An immunotherapy approach to treating advanced Hodgkin lymphoma may drastically increase patients’ chances of survival, including in those as young as 12, according to a recent clinical trial.
The regimen, which involves the immunotherapy drug nivolumab along with three different chemotherapies, was found to result in a two-year progression-free survival rate of 92% in a phase 3 trial, reports CNN.
The results were published in the New England Journal of Medicine.
“At two years, 92% of the patients did not relapse, did not have progression of Hodgkin lymphoma and did not die,” said Dr Jonathan Friedberg, lead study author and director of the Wilmot Cancer Institute at the University of Rochester.
“The standard endpoint in studies of Hodgkin lymphoma is progression-free survival, because we think that best predicts the future,” he said. “If you can keep people disease-free and alive for two years, generally speaking, it’s very unlikely that beyond two years you’re going to have a lot of events, so we’re quite optimistic these results are going to be durable. But of course, it’s going to be important to follow these patients for a longer period of time.”
Hodgkin lymphoma is a type of cancer that originates in white blood cells called lymphocytes, affecting the lymphatic system, part of the immune system.
The American Cancer Society estimates that more than 8 000 cases will be diagnosed in the US this year, and about 900 people will die from the disease. Hodgkin lymphoma can develop at any age, but it’s most common in early adulthood. The average age at diagnosis is 39, and it’s the most common cancer diagnosed in adolescents aged 15 to 19.
‘An immunotherapy revolution’
The recent study included nearly 1 000 people who were at least 12-years-old and newly diagnosed with stage 3 or 4 Hodgkin lymphoma that had previously been untreated.
Between July 2019 and October 2022, they were randomly assigned to receive one of two treatment regimens; 496 patients were assigned to receive the antibody drug brentuximab vedotin along with the chemotherapy drugs doxorubicin, vinblastine and dacarbazine, while 498 others received nivolumab along with that same trio of chemotherapies.
The patients received the treatments intravenously on the first day and then about two weeks later within a 28-day cycle. This was repeated for six cycles.
The patients were based at 256 sites across the US and Canada. One of the sponsors was Bristol-Myers Squibb, which makes nivolumab and supplied the drug for the study.
A combination of chemotherapies has been the standard treatment for advanced-stage Hodgkin lymphoma for decades, but the researchers watched each patient closely to analyse how they responded to the drug combinations.
They found that the nivolumab treatment regimen significantly improved survival compared with the brentuximab vedotin regimen.
About two years after starting treatment, 92% of those in the nivolumab group survived without relapse and without seeing the cancer progress, compared with 83% of those in the brentuximab vedotin group.
These patients who survived without cancer progression also did not need radiation therapy, which can result in significant side effects, such as the risk of additional cancers or fertility problems. In the study, only seven patients overall received radiation therapy.
The researchers noted that there were more adverse side effects in the brentuximab vedotin group than the nivolumab group, but a condition called neutropenia – in which the body has low levels of a type of white blood cell – was more prevalent in the nivolumab group.
Neutropenia occurred in 56% of patients taking nivolumab versus 34% of those who got the brentuximab vedotin treatment.
“Neutropenia can result in an increased risk of infection,” Friedberg said.
The researchers knew the condition might be a risk with brentixuimab, so more than 90% of the patients given that treatment also received a “growth factor” medication to help evade neutropenia as a side effect. In the nivolumab group, only 50% of patients got that “growth factor” support.
“So it’s really not surprising that we’d see a slightly higher risk of neutropenia,” Friedberg said.
Overall, found the researchers, the nivolumab approach had a better side effect profile, with fewer patients stopping treatment early, fewer deaths during treatment and a low incidence of immune-related toxic effects.
There were seven deaths from any cause in the nivolumab group, among which three were during treatment, compared with 14 in the brentuximab vedotin group, among which eight were during treatment, according to the study.
“In the context of a disease in which a high proportion of patients are cured with standard therapy and the bar to change practice is set high, the improvement in efficacy and in the risk of adverse events was clinically meaningful,” the researchers wrote.
As the study followed patients for only two years, the researchers plan to continue to monitor them and provide updates, Friedberg said. They also hope the US Food and Drug Administration soon will determine whether nivolumab should be added as a standard treatment for stage III or IV Hodgkin lymphoma, and plan to start the formal process to ask for expand approval of nivolumab.
Nivolumab, sold under the brand name Opdivo, has been approved by the FDA to be included in treatment regimens for many other types of cancer, including small cell lung cancer, melanoma and urothelial carcinoma.
“We’re in the midst of an immunotherapy revolution in cancer treatment,” Friedberg said.
“For decades, people tried and failed, and within the past six to 10 years, we’ve seen dramatic changes in not just Hodgkin lymphoma but many more common cancers like lung cancer and melanoma.
“Unfortunately, for many of the more common cancers, although immunotherapy seems to work, it’s not a definitive cure, and a lot of the research now is looking to join immunotherapy with other standard approaches to see if that one-two punch, so to speak, may ultimately be curative.”
Study details
Nivolumab+AVD in Advanced-Stage Classic Hodgkin’s Lymphoma
Alex Herrera, Michael LeBlanc, Sharon Castellino et al.
Published in the New England Journal of Medicine on 16 October 2024
Abstract
Background
Incorporating brentuximab vedotin into the treatment of advanced-stage classic Hodgkin’s lymphoma improves outcomes in adult and paediatric patients. However, brentuximab vedotin increases the toxic effects of treatment in adults, more than half of paediatric patients who receive the drug undergo consolidative radiation, and relapse remains a challenge. Programmed death 1 blockade is effective in Hodgkin’s lymphoma, including in preliminary studies involving previously untreated patients.
Methods
We conducted a phase 3, multicentre, open-label, randomised trial involving patients at least 12 years of age with stage III or IV newly diagnosed Hodgkin’s lymphoma. Patients were randomly assigned to receive brentuximab vedotin with doxorubicin, vinblastine, and dacarbazine (BV+AVD) or nivolumab with doxorubicin, vinblastine, and dacarbazine (N+AVD). Prespecified patients could receive radiation therapy directed to residual metabolically active lesions. The primary end point was progression-free survival, defined as the time from randomisation to the first observation of progressive disease or death from any cause.
Results
Of 994 patients who underwent randomisation, 970 were included in the intention-to-treat population for efficacy analyses. At the second planned interim analysis, with a median follow-up of 12.1 months, the threshold for efficacy was crossed, indicating that N+AVD significantly improved progression-free survival as compared with BV+AVD (hazard ratio for disease progression or death, 0.48; 99% confidence interval [CI], 0.27 to 0.87; two-sided P=0.001). Owing to the short follow-up time, we repeated the analysis with longer follow-up; with a median follow-up of 2.1 years (range, 0 to 4.2 years), the 2-year progression-free survival was 92% (95% CI, 89 to 94) with N+AVD, as compared with 83% (95% CI, 79 to 86) with BV+AVD (hazard ratio for disease progression or death, 0.45; 95% CI, 0.30 to 0.65). Overall, 7 patients received radiation therapy. Immune-related adverse events were infrequent with nivolumab; brentuximab vedotin was associated with more treatment discontinuation.
Conclusions
N+AVD resulted in longer progression-free survival than BV+AVD in adolescents and adults with stage III or IV advanced-stage classic Hodgkin’s lymphoma and had a better side-effect profile.
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