Kyle Doherty

In heavily pretreated patients with advanced non-small cell lung cancer (NSCLC) without 

-activating mutations, including those with other identified driver genomic alterations, treatment with patritumab deruxtecan (HER3-DXd) displayed promising clinical activity, according to results from the dose-expansion cohort of an ongoing phase 1 study (NCT03260491) presented during the 2022 ASCO Annual Meeting.

“Patritumab deruxtecan showed promising clinical activity in heavily pretreated patients with advanced NSCLC with or without identified variant genomic alterations,” said lead author Conor E. Steuer, MD, an assistant professor in the department of hematology and medical oncology at Emory University School of Medicine in Atlanta, Georgia. “Some of this antitumor activity was found to be quite durable.”

At the January 28, 2022, data cut-off date, the confirmed overall response rate (ORR) by blinded independent central review (BICR) per RECIST 1.1 was 28.6% (95% CI, 11.3%-52.2%) among patients with identified genomic driver alterations (n = 21). The disease control rate (DCR) in this cohort of patients was 76.2% (95% CI, 52.8%-91.8%) and the median time to response was 2.8 months (range, 1.3-4.6). The median duration of response (DOR) was 9.4 months (95% CI, 4.2-not evaluable [NE]) and the median progression-free survival (PFS) was 10.8 months (95% CI, 2.8-16.0).

In patients without identified genomic driver alterations (n = 26), the confirmed ORR was 26.9% (95% 11.6%-47.8%) and the DCR was 73.1% (95% CI, 52.2%-88.4%). The median DOR was 9.6 months (95% CI, 1.6-NE) and the median PFS was 4.2 months (95% CI, 2.5-10.8). The median time to response was 2.1 months (range, 1.2-6.0).

The median follow-up time was 19.7 months (range, 13.8-29.2).

““These results demonstrate the promising clinical activity of patritumab deruxtecan in patients with NSCLC harboring a broad range of genomic alterations, or without identified genomic alterations,” Steuer said. “They warrant further clinical evaluation.”

He added that this was a heavily pretreated cohort, with an average of 3 (range, 1-8) previous lines of systemic therapy.

Investigators noted that 83% of NSCLC tumors express HER3, and that HER3 overexpression has been associated with poor clinical outcomes. Moreover, patients with advanced NSCLC without 

-activating mutations have limited options after treatment failure with]molecularly targeted therapies or platinum-based chemotherapy with or without immunotherapy.

Patritumab deruxtecan is an antibody drug conjugate composed of a fully human anti-HER3 IgG1 monoclonal antibody. The monoclonal antibody is covalently linked to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker.

The dose-expansion part (cohort 2) of the phase 1 trial enrolled patients with squamous or nonsquamous NSCLC that did not harbor the common 

 mutations, or without any identified driver genomic alterations. Patients with non-

 oncogenic alterations were eligible for the trial if they had undergone at least 1 previous treatment with targeted therapy, if available. All patients in the dose-expansion portion of the trial were treated with intravenous 5.6 mg/kg patritumab deruxtecan every 3 weeks.

The primary end point was confirmed ORR by BICR per RECIST 1.1. Secondary end points included DCR, time to response, DOR, PFS, and safety.

At the data cut-off date, 47 patients in cohort 2 with a median age of 62 years (range, 29-79) had been treated with patritumab deruxtecan. Most patients in the cohort were female (53.2%) and most had an ECOG performance status of 1 (66.0%). The median sum of diameters at baseline was 67 mm (range, 18-205) and 31.9% of patients had a history of central nervous system metastases. Disease histology included adenocarcinoma (74%), squamous (17%), large cell (2%), and other (6%).

All patients had undergone prior treatment with platinum-based chemotherapy, and 95.7% had received previous immunotherapy, including anti-PD-1/anti-PD-L1 treatment. One patient previously received an anti-CTLA-4 agent. Genomic-directed therapy was previously used in 19.1% of patients.

Five (10.6%) patients remained on study at data cut-off and 89.4% discontinued treatment. Primary reasons for discontinuation included progressive disease (51.1%), clinical progression (12.8%), adverse events (AEs; 10.6%), withdrawal of consent by patient (8.5%), and death (6.4%).

Steuer said treatment with patritumab deruxtecan was manageable and led to an overall safety profile consistent with previous findings in patients with 

-mutant NSCLC. Treatment-emergent adverse events (TEAEs) associated with treatment discontinuation occurred in 10.6% of patients. There were no drug-related deaths reported.

TEAEs that led to dose reduction or dose interruption were reported in 23.4% and 51.1% of patients, respectively. TEAEs associated with death occurred in 14.9% of patients and 40.4% of patients experienced serious AEs.

TEAEs of grade 3 or greater included neutropenia (26%), fatigue (17%), thrombocytopenia (15%), hypokalemia (13%), anemia (11%), leukopenia (11%), and pneumonia (11%). All patients experienced a treatment-related TEAE; none of these were associated with death. Slightly more than half (51.1%) of TEAEs were grade 3 or higher and 12.8% were serious TEAEs.

Five patients developed drug-related interstitial lung disease (ILD) by central adjudication with a median time to onset of 140 days (range, 43-331). Grade 1 ILD was reported in 2.1% of patients and grade 2 ILD in 8.5% of patients. No patients experienced grade 3 or greater ILD.

CE Steuer, H Hayashi, WC Su, et al. Efficacy and safety of patritumab deruxtecan (HER3-DXd) in advanced/metastatic non-small cell lung cancer (NSCLC) without EGFR-activating mutations. 

. 2022;40(suppl 16):9017. doi:10.1200/JCO.2022.40.16_suppl.9017

Articles

According to Conor E. Steuer, MD,  patritumab deruxtecan showed promising clinical activity in heavily pretreated patients with advanced non–small cell lung cancer with or without identified variant genomic alterations.

Clinical Activity Shown With Patritumab Deruxtecan NSCLC Regardless of Identified Driver Genomic Alterations

In the phase 2/3 rEECur trial, treatment with ifosfamide (Ifex) induced small improvements in terms of prolonging event-free survival (EFS) and overall survival (OS) compared with topotecan (Hycamtin) plus cyclophosphamide in patients with relapsed/refractory Ewing sarcoma, according results presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

At a median follow-up of 40 months, patients treated with ifosfamide experienced a median EFS of 5.7 months (95% CI, 3.8-6.9) compared with 3.5 months (95% CI, 3.8-6.9) for patients who received topotecan plus cyclophosphamide. The 6-month EFS rates were 47% (95% CI, 35%-58%) and 37% (95% CI, 26%-48%), respectively.

Additionally, patients who received ifosfamide achieved a median OS of 15.4 months (95% CI, 11.3-20.9) compared with 10.5 months (95% CI, 7.2-15.0) among patients treated with topotecan plus cyclophosphamide. The 1-year OS rates were 55% (95% CI, 43%-66%) and 45% (95% CI, 33%-56%), respectively.

“Given the observed data, there is a 96% probability that ifosfamide is better than topotecan plus cyclophosphamide for EFS,” Martin McCabe, PhD, said in a presentation of the data. “[However], the numbers [of patients] beyond 6 months are extremely small. There was a 94% probability that ifosfamide is better than topotecan plus cyclophosphamide for OS. Again, [there are] very small numbers [of patients] beyond about 2 years. The benefits of ifosfamide over topotecan plus cyclophosphamide were more obvious in children than in adolescents and adults.”

McCabe is a clinical senior lecturer at the University of Manchester in England.

The rEECur trial was a multi-arm, multi-stage adaptive design study with Bayesian analysis. Patients were randomly assigned to receive topotecan plus cyclophosphamide (n = 163), irinotecan plus temolozomide (Temodar; n = 127), gemcitabine and docetaxel (n = 72), or ifosfamide (n = 83). The phase 3 comparison between ifosfamide and topotecan plus cyclophosphamide reported in the presentation included 73 patients in both arms.

Patients were treated with intravenous ifosfamide at a dose of 3000 mg/m2 on days 1 through 5. Topotecan was given at a dose of 0.75 mg/m2 and cyclophosphamide at a dose of 250 mg/m2, both intravenously on days 1 through 5. The phase 2 arms were dropped based on worse imaging response and EFS, although there was little difference, McCabe noted.

The median age of patients in the trial was 19 years (range, 4-49). Most patients had first recurrent disease (66%) and 18% had refractory disease. Seventy percent of patients had bone as their initial disease site. Sites of progression included pleuropulmonary metastases only (34%), primary site only (15%), and other metastatic (51%).

The primary end point of the trial was EFS. Secondary end points included OS, toxicity, and quality of life.

In terms of safety, both ifosfamide and topotecan plus cyclophosphamide caused similar rates of neutropenic infection. Ifosfamide caused more severe kidney toxicity and brain toxicity compared with topotecan plus cyclophosphamide, however both were observed in less than 10% of patients. Common grade 3/4 adverse events for topotecan plus cyclophosphamide vs ifosfamide, respectively, included febrile neutropenia (26% vs 25%), infections (8% vs 14%), vomiting (1% vs 1%), nausea (0% vs 3%), diarrhea (1% vs 1%), encephalopathy (0% vs 7%), and renal toxicity (0% vs 8%).

“This is the first ever randomized, controlled trial of chemotherapy in this disease setting,” McCabe concluded. “Importantly, we now have data both to inform patients and to develop future studies. The differences [between these regimens] are quite subtle. What we actually need are better drugs to cure more patients.”

McCabe M, Kirton L, Khan M, et al. Phase III assessment of topotecan and cyclophosphamide and high-dose ifosfamide in rEECur: An international randomized controlled trial of chemotherapy for the treatment of recurrent and primary refractory Ewing sarcoma (RR-ES). 

. 2022;40(suppl 17):LBA2. doi:10.1200/JCO.2022.40.17_suppl.LBA2

IfIosfamide treatment improved event-free survival compared with topotecan  plus cyclophosphamide in patients with relapsed/refractory Ewing sarcoma, phase 2/3 study results show.

Ifosfamide Prolongs Survival in Relapsed/Refractory Ewing Sarcoma

In the phase 3 PALOMA-2 trial (NCT01740427), frontline treatment with palbociclib (Ibrance) plus letrozole (Femara) missed its survival endpoint when compared with first-line treatment with letrozole monotherapy in patients with ER-positive/HER2-negative advanced breast cancer (ABC), according to findings from the final overall survival (OS) analysis presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

At the November 15, 2021, data cutoff, at a median follow-up of 90 months, patients who received the CDK4/6 inhibitor palbociclib plus letrozole (n = 444) had a median OS of 53.9 months (95% CI, 49.8-60.8) compared with 51.2 months (95% CI, 43.7-58.9) for patients who received placebo plus letrozole (n = 222; HR, 0.956; 95% CI, 0.777-1.777; 

 = .3378). However, in a post-hoc sensitivity analysis that adjusted for missing survival data, the median OS for patients treated with the combination (n = 385) was 51.6 months (95% CI, 46.9-57.1) compared with 44.6 months (95% CI, 37.0-52.3) for the 175 patients in the control arm (HR, 0.869; 95% CI, 0.706-1.069). The median duration of treatment was 22.0 months and 13.8 months, respectively.

Both arms of the trial had significant amounts of missing survival data; results were missing for 59 patients in the palbociclib plus letrozole arm and for 47 patients in the letrozole monotherapy. Most patients in both arms had died at the time of the analysis (62% and 60%, respectively). Patients were still alive at a rate of 25% and 19%, respectively.

“The OS is numerically longer with palbociclib and letrozole compared with the control arm, though these results were not statistically significant,” Richard S. Finn, MD, professor of medicine, Geffen School of Medicine, University of California Los Angeles, said during the presentation. “However, the median OS of 50 months in this population represents a significant improvement in the natural history of HR-positive breast cancer. Interpretation of OS in PALOMA-2 is limited by the large and disproportionate percentage of patients with missing survival data between the treatment arms.”

In PALOMA-2, patients with ER-positive/HER2-negative ABC who had not undergone any prior treatments for advanced disease and had an ECOG performance status of 2 or less were randomized 2:1 into the palbociclib plus letrozole arm or the placebo plus letrozole arm. Patients received 125 mg of palbociclib per day, for 3 weeks on and 1 week off, and 2.5 mg of letrozole per day. In the placebo arm, the same dose of letrozole was given and placebo was given in place of palbociclib at the same dose as the investigational arm.

The primary end point of the trial was investigator assessed progression-free survival (PFS). Secondary end points included OS, response, safety, biomarkers, and patient reported outcomes. Patients were stratified by disease site (visceral vs non-visceral), disease-free interval (DFI; de novo metastatic for 12 months or less vs more than 12 months), and prior treatment with neoadjuvant hormonal therapy (yes vs no).

The baseline patient characteristics were well-balanced between the 2 arms; the median age was 62 years (range, 30-89) in the combination arm and 61 years (range, 28-88). Most patients in both arms had prior endocrine therapy (56% and 57%, respectively). A majority of patients in the combination arm had non-visceral disease (52%) and the disease site was evenly split in the placebo arm. Patients had an ECOG performance status of 0 at a rate of 58% and 46%, respectively, and a status of 1 or 2 at a rate of 42% and 54%, respectively.

The hazard ratios between the 2 arms were approximately 1 for almost all of the subgroups examined in the analysis. However, in subgroups that had approximately equal amounts of missing survival data, the hazard ratios favored the combination.

Patients with an ECOG performance status of 1 or 2 achieved a median OS of 47.3 months (95% CI, 41.3-60.8) compared with 35.8 months (95% CI, 32.2-49.8) in the combination and placebo arms, respectively. In patients previously treated with endocrine therapy, the median OS was 53.3 months (95% CI, 48.0-62.9) and 44.6 months (95% CI, 34.3-52.8), respectively. Patients with bone-only disease achieved a median OS of 63.5 months (95% CI, 53.9-79.7) and 52.3 months (95% CI, 42.3-59.7), respectively.

At the time of the analysis, most patients in the combination arm (90%) and the placebo arm (98%) had discontinued study treatment. Patients went on to receive post-study systemic treatment at a rate of 81% and 88%, respectively. Most patients in both arms went on to receive endocrine therapy (66% and 74%) as well as chemotherapy (55% and 62%). CDK4/6 inhibitors were subsequently given to 12% and 27% of patients, respectively.

The median time to chemotherapy in the combination arm was 38.1 months (95% CI, 34.1-42.2) compared with 29.8 months (95% CI, 24.7-34.8) in the placebo arm (HR, 0.730; 95% CI, 0.607-0.879). A combined OS analysis of PALOMA-2 and the phase 2 PALOMA-1 trial (NCT00721409) revealed that patients who received the palbociclib plus letrozole combination (n = 528) achieved a median OS of 51.8 months (95% CI, 47.8-56.9) compared with 46.8 months (95% CI, 38.8-52.3) for patients in the control group (n = 303; HR, 0.934; 95% CI, 0.780-1.120).

Among patients with a DFI greater than 12 months, the combined analysis indicated that the median OS was 64.0 months (95% CI, 49.2-73.4) and 44.6 months (95% CI, 37.0-53.2), respectively (HR, 0.736; 95% CI, 0.551-0.982).

The most common all-cause, any-grade adverse effects (AEs) in the combination arm of PALOMA-2 included neutropenia (82%), infections (64%), and leukopenia (43%). Common grade 3/4 AEs consisted of neutropenia (69%) leukopenia (27%), and infections (9%).

In the placebo arm, common AEs of any grade included infections (46%), arthralgia (40%), and hot flush (31%). Grade 3 AEs included infections (3%), nausea (2%), and headache (2%).

“The safety profile with this regimen is predictable and is consistent now with seven and a half years of follow-up with no long-term toxicity, and quality of life has been maintained,” Finn noted.

Finn RS, Rugo HS, Dieras VC, et al. Overall survival (OS) with first-line palbociclib plus letrozole (PAL+LET) versus placebo plus letrozole (PBO+LET) in women with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ER+/HER2− ABC): Analyses from PALOMA-2. 

. 2022;40(suppl 17):LBA1003. doi:10.1200/JCO.2022.40.17_suppl.LBA1003

First-line treatment with palbociclib plus letrozole demonstrated survival improvement vs letrozole monotherapy in patients with ER-positive/HER2-negative advanced breast cancer.

Significant Survival Benefit Not Shown With Palbociclib Plus Letrozole in ER+/HER2- Advanced Breast Cancer

Antibody-drug conjugates, TROP-2 and Nectin-4, are highly expressed in urothelial cancer (UC) and variant histology bladder cancer, according to findings presented at the 2022 American Urological Association Annual Meeting.

However, investigators found that those transmembranes are not highly expressed in patients with neuroendocrine histology. Investigators, including lead author Fady Ghali, MD, an acting instructor and Society of Urologic Oncology fellow at the University of Washington Department of Urology in Seattle, say they are launching clinical trials to assess the implications of these findings on treatment response for variant histology bladder cancer.

Nectin-4 localized primarily in the cytoplasm rather than the membrane in plasmacytoid UC and squamous cell carcinoma (SCC) in primary, lymph node, and metastatic sites. Investigators found that Nectin-4 distribution was relatively even between membrane and cytoplasm.

TROP-2 was expressed at equal levels in both membrane and cytoplasm for both plasmacytoid UC and SCC. Investigators added the high expression was conserved from primary to metastases.

In July 2021, the FDA approved enfortumab vedotin for adults with locally advanced or metastatic UC who are ineligible for cisplatin-containing chemotherapy and who have received 1 or more prior lines of therapy. The agent was previously indicated for patients with locally advanced or metastatic UC who have received a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy.

The agency granted accelerated approval to sacituzumab govitecan for patients with locally advanced or metastatic UC who previously received a platinum-containing chemotherapy and either a PD-1 or a PD-L1 inhibitor in April 2021.3

Fady et al noted that the role of these novel humanized monoclonal antibody-drug conjugates (ADCs) in the treatment of variant histology bladder cancer is unknown. They designed this study to better understand how these agents affect the disease at both primary and metastatic sites.

Investigators collected 68 metastatic bladder cancer tissue samples from 20 total patients. Twenty-seven samples were UC, 19 were SCC, 17 were plasmacytoid, and 5 were neuroendocrine. They then performed immunohistochemistry for Nectin-4 and TROP-2 on matched primary and metastatic tumors. Staining was scored by intensity (0-3) and multiplied by percent of positive cells resulting in a range of 0 to 300 H-score; H-score greater than or equal to 30% was considered positive for Nectin-4 and greater than or equal to 100 was considered positive for TROP-2. Investigators separately evaluated membranous and cytoplasmic staining for each sample.

Investigators collected 11 samples from primary tumor sites, 20 from the lymph nodes, and 37 from various metastatic sites. Seventeen (85%) patients previously received systemic chemotherapy and 35% had received immunotherapy. No patient had received enfortumab vedotin or sacituzumab govitecan.

For Nectin-4, investigators found that positive H scores were higher in cytoplasmic localization for primary tumors (60.0% vs 30.0%), lymph node tumors (80.0% vs 26.7%), and metastatic tumors (66.7% vs 23.8%) compared with membranous localization. When assessed by histology, positive H scores were higher in cytoplasmic localization vs membranous localization for UC (57.7% vs 30.8%), plasmacytoid UC (94.1% vs 5.9%), and SCC (78.9% vs 42.1%). Nectin-4 was not expressed in neuroendocrine tumors in either membranous (0%) or cytoplasmic (0%) localization.

For TROP-2, investigators found that positive H scores were 90.9% for both localizations for primary tumors and 90.2% in both localizations for metastatic tumors. However, positive H score was significantly higher for cytoplasmic lymph node tumors (93.8% vs 43.8%).

When assessed by histology, positive H scores favored cytoplasmic localization for UC (100% vs 96.2%) and plasmacytoid UC (100% vs 55.6%) but favored membranous localization in SCC (100% vs 89.5%). Again, the transmembrane was not highly expressed in neuroendocrine tumors at either the membranous (0%) or cytoplasmic localizations (20.0%).

Investigators added that it is not clear whether differences in membranous vs cytoplasmic localization affects response to treatment with ADCs.

Ghali, F, Roudier M, Vakar-Lopez F, et al. Antibody drug conjugates and variant histology muscle-invasive bladder cancer: are the targets present in primary and/or metastatic tumors? J Urol. 2022;207(suppl 5):e913. doi:10.1097/JU.0000000000002630.09

FDA grants regular approval to enfortumab vedotin-ejfv for locally advanced or metastatic urothelial cancer. News release. July 9, 2021. Accessed May 16, 2022. https://bit.ly/3lfWa5Y

FDA grants accelerated approval to sacituzumab govitecan for advanced urothelial cancer. News release. April 13, 2021. Accessed May 16, 2022. https://bit.ly/38AQaSq

Both TROP-2 and Nectin-4 were shown to be highly expressed in urothelial cancer and variant histology bladder cancer, but not in patients with neuroendocrine histology.

Antibody-Drug Conjugate Targets' Expression Levels Analyzed in Bladder Cancers

IS-002, a novel, near-infrared, prostate-specific membrane antigen targeteing fluorophore, was shown to be safe, well-tolerated, and allow for enhanced intraoperative tumor detection in patients who were undergoing robotic prostatectomy, according to findings from a phase 1 study (NCT04574401) presented at the 2022 American Urological Association Annual Meeting.

IS-002 in combination with fluorescence-guided surgery (FGS) detected residual adenocarcinoma in the resection bed of 9 of 24 (37.5%) patients with high-risk prostate cancer that was not identified using conventional white light imaging. This included invasions in the neurovascular bundle (n = 4), bladder neck (n = 2), seminal vesicles (n = 1), levator ani (n = 1), and Denonvilliers’ fascia (n = 1).

Use of IS-002 plus FGS also intraoperatively detected regional nodal metastases in 12.5% of patients. Additionally, ex vivo imaging confirmed IS-002 prostate tumor signal in 95.8% of patients. Study authors noted that the study treatment provided excellent tumor discrimination over background.

Investigators found that IS-002 plus FGS was well tolerated. Among patients who received IS-002 experienced only grade 1 adverse effects (AEs), consisting of green urine/feces (n = 23) and bruising/rash (n = 2).

In the phase 1 dose-escalation study, patients received intravenous IS-002 24 hours prior to surgery. IS-002 was given at 4 dose levels (25 µg/kg, 50 µg/kg, 100 µg/kg, and 150 µg/kg) with 6 patients in each group. Surgeons performed robotic prostatectomy using the da Vinci X/Xi Surgical System and Sensitive Firefly Fluorescence Imaging. The pharmacokinetic and safety profile of IS-002 were assessed over a 14-day period.

The primary end point of the trial was treatment-emergent AEs assessed by Common Terminology Criteria for Adverse Events v5.0. Secondary end points included IS-002 maximum plasma concentration, IS-002 half-life, IS-002 clearance, and IS-002 area under the plasma concentration vs time curve. The number of lymph nodes with IS-002 fluorescent signal that contain metastatic disease and the number of patients with above-background IS-002 fluorescent signal observed on the prostate surface were also included as exploratory end points.

To be eligible for the trial, patients needed to be treatment-naïve and between the ages of 18 and 75. Patients also needed to have a Cancer of the Prostate Risk Assessment score greater than 6, T3 a or b disease upon imaging, or regional lymphadenopathy suspicious for nodal metastases.

Patients with active hepatitis B virus or hepatitis C virus infection, a known history of bone metastasis, or a known history of acute or chronic liver or kidney disease were not eligible for the trial. Patients who were currently participating in another study or received study therapy within the past 6 months were also not permitted.

“Based on the very encouraging results of this phase 1 study, a randomized phase 2 study is planned,” lead author Hao Nguyen, MD, PhD, and colleagues wrote in conclusion. Nguyen is a urologic oncologist at the UCSF Helen Diller Family Comprehensive Cancer Center.

Nguyen H, Antaris A, Van den Berg N, et al. Results of the Phase 1 safety and efficacy prostate specific membrane antigen (PSMA) targeting fluorophore for image guided surgery in patients undergoing robotic prostatectomy. Paper presented at: 2022 American Urological Association Annual Meeting; May 13-16. New Orleans, LA. Abstract PD54-11.

A phase 1 study of IS-002 injection in patients undergoing robotic prostatectomy. ClinicalTrials.gov. Updated October 22, 2021. Accessed May 16, 2022. clinicaltrials.gov/ct2/show/NCT04574401

IS-002 was shown to be safe, well-tolerated, and allow for enhanced intraoperative tumor detection in patients undergoing robotic prostatectomy, according to findings from a phase 1 study.

 IS-002 is Well-Tolerated in Patients Undergoing Robotic Prostatectomy

In patients with high-risk, muscle-invasive urothelial carcinoma treated in the phase 3 CheckMate 274 trial (NCT02632409), adjuvant nivolumab (Opdivo) achieved clinically meaningful improvements in disease-free survival (DFS) compared with placebo, according to longer follow-up data presented during the AUA 2022 Annual Meeting.

With an additional 5 months of follow-up patients in the intention-to-treat (ITT) population who received nivolumab (n = 353) experienced a median DFS of 22.0 months (95% CI, 17.7-36.9) compared with 10.9 months (95% CI, 8.3-14.0) among the 356 patients who received placebo (HR, 0.70; 95% CI, 0.57-0.85). The 12-month DFS rates were 63.5% vs 46.9%, respectively.

The DFS benefit was even more pronounced in patients with PD-L1 expression of at least 1%; the median DFS was not reached (NR; 95% CI, 22.1-not estimable [NE]) in the nivolumab cohort (n = 140) vs 8.4 months (95% CI, 5.6-20.0) in the placebo cohort (n = 142; HR, 0.53; 95% CI, 0.38-0.75).1 The 12-month DFS rates were 67.6% vs 46.3%, respectively.

In terms of non–urothelial tract recurrence-free survival (NUTRFS), the median was 26.0 months (95% CI, 19.5-41.1) in the nivolumab arm compared vs 13.7 months (95% CI, 8.4-20.0), in the placebo arm (HR 0.71; 95% CI, 0.58-0.88), with 46.7% vs 55.9% of patients experiencing events, respectively. Among patients with a PD-L1 expression of at least 1%, the median NUTRFS was NR (95% CI, 25.8-NE) vs 10.8 months (95% CI, 5.7-20.7), respectively (HR, 0.54; 95% CI, 0.39-0.77).

Investigators also observed a benefit indistant metastasis-free survival (DMFS) among patients who received nivolumab compared with placebo; the median DMFS was 41.1 months (95% CI, 26.0-NE) vs 29.2 months (95% CI, 15.2-NE), respectively (HR, 0.73; 95% CI, 0.58-0.92). Patients with PD-L1 at or over 1% had a median DMFS of NR (95% CI, 26.0-NE) when treated with nivolumab compared with 20.7 months (95% CI, 10.8-NE) when treated with placebo (HR, 0.60; 95% CI, 0.41-0.88).

DFS benefits were also seen with nivolumab treatment across most of the subgroups analyzed, including age, sex, ECOG performance status, nodal status, and use of prior cisplatin-based chemotherapy.

“These results support adjuvant nivolumab as a standard of care for high-risk [patient with] muscle-invasive urothelial carcinoma after radical surgery,” Matthew Galsky, MD, and colleagues wrote. Galsky is a professor medicine (hematology and medical Oncology), director of genitourinary medical oncology at the Icahn School of Medicine at Mount Sinai, in New York, New York. He also serves at the codirector of the Center of Excellence for Bladder Cancer and associate director for translational research at The Tisch Cancer Institute.

Adjuvant nivolumab monotherapy was previously approved on August 19, 2021, for patients with urothelial carcinoma who are at high risk of recurrence after undergoing radical resection based on findings from CheckMate 274.

The double-blind CheckMate 274 trial randomly assigned patients 1:1 to receive either nivolumab 240 mg twice weekly or placebo for a total adjuvant treatment time of 1 year or until disease recurrence or discontinuation. Eligible patients underwent radical surgery within 120 days before randomization with or without neoadjuvant cisplatin therapy. Patients were stratified by PD-L1 status, pathological nodal status, and prior chemotherapy use.

The coprimary end points of the study were DFS in the entire population and among patients with PD-L1 expression of 1% or greater. Secondary end points included NUTRFS, overall survival, and disease-specific survival. DMFS was also included as an exploratory end point.

The baseline patient characteristics in the trial were well balanced between the 2 arms. The mean age was 65.3 years (range, 30-92) and 65.9 years (range, 42-88) in the nivolumab and placebo arms, respectively. Most patients in both cohorts were males (75.1% vs 77.2%), white (74.8% vs 76.4%), and had an ECOG performance status of 0 (63.5% vs 62.1%).

Regarding safety, 351 patients in the experimental arm and 348 in the placebo arm were evaluable. Adverse effects (AEs) of any cause and any grade occurred in 98.9% and 95.4% of patients, respectively. Common AEs of any grade in the nivolumab arm included pruritus (23.1%), fatigue (17.4%), and diarrhea (16.8%). In the placebo arm, the most common AEs of any grade were fatigue (12.1%), pruritus (11.5%), and diarrhea (10.9%).

Two patients in the nivolumab group died, with both deaths attributed to pneumonitis. Treatment-related AEs of any grade led to discontinuation in 12.8% of patients in the nivolumab arm compared with 2.0% of patients in the placebo arm. The most common treatment-related AEs in the investigative arm were pneumonitis (1.7%), rash (1.1%), and colitis (0.9%).

1. Galsky M, Witjes JA, Gschwend JE, et al. Disease-free survival with longer follow-up from the CheckMate 274 trial of adjuvant nivolumab in patients after surgery for high-risk muscle-invasive urothelial carcinoma. 

. 2022;207(suppl 5):e183. doi:10.1097/JU.0000000000002536.01 

2. FDA approves nivolumab for adjuvant treatment of urothelial carcinoma. News release. FDA. Updated February 2, 2022. Accessed May 13, 2022. bit.ly/39nf4Fq 

3. Bajorin DF, Witjies JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. 

. 2021;384(22):2102-2114. doi:10.1056/NEJMoa2034442

In patients with high-risk, muscle-invasive urothelial carcinoma treated in the adjuvant nivolumab lead to clinically meaningful improvements in disease-free survival compared with placebo.