Special guest Shilpa Gupta, MD joins us to discuss the various ways to individually approach the adjuvant treatment setting for your patients with radically resected urothelial carcinoma along with their multidisciplinary care team. Dr. Gupta is a genitourinary oncologist at the Cleveland Clinic. Dr Gupta is a paid consultant of BMS. This podcast was sponsored by Bristol-Myers Squibb Company.
There is ongoing progress in the urothelial carcinoma treatment landscape, but after radical resection, what adjuvant options are there for your patient? Special guest Shilpa Gupta, MD, joins us to discuss the various ways to individually approach the adjuvant treatment setting for your patients with radically resected urothelial carcinoma along with their multidisciplinary care team. Dr. Gupta is a genitourinary oncologist at the Cleveland Clinic. She has led several investigator-initiated trials in genitourinary cancers, help leadership roles within National Cancer Institute Trials, and is the chair of the Alliance-led phase 3 trial in bladder cancer, co-chair of the Southwest Chemotherapy Study Group (SWOG) S1206 trial in prostate cancer and SWOG champion of the Alliance A031701 trial in bladder cancer.
Learn more about an adjuvant treatment option for patients with urothelial carcinoma.
https://www.opdivohcp.com/efficacy/uc/adjuvant
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 https://packageinserts.bms.com/pi/pi_opdivo.pdf
(C) 2023 Bristol-Myers Squibb Company. OPDIVO® and the related logos are registered trademarks of Bristol-Myers Squibb Company. All other trademarks are the property of their respective owners.
This podcast is intended for US Healthcare Professionals only.
1506-US-2300172 04/23
Viviana Del Tejo:
Welcome to the Bristol-Myers Squibb Immuno-Oncology Podcast. A podcast dedicated to keeping listeners updated on current Bristol-Myers Squibb findings in the immuno-oncology treatment space. Today's program is intended for US healthcare professionals only.
I'm Viviana Del Tejo, a US Medical Director with Bristol-Myers Squibb, and I'm joined today by our esteemed guest, Dr. Shilpa Gupta, a genitourinary oncologist from the Cleveland Clinic in Ohio.
Please note that Dr. Gupta is a consultant for Bristol-Myers Squibb, and was compensated for her role in this podcast. Thank you again for joining us today, Dr. Gupta. Before we dive into the data, can you please tell us a bit more about your background and practice?
Dr. Shilpa Gupta:
Of course, thanks for having me, Viviana. I'm a genitourinary medical oncologist, and the director for the Genitourinary Oncology program at the Cleveland Clinic Taussig Cancer Institute.
I see a lot of patients with urothelial cancer in my clinic, and I've led several investigator initiated trials focusing on urothelial cancer. In fact, I'm leading an NCI led Phase 3 trial with maintenance immunotherapy intensification in urothelial cancer, and also have several leadership roles for cooperative group trials in bladder cancer.
Viviana Del Tejo:
Thank you, Dr. Gupta. For our listeners today, we will be discussing immuno-oncology, or IO, therapy with the programmed death receptor-1 or PD-1 blocking antibody Opdivo, or nivolumab, in the adjuvant treatment of muscle invasive urothelial carcinoma; as well as the recently published data from the CheckMate 274 study.
Opdivo as a single agent is approved for use as the adjuvant treatment of adult patients with urothelial carcinoma, who are at high risk of recurrence after undergoing radical resection of urothelial carcinoma, based upon findings from the pivotal CheckMate 274 study, which we will be discussing today.
Before we discuss the data from this trial, I want to mention that Opdivo, or nivolumab, is associated with the following warnings and precautions: severe and fatal immune mediated adverse reactions; infusion related reactions; complications of allogeneic and hematopoietic stem cell transplantation; embryo fetal toxicity; and increased mortality in the patients with multiple myeloma, when Opdivo is added to a thalidomide analog and dexamethasone.
Immune mediated adverse reactions, which may be severe fatal, can occur in any organ system or tissue including the following: immune mediated pneumonitis; immune mediated colitis; immune mediated hepatitis and hepatoxicity; immune mediated endocrinopathies; immune mediated dermatologic adverse reactions; and immune mediated nephritis with renal dysfunction.
Monitor for early identification and management, evaluate liver enzymes, creatinine, and thyroid functions at baseline, and periodically during treatment. Withhold or permanently discontinue based on the severity and type of reaction.
Infusion related reactions: interrupt, slow the rate of infusion, or permanently discontinue Opdivo, nivolumab, based on severity of reaction.
Complications of allogeneic hematopoietic stem cell transplantation. Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation before or after being treated with PD-1 or PD-L1 blocking antibody.
Embryo fetal toxicity. Opdivo can cause fetal harm. Advise females of reproductive potential of potential risks to a fetus, and to use effective contraception.
Increased mortality in patients with multiple myeloma, when Opdivo is added to a thalidomide analog and dexamethasone. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analog, plus dexamethasone, is not recommended outside of control clinical trials.
Please continue listening for more important safety information about Opdivo later in this podcast.
Thank you again, Dr. Gupta, for taking the time to speak with me today. Before we dive into the information on CheckMate 274, and the Opdivo approval, could you share a little bit about the standard of care for urothelial carcinoma treatment in your practice?
Of course, Viviana. So for patients with localized bladder cancer, or muscle invasive urothelial cancer, a standard of care for patients who are eligible to receive cisplatin-based chemotherapy, is neoadjuvant gemcitabine and cisplatin or neoadjuvant dose dense MVAC, which is methotrexate, vinblastine, doxorubicin, and cisplatin.
And then after completion of neoadjuvant chemotherapy, patients undergo radical cystectomy, and if the patients are at high risk of recurrence such as having a pathologic stage of ypT2 to ypT4a or YP node positive disease, then we discuss Opdivo as an adjuvant treatment option based on the FDA approval, as you mentioned just now.
And additionally, for patients who did not receive neoadjuvant cisplatin-based chemotherapy for a variety of comorbidities, or kidney disease and whatnot, those patients can also receive Opdivo after surgery. And this is very commonly seen in our patient population, where a lot of our patients cannot get cisplatin due to their comorbidities, like chronic kidney disease, heart failure, hearing loss, or any of the criteria that have been established for cisplatin eligibility.
And there's a lot of ongoing progress in the urothelial cancer treatment landscape, and we need additional treatment options in the muscle invasive setting. Right now, having the first immunotherapy Opdivo in this adjuvant space is a big progress.
Viviana Del Tejo:
Thank you for that context. So understanding that the treatment landscape continues to evolve, even if we think about our currently approved options, there doesn't seem to be many options for high risk patients with urothelial carcinoma post-surgery.
So in your opinion, where does Opdivo fit in terms of the adjuvant landscape? What is Opdivo addressing in these patients, in this setting, if they are at a higher risk of recurrence after their surgery?
Dr. Shilpa Gupta:
Before Opdivo'S approval, there were no FDA approved options for adjuvant treatment in patients with urothelial cancer, who have had prior cisplatin-based neoadjuvant chemotherapy. And patients with urothelial cancer really need approved adjuvant options that can help extend disease free survival, or DFS.
Those actually retrospective observational cohort study done in patients who are 65 years and older with urothelial cancer at high risk of recurrence after cystectomy, it had around 665 patients from the SEER database, who had either urothelial cancer of the bladder, or upper tract, and who were at high risk of recurrence.
And in that study, it was found that the median disease-free survival was just over one year or 13.5 months. So I think the aim of adjuvant therapy is to help decrease the risk of recurrence. And currently Opdivo is the first and only FDA approved option for adult patients with urothelial cancer, who are at high risk of recurrence after radical surgery; either radical cystectomy or nephroureterectomy, depending on the location of the primary tumor, regardless of prior neoadjuvant chemotherapy, nodal involvement or PD-L1 status.
Viviana Del Tejo:
It sounds like Opdivo provides a chance to impact the future of high risk adult patients with urothelial carcinoma, and we know the approval for Opdivo for high risk adult patients with urothelial carcinoma in the adjuvant setting was based on the results of the CheckMate 274 study.
So let's dive into that data. To start us off, how was the CheckMate 274 study designed?
Dr. Shilpa Gupta:
So the CheckMate 274 study, as you know, was a Phase 3 multi-center double blind randomized trial, evaluating adjuvant use of Opdivo at a dose of 240 milligrams intravenous versus placebo, in adult patients with urothelial cancer at high risk of recurrence after radical [inaudible 00:09:53]. This included patients with bladder cancer, as well as upper tract urothelial cancer.
And this was administered every two weeks as a 30-minute infusion intravenously for up to one year, or until disease recurrence, or discontinuation from the trial, whatever was sooner. All eligible patients were required to have had radical surgery within 120 days prior to randomization to Opdivo or placebo, with or without prior neoadjuvant cisplatin-based chemotherapy.
And based of the results of this study, Opdivo is indicated for the adjuvant treatment of adult patients with urothelial cancer at high risk of recurrence after undergoing radical resection of the urothelial cancer.
And there are two important things to note about the patient population, and the indication of Opdivo in this setting. Firstly, the inclusion of patients at high risk of recurrence after radical resection, such as patients who are at pathologic stage of ypT2, ypT3 or ypT4a, or any node positive disease with prior neoadjuvant cisplatin-based chemotherapy, Opdivo is the only adjuvant treatment which is indicated post surgery.
It is also important to note that patients in the study must have had pathologic evidence of urothelial cancer originating in the bladder, ureter, or renal pelvis. Enrollment of patients with upper tract urothelial cancer was capped at around 20% to prevent significant deviation from the natural prevalence of bladder cancer disease, in comparison with upper tract disease.
And the study included a broad range of patients, including high risk population of patients at a pathologic stage of pT2, pT4a or node positive disease, without prior neoadjuvant cisplatin-based chemotherapy, and were not eligible for, or refused, adjuvants cisplatin-based chemotherapy.
CheckMate 274 also included patients who had achieved disease free status within four weeks prior to randomization, as well as eco performance status zero to one, or a performance status of two, if the patient had no prior neoadjuvant cisplatin-based chemotherapy and was ineligible for adjuvant cisplatin-based chemotherapy.
This trial excluded patients with any condition requiring systemic treatment with immunosuppressants, such as glucocorticoids within two weeks of treatment. In the study, a total of 709 patients received randomized assignments to the trial groups. Randomization was in a one to one ratio.
Stratification was done based on the tumor PD-L1 expression level, noted as less than 1% or greater than or equal to 1%, pathologic nodal status as node positive or node negative, or NX with less than 10 nodes removed versus N0 with 10 or more nodes removed. And lastly, whether they had received neoadjuvant cisplatin-based chemo.
353 patients received Opdivo and 356 patients were randomized to the placebo arm. And there were 140 patients in the Opdivo group with PD-L1 expression of 1% or more in their tumors, and 142 patients in the placebo group. Minimum follow up in all the randomized patients was 5.9 months.
The co-primary endpoints were disease-free survival among all randomized patients in the intent to treat population, and in the subset of patients with high PD-L1 expression in their tumors, noted as one or greater than 1%. The key secondary endpoint was overall survival, including non urothelial tract recurrence free survival, and disease specific survival.
However, at the time of the planned interim analysis OS data was deemed immature. Additionally, health related quality of life was an exploratory endpoint.
Viviana Del Tejo:
Thank you so much for walking us through the CheckMate 274 study design, Dr. Gupta. So you have just briefly mentioned the study endpoints. Could you delve a little more into the efficacy endpoints of the study?
Dr. Shilpa Gupta:
Absolutely. So disease-free survival, or DFS, which was the primary endpoint, was defined as the time between the date of randomization and the date of first recurrence in the local urothelial tract, local non urothelial tract, distant metastases or death.
Non urothelial tract recurrence-free survival was a secondary endpoint, and it was defined as the time between date of randomization and the date of first local recurrence outside the urothelial tract distant recurrence or death.
Viviana Del Tejo:
Thank you for highlighting how the study defined a few of those endpoints. Is there anything else that you wanted to clarify regarding the patient inclusion criteria?
Dr. Shilpa Gupta:
Yes, I would like to emphasize that the patients with urothelial cancer, who are at high risk of recurrence after radical resection, the key difference here is that for patients who did not receive prior neoadjuvant cisplatin-based chemotherapy, their pathologic stage at surgery was pT3 or higher.
However, for patients who receive prior neoadjuvant cisplatin-based chemotherapy, their pathologic stage was ypT2 or higher. So this is an important distinction to make, because practitioners may not always realize that these patients are at high risk of recurrence.
Viviana Del Tejo:
Yes, and I think it's also important to note that prior neoadjuvant cisplatin-based chemotherapy is not a requirement, nor is it a critical step prior to receiving Opdivo based on the study.
But let's switch gears and dive deeper into the data. What were the primary results that led to the approval of Opdivo in the adjuvant setting for high risk urothelial carcinoma?
Dr. Shilpa Gupta:
In the primary analysis, the median follow up time in all randomized patients was 20.9 months for Opdivo, and 19.5 months for placebo. Notably, in the intention to treat population, the minimum follow up was 5.9 months and the median DFS was 20.8 months in the Opdivo group, and 10.8 months in the placebo group, with a hazard ratio of 0.70 and a P value of 0.0008.
Nearly double median disease free survival was achieved with Opdivo versus placebo. Opdivo reduced the risk of disease recurrence or death by 30%, in comparison to placebo.
In the subset of patients with PD-L1 expression greater than or equal to 1%, the median follow up time was 22.1 months for Opdivo and 18.7 months for placebo. The minimum follow up time was 6.3 months. Median DFS was not reached in the Opdivo group, but was achieved in 8.4 months in the placebo group, with a hazard ratio of 0.55 and a P value of 0.0005.
And more recently at SUO 2021, we saw the results of the extended follow up analysis in the intention to treat population, which had a minimum follow up time of 11 months, and a median follow up time for Opdivo versus placebo, which was now 24.4 and 22.5 months respectively.
In this analysis, the Opdivo group reached median DFS at 22 months and placebo at 10.9 months with a hazard ratio of 0.70. Opdivo patients had double median DFS in comparison to placebo, so find it encouraging to view this additional data.
However, I want to highlight a limitation, that CheckMate 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.
Viviana Del Tejo:
Nearly double median DFS with Opdivo is very impressive, but we know that following radical resection, treatment burden on patients can be a major concern. Can you share the common and serious adverse events reported in the CheckMate 274 study?
Dr. Shilpa Gupta:
A total of 351 patients in the Opdivo group and 348 patients in the placebo group received at least one dose of the trial regimen. Serious adverse reactions occurred in 30% of patients receiving Opdivo. The most frequent serious adverse reactions occurring in greater than 2% of patients was urinary tract infection.
Fatal adverse reactions occurred in 1% of patients. These included events of pneumonitis. In CheckMate 274, the most common adverse reactions occurring in greater than 20% patients were rash, fatigue, diarrhea, pruritus, musculoskeletal pain, and urinary tract infection. Median duration of Opdivo treatment was 8.8 months.
Treatment related adverse events of any grade, that led to discontinuation of the trial regimen, occurred in 12.8% of patients in the Opdivo group and 2% of those in the placebo group. The most frequent treatment related adverse event leading to discontinuation of Opdivo, was pneumonitis at 1.7%, rash at 1.1%, colitis at 0.9%, and an increased alanina aminotransferase level at 0.9%.
Treatment related deaths due to pneumonitis occurred in two patients in the Opdivo group. Both patients began glucocorticoid treatment at the onset of pneumonitis. There was one treatment related death due to bowel perforation in the Opdivo group. As noted earlier, we will review more safety information about Opdivo toward the end of the podcast, so continue to stay tuned.
Viviana Del Tejo:
Based on your perspective, are there any of these adverse events surprising with the use of Opdivo?
Dr. Shilpa Gupta:
From my experience, I was not surprised when reviewing the safety results.
Viviana Del Tejo:
And in the context of the adverse events you've just described and understanding that there were quality of life assessments in this trial, can you share your thoughts about what these data can help inform?
Dr. Shilpa Gupta:
With any treatment, we want to monitor the effect on the patient's quality of life. So in this study, one of the exploratory endpoints was to evaluate the effects of Opdivo on health related quality of life after surgery. And that was assessed using the European Organization for Research and Treatment of Cancer Quality of Life questionnaire, or the EORTC QLQ-C30, which we usually use for patients with urothelial cancer.
Another tool used was the Euro QL Group five dimension three level questionnaire, or EQ 5D-3L. However, please note that the study was not powered to assess statistical significance in exploratory endpoints.
Viviana Del Tejo:
How do you communicate with your patients with urothelial carcinoma about Opdivo as a treatment option in the adjuvant setting?
Dr. Shilpa Gupta:
In my practice, we follow guidance from the primary literature, and if patients can receive adjuvant cisplatin-based chemotherapy after surgery, or if they've not had it before and they're eligible candidates, we talk about their available options, such as ongoing trials for targeted therapies.
However, outside of those patients who can receive adjuvant cisplatin-based chemotherapy, the only viable approved option is Opdivo and we present this option to our patients.
As I mentioned earlier, the dosing regimen in the CheckMate 274 was 240 milligrams of Opdivo every two weeks. Approved dosing for Opdivo in the adjuvant treatment of urothelial cancer is 240 milligrams every two weeks, or 480 milligrams every four weeks, until disease recurrence, or unacceptable toxicity, for up to one year.
Our patients prefer the 480 milligram Opdivo dose every four weeks. We also continue patients on their scans as per the guidelines, and continue treatment as long as they can tolerate for up to a year.
Viviana Del Tejo:
How do you coordinate care and engage with the patient's urologist?
Dr. Shilpa Gupta:
When we see the patients after surgery, and if they meet the criteria for high risk of recurrence, we initiate treatment. And for the most part, as an oncologist, I'm following the patient, unless the patient has a urologic intervention that is needed. And we keep our urology colleagues updated.
But if for some reason a patient has to come off Opdivo because of disease progression or side effect, then we are the ones managing it. And if the patient has disease recurrence, we proceed to the next line of therapy. We usually discuss patients who are deemed to be at high risk of recurrence with our urology colleagues.
Viviana Del Tejo:
For high risk adult patients, based on your experiences, what is your approach to initiating adjuvant treatment? And how have you seen this affect patient outcomes?
Dr. Shilpa Gupta:
Based on my experiences in practice, it is important that I offer adjuvant therapy to my appropriate patients post-surgery, within 120 day window. Once that window of time has expired, I would consider a surveillance.
So I think this is an important point and a urologist usually discuss the patient's condition with us pretty soon after surgery. In our practice, we ensure that the patient has not had disease recurrence already, by doing staging scans and that the patient has healed well from surgery, and then we initiate treatment.
However, if the patient is struggling to recover from the surgery, we initiate closer to the end of the 120 day window. Treatment initiation post surgery is also dependent on the patient's recovery and enthusiasm, so we time it accordingly. But I would note that sticking to that time window is very important in adjuvant studies.
Viviana Del Tejo:
That makes sense. So based on your experience, what are some examples of best practices when managing treatment across different specialties?
Dr. Shilpa Gupta:
Urologists are usually enthusiastic about offering adjuvant therapies post-surgery, as it leads to improved outcomes from surgery. And during tumor board meetings, we discuss if treatment should be offered, if a patient is not meeting the classic high risk criteria.
Sometimes we have discussions with other specialties about when to communicate with medical oncologists, and where to go from there.
Many times patients with urothelial cancer have surgery do not receive adjuvant Opdivo, even if they meet the criteria, which is a missed opportunity. And if we are discussing these patients at six months post surgery, then it's certainly not an appropriate time to start Opdivo.
And if something has shown up a scan at that time, then it's not considered adjuvant therapy anymore. So I think the highlight is to discuss all the high risk patients, and reach out to the medical oncologist to start adjuvant treatment as soon as possible.
Viviana Del Tejo:
Thanks for walking us through the data and sharing your experiences today, Dr. Gupta. To close, would you mind sharing key takeaways from the data that we discussed today for our listeners to consider?
Dr. Shilpa Gupta:
CheckMate 274 was a randomized double blind placebo controlled study of adjuvant Opdivo, in patients who are within 120 days of radical resection of urothelial cancer of the bladder, or upper urinary tract at high risk of recurrence. Nearly double median disease-free survival was achieved with Opdivo versus placebo.
Furthermore, Opdivo managed to reduce the risk of disease recurrence, or death, by 30% in comparison to placebo. In CheckMate 274, the most common adverse reactions occurring in greater than 20% of patients were rash, fatigue, diarrhea, pruritus, musculoskeletal pain, and urinary tract infection.
I would like to point out that Opdivo is the first and only FDA approved option for patients with urothelial cancer, at high risk of recurrence after radical resection, regardless of prior neoadjuvant chemotherapy, nodal involvement, or PD-L1 status.
Viviana Del Tejo:
Thank you so much Dr. Gupta. I really appreciate you taking the time to discuss the Checkmate 274 trial, and providing us with some of your insights into how you treat urothelial carcinoma in the adjuvant setting.
Now I'll read through the full important safety information for Opdivo.
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 Two: Dosage and Administration in the full prescribing information. In general, if Opdivo interruption, or discontinuation, is required, administer systemic corticosteroid therapy, one to two milligrams per kilogram per day of prednisone, or equivalent, until improvement to Grade one or less.
Upon improvement to Grade one or less, initiate corticosteroid taper, and continue to taper over at least one 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, for example, endocrinopathies and dermatologic reactions, are discussed in the next section.
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%, or 61 out of 1,994 patients, including Grade four in less than 0.1% of patients; Grade three in 0.9% of patients; and Grade two in 2.1% of patients.
Immune mediated colitis. Opdivo can cause immune mediated colitis. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus infection, and 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% of patients, or 58 out of 1,994 patients, including Grade three in 1.7% of patients; and Grade two in 1% of patients.
Immune mediated hepatitis and hepatoxicity. Opdivo can cause immune mediated hepatitis. In patients receiving Opdivo monotherapy, immune mediated hepatitis occurred in 1.8% of patients, or 35 out of 1,994 patients; including Grade four in 0.2% of patients; Grade three in 1.3% of patients; and Grade two in 0.4% of patients.
Immune medicated endocrinopathies. Opdivo can cause primary or secondary adrenal insufficiency, immune mediated hypophysitis, immune mediated thyroid disorders, and Type One diabetes melitis, which can present with diabetic ketoacidosis. Withhold Opdivo depending on severity. Please see Section Two: Dosage and Administration in the full prescribing information.
For Grade two or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement, as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effects such as headache, photophobia, or visual field defects. Hypophysitis can cause hypo pituitarism. 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%, or 20 out of 1,994 patients; including Grade three in 0.4% of patients; and Grade two in 0.6% of patients.
In patients receiving Opdivo monotherapy, hypophysitis occurred in 0.6% of patients, or 12 out of 1,994 patients; including Grade three in 0.2% of patients; and Grade two in 0.3% of patients.
In patients receiving Opdivo monotherapy, thyroiditis occurred in 0.6% of patients, or 12 out of 1,994 patients; including Grade two in 0.2% of patients.
In patients receiving Opdivo monotherapy, hyperthyroidism occurred in 2.7% of patients, or 54 out of 1,994 patients; including Grade three in less than 0.1% of patients; and Grade two in 1.2% of patients. In patients receiving Opdivo monotherapy, hypothyroidism occurred in 8% of patients, or 163 out of 1,994 patients; including Grade three in 0.2% of patients; and Grade two in 4.8% of patients.
In patients receiving Opdivo monotherapy, diabetes occurred in 0.9% of patients, or 17 out of 1,994 patients; including Grade three in 0.4% of patients; and Grade two in 0.3% of patients; and two cases of diabetic ketoacidosis.
Immune mediated nephritis and renal dysfunction. Opdivo can cause immune mediated nephritis. In patients receiving Opdivo monotherapy, immune mediated nephritis and renal dysfunction occurred in 1.2% of patients, or 23 out of 1,994 patients; including Grade four in less than 0.1% of patients; Grade three in 0.5% of patients; and Grade two in 0.6% of patients.
Immune mediated dermatologic adverse reactions. Opdivo can cause immune mediated rash or dermatitis. Exfoliative dermatitis including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms, also known as DRESS, has occurred with PD-1 and PD-L1 blocking antibodies.
Topical emollients, and/or topical corticosteroids, may be adequate to treat mild to moderate non exfoliative rashes. Withhold or permanently discontinue Opdivo depending on severity.
Please see Section 2: Dosage and Administration in the full prescribing information.
In patients receiving Opdivo monotherapy, immune mediated rash occurred in 9% of patients, or 171 out of 1,994 patients; including Grade three in 1.1% of patients; and Grade two in 2.2% of patients.
Other immune mediated adverse reactions. The following clinically significant immune mediated adverse reactions occurred at an incidence of less than 1%, unless otherwise noted, in patients who receive Opdivo monotherapy, or were reported with the use of other PD-1 or PD-L1 blocking antibodies.
Severe or fatal cases have been reported for some of these adverse reactions: cardiac and vascular myocarditis; pericarditis vasculitis. Within the nervous system, meningitis; encephalitis; myelitis and demyelination; myasthenia syndrome; myasthenia gravis, including exacerbation; Guillain-Barre syndrome; nerve paresis; autoimmune neuropathy. Ocular including uveitis, iritis and other ocular inflammatory toxicities can occur.
Gastrointestinal. Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis. In musculoskeletal and connective tissue, myositis and polymyositis; rhabdomyolysis and associated sequelae, including renal failure, arthritis, polymyalgia rheumatica.
Endocrine including hypoparathyroidism and other hematologic and immune, which include hemolytic anemia, aplastic anemia, hemo phytocytotic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis or Kikuchi lymphadenitis, sarcoidosis, immune thrombocytopenic purpura, and solid organ transplant rejection.
Some ocular immune mediated adverse reaction cases can be associated with renal 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 three, or life threatening Grade four infusion related reactions. Interrupt or slow the rate of infusion in patients with mild, such as Grade one, or moderate like Grade two infusion related reactions.
In patients receiving Opdivo monotherapy as a 60 minute infusion, infusion related reactions occurred in 6.4% of patients, or 127 out of 1,994 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% of patients, or eight out of 368 patients; and 2.7% of patients, or 10 out of 369 patients respectively.
Additionally, 0.5%, or two out of 368 patients, and 1.4%, or five out of 369 patients, respectively experience adverse reactions with 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 before, or after, being treated with Opdivo. Transplant related complications include hyperacute graft versus host disease, acute graft versus host disease, chronic graft versus host disease, hepatic veno occlusive disease, after reduced insensitive conditioning and steroid requiring febrile syndrome without an identified infectious cause.
These complications may occur despite intervening therapy between Opdivo and allogeneic hematopoietic stem cell transplantation. Follow patients closely for evidence of transplant related complications and intervene promptly. Consider the benefit versus risk of treatment with Opdivo prior to or after an allogeneic hematopoietic stem cell transplantation.
Embryo fetal toxicity. Based on its mechanism of action and finding from the 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 the treatment with Opdivo, and for at least five months after the last dose.
Increased mortality in patients with multiple myeloma when Opdivo is added to a thalidomide analog and dexamethasone. In randomized clinical trials in patients with multiple myeloma, the addition of Opdivo to a thalidomide analog plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody and combination with a thalidomide analog plus dexamethasone is not recommended outside of controlled clinical trials.
Lactation. There are no data on the presence of Opdivo and 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 five months after the last dose.
Serious adverse reactions. In CheckMate 274, serious adverse reactions occurred in 30% of patients receiving Opdivo, a total of 351 patients. The most frequent serious adverse reactions reported in 2%, or greater, 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, either greater or equal to 20%, reported in patients receiving Opdivo, which is a total of 351 patients, were rash at 36%; fatigue, also 36%, diarrhea at 30%; pruritus 30%; musculoskeletal pain at 28%, and urinary tract infection, 22%.
Please see the US full prescribing information for Opdivo at opdivohcp.com and click on the US full prescribing information link for Opdivo at the top of the page.
Thank you again for your insights today, Dr. Gupta, and thank you listener for joining us.
Dr. Shilpa Gupta:
Thank you so much for having me here today. I'm happy to talk about this unique treatment option that is FDA approved for my high-risk adult patients with urothelial cancer after resection in the adjuvant setting.
Viviana Del Tejo:
This concludes our discussion of recent clinical efficacy and safety findings for Opdivo in the adjuvant treatment of urothelial carcinoma.
References for the data described in this podcast may be found on the listening platform.
References