Brentuximab Vedotin and Nivolumab Explored in Frontline Hodgkin Lymphoma Regimen

Stephen M. Ansell, MD, PhD, professor of medicine at Mayo Clinic

Stephen M. Ansell, MD, PhD

The addition of the antibody-drug conjugate (ADC) brentuximab vedotin (Adcetris) and the PD-1 inhibitor nivolumab (Opdivo) to chemotherapy in patients with stage I/II Hodgkin lymphoma is under investigation in an ongoing phase II trial (NCT03233347).¹

“Novel agents, such as the anti-CD30 ADC brentuximab vedotin and PD-1 blocking antibodies, that are effective in patients with relapsed/refractory Hodgkin lymphoma, are now being tested as part of initial therapy,” said Stephen M. Ansell, MD, PhD, professor of medicine, of Mayo Clinic in a statement to OncLive.

The rationale to combine the chemotherapy regimen comprised of doxorubicin hydrochloride, vinblastine, and dacarbazine (AVD) with brentuximab vedotin is based on prior data demonstrating that these agents work together in different ways to stop the growth of cancer cells. By pairing this regimen with a targeted agent such as nivolumab, investigators hope to interfere with the ability of the cancer cells to propagate by boosting immune system response.

In the trial, patients will be administered intravenous (IV) AVD as well as IV brentuximab vedotin on days 1 and 15. Treatment will be repeated every 28 days for 3 cycles in the absence of progressive disease or unacceptable toxicity.

Patients who are PET-positive after the initial 3 cycles of treatment will receive IV brentuximab vedotin plus nivolumab on day 1; this treatment is to be repeated biweekly for 4 cycles, in the absence of disease progression or unacceptable toxicity. This will then be followed by nivolumab consolidation therapy, which will be administered every 2 weeks for 8 cycles.

If patients are PET-negative after the initial cycles of treatment, they will receive IV nivolumab as consolidation therapy on day 1; this treatment will be repeated every 2 weeks for the duration of 8 cycles in the absence of progressive disease or unacceptable toxicity.

“With this risk-adapted approach, the hope is that patient outcomes will be improved, and that toxicity of treatment will be diminished,” explained Ansell. “If this is a positive trial, the addition of novel agents to treatment may allow us to provide less chemotherapy and possibly omit radiation treatment in patients with early-stage disease.”

The primary endpoint of the trial is 3-year progression-free survival (PFS) rate, while key secondary endpoints include 3-year overall survival (OS) rate; the percentage of patients who are PET-positive versus those who are PET-negative after 3 cycles of AVD plus induction brentuximab vedotin; and 3- and 5-year PFS and OS rates, separately, for patients who are PET-negative versus PET-positive after 3 cycles of AVD/brentuximab vedotin induction therapy followed by nivolumab consolidation therapy.

Other key endpoints include time to progression, evaluating overall response rates and the number of patients who were able to convert to a complete response after consolidation therapy after having achieved a partial response at the end of induction therapy, and toxicity and tolerability of AVD plus brentuximab vedotin followed by nivolumab consolidation therapy.

After completion of study treatment, patients will be followed up at 4 and 8 weeks, every 3 or 6 months for the duration of 2 years, and then once annually for 3 years.

“This is an interesting trial and trial design that will likely answer issues related to toxicity/safety,” Anas Younes, MD, a medical oncologist, of Memorial Sloan Kettering Cancer Center said in a statement to OncLive. “However, given the recently reported data with A+AVD in early-stage classic Hodgkin lymphoma by 3 independent groups, the added value of nivolumab in the context of this study design and number of patients will be difficult to assess—especially in the PET-negative patients.”

The trial is enrolling previously untreated patients between 18 and 60 years of age with stage I or II nonbulky classical Hodgkin lymphoma who have measurable disease ≥1.5 cm as assessed by CT, and an ECOG performance status ranging from 0 to 2.

Notably, pregnant or nursing women as well as men or women of childbearing potential who are unwilling to use adequate contraception are not eligible for enrollment. Furthermore, patients who have received prior therapies, such as involved field radiation therapy, those who have bulky disease, defined as a nodal mass measuring ≥10 cm by CT, or those with known CNS involvement are also ineligible to participate.

Sites in California, Minnesota, Nebraska, New Jersey, North Carolina, Pennsylvania, Tennessee, Texas, and Washington are in the process of recruiting patients. The estimated primary completion date is August 1, 2023, while the estimated study completion date is August 7, 2024.

“Additionally, we know that ABVD is probably a little less toxic overall than AVD + [brentuximab vedotin] as far as neuropathy and myelosuppression, at the expense of slightly more lung toxicity, and ABVD in early-stage nonbulky disease is already associated with very high cure rates, so I am not sure that this trial will move the needle very far towards the incorporation of brentuximab vedotin into the management of frontline early-stage classical Hodgkin lymphoma,” said Matthew Genyaeh Mei, MD, assistant clinical professor, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, said in a statement to OncLive. “Consolidation nivolumab probably has less long-term side effects than radiation therapy and is an interesting concept worthy of further study.”

Brentuximab vedotin was approved by the FDA in March 2018 for use in combination with chemotherapy as a frontline treatment for adult patients with stage III or IV classic Hodgkin lymphoma based on findings from the ECHELON-1 trial.² In the trial, brentuximab vedotin plus AVD showed superior PFS over AVD plus bleomycin.

The agent also has indications in Hodgkin lymphoma after progression on autologous stem cell transplant or 2 prior chemotherapy treatments, in systemic anaplastic large cell lymphoma (ALCL) after disease progression on 1 prior chemotherapy treatment, primary cutaneous ALCL and CD30-expressing mycosis fungoides in those who have received prior systemic therapy, and previously untreated ALCL or other CD30-expressing peripheral T-cell lymphomas.

References

1. Doxorubicin hydrochloride, vinblastine, dacarbazine, brentuximab vedotin, and nivolumab in treating patients with stage I-II Hodgkin lymphoma. NIH US National Library of Medicine. Last updated June 11, 2019. Accessed September 23, 2019. https://bit.ly/2mBnO2j.
2. Connors JM, Jurczak W, Straus DJ, et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med. 2018;378(4)331-334. doi: 10.1056/NEJMoa1708984.