Tag: Urothelial Cancer (Bladder-Ureters-Renal-Pelvis)

OPDIVO® (nivolumab) for the Adjuvant Treatment of High-Risk Urothelial Carcinoma*

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*Urothelial carcinoma at high risk of recurrence after undergoing radical resection.
Written by: Terence Friedlander, MD
Professor of Medicine, Division of Hematology/Oncology, Zuckerberg San Francisco General Hospital, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco

Content sponsored by: Bristol Myers Squibb
Dr Friedlander is a paid consultant for BMS and was compensated for his contribution in drafting this content.

Overview of High-Risk Urothelial Carcinoma*
Currently, radical resection with or without perioperative therapy is the standard of care for treating high-risk urothelial carcinoma (UC).1* However, there is still a high chance of recurrence within 2 years of radical resection, with less favorable survival rates for the high-risk patient population.1 While neoadjuvant therapy has an established role in treating high-risk UC,* data are less clear regarding the role of adjuvant therapy.2 In a retrospective observational cohort study of patients 65 years or older with UC at high risk of recurrence after radical resection, including patients who received neoadjuvant chemotherapy, median disease-free survival (mDFS) was determined to be 13.5 months.1 Cisplatin-based chemotherapy is the neoadjuvant standard of care, but prior to 2021 there were no FDA-approved adjuvant therapy options.1-3 Studies have shown that adjuvant chemotherapy may delay recurrence and improve overall survival (OS), but these studies have not definitively shown a survival benefit, largely due to inadequate sample sizes.2 Additionally, approximately 50% of patients are ineligible for cisplatin-based treatment.1 As a result, there is a high unmet need for this difficult-to-treat population, and it is important for the urologist, oncologist, and patient to discuss and align on perioperative treatments at the time of diagnosis and early in the patient journey.1,2,4 Entering the adjuvant treatment landscape, immune checkpoint inhibitors may be an additional treatment option for HCPs to consider for their patients with high-risk UC.1,2*

Adjuvant OPDIVO in High-Risk Urothelial Carcinoma*
OPDIVO is approved and indicated for the adjuvant treatment of adult patients with UC who are at high risk of recurrence after undergoing radical resection, regardless of prior neoadjuvant chemotherapy, nodal involvement, or PD-L1 status.5 The approval is based on Checkmate 274, a phase 3, multicenter, double-blind, randomized trial of adjuvant OPDIVO versus placebo.6 More information on the study design can be found in the images below. Baseline characteristics were balanced across treatment arms.6
Checkmate 274Important Safety Information
Select Important Safety Information
In Checkmate 274, serious adverse reactions occurred in 30% of OPDIVO patients. The most frequent serious adverse reaction reported in ≥2% of patients was urinary tract infection. Fatal adverse reactions occurred in 1% of patients; these included events of pneumonitis (0.6%). The most-common adverse reactions reported in ≥20% of patients were rash, fatigue, diarrhea, pruritus, musculoskeletal pain, and UTI. OPDIVO was discontinued or delayed due to adverse reactions in 18% and 33% of patients, respectively.5

OPDIVO is associated with the following Warnings and Precautions: severe and fatal immune-mediated adverse reactions including pneumonitis, colitis, hepatitis and hepatotoxicity, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions, other immune-mediated adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation; embryo-fetal toxicity; and increased mortality in patients with multiple myeloma when OPDIVO is added to a thalidomide analogue and dexamethasone, which is not recommended outside of controlled clinical trials.

OPDIVO may cause severe infusion-related reactions. In patients who received OPDIVO as a 60-minute intravenous infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients.5 For additional information regarding infusion-related reactions, please see Important Safety Information for OPDIVO.
Checkmate-274-Defined-High-Risk-PatientsDouble-median-DFS-with-OPDIVOCheckmate 274 was not powered to detect differences in the treatment effect at extended follow-up analysis; therefore, results from this exploratory analysis should be interpreted with caution.

Adjuvant OPDIVO demonstrated superior disease-free survival (DFS) compared with placebo at the primary analysis (minimum follow-up of 5.9 months).5,6 Median DFS was 20.8 months with OPDIVO versus 10.8 months with placebo (HR=0.70 [95% CI: 0.57–0.86];P=0.0008).5 OS was also evaluated as a secondary endpoint, but at the time of the planned interim analysis, these data were immature with 33% of deaths in the ITT population; in the UTUC subpopulation, 37 deaths occurred, 20 of which occurred with OPDIVO versus 17 with placebo.5 Although the subgroup analyses were not statistically powered, for patients with prior neoadjuvant cisplatin therapy (n=308), the DFS hazard ratio was 0.52 [95% CI: 0.38–0.71] and for patients without prior neoadjuvant cisplatin therapy (n=401), the DFS hazard ratio was 0.92 [95% CI: 0.69–1.21].6 In additional exploratory subgroup analyses, no improvement in DFS was observed with nivolumab compared to placebo in patients with UTUC (n=149) the unstratified DFS hazard ratio was 1.15 (95% CI: 0.74–1.80); in patients with PD-L1 expression of <1% (n=414), the unstratified DFS hazard ratio was 0.83 (95% CI: 0.64–1.08).5

At the extended follow-up analysis (minimum follow-up of 11.0 months), mDFS was doubled with adjuvant OPDIVO compared with placebo. Median DFS was 22.0 months with OPDIVO versus 10.9 months with placebo (HR=0.70 [95% CI: 0.57–0.85]).12

Summary/conclusions
Given the high unmet need in this difficult-to-treat population, the call for approved adjuvant treatment options continues to rise.1,2 Adjuvant OPDIVO offers a chance to change the future for patients with high-risk UC as the only FDA-approved adjuvant option for adult patients with UC at high risk of recurrence after radical resection regardless of prior neoadjuvant chemotherapy, nodal involvement, or PD-L1 status.5,6,12 In Checkmate 274, OPDIVO significantly extended mDFS at the time of primary analysis and doubled mDFS at the time of extended follow-up analysis.5,6,12 Further data will be generated for the secondary endpoint of OS, which may provide greater insight into the efficacy of OPDIVO in this context.6,8 Given the clinical profile of Checkmate 274 and subsequent FDA approval, OPDIVO may help extend DFS for appropriate patients in need of treatment in the adjuvant UC setting.5,6,12

*Urothelial carcinoma at high risk of recurrence after undergoing radical resection.

Additional Definitions
CI=confidence interval; HCP=healthcare provider; HR=hazard ratio; ITT=intent to treat; PD-L1=programmed death ligand 1; UTUC=upper tract urothelial carcinoma.

Indication
OPDIVO® (nivolumab), as a single agent, is indicated for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC.

Important Safety Information
Severe and Fatal Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune-mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO. Early identification and management are essential to ensure safe use of OPDIVO. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment with OPDIVO. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue OPDIVO depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis
OPDIVO can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO monotherapy, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%).

Immune-Mediated Colitis
OPDIVO can cause immune-mediated colitis. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%) and Grade 2 (1%).

Immune-Mediated Hepatitis and Hepatotoxicity
OPDIVO can cause immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%).

Immune-Mediated Endocrinopathies
OPDIVO can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune- mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.

In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2 (0.6%).

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%).

In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%).

In patients receiving OPDIVO monotherapy, hyperthyroidism occurred in 2.7% (54/1994) of patients, including Grade 3 (<0.1%) and Grade 2 (1.2%).

In patients receiving OPDIVO monotherapy, hypothyroidism occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and Grade 2 (4.8%).

In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2 (0.3%), and 2 cases of diabetic ketoacidosis.

Immune-Mediated Nephritis with Renal Dysfunction
OPDIVO can cause immune-mediated nephritis. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%).

Immune-Mediated Dermatologic Adverse Reactions
OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.

Withhold or permanently discontinue OPDIVO depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%).

Other Immune-Mediated Adverse Reactions
The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO monotherapy or were reported with the use of other PD-1/PD- L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions: cardiac/vascular: myocarditis, pericarditis, vasculitis; nervous system: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur; gastrointestinal: pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis; musculoskeletal and connective tissue: myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatica; endocrine: hypoparathyroidism; other (hematologic/immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Some ocular IMAR cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada–like syndrome, which has been observed in patients receiving OPDIVO, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Infusion-Related Reactions
OPDIVO can cause severe infusion-related reactions. Discontinue OPDIVO in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions. In patients receiving OPDIVO monotherapy as a 60- minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate trial in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation
Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with OPDIVO. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between OPDIVO and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity
Based on its mechanism of action and findings from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose.

Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone
In randomized clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Lactation
There are no data on the presence of OPDIVO in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 5 months after the last dose.

Serious Adverse Reactions
In Checkmate 274, serious adverse reactions occurred in 30% of patients receiving OPDIVO (n=351). The most frequent serious adverse reaction reported in ≥2% of patients receiving OPDIVO was urinary tract infection. Fatal adverse reactions occurred in 1% of patients; these included events of pneumonitis (0.6%).

Common Adverse Reactions
In Checkmate 274, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=351) were rash (36%), fatigue (36%), diarrhea (30%), pruritus (30%), musculoskeletal pain (28%), and urinary tract infection (22%).

Please see US Full Prescribing Information for OPDIVO.

References
1. Drakaki A, Pantuck A, Mhatre SK, et al. “Real-world” outcomes and prognostic indicators among patients with high-risk muscle-invasive urothelial carcinoma. Urol Oncol. 2021;39:76.e15-76.e22.
2. Referenced without permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Bladder Cancer V.2.2022. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed August 4, 2022. To view the most recent and complete version of the guidelines, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
3. Apolo AB, Msaouel P, Niglio S, et al. Evolving Role of Adjuvant Systemic Therapy for Kidney and Urothelial Cancers. Am Soc Clin Oncol Educ Book. 2022;42:1-16. doi:10.1200/EDBK_350829.
4. Nayan M, Bhindi B, Yu JL, et al. The initiation of a multidisciplinary bladder cancer clinic and the uptake of neoadjuvant chemotherapy: A time-series analysis. Can Urol Assoc J. 2016;10(1-2):25-30.
5. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.
6. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021;384(22):2102-2114.
7. Bajorin DF, Witjes JA, Gschwend JE, et al. First results from the phase 3 CheckMate 274 trial of adjuvant nivolumab versus placebo in patients who underwent radical surgery for high-risk muscle-invasive urothelial carcinoma. Oral presentation at ASCO GU 2021. Abstract 391.
8. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021;384(22):2102-2114 [supplementary appendix].
9. American Cancer Society. Bladder cancer early detection, diagnosis, and staging. Accessed August 5, 2022. https://www.cancer.org/content/dam/CRC/PDF/Public/8559.00.pdf.
10. Data on file. NIVO 639. Princeton, NJ: Bristol-Myers Squibb Company; 2021.
11. Witjes JA, Bajorin DF, Galsky MD, et al. Results for patients with muscle-invasive bladder cancer in the CheckMate 274 trial. Poster presentation at ASCO 2022. Abstract 4585.
12. Galsky MD, Witjes JA, Gschwend JE, et al. Disease-free survival with longer follow-up from the phase 3 CheckMate 274 trial of adjuvant nivolumab in patients who underwent surgery for high-risk muscle-invasive urothelial carcinoma. Oral presentation at the American Urological Association (AUA) Annual Meeting 2022. Abstract 22-3807.

© 2022 Bristol-Myers Squibb Company. OPDIVO® and the related logos are trademarks of Bristol-Myers Squibb Company. 1506-US-2200368 8/22

Late Breaking Abstract – ESMO 2022: PADCEV® plus KEYTRUDA® in Previously Untreated Cisplatin-Ineligible Patients with Locally Advanced or Metastatic Urothelial Cancer

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SUMMARY: The American Cancer Society estimates that in the United States for 2022, about 81,180 new cases of bladder cancer will be diagnosed and approximately 17,100 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. A third of the patients initially present with locally invasive or metastatic disease. Patients with urothelial carcinoma are currently treated in the first line setting with a Platinum based chemotherapy regimen, and a checkpoint Inhibitor (PD-1 or PD-L1 inhibitor) in the second line setting. Approximately 50% of patients with advanced urothelial carcinoma are ineligible for Cisplatin-based chemotherapy. There is therefore a critical need for effective and tolerable first line treatment options in locally advanced or metastatic Urothelial Carcinoma.

Enfortumab vedotin-ejfv (PADCEV®) is an Antibody-Drug Conjugate (ADC) that targets Nectin-4, a cell adhesion molecule highly expressed in urothelial cancers and other solid tumors. Nectin-4 has been implicated in tumor cell growth and proliferation. Following binding to Nectin-4 on the cell surface, Enfortumab vedotin becomes internalized and is processed by lysosomes, with the liberation of its cytotoxic payload, Monomethyl auristatin E, which in turn disrupts microtubule assembly, leading to cell cycle arrest and apoptosis. Enfortumab vedotin resulted in significantly longer Overall Survival, Progression Free Survival, and a higher Overall Response Rate, than standard chemotherapy, in patients with locally advanced or metastatic urothelial carcinoma, who had previously received Platinum-based treatment and a PD-1 or PD-L1 inhibitor. Preclinical studies with Enfortumab vedotin have shown hallmarks of immune cell death potentially augmented by PD-1/PD-L1 inhibitors, and the rationale for this clinical trial was based on results from a previous cohort study.

Pembrolizumab (KEYTRUDA®) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response. Pembrolizumab is the first agent to improve Overall Survival over chemotherapy, in the second line setting, for patients with recurrent, advanced urothelial carcinoma, and a significant proportion of patients who respond, have very durable responses.

EV-103 is a clinical trial conducted to examine the safety and efficacy of Enfortumab vedotin given as monotherapy, and in combination with other anticancer therapies, as first line and second line treatment, for patients with urothelial cancer. This study was conducted in multiple parts for both locally advanced or metastatic urothelial cancer and muscle invasive bladder cancer.

EV-103/KEYNOTE-869 Cohort K is a randomized cohort investigating Enfortumab vedotin alone or in combination with Pembrolizumab as first line treatment in patients with unresectable locally advanced or metastatic urothelial cancer, who are ineligible to receive Cisplatin-based chemotherapy. In this Phase Ib/II randomized study, 149 eligible patients (N=149) were randomly assigned to receive a combination of Enfortumab vedotin 1.25 mg/kg given intravenously on days 1 and 8, and Pembrolizumab 200 mg given intravenously on day 1, every 21 days (N=76) or Enfortumab vedotin monotherapy given on the same schedule (N=73). Ineligibility for Cisplatin-based chemotherapy could be due to at least one of the following: Glomerular filtration rate (GFR) less than 60 mL/min, ECOG Performance Status of 2, Grade 2 or more hearing loss, or New York Heart Association Class III heart failure. No prior systemic treatment for locally advanced or metastatic disease, and adjuvant/neoadjuvant Platinum-based therapy within 12 months prior to randomization, were allowed. The Primary endpoint was confirmed Objective Response Rate (ORR) by BICR (Blinded Independent Central Review). Secondary endpoints included Duration of Response (DOR), Safety, Progression Free Survival (PFS) and Overall Survival (OS).

At a median follow up of 14.2 months, the confirmed Objective Response Rate was 64.5% with the Enfortumab vedotin and Pembrolizumab combination, with 10.5% of patients experiencing a Complete Response and 53.9% of patients experiencing a Partial Response. The median Duration of Response was not reached. The most common Treatment-Related Adverse Events (TRAEs) were peripheral sensory neuropathy (55.6%), fatigue (51.1%), and alopecia (48.9%).

It was concluded that in Cisplatin-ineligible patients with unresectable locally advanced or metastatic urothelial cancer, treatment with Enfortumab vedotin and Pembrolizumab combination in chemo naïve patients, resulted in high Overall Response Rate, along with a safety profile that was tolerable. The authors added that Antibody-Drug Conjugates have the potential to make a greater impact in treating bladder cancer, especially in combination with checkpoint inhibitors, as shown in this trial and these data support ongoing investigations of first line Enfortumab vedotin and Pembrolizumab in patients with locally advanced or metastatic urothelial cancer.

Study EV-103 Cohort K: Antitumor activity of enfortumab vedotin (EV) monotherapy or in combination with pembrolizumab (P) in previously untreated cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC). Rosenberg JE, Milowsky M, Ramamurthy C, et al. Annals of Oncology (2022) 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089. LBA73

Long Term Disease Free Survival Benefits with Adjuvant OPDIVO® in Urothelial Carcinoma

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SUMMARY: The American Cancer Society estimates that in the United States for 2022, about 81,180 new cases of bladder cancer will be diagnosed and approximately 17,100 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. A third of the patients initially present with locally invasive disease. Even though radical cystectomy is considered the standard of care for patients with localized Muscle Invasive Bladder Cancer (MIBC), two large randomized trials and two meta-analyses have shown greater survival benefit with neoadjuvant Cisplatin-based combination chemotherapy for patients with MIBC, compared to surgery alone. However, not all patients with MIBC benefit from neoadjuvant Cisplatin based therapy, with only 25-50% attaining a pathologic response. More than 50% of patients with MIBC or regional lymph node involvement will develop metastatic disease following radical cystectomy. There is presently no clear consensus with regards to the routine use of adjuvant Cisplatin-based chemotherapy. Further, not all patients are eligible for adjuvant or neoadjuvant Cisplatin-based chemotherapy.

OPDIVO®(Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2. Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response. OPDIVO® has been shown to have antitumor activity in patients with metastatic urothelial carcinoma who had previously received platinum treatment, and is presently approved by the FDA for this patient group, as well as adjuvant treatment of patients with urothelial carcinoma who are at high risk of recurrence after undergoing radical resection.

CheckMate 274 is a multicenter, double-blind, randomized, Phase III trial conducted to evaluate the efficacy and safety of adjuvant OPDIVO®, as compared with placebo, in patients with muscle-invasive urothelial carcinoma following radical surgery (with or without previous neoadjuvant Cisplatin-based combination chemotherapy). A total of 709 patients with muscle-invasive urothelial carcinoma who had undergone radical surgery were randomly assigned in a 1:1 ratio to receive either OPDIVO® 240 mg as a 30-minute IV infusion (N=353) or placebo (N=356), every 2 weeks for up to 1 year. To be eligible, patients must have had radical surgery (R0, with negative surgical margins), with or without neoadjuvant Cisplatin-based chemotherapy. Patients must have had pathological evidence of urothelial carcinoma (originating in the bladder, ureter or renal pelvis) with a high risk of recurrence defined as follows: pathological stage of pT3, pT4a, or pN+ and patients not eligible for or declined adjuvant Cisplatin-based combination chemotherapy, patients who had not received neoadjuvant Cisplatin-based chemotherapy, and pathological stage of ypT2 to ypT4a or ypN+ for patients who received neoadjuvant Cisplatin. The mean age was 65.3 years and both treatment groups were well balanced. Approximately 40% of patients in both treatment groups had PD-L1 expression of 1% or more and 43% of patients had received previous neoadjuvant Cisplatin therapy. The two Primary endpoints were Disease Free Survival (DFS) among all the patients, and among patients with a tumor Programmed Death-Ligand 1 (PD-L1) expression level of 1% or more. Secondary endpoints included NonUrothelial Tract Recurrence-Free Survival (NUTRFS) and Distant Metastasis-Free Survival (DMFS), Overall Survival and Safety.

The authors in this publication reported the DFS outcomes, with 5 additional months of follow up, in all randomized patients. Patients with high-risk, muscle-invasive urothelial carcinoma continued to experience clinically meaningful improvements in Disease Free Survival (DFS), with a median DFS of 22.0 months among those receiving OPDIVO® (95% CI, 17.7-36.9) compared with 10.9 months (95% CI, 8.3-14.0) among those receiving placebo (HR=0.70; 95% CI, 0.57-0.85). The DFS probability at 12 months was 63.5% with OPDIVO® versus 46.9% with placebo. The DFS benefit was even more significant in patients with PD-L1 expression of 1% or more and was Not Reached in the OPDIVO® group versus 8.4 months in the placebo group (HR, 0.53; 95% CI, 0.38-0.75). The DFS probability at 12 months was 67.6% with OPDIVO® versus 46.3% with placebo. The DFS benefits was observed with OPDIVO® among most subgroups analyzed, including age, sex, ECOG PS, nodal status and use of prior Cisplatin-based chemotherapy.

NonUrothelial Tract Recurrence-Free Survival (NUTRFS) and Distant Metastasis-Free Survival (DMFS) were also improved with OPDIVO® when compared to placebo, both in all randomized patients, as well as patients with PD-L1 expression of 1% or more.

It was concluded that with longer follow up, OPDIVO® continued to show clinically meaningful improvement in Disease Free Survival among patients with high-risk muscle-invasive urothelial carcinoma, when compared to placebo, both in all randomized patients, as well as patients with PD-L1 expression of 1% or more. OPDIVO® also improved NonUrothelial Tract Recurrence-Free Survival (NUTRFS) and Distant Metastasis-Free Survival when compared to Placebo. The authors added that these results support adjuvant OPDIVO® as a Standard of Care for high risk muscle-invasive urothelial carcinoma patients after radical surgery.

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

Early-Stage Multi-Cancer Detection Using an Extracellular Vesicle Protein-Based Blood Test

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SUMMARY: The American Cancer Society’s estimates that in 2022, about 62,210 people will be diagnosed with pancreatic cancer and 49,830 people will die of the disease, 19,880 women will receive a new diagnosis of ovarian cancer and about 12,810 women will die of the disease, and about 81,800 new cases of bladder cancer will be diagnosed in 2022 and about 17,100 patients will die of the disease. These three cancer types are estimated to account for approximately 80,000 deaths in the US in 2022. Detecting cancer at early stages can significantly increase survival rates and outcomes.

Several multi-cancer early detection tests are being developed that involve blood-based circulating cell-free tumor DNA (cfDNA) in the plasma, to track hundreds of patient-specific mutations, to detect Minimal Residual Disease (MRD) , as well as detection of abnormal methylation patterns, followed by machine learning approaches, to differentiate between cancer and non-cancer, for detecting clinically significant, late-stage (III and IV) cancers. Early detection of cancer however is the key to improving survival. This is particularly relevant for certain cancer types. Pancreatic Ductal AdenoCarcinoma (PDAC) is one of the deadliest cancers, and a leading cause of all cancer-related deaths in the United States, and is typically detected when the disease is advanced. However, when detected at Stage I, survival rates can be as high as 80%. Ovarian cancer is often detected when the disease is advanced and the 5-year survival rates are less than 30%, but can be as high as 93% when detected early. The same holds true for metastatic bladder cancer, with 5-year survival rates of only 6%, whereas while detected when the tumor is still localized to the bladder wall inner layer results in a 5-year survival rate of 96%. Even though serum CA19-9 is intended as an aid in the management of patients with confirmed pancreatic cancer for serial monitoring of their response to therapy and disease progression, it is not recommended by the FDA for screening, as it may be elevated in several benign conditions. Similarly, serum CA-125 is FDA approved for use in monitoring patients with ovarian cancer for disease persistence and recurrence, but is not recommended to screen for ovarian cancer. Currently, there are few general screening strategies to detect asymptomatic, early-stage PDAC, ovarian, or bladder cancer and there is therefore a significant unmet need in this patient group.

Exosomes are 30-150 nm-sized Extracellular Vesicles (EVs) secreted by multiple different cell types and ejected by tumors into the bloodstream. They mediate intercellular signaling by transferring mRNAs and microRNAs between distant cells and tissues and therefore carry functional protein biomarkers representing the tumor proteome. Exosomes represent one potential approach for more sensitive detection of cancer-related biomarkers from blood.

The researchers in this study used an Alternating Current Electrokinetic (ACE)-based platform (Verita™ System) to efficiently isolate EVs from soluble contaminants such as cells, small proteins, or other vesicles from patient samples, and then measured the concentrations of associated protein biomarkers (“EV proteins”) present in the purified EV samples from our case-control study subjects. The researchers chose this platform over the current gold standard ultracentrifugation method, which the authors felt was inefficient and not suitable for point-of-care applications. Artificial Intelligence machine-learning algorithm developed by the researchers, enabled detection of early-stage pancreatic, ovarian, and bladder cancers.

In this case-control pilot study, 139 pathologically confirmed Stage I and II cancer cases representing pancreatic, ovarian, or bladder patients were compared with 184 control subjects, using the Verita™ System. The Extracellular Vesicles (EVs) isolated using this technology, were consistent with the presence of Exosomes, in accordance with the International Society for Extracellular Vesicles (ISEV) 2018 guidelines. The researchers selected a panel of 13 Extracellular Vesicle (EV) proteins along with age, a known cofactor in cancer. In order to simulate a real-world screening scenario, all cancer cases were treatment-naïve and to ensure that these were early-stage patients, the histopathologic staging was confirmed using the American Joint Commission on Cancer (AJCC) guidelines. The median age of the cancer cases was 60 years and 63.3% of the overall cancer cases were Stage I, with the remaining 36.7% at Stage II. The median age of the control group was 57 years and had no known history of cancer, autoimmune diseases, neurodegenerative disorders or diabetes mellitus.

When the overall cancer case cohort was compared with the control individuals using the EV protein biomarker test, the average sensitivity was 71.2%, at a specificity of 99.5%. When considered across all the three cancers studied, EV protein biomarker test using this technology demonstrated similar sensitivities of 70.5% and 72.5% for Stage I and II patients, respectively. This new technology detected 95.5% of Stage I pancreatic cancers, 73.1% of pathologic Stage IA lethally aggressive serous ovarian adenocarcinomas and 43.8% in bladder cancer, demonstrating the potential value of this platform for detection of early stage cancers. The lower sensitivity for detecting early stage bladder cancer may be due to high molecular and histologic heterogeneity of bladder tumors.

It was concluded from this study that blood-based EV protein detection test has potential clinical value for early cancer detection and the use of Verita™ platform resulted in the accurate detection of early stage pancreatic, ovarian, or bladder cancer. The authors added that mortality from pancreatic cancer which will soon become the second leading cause of cancer mortality in the U.S., can be greatly reduced if this study results are validated.

Early-stage multi-cancer detection using an extracellular vesicle protein-based blood test. Hinestrosa, J.P., Kurzrock, R., Lewis, J.M. et al. Commun Med 2, 29 (2022). https://doi.org/10.1038/s43856-022-00088-6.

Platelet-to-Lymphocyte Ratio Predicts the Efficacy of KEYTRUDA® in Patients with Urothelial Carcinoma

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SUMMARY: Immunotherapy with PD-1/PD-L1 (Programmed Death-1/Programmed Death-Ligand 1) inhibitors, also called Immune Checkpoint Inhibitors (ICIs), has dramatically changed the treatment paradigm for patients with solid tumors, with significant improvement in outcomes. However, even among those with tumors expressing high PD-L1 expression and high Tumor Mutation Burden, not all patients benefit from Immunotherapy with ICIs. Therefore identifying biomarkers for patients likely to respond to ICI therapy, and predicting resistance is important and relevant, in selecting the appropriate patients for treatment with ICIs.

There is growing body of evidence on the role of inflammation in cancer biology, and systemic inflammatory response may have prognostic significance in different cancer types. Inflammatory process in various cancers imparts immunoresistance to ICIs, by activating oncogenic signaling pathways, there by promoting cancer growth and dissemination, with resulting poor outcomes.

More recently, attention has been focused on the predictive role of Platelet-Lymphocyte ratio (PLR) as an effective indicator of the severity of systemic inflammatory response. PLR is defined as the ratio of platelets to lymphocytes. Platelets and lymphocytes play multiple roles in the inflammatory response. Increased platelet count accelerates tumor progression by promoting neoangiogenesis and the production of adhesion molecules, whereas lymphocytes activate anti-tumor immunity by releasing a range of cytokines. Elevated PLR has been associated with poor prognosis in multiple solid tumors. In a meta-analysis of data from 12 related studies involving a total of 1340 patients, high PLR in cancer patients was associated with poor efficacy when treated with Immune Checkpoint Inhibitors, and poor prognosis. (https://doi.org/10.1016/j.intimp.2019.105957Get rights and content). Several other studies suggest that using PLR to predict the prognosis of cancer patients treated with immunotherapy remains controversial. The role of PLR in the prognosis of cancer patients treated with immunotherapy has thus remained unclear.

The present study was conducted to determine meaningful predictive factors for selecting patients with advanced Urothelial Carcinoma (UC) who might benefit clinically from treatment with Immune Checkpoint Inhibitor, KEYTRUDA® (Pembrolizumab). KEYTRUDA® is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response, and unleashes the tumor-specific effector T cells. The researchers retrospectively analyzed 54 patients who received treatment with KEYTRUDA® for Urothelial Carcinoma. Patient’s Hemoglobin, Albumin, Lymphocyte and Platelet (HALP) score, Neutrophil-to-Lymphocyte Ratio (NLR), and Platelet-to-Lymphocyte Ratio (PLR) were calculated as indices of systemic inflammatory response. The relationships between these scores and the initial tumor response or Overall Survival, as well as other clinicopathological factors, were then assessed.

It was noted that a high NLR and PLR were associated with a poor initial tumor response to KEYTRUDA®. A HALP score less than 30.05 and a PLR of 173.73 or more were associated with worse Overall Survival. In the multivariate analysis, a high PLR was a significant independent prognostic factor for unfavorable outcomes.

The authors concluded from this study that a high pretreatment Platelet-to-Lymphocyte Ratio may be a valuable indicator for choosing therapy other than KEYTRUDA® in patients with advanced Urothelial Carcinoma, and may be a potential biomarker for immunotherapy.

Platelet-to-Lymphocyte Ratio Predicts the Efficacy of Pembrolizumab in Patients With Urothelial Carcinoma. Kurashina R, Ando K, Inoue M, et al. Anticancer Research February 2022;42:1131-1136.

KEYTRUDA® for BCG-Unresponsive High-Risk Non-Muscle Invasive Bladder Cancer

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SUMMARY: The American Cancer Society estimates that for 2021, about 83,730 new cases of bladder cancer will be diagnosed in the US and about 17,200 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but is less common in women and the average age at the time of diagnosis is 73. With regards to racial predisposition, Caucasians are more likely to be diagnosed with bladder cancer than African Americans or Hispanic Americans.

Approximately 50% of all bladder cancers are non-invasive or in situ cancers. Patients with high-risk, Non-Muscle Invasive Bladder Cancer that has become unresponsive to BCG (Bacillus Calmette-Guerin) treatment, are often given the treatment option of radical cystectomy, which includes removing the entire urinary bladder and a prostatectomy for men or total hysterectomy in women. While highly curative, this surgical procedure carries substantial risk for morbidity and mortality, and can negatively impact patient’s quality of life. Further, a significant proportion of patients are medically ineligible for a radical cystectomy, and even if eligible, refuse surgery and opt for other less effective treatments, which could compromise outcomes.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response. KEYTRUDA® is presently approved by the FDA for the treatment of patients with locally advanced or metastatic Urothelial carcinoma who are not eligible for Cisplatin-containing chemotherapy or for those with disease progression during or following platinum-containing chemotherapy, based on its durable antitumor activity in this patient group. Upregulation of the PD-1 pathway has been observed in BCG-resistant NMIBC, suggesting that KEYTRUDA® may be of benefit in this group of patients. The FDA in 2020, approved KEYTRUDA® for the treatment of patients with BCG-unresponsive, high-risk, Non-Muscle Invasive Bladder Cancer (NMIBC) with Carcinoma In Situ (CIS) with or without papillary tumors, who are ineligible for or have elected not to undergo cystectomy, based on the KEYNOTE-057 study.

KEYNOTE-057 study is an international, multicenter, single arm, open-label, Phase II trial that enrolled 101 eligible patients with high-risk NMIBC, who had BCG-unresponsive CIS with or without papillary tumors. BCG-unresponsive high-risk Non-Muscle Invasive Bladder Cancer was defined as persistent disease despite adequate BCG therapy, disease recurrence after an initial tumor-free state following adequate BCG therapy, or T1 disease following a single induction course of BCG. Eligible patients had received adequate BCG therapy and were unable/unwilling to undergo radical cystectomy. All patients had undergone TransUrethral Resection of Bladder Tumor (TURBT) to remove resectable disease. Patients with residual Carcinoma In Situ, not amenable to complete resection were permitted. Patients received KEYTRUDA® 200 mg IV every 3 weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC or progressive disease, or up to 24 months of therapy without disease progression. The efficacy analysis included 96 patients, as 5 patients did not meet the FDA BCG-unresponsive criteria.

The median age was 73 years and the median number of prior BCG instillations was 12. More than half of patients (56.9%) had a PD-L1 Combined Positive Score (CPS) of less than 10, and most patients in this analysis had refused prior cystectomy. The Primary end point was Complete Response Rate (CRR-absence of high-risk non-muscle invasive bladder cancer or progressive disease) as defined by negative results for cystoscopy with TURBT/biopsies as applicable, urine cytology, and CT Urography imaging, approximately 3 months after the first dose of KEYTRUDA®. Secondary end points included Duration of Response and Safety.

At a median follow up of 36.4 months, the Complete Response Rate at 3 months was 41% and the median Duration of Response was 16.2 months. Forty-six percent (46%) of responding patients experienced a Complete Response lasting 12 months or more. The Complete Response Rate was consistent with the primary analysis across protocol-prespecified subgroups, including PD-L1 expression status. The most frequent adverse reactions were fatigue, diarrhea, rash, pruritis, arthralgia, musculoskeletal pain, peripheral edema and hypothyroidism.

It was concluded that with extended follow up, KEYTRUDA® monotherapy continued to show durable and clinically meaningful antitumor activity in patients with high risk BCG-unresponsive, non-muscle invasive bladder cancer, who declined or were ineligible for radical cystectomy. The authors added that KEYTRUDA® should be considered a clinically active non-surgical treatment option in this difficult-to-treat population.

Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Balar AV, Kamat AM, Kulkarni GS, et al. The Lancet Oncology. 2021;22:919-930.

FDA Approves TRODELVY® for Advanced Urothelial Cancer

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SUMMARY: The FDA on April 13, 2021, granted accelerated approval to TRODELVY® (Sacituzumab Govitecan) for patients with locally advanced or metastatic Urothelial Cancer who previously received a Platinum-containing chemotherapy, and either a Programmed Death receptor-1 (PD-1) or a Programmed Death-Ligand 1 (PD-L1) inhibitor. The American Cancer Society estimates that in the United States for 2021, about 83,730 new cases of bladder cancer will be diagnosed and approximately 17,200 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. A third of the patients initially present with locally invasive or metastatic disease. Patients with Urothelial Carcinoma are currently treated in the first line setting with a Platinum based chemotherapy regimen, and a checkpoint Inhibitor (PD-1 or PD-L1 inhibitor) in the second line setting. Treatment options for patients who progress after first and second line therapies are limited, with poor outcomes. The response rates with standard chemotherapy in this patient population, is about 10%, with a median Overall Survival (OS) of 7-8 months.

Two new agents approved by the FDA include BALVERSA® (Erdafitinib), a pan-Fibroblast Growth Factor Receptor (FGFR) inhibitor, for patients with locally advanced or metastatic Urothelial Carcinoma with susceptible FGFR3 or FGFR2 genetic alterations, that has progressed during or following Platinum-containing chemotherapy, as well as PADCEV® (Enfortumab Vedotin), an Antibody-Drug Conjugate (ADC) that targets Nectin-4, a cell adhesion molecule, highly expressed in Urothelial Cancers and other solid tumors. These two agents have Objective Response Rates (ORRs) of approximately 40%, and most patients will progress on these therapies. Further, FGFR alterations occur in only 20% of patients with metastatic Urothelial Carcinoma, limiting the use of BALVERSA®. Hence, there is an unmet need for novel therapies.

Trop-2 is a transmembrane glycoprotein and calcium signal transducer. It stimulates cancer-cell growth, and this cell surface receptor is overexpressed in several epithelial cancers including cancers of the Breast, Colon, Lung and Urothelial Cancer, and has limited expression in normal human tissues. TRODELVY® is an Antibody-Drug Conjugate (ADC) in which SN-38, an active metabolite of Irinotecan, a Topoisomerase I inhibitor, is coupled to the humanized Anti-Trophoblast cell-surface antigen 2 (Trop-2) monoclonal antibody (hRS7 IgG1κ), through the cleavable CL2A linker. SN-38 cannot be given directly to patients because of its toxicity and poor solubility. Upon binding to Trop-2, the anti-TROP-2 monoclonal antibody is internalized and delivers SN-38 directly into the tumor cell, making it a suitable transporter for the delivery of cytotoxic drugs. Further, the cleavable linker enables SN-38 to be released both intracellularly into the tumor cells, as well as the tumor microenvironment, thereby allowing for the delivery of therapeutic concentrations of the active drug in bystander cells to which the conjugate has not bound. Thus, TRODELVY®-bound tumor cells are killed by intracellular uptake of SN-38, whereas the adjacent tumor cells are killed by the extracellular release of SN-38.

TRODELVY® in a Phase I/II trial involving patients with advanced epithelial cancers, showed encouraging clinical activity across various solid tumors and was associated with a Objective Response Rate (ORR) of 31% in patients with relapsed or refractory metastatic Urothelial Carcinoma, including a 27% ORR among patients who had received prior checkpoint inhibitor and Platinum based therapy. The TROPHY-U-01 Phase II trial was designed to assess the activity of TRODELVY® and confirm these findings in patients with locally advanced unresectable or metastatic Urothelial Carcinoma. This trial includes 5 patient cohorts, evaluating the role of TRODELVY® in various groups of patients and in combination with various agents including checkpoint inhibitors. The authors in this publication reported the primary results from the full Cohort 1 of the TROPHY-U-01 study in patients with metastatic Urothelial Cancer who progressed after prior Platinum based and checkpoint inhibitor based therapies.

Cohort 1 included 113 patients who had received a median of three prior therapies. Patients received TRODELVY® 10 mg/kg IV, on days 1 and 8 of a 21-day treatment cycle, until disease progression or unacceptable toxicities. The median patient age was 66 years and 66% of patients had visceral metastases. The main efficacy endpoints were Objective Response Rate (ORR) and Duration of Response (DOR), evaluated by Independent Review, using RECIST 1.1 criteria.

At a median follow up of 9.1 months, the ORR was 27.7%, and 77% of patients had decrease in measurable disease. The Complete Response rate was 5.4% and 22.3% had Partial Responses. The median DOR was 7.2 months. The median Progression Free Survival was 5.4 months and Overall Survival was 10.9 months. Important Grade 3 or more treatment related adverse events included, neutropenia, anemia, diarrhea, and febrile neutropenia, with 6% of patients discontinuing treatment due to adverse events because of treatment-related adverse events.

It was concluded that TRODELVY® is an active agent and has notable efficacy, compared with historical controls, in pretreated metastatic Urothelial Cancer, that has progressed on both prior Platinum regimens and checkpoint inhibitors, and has manageable safety profile.

TROPHY-U-01: A Phase II Open-Label Study of Sacituzumab Govitecan in Patients With Metastatic Urothelial Carcinoma Progressing After Platinum-Based Chemotherapy and Checkpoint Inhibitors. Tagawa, ST, Balar AV, Petrylak DP, et al. J Clin Oncol. 2021;39:2474-2485.

PADCEV® (Enfortumab Vedotin-ejfv)

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The FDA on July 9, 2021 approved PADCEV®, a Nectin-4-directed antibody and microtubule inhibitor conjugate, for adult patients with locally advanced or metastatic urothelial cancer who

  • have previously received a Programmed Death receptor-1 (PD-1) or Programmed Death-Ligand (PD-L1) inhibitor and Platinum-containing chemotherapy, or
  • are ineligible for Cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.

PADCEV® is a product of Astellas Pharma US, Inc.

Adjuvant Treatment with OPDIVO® in Muscle-Invasive Urothelial Carcinoma

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SUMMARY: The American Cancer Society estimates that in the United States for 2021, about 83,730 new cases of bladder cancer will be diagnosed and approximately 17,200 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. A third of the patients initially present with locally invasive or metastatic disease. Even though radical cystectomy is considered the standard of care for patients with localized Muscle Invasive Bladder Cancer (MIBC), two large randomized trials and two meta-analysis have shown greater survival benefit with neoadjuvant Cisplatin-based combination chemotherapy for patients with MIBC, compared to surgery alone. However, not all patients with MIBC benefit from neoadjuvant Cisplatin based therapy, with only 25-50% attaining a pathologic response. More than 50% of patients with MIBC or regional lymph node involvement will develop metastatic disease following radical cystectomy. There is presently no clear consensus with regards to the routine use of adjuvant Cisplatin-based chemotherapy. Further, not all patients are eligible for adjuvant or neoadjuvant Cisplatin-based chemotherapy.

OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2. Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response. OPDIVO® has been shown to have antitumor activity in patients with metastatic urothelial carcinoma who had previously received platinum treatment, and is presently approved by the FDA for this patient group.

CheckMate 274 is a multicenter, double-blind, randomized, Phase III trial conducted to evaluate the efficacy and safety of adjuvant OPDIVO®, as compared with placebo, in patients with muscle-invasive urothelial carcinoma following radical surgery (with or without previous neoadjuvant Cisplatin-based combination chemotherapy). A total of 709 patients with muscle-invasive urothelial carcinoma who had undergone radical surgery were randomly assigned in a 1:1 ratio to receive either OPDIVO® 240 mg as a 30-minute IV infusion (N=353) or placebo (N=356), every 2 weeks for up to 1 year. To be eligible, patients must have had radical surgery (R0, with negative surgical margins), with or without neoadjuvant Cisplatin-based chemotherapy. Patients must have had pathological evidence of urothelial carcinoma (originating in the bladder, ureter or renal pelvis) with a high risk of recurrence defined as follows: pathological stage of pT3, pT4a, or pN+ and patients not eligible for or declined adjuvant Cisplatin-based combination chemotherapy, patients who had not received neoadjuvant Cisplatin-based chemotherapy, and pathological stage of ypT2 to ypT4a or ypN+ for patients who received neoadjuvant Cisplatin. Both treatment groups were well balanced and approximately 40% of patients in both treatment groups had PD-L1 expression of 1% or more and 43% of patients had received previous neoadjuvant cisplatin therapy. The two Primary endpoints were Disease Free Survival (DFS) among all the patients, and among patients with a tumor Programmed Death-Ligand 1 (PD-L1) expression level of 1% or more. Secondary endpoints included Survival free from recurrence outside the urothelial tract, Overall Survival and Safety. The median follow up was 20.9 months among patients who received OPDIVO® and 19.5 months among those who received placebo.

The median DFS was 20.8 months in the OPDIVO® group and 10.8 months in the placebo group in the intention-to-treat population, which was nearly double that with placebo. The percentage of patients who were alive and disease-free at 6 months was 74.9% with OPDIVO® and 60.3% with placebo, in the intention-to-treat population (HR for disease recurrence or death=0.70; P<0.001). Among patients with a PD-L1 expression level of 1% or more, the percentage who were alive and disease-free at 6 months was 74.5% with OPDIVO® and 55.7% with placebo, in the Intention-to-Treat Population (HR=0.55; P<0.001). The subgroup analysis showed that there was a higher probability of DFS with OPDIVO® than with placebo, and this benefit was observed regardless of nodal status, PD-L1 status, or use or nonuse of previous neoadjuvant Cisplatin-based chemotherapy.

The median survival free from recurrence outside the urothelial tract, in the intention-to-treat population, was 22.9 months among patients who received OPDIVO® and 13.7 months with placebo. The percentage of patients who were alive and free from recurrence outside the urothelial tract at 6 months was 77% with OPDIVO® and 62.7% with placebo (HR for recurrence outside the urothelial tract or death=0.72). Among those with a PD-L1 expression level of 1% or more, the percentage who were alive and free from recurrence outside the urothelial tract at 6 months was 75.3% and 56.7%, respectively (HR=0.55). Grade 3 or higher toxicities were noted in 17.9% of patients in the OPDIVO® group and 7.2% of patients in the placebo group.

It was concluded that among patients with high risk muscle-invasive urothelial carcinoma who had undergone radical surgery with curative intent, adjuvant treatment with OPDIVO® significantly improved Disease Free Survival, compared to placebo, in both intention-to-treat population and among patients with a PD-L1 expression level of 1% or more.

Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. Bajorin DF, Witjes JA, Gschwend JE, et al. N Engl J Med 2021;384:2102-2114.