The first approval of a systemic adjuvant treatment for melanoma was over 25 years ago.1 Since then, research efforts have introduced recent options that have greatly enhanced patient outcomes by significantly delaying disease recurrence and improving safety and tolerability.2 Now, the impact of COVID-19 raises new questions around how best to support patients and manage the disease in the midst of these challenging times.
Here to share his perspective on the role of adjuvant treatment in melanoma and considerations in today’s environment is Ahmad Tarhini, M.D., Ph.D., director of cutaneous clinical and translational research at Moffitt Cancer Center and Research Institute in Tampa, Fla.
Why is adjuvant therapy particularly important for melanoma patients?
Adjuvant therapy in advanced melanoma targets micrometastatic disease that can be the source of melanoma future relapse and death – it provides the opportunity to treat melanoma before it progresses to more advanced inoperable stages.3 Systemic adjuvant therapy options have improved greatly since the advent of interferon-alfa in 1995.1 Without adjuvant therapy, there is an approximately 40-90% risk of melanoma recurrence or death within five years post-surgery for stage III melanoma patients.4 The more advanced the cancer, the higher the risk: by AJCC7 stage grouping, in stage IIIA, the risk is 37%; at stage IIIB it leaps to 68%; and at stage IIIC, the risk is probable at 89%.4 The good news is that research efforts in the adjuvant setting have made major progress, and we now have systemic therapy options that have been shown to significantly improve recurrence-free survival (RFS) for a broader swath of patients compared to what we historically had to offer.1
Research over the last decade greatly changed the adjuvant therapy landscape, bringing advances in immunotherapy and targeted therapies. Can you tell us a bit about the role of immunotherapy in this setting, particularly Opdivo (nivolumab)?
Immunotherapy can play an important role as adjuvant treatment for melanoma patients after surgery and has shown positive outcomes, regardless of BRAF mutation status.5 Furthermore, longer-term follow up of completed Phase 3 clinical trials is revealing a lasting impact for some patients. Relevant to this topic, data from a four-year analysis of the CheckMate -238 trial studying Opdivo for the adjuvant treatment of patients with resected stage III or stage IV disease, including BRAF mutant (MT) and BRAF wild-type (WT) patients, were recently presented, marking the longest follow-up for any PD-1 agent in the melanoma adjuvant setting.2,6,7
It is important to mention that Opdivo is associated with the following Warnings & Precautions: severe and fatal immune-mediated adverse reactions including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions, other immune-mediated adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation (HSCT); 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.5 Please see the Important Safety Information section below.
The trial, CheckMate -238, was a randomized, double-blind trial of 906 patients with completely resected stage IIIB/C or stage IV melanoma.5 Patients were randomized to receive Opdivo (n=453) or ipilimumab (n=453).5 The major efficacy outcome was RFS and the trial compared Opdivo to ipilimumab, an active comparator with a proven overall survival benefit.5 In the 18-month interim analysis, Opdivo reduced the risk of disease recurrence by 35% versus ipilimumab [Hazard Ratio (HR): 0.65; 95% CI: 0.53 to 0.80; p < 0.0001)].5 In the final planned analysis at three years, Opdivo continued to demonstrate improved or prolonged RFS compared to ipilimumab with three-year RFS rates of 58% and 45%, respectively [HR 0.68; 95% CI: 0.56-0.82; p<0.0001].8
In the follow-up analysis of the trial at four years, 52% of patients treated with Opdivo did not experience disease recurrence (95% CI: 46.8-56.3), compared to 41% treated with ipilimumab (95% CI: 36.4-45.9).2 These results included BRAF MT and WT patients, as well as patients with poor prognosis.2 Four-year RFS rates were also similar across BRAF status: the four-year RFS rate for those treated with Opdivo was 52% for BRAF MT mutant patients (95% CI: 43.9-58.5) and 50% of BRAF WT mutant patients (95% CI: 42.5-56.9) compared to 44% and 39% of patients treated with ipilimumab (MT 95% CI: 36.3-50.7; WT 95% CI: 31.8-45.6), respectively.2
In the interim analysis at 18 months, serious adverse reactions occurred in 18% of patients receiving Opdivo.5 The most frequent serious adverse reactions reported in ≥2% of Opdivo-treated patients were diarrhea and increased lipase and amylase. The most common adverse reactions, reported in at least 20% of Opdivo-treated patients, were fatigue (57%), diarrhea (37%), rash (35%), musculoskeletal pain (32%), pruritus (28%), headache (23%), nausea (23%), upper respiratory infection (22%) and abdominal pain (21%).5 The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%).5 Safety results from the three-year and four-year analyses were consistent with the primary analysis and no new safety signals were observed.2,8
Dosing schedules and compliance are, of course, critical to improving positive outcomes – particularly in the age of COVID-19. What do you recommend for your patients?
Treating cancer is a major challenge in and of itself. With COVID-19, we are faced with new considerations as we strive to do what’s best for our patients. For many patients, it is important that we aim to reduce potential exposure to COVID-19 while seeing them regularly enough to ensure both compliance with the indicated treatment regimen and ongoing appraisal of their health condition. Obviously, finding that balance is important. Every patient is different, but in the case of selecting Opdivo for adjuvant treatment, the Q4W dosing option enables us to confidently treat our patients based on the established safety and efficacy data while balancing dosing frequency with regular monitoring.
How do you view the future of melanoma treatment in the adjuvant setting?
I’m quite optimistic. Immunotherapy has been critical in transforming the treatment landscape for patients.1,3 Comparing where we are now – our understanding of the disease and the options for melanoma in the adjuvant setting – to where we were just one decade ago is astounding.2 We are at an exciting time in oncology research, with an end result of more advanced cancer patients living longer and healthier lives. I look forward to more exciting discoveries that will allow myself and my colleagues to be conduits toward that end goal.
For more information about Opdivo, please visit www.opdivohcp.com.
OPDIVO® (nivolumab) is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.
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.
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%).
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%).
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%).
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.
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.
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.
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 238, serious adverse reactions occurred in 18% of patients receiving OPDIVO (n=452). Grade 3 or 4 adverse reactions occurred in 25% of OPDIVO-treated patients (n=452). The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of OPDIVO-treated patients were diarrhea and increased lipase and amylase.
Common Adverse Reactions
In Checkmate 238, the most common adverse reactions (≥20%) reported in OPDIVO-treated patients (n=452) vs ipilimumab-treated patients (n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%), rash (35% vs 47%), musculoskeletal pain (32% vs 27%), pruritus (28% vs 37%), headache (23% vs 31%), nausea (23% vs 28%), upper respiratory infection (22% vs 15%), and abdominal pain (21% vs 23%). The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%).
Please see U.S. Full Prescribing Information for OPDIVO.
Opdivo® is a registered trademark of Bristol-Myers Squibb Company.
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