumulative risk of marginal or out of field failure, regional recurrence, and distant metastases.

For patients with a planning target volume (PTV) of 10 cc or less who weren't active smokers, 42.5 Gy was administered in 5 fractions twice per week. Active smokers with a PTV of more than 10 cc received 58.08 Gy in 16 daily fractions. The typical beam arrangement included 2 coplanar arcs and 2 non-coplanar arcs at 40 degrees. Therapy was delivered via VisionRT-based swallow gating.

A total of 25 patients were enrolled on the study from July 2018 to April 2021.

Patients had a median age of 72 years and almost all patients were men (96%). The most common disease stages were T1a (64%) and T1b (20%). In total, 74% of patients previously smoked.

In terms of PROs, patients had a voice handicap index of 49.5 at baseline, 9.8 at 6 months, and 15.9 at 12 months (

 <.001). Additionally, patients had an EORTC swallowing subscale score of 1.4 at baseline, 3.6 at 1 month, and 2.5 at 12 months.

Investigators did not observe any acute or late grade 3 toxicities.

Sher DJ. Stereotactic ablative radiotherapy for early-stage glottic larynx carcinoma: results from the phase II LT-SABR study. Presented at: 2022 Multidisciplinary Head and Neck Symposium; February 24-26, 2022. Phoenix, AZ. https://bit.ly/3K1SVJF

In patients with early stage glottic larynx tumor-focused stereotactic radiotherapy showed benefit in a phase 2 study.

Tumor-Focused Stereotactic RT Signals Efficacy in Early-Stage Glottic Larynx Carcinoma

In the phase 2 TROPHY-U-01 trial (NCT03547973) of sacituzumab govitecan-hziy (Trodelvy) plus pembrolizumab (Keytruda) administered in the second line to patients with checkpoint inhibitor–naïve metastatic urothelial cancer, promising anti-tumor efficacy was induced, according to the cohort 3 results presented at the 

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.”

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

Patients with checkpoint inhibitor–naïve metastatic urothelial cancer had promising anti-tumor activity when treated with sacituzumab govitecan and pembrolizumab in the second-line setting.