Immune Checkpoint Inhibitors and Novel Agents Are Explored in Hodgkin Lymphoma

As the brentuximab vedotin plus AVD combination gains widespread use, clinicians should recognize the toxicities, such as the risk of neutropenic fever or peripheral neuropathy, according to Alison Moskowitz, MD.

The frontline combination of chemotherapy and radiation therapy in patients with Hodgkin lymphoma (HL) can achieve excellent responses and survival rates, but about 10% to 15% of patients will experience relapse resulting in poor outcomes.1 Improved biologic insight has led to development of novel therapies including brentuximab vedotin (Adcetris®; Seagen) and the checkpoint inhibitors nivolumab (Opdivo®; Bristol Myers Squibb) and pembrolizumab (Keytruda®; Merck).

“All 3 of these drugs are highly active in the relapsed and refractory [R/R] setting and are now being evaluated and, in some situations, routinely used in the frontline and second-line setting,” Alison Moskowitz, MD, said in an interview with The SOHO Daily News before the 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022). Moskowitz, clinical director of lymphoma at Memorial Sloan Kettering Cancer Center in New York, New York, will be addressing the role of novel agents in the frontline and second-line setting in HL on Friday, September 30, 2022, from 5:12 to 5:58 PM. Moskowitz noted that although the combination of brentuximab vedotin plus AVD (doxorubicin [Adriamycin], vinblastine, and dacarbazine) has gained widespread adoption, clinicians should be aware of the toxicities associated with the regimen.

The FDA approved brentuximab vedotin to treat adult patients with previously untreated stage III or IV classical HL in combination with chemotherapy in March 2018.2 Findings from ECHELON-1 (NCT01712490) served as the basis for the approval.3 The multicenter trial randomized 1334 patients to receive either brentuximab vedotin plus AVD or bleomycin plus AVD (ABVD).

The trial measured modified progression-free survival (mPFS), death to occur, or new therapy to be initiated in patients who did not achieve a complete response (CR). In the trial, after patients received an average of six 28-day cycles of treatment, those treated with brentuximab plus AVD were 23% less likely to experience progression, death, or initiation of new therapy compared with those receiving ABVD. There were 117 (18%) patients in the treatment arm who experienced disease progression, death, or began new therapy compared with 146 (22%) patients in the control arm. “Initially, many clinicians were hesitant about changing their practice based on those findings, but with longer follow-up we’ve seen sustained improvement in [PFS] and now improvement in overall survival [OS],” Moskowitz said.

Longer follow-up from ECHELON-1 reported that at patients who received brentuximab vedotin (A) and AVD for the treatment of stage III or IV Hodgkin lymphoma had a survival advantage over those who received ABVD.

In the trial, at a median follow-up of 73.0 months, 39 patients in the A and AVD group and 64 in the ABVD group had died (HR, 0.59; 95% CI, 0.40 to 0.88; P = .009). Investigators reported that the 6-year overall survival estimates were 93.9% (95% CI, 91.6%-95.5%) in the A and AVD group and 89.4% (95% CI, 86.6%-91.7%) in the ABVD group. Progression-free survival was longer with A and AVD than with ABVD (HR for disease progression or death, 0.68; 95% CI, 0.53-0.86).4

“These findings have led many clinicians, myself included, to change our practice in patients with newly diagnosed stage III or stage IV disease,” Moskowitz continued.

Immune Checkpoint Inhibitors

The PD-1 inhibitors nivolumab and pembrolizumab are not approved for use in the frontline setting, Moskowitz said, but ongoing clinical trials appear promising. A phase 3 randomized study (NCT03907488) of nivolumab plus AVD vs brentuximab vedotin plus AVD has almost completed patient accrual. Moskowitz said findings from the trial and other correlative studies will help identify optimal patients for each of those treatments.

Additional checkpoint inhibitor combination regimens undergoing evaluation include a regimen of pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin in the second line for R/R classic HL (NCT03618550).5 Thirty-nine patients received 2 to 4 cycles of 200 mg intravenous pembrolizumab, 1000 mg/m2 of gemcitabine, 20 mg/m2 of vinorelbine, and 15 mg/m2 of doxorubicin. In the trial, the primary end point was CR. Patients who achieved CR as determined by positron emission tomography (PET) after 2 or 4 cycles went on to high-dose therapy and autologous hematopoietic cell transplantation (AHCT). Investigators reported that the regimen was highly effective and well tolerated and may bridge patients with R/R HL to high-dose therapy and AHCT. Moskowitz was lead author on that study.

“At the time of publication, our median follow-up was only about 13 months. But now, a year after publication, we have only seen 1 patient relapse and all other patients have remained in remission,” Moskowitz said.

Combination and Sequential Therapies

Combination therapies and sequential therapies that explore immune checkpoint inhibitors and targeted therapies also have shown promise. Updated results from a phase 1/2 study (NCT02572167; n=61) that evaluated brentuximab vedotin and nivolumab reported a CR rate among all treated patients of 67% and an objective response rate of 91%.6 Once treatment was completed, patients could undergo autologous stem cell transplantation. Investigators reported that the combination of brentuximab vedotin plus nivolumab was an active, well-tolerated first salvage regimen, potentially providing patients with R/R HL an alternative to traditional chemotherapy.

In NCT03226249, investigators explored the complete metabolic response (CMR) rate and safety of sequential pembrolizumab and AVD.7 In the trial, 30 patients were treated with 3 cycles of pembrolizumab monotherapy followed by AVD for 4 to 6 cycles, depending on stage and bulk. Twelve patients had either large mediastinal masses or bulky disease (>10 cm).

After pembrolizumab monotherapy, 11 patients (37%) demonstrated CMR, and an additional 25% of patients with PET-CT had greater than 90% reduction in metabolic tumor volume. All patients achieved CMR after 2 cycles of AVD and maintained their responses at the end of treatment.

After a median follow-up of 22.5 months (range, 14.2-30.6), investigators reported no changes in therapy, progressions, or deaths. The investigators concluded that brief pembrolizumab monotherapy followed by AVD was highly effective and safe in patients with newly diagnosed classic HL, including those with bulky disease.

How Age Affects Treatment Decisions

Clinicians tend to use age as a factor that determines treatment decisions, according to Moskowitz, but the cutoff for treatment is somewhat arbitrary. Although outcomes in patients who are 60 and older are less favorable compared with younger patients, Moskowitz noted that disease biology has a role but the major contributing factor is treatment toxicity.

“Not all patients who are over 60…are the same, and there are patients who are older than 60 years who certainly would tolerate their treatment just as well as someone who is in their 40s [or] 50s,” Moskowitz said. She did emphasize the tendency to avoid using or limiting exposure to bleomycin, which can lead to higher risk of pulmonary toxicity.

A multicenter phase 2 study (NCT01476410) investigated the use of brentuximab vedotin sequentially before and after AVD for untreated patients with HL who were 60 or older.8

Thirty-seven (77%) of 48 patients completed 6 cycles of AVD, and 35 patients (73%) received at least 1 brentuximab vedotin consolidation dose. Treatment with the brentuximab vedotin lead-in dose led to an overall response rate (ORR) of 82% and CMR of 36%, respectively. After 6 cycles of AVD, the ORR was 95% and CMR was 90%, respectively.

Investigators reported that 20 of 48 patients (42%) experienced a grade 3/4 adverse event (AE) and the most common AEs were neutropenia (44%), febrile neutropenia and pneumonia (8%), or diarrhea (6%). Peripheral neuropathy (grade 2) was reported in 33% of patients, and was reversible in most patients. By intent-to-treat, the 2-year event-free survival, PFS, and OS rates were 80%, 84%, and 93%, respectively.

Moskowitz concluded that as the brentuximab vedotin plus AVD combination gains widespread use, clinicians should recognize the toxicities, such as the risk of neutropenic fever or peripheral neuropathy. Use of granulocyte colony-stimulating factor is mandated to the reduce the risk of neutropenic fevers. In addition, reducing or holding brentuximab needs to be considered when addressing peripheral neuropathy.

REFERENCES:

1. Andrade-Gonzalez X, Ansell SM. Novel therapies in the treatment of Hodgkin lymphoma. Curr Treat Options Oncol. 2021;22(5):42. doi:10.1007/s11864-021-00840-5

2. FDA expands approval of Adcetris for first-line treatment of stage III or IV classical Hodgkin lymphoma in combination with chemotherapy. News release. FDA. March 20, 2018. Accessed September 12, 2022. https://bit.ly/3L5AllK

3. Adcetris combination significantly improves overall survival in newly diagnosed patients with advanced Hodgkin lymphoma. News release. Seagen. February 3, 2022. Accessed September 12, 2022. https://bit.ly/3S0iPBM

4. Ansell SM, Radford J, Connors JM, et al. Overall survival with brentuximab vedotin in stage III or IV Hodgkin’s lymphoma. N Engl J Med. 2022; 387:310-320. doi: 10.1056/NEJMoa2206125

5. Moskowitz AJ, Shah G, Schöder H, et al. Phase II trial of pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin as second-line therapy for relapsed or refractory classical Hodgkin lymphoma. J Clin Oncol. 2021;39(28):3109-3117. doi:10.1200/JCO.21.01056

6. Advani RH, Moskowitz AJ, Bartlett NL, et al. Brentuximab vedotin in combination with nivolumab in relapsed or refractory Hodgkin lymphoma: 3-year study results. Blood. (2021) 138 (6): 427–438. doi: 10.1182/blood.2020009178

7. Allen PB, Savas H, Evens AM, et al. Pembrolizumab followed by AVD in untreated early unfavorable and advanced-stage classical Hodgkin lymphoma. Blood. 2021;137(10):1318-1326. doi:10.1182/blood.2020007400

8. Evens AM, Advani RH, Helenowski IB, et al. Multicenter phase II study of sequential brentuximab vedotin and doxorubicin, vinblastine, and dacarbazine chemotherapy for older patients with untreated classical Hodgkin lymphoma. J Clin Oncol. 2018;36(30):3015-3022. doi:10.1200/JCO.2018.79.0139