Transcript
My name is Kirollos Hanna. I'm the director of pharmacy with Minnesota Oncology. I'm also an assistant professor at the Mayo Clinic College of Medicine. Really excited to spend a few minutes with you talking about the role of nivolumab in combination with AVD for patients with advanced classical Hodgkin's lymphoma as a front-line treatment option.
As of March of 2026, nivolumab did receive FDA approval in the United States in combination with doxorubicin/vinblastine as well as dacarbazine for the management of patients with classical Hodgkin's lymphoma. Before we get into the clinical trial that led to this particular approval, I think it's important for us to understand a couple of things about classical Hodgkin's lymphoma, what it means to be diagnosed with advanced disease, to understand nivolumab in terms of mechanism of action, but I'm sure many of us are going to be familiar with it as it's been in the United States for quite some time, and then run into the clinical trial as well as NCCN guideline recommendations for this particular combination.
When we look at classical Hodgkin's lymphoma, it's important for us to understand that across all stages of disease, our treatment intent for these patients is curative. So even if we have patients with stage III/stage IV classical Hodgkin's lymphoma, that we still try to cure these patients. Now, of course, some of these patients may be presenting with bulky disease or unfavorable risk factors utilizing the Lugano scale, but in the grand scheme of things, regardless of stage of disease, we do try to cure our patients.
It is important also for us to highlight that Hodgkin's lymphoma does have a bimodal distribution. When we look at Hodgkin's lymphoma, there oftentimes tends to be a group of patients who are younger, maybe mid 20s to mid 30s, early 40s, and then the other side of that bimodal distribution is that a good portion of patients may be well over 60, 65 years of age or older. So clearly when we try to differentiate between these two groups of patients, there's going to be quite a bit of variability. Some patients may be frail, have comorbidities, but then in contrast to that, when we're thinking maybe of a younger patient we're treating with classical Hodgkin's lymphoma, things like long-term side effects are going to be important considerations, things like fertility preservation, given that it's a younger patient versus an older patient. A lot of considerations. But regardless of the group of patients that we're treating, we are going to aim for a cure for these patients.
It is also important to highlight that specific to classical Hodgkin's lymphoma, this is a lot different than your non-Hodgkin's lymphomas, Hodgkin's lymphoma is characterized by a unique cell type. It's called the Reed-Sternberg cell. So if our pathologists are looking at tumor sampling under the microscope, they sometimes call these the "owl eye cells". They're binucleated cells and they're referred to as Reed-Sternberg cells. Reed-Sternberg is ultimately the person who had discovered these cells and discovered the disease.
Now, for a long, long time, understanding the history of Hodgkin's lymphoma, the standard of care for almost 40 years prior to some of these newer approvals has been what we call the ABVD regimen. Within Hodgkin's lymphoma, we break down patients into two groups. Oftentimes it's patients with stage I and II disease, maybe stage II unfavorable, but usually the stage II unfavorable is bucketed with the stage III and IV. And then your other bucket is that stage II unfavorable grade III and IV. And the reason why we do that, you look at the survival trend for these two different buckets of patients, it varies significantly.
Oftentimes for your patients with early-stage, stages I and II, we might treat these patients with less cycles of chemotherapy. ISRT radiotherapy also plays a role within that patient population. But then when you start to get into stage II unfavorable, stage III, and stage IV, oftentimes, instead of treating these patients maybe with four cycles of therapy, we treat them with six cycles. The role of bleomycin in this patient population, maybe in early-stage we can omit it. There is some data where we can omit it in late-stage, but it's very important just to understand the variability there. The focus of today's presentation is that nivolumab with AVD is for stage III and stage IV disease predominantly, and patients do receive six cycles of treatment.
As I've said, the historical standard has been ABVD up until about a few years ago. A drug entered the market called brentuximab vedotin, and I bring that up because it was the first time we've seen something demonstrate an overall survival benefit over ABVD, but it also served as the comparator arm in the SWOG1826 study, which we'll cover today, that established the role of nivolumab in this patient population.
So we all are familiar with nivolumab, as I mentioned. It's a PD-1 inhibitor. In the grand scheme of things, this helps rev up T-cell activity. It prevents the binding of PD-1 to PD-L1, it's ligand, programmed cell death or programmed cell death ligand-1. When the ligand binds to the receptor, tumors can evade the immune system and turn off T-cell activity. So when you utilize a PD-1 inhibitor, or even a PD-L1 inhibitor, you stop that binding mechanism, ultimately revving up T cells to have an antitumor effect. But in combination with nivolumab, we have these cytotoxic agents that I mentioned that are part of the AVD component, so doxorubicin/vinblastine, as well as dacarbazine, that will have direct cytotoxicity in nature.
Now, we're going to delve right in and talk about the SWOG1826 study. We'll talk about the study design. This was a randomized, open-label, multicenter trial and it included patients who are 12 years of age or older with previously untreated stage III or stage IV classical Hodgkin's lymphoma. This clinical trial looked at just under a thousand patients, so 994 patients to be exact, and it randomized patients in a 1:1 fashion. It looked at nivolumab plus AVD or brentuximab vedotin plus AVD for six cycles. So ABVD, the historical standard for 40 years, wasn't the comparator arm, it was brentuximab vedotin plus AVD. And as I've already mentioned, the ECHELON-1 study is the first time we've seen something have an improvement in modified progression-free survival as well as overall survival versus ABVD. So that's what made brentuximab vedotin a very attractive comparator arm in the SWOG1826 versus Nivo plus AVD.
And ultimately what they looked at in this particular clinical trial was progression-free survival. That was the primary endpoint, with various other aspects of responses as well as safety. I do want to mention that, per the FDA label and how this was studied in the clinical trial, for patients who were 18 years of age or older, they did receive nivolumab at 240 milligram flat dose. This is given on days 1 and 15 of a 28-day cycle for six cycles. And in the patient group that fell between 12 and 17 years of age, this was a weight-based dosing up to a maximum of 240 milligrams. So the patients were given 3 milligram per kilo with a max of 240 milligram. Everything else in the AVD regimen, and even the brentuximab vedotin component in the control arm, was pretty much the standard that we're already familiar with.
And what was observed in the clinical trial? So when they looked at the primary efficacy endpoint of progression-free survival, these patients who received nivolumab plus AVD, the complete response rate, actually, was 79% versus 64% in the patients who received BV plus AVD. When we look at the number of events, there were much fewer events in the patients who received nivolumab with AVD versus those patients who received BV/AVD. So you look at your nivolumab-treated patients, there were only 28 events that occurred out of 496 patients, that was 5.6%. And then you look at the BV/AVD-treated patients, there were 62 events out of 498 patients, ultimately that was 12.4%.
Now, it is also important for us to highlight some of the safety that was observed. One thing that I like about this clinical trial is that your chemotherapy backbone is AVD in both, but then you have an immune checkpoint inhibitor with nivolumab and you have an antibody-drug conjugate with brentuximab vedotin. And what we learned in this clinical trial is that the incorporation of nivolumab in this particular patient population actually led to a more favorable safety profile.
A lot of the adverse events that were observed were pretty consistent with what we would expect with each respective agent. There were generalized toxicities, so GI side effects, nausea, vomiting. That was pretty consistent across the board. And for both regimens, the grade 3 or 4 GI toxicities were fairly low, under 5% across the board.
Now, a couple of things to call out, in the patients who received brentuximab vedotin, we did observe higher rates of peripheral neuropathy. This is something due to the nature of brentuximab vedotin being an antibody-drug conjugate that has MMAE as a payload. Whereas when we looked at the patients who received nivolumab, we saw some rates of skin toxicities, some low rates of endocrinopathies like hypothyroidism, but it wasn't anything that was deemed to be a major red flag or too concerning for the incorporation of immunotherapy.
So overall, what we saw from SWOG1826 was something even more unprecedented than what we have observed from ECHELON-1 utilizing BV plus AVD. And that has been around now for about five or 6 years from the ECHELON-1 study, but now we see that the incorporation of nivolumab plus AVD can continue to add on this incremental value for these patients. Lesser events, longer time on therapy, and ultimately working to achieve that cure.
I do also want to mention that in the NCCN guidelines, this regimen has been incorporated, especially for patients with stage III and IV disease. If you look at the NCCN guidelines, classical Hodgkin's lymphoma, stage III and IV, nivolumab plus AVD for six cycles is now the only Category 1 preferred treatment option over anything else that has historically been there.
Now, I will mention that the NCCN guidelines does call out, if you have a patient with a contraindication to checkpoint inhibition, so if they have an uncontrolled autoimmune condition or autoimmune disease, you don't feel that they might be a good candidate for PD-1 inhibition, the BV plus AVD regimen is still certainly an appropriate therapeutic option for these patients. But it is really interesting to see that drastic shift within the NCCN guidelines given the value that we saw from this particular SWOG trial.
I hope this was beneficial to you and please reach out if you have any questions. Thank you.
Initial US Approval:
2014
Key Clinical Studies:
Study CA209-8UT (SWOG 1826; NCT03907488)
Drug Class/Description:
programmed death receptor-1 (PD-1)-blocking antibody
Indications and Usage:
OPDIVO is a programmed death receptor-1 (PD-1)-blocking antibody indicated for the treatment of:
Melanoma
- adult and pediatric (12 years and older) patients with unresectable or metastatic melanoma, as a single agent or in combination with ipilimumab.
- for the adjuvant treatment of adult and pediatric patients 12 years and older with completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma.
Non-Small Cell Lung Cancer (NSCLC)
- adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer in the neoadjuvant setting, in combination with platinum-doublet chemotherapy.
- adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer and no known EGFR mutations or ALK rearrangements, for neoadjuvant treatment, in combination with platinum-doublet chemotherapy, followed by single-agent OPDIVO as adjuvant treatment after surgery.
- adult patients with metastatic non-small cell lung cancer expressing PD-L1 (≥1%) as determined by an FDA-authorized test, with no EGFR or ALK genomic tumor aberrations, as first-line treatment in combination with ipilimumab.
- adult patients with metastatic or recurrent non-small cell lung cancer with no EGFR or ALK genomic tumor aberrations as first-line treatment, in combination with ipilimumab and 2 cycles of platinum-doublet chemotherapy.
- adult patients with metastatic non-small cell lung cancer and progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.
Malignant Pleural Mesothelioma
- adult patients with unresectable malignant pleural mesothelioma, as first-line treatment in combination with ipilimumab.
Renal Cell Carcinoma (RCC)
- adult patients with intermediate or poor risk advanced renal cell carcinoma, as a first-line treatment in combination with ipilimumab.
- adult patients with advanced renal cell carcinoma, as a first-line treatment in combination with cabozantinib.
- adult patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy.
Classical Hodgkin Lymphoma (cHL)
- adult and pediatric (12 years and older) patients with previously untreated Stage III or IV classical Hodgkin lymphoma in combination with doxorubicin, vinblastine, and dacarbazine (AVD).
- adult patients with classical Hodgkin lymphoma that has relapsed or progressed after:
- autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin, or
- 3 or more lines of systemic therapy that includes autologous HSCT.
Squamous Cell Carcinoma of the Head and Neck (SCCHN)
- adult patients with recurrent or metastatic squamous cell carcinoma of the head and neck with disease progression on or after a platinum-based therapy.
Urothelial Carcinoma
- adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC.
- adult patients with unresectable or metastatic urothelial carcinoma, as first-line treatment in combination with cisplatin and gemcitabine.
- adult patients with locally advanced or metastatic urothelial carcinoma who:
- have disease progression during or following platinum-containing chemotherapy.
- have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
Colorectal Cancer
- adult and pediatric (12 years and older) patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC) in combination with ipilimumab.
- adult and pediatric (12 years and older) patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
Hepatocellular Carcinoma (HCC)
- adult patients with unresectable or metastatic hepatocellular carcinoma (HCC), as a first-line treatment in combination with ipilimumab.
- in combination with ipilimumab in adult patients with unresectable or metastatic HCC who have been previously treated with sorafenib.
Esophageal Cancer
- adult patients with completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease, who have received neoadjuvant chemoradiotherapy (CRT).
- adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma as first-line treatment in combination with fluoropyrimidine- and platinum- containing chemotherapy whose tumors express PD-L1 (≥1).
- adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma as first-line treatment in combination with ipilimumab whose tumors express PD-L1 (≥1).
- adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy.
Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma
- adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma whose tumors express PD-L1 (≥1) in combination with fluoropyrimidine- and platinum-containing chemotherapy.
Dosage and Administration:
- Administer by intravenous infusion after dilution based upon recommended infusion rate for each indication.
- Unresectable or metastatic melanoma
- Adult and pediatric patients weighing 40 kg or greater: 240 mg every 2 weeks or 480 mg every 4 weeks.
- Pediatric patients weighing less than 40 kg: 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks.
- Adult and pediatric patients weighing 40 kg or greater: 1 mg/kg followed by ipilimumab 3 mg/kg on the same day every 3 weeks for 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks.
- Pediatric patients weighing less than 40 kg: 1 mg/kg followed by ipilimumab 3 mg/kg on the same day every 3 weeks for 4 doses, then 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks.
- Adjuvant treatment of melanoma
- Adult and pediatric patients weighing 40 kg or greater: 240 mg every 2 weeks or 480 mg every 4 weeks.
- Pediatric patients weighing less than 40 kg: 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks.
- Neoadjuvant treatment of resectable (tumors ≥4 cm or node positive) non-small cell lung cancer
- 360 mg with platinum-doublet chemotherapy on the same day every 3 weeks for 3 cycles.
- Neoadjuvant and adjuvant treatment of resectable non-small cell lung cancer
- 360 mg with platinum-doublet chemotherapy on the same day every 3 weeks for up to 4 cycles, then continued as single-agent OPDIVO 480 mg every 4 weeks after surgery for up to 13 cycles (~1 year).
- Metastatic non-small cell lung cancer
- 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks.
- 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks and 2 cycles of platinum-doublet chemotherapy.
- 240 mg every 2 weeks or 480 mg every 4 weeks.
- Malignant pleural mesothelioma
- 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks.
- Advanced renal cell carcinoma
- 3 mg/kg followed by ipilimumab 1 mg/kg on the same day every 3 weeks for 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks.
- 240 mg every 2 weeks or 480 mg every 4 weeks administered in combination with cabozantinib 40 mg once daily without food.
- 240 mg every 2 weeks or 480 mg every 4 weeks.
- Classical Hodgkin lymphoma
- Adult and pediatric patients weighing 40 kg or greater: 240 mg in combination with doxorubicin, vinblastine, and dacarbazine (AVD) every 2 weeks for 6 cycles.
- Pediatric patients weighing less than 40 kg: 3 mg/kg in combination with AVD every 2 weeks for 6 cycles.
- 240 mg every 2 weeks or 480 mg every 4 weeks.
- Recurrent or metastatic squamous cell carcinoma of the head and neck
- 240 mg every 2 weeks or 480 mg every 4 weeks.
- Adjuvant treatment of urothelial carcinoma
- 240 mg every 2 weeks or 480 mg every 4 weeks.
- First-line unresectable or metastatic urothelial carcinoma
- 360 mg every 3 weeks with cisplatin and gemcitabine on the same day for up to 6 cycles, then 240 mg every 2 weeks or 480 mg every 4 weeks.
- Previously treated locally advanced or metastatic urothelial carcinoma
- 240 mg every 2 weeks or 480 mg every 4 weeks.
- Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer
- Adult and pediatric patients weighing 40 kg or greater: 240 mg followed by ipilimumab 1 mg/kg on the same day every 3 weeks for a maximum of 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks.
- Pediatric patients weighing less than 40 kg: 3 mg/kg followed by ipilimumab 1 mg/kg on the same day every 3 weeks for a maximum of 4 doses, then 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks.
- Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following prior treatment for metastatic disease.
- Adult and pediatric patients weighing 40 kg or greater: 240 mg every 2 weeks or 480 mg every 4 weeks.
- Pediatric patients weighing less than 40 kg: 3 mg/kg every 2 weeks.
- Hepatocellular carcinoma
- 1 mg/kg followed by ipilimumab 3 mg/kg on the same day every 3 weeks for 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks.
- Adjuvant treatment of resected esophageal or gastroesophageal cancer
- 240 mg every 2 weeks or 480 mg every 4 weeks for total treatment duration of 1 year.
- Esophageal squamous cell carcinoma
- 240 mg every 2 weeks or 480 mg every 4 weeks in combination with chemotherapy regimen of fluoropyrimidine- and platinum-containing chemotherapy.
- 3 mg/kg every 2 weeks or 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks.
- 240 mg every 2 weeks or 480 mg every 4 weeks.
- Gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma (GC, GEJC, or EAC)
- 360 mg every 3 weeks with fluoropyrimidine- and platinum-containing chemotherapy every 3 weeks.
- 240 mg every 2 weeks with fluoropyrimidine- and platinum-containing chemotherapy every 2 weeks.
- See full Prescribing Information for preparation and administration instructions and dosage modifications for adverse reactions.
Dosage Forms and Strengths:
- Injection: 40 mg/4 mL (10 mg/mL), 100 mg/10 mL (10 mg/mL), 120 mg/12 mL (10 mg/mL), and 240 mg/24 mL (10 mg/mL) solution in a single-dose vial.
Contraindications:
- None.
Warnings and Precautions:
- Immune-Mediated Adverse Reactions:
- Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis and hepatotoxicity, immune-mediated endocrinopathies, immune-mediated dermatologic adverse reactions, and immune-mediated nephritis and renal dysfunction.
- Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment.
- Withhold or permanently discontinue based on severity and type of reaction.
- Infusion-related reactions: Interrupt, slow the rate of infusion, or permanently discontinue OPDIVO based on severity of reaction.
- Complications of allogeneic HSCT: Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with a PD-1/PD-L1 blocking antibody.
- Embryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception.
- 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.
Adverse Reactions:
Most common adverse reactions (incidence ≥20%) in patients were:
- As a single agent: fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia, headache, abdominal pain, vomiting, and urinary tract infection.
- In combination with ipilimumab: fatigue, diarrhea, rash, pruritus, nausea, musculoskeletal pain, pyrexia, cough, decreased appetite, vomiting, abdominal pain, dyspnea, upper respiratory tract infection, arthralgia, headache, hypothyroidism, constipation, decreased weight, and dizziness.
- In combination with platinum-doublet chemotherapy: nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, and peripheral neuropathy.
- In combination with ipilimumab and platinum-doublet chemotherapy: fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus.
- In combination with cabozantinib: diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysesthesia syndrome, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.
- In combination with fluoropyrimidine- and platinum-containing chemotherapy: nausea, peripheral neuropathy, decreased appetite, fatigue, constipation, stomatitis, diarrhea, vomiting, abdominal pain, and musculoskeletal pain.
Most common adverse reactions (incidence ≥30%) in patients were:
- In combination with AVD: nausea, neutropenia, fatigue, anemia, constipation, leukopenia, musculoskeletal pain, peripheral neuropathy, transaminases increase, vomiting, and stomatitis.
Use in Specific Populations:
- Lactation: Advise not to breastfeed.
Adapted From:
https://packageinserts.bms.com/pi/pi_opdivo.pdf
Every health-care provider should make their own determination regarding specific safe and appropriate patient care practices, including drug dosages and indications. The provider should always consult the most recent prescribing/product information. FDA Focus information is not guaranteed to be accurate, complete, or current. JADPRO and its editors, authors, reviewers, and commentators cannot be held responsible for any liability incurred as a consequence of the application of any of the information listed within.
