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Novel frontline treatment approaches, including PET-adapted therapy and BEACOPP-based regimens, have contributed to the improvement of disease control and treatment tolerability for patients with Hodgkin lymphoma (HL) in recent years; however, they have not shown a meaningful overall survival (OS) advantage.1 Additionally, an estimated 10–30% of patients experience disease progression or are refractory to first-line treatment.2 The introduction of novel immunotherapies, such as antibody–drug conjugates (ADCs) and checkpoint inhibitors, either as monotherapy or in combination with chemotherapy, have changed clinical practice and are paving the way for the treatment of patients with HL in the frontline and relapsed and refractory (R/R) settings.3
In this educational theme article, we highlight the latest advances in the treatment of HL presented at the European Hematology Association (EHA) 2022 Congress. For frontline therapeutics, we will look at two treatment studies: a 6-year analysis of the ECHELON-1 study examining first-line brentuximab vedotin plus chemotherapy in adult patients with Stage III or IV HL (NCT01712490); and pembrolizumab plus chemotherapy in children and young adults with newly diagnosed classical HL (cHL) with a slow early response (SER) to frontline chemotherapy (KEYNOTE-667; NCT03407144).1,4 For R/R HL, we will report on the updated efficacy and safety results of a phase II study examining camidanlumab tesirine in patients with R/R HL (NCT04052997) and an interim analysis of the international GHSG phase II AERN trial, evaluating the abscopal effect of radiotherapy (RT) and nivolumab (NCT03480334).5,6
In the primary analysis of the phase III ECHELON-1 study, published in New England Journal of Medicine and reported on the Lymphoma Hub, the ADC BV plus doxorubicin, vinblastine, and dacarbazine (AVD) chemotherapy provided superior efficacy compared with standalone doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). The 2-year modified progression-free survival (PFS) was 82.1% vs 77.2% for AVD vs ABVD, respectively.1
The 5-year follow-up analysis of ECHELON-1, also reported on the Lymphoma Hub, demonstrated a sustained overall PFS of 82.2%.
The focus of the 6-year follow-up, presented by John Radford,1 was the key secondary endpoint of an alpha-controlled, event driven analysis of OS. Other endpoints included longer-term safety updates (including specified PFS carried out by the investigator), subsequent treatment use, second malignancies, outcomes of pregnancy among patients and their partners, and peripheral neuropathy (PN) resolution and improvement rates.
There was a significant improvement in OS for BV + AVD over ABVD at the 6-year mark (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.396–0.879; p = 0.009), translating to a 41% reduction in risk of death. The 6-year estimated OS rates for BV + AVD and ABVD were 93.9% and 89.4%, and the OS events were 39 and 64, respectively. Consistent with the 5-year follow-up results, the 6-year analysis showed an improved PFS for BV + AVD vs ABVD (PFS, 82.3% vs 74.5%; HR, 0.68; 95% Cl, 0.53–0.86) that translated to a 32% reduction in risk of progression or death.
In terms of the safety profile, fewer patients in the BV + AVD arm died from HL and disease or treatment-related complications (n = 39) in comparison with the ABVD arm (n = 64). Although comparable, the use of subsequent therapy was slightly less common in the BV + AVD arm compared with the ABVD arm at 20% and 24%, respectively. The number of pregnancies and live births was higher among patients treated with BV + AVD compared with ABVD, with 49 vs 28 pregnancies and 56 vs 23 live births, respectively. Although the incidence of PN was higher in the BV + AVD arm than the ABVD arm at completion of therapy, the recovery rate in both arms was very good at the 6-year follow-up; PN continued to resolve or improve in 86% of cases for BV + AVD and 87% of cases for ABVD. For patients experiencing persisting PN symptoms, the majority were low grade—either Grade 1 or 2.
Pembrolizumab is a U.S. Food and Drug Administration (FDA) approved treatment for adults and pediatric patients with R/R cHL that is now under investigation as a frontline therapy.4 At EHA2022, Luciana Vinti4 presented the interim analysis results of the phase II KEYNOTE-667 study evaluating the safety and efficacy of sequential pembrolizumab and chemotherapy use in pediatric patients with high-risk cHL and SER to initial chemotherapy.
The focus of this analysis was patients in Group 2, who received an induction of two cycles of vincristine, etoposide, prednisone/prednisolone, and doxorubicin (OEPA) followed by non-study therapy in patients with a rapid early response and four cycles of cyclophosphamide, vincristine, prednisone/prednisolone, and dacarbazine (COPDAC-28) plus pembrolizumab at 2 mg/kg every 3 weeks, totaling 17 infusions in patients with an SER. All patients with PET-positivity at late-stage PET response assessment received RT, and those with PET-negativity received maintenance pembrolizumab for a total of 17 doses.
The primary endpoint was the overall response rate (ORR), determined by an International Working Group criteria and assessed by a blinded independent central review in patients with SER. The secondary endpoints included PET-negativity after consolidation, event-free survival (EFS), OS, details of RT, and safety.
Of the 30 patients with high-risk SER, 25 patients (83%) responded at the late response assessment, of which 17 patients (68%) achieved PET-negativity. For safety, 23 (77%) adverse events were reported, the majority Grade 1 or 2; six patients experienced Grade ≥3 events, and three patients experienced a serious adverse event.
The initial phase I trial of the ADC camidanlumab tesirine, reported on the Lymphoma Hub, demonstrated its effectiveness in patients with R/R cHL, with an ORR of 70% and a complete response (CR) rate of 40%; however, it had a significant toxicity profile. The phase II results, also reported on the Lymphoma Hub, achieved an ORR of 66% and a CR of 27.7%, with no new safety signals reported; however, the incidence of Guillain–Barré syndrome (GBS) was still of concern.
Here, we focus on the updated phase II efficacy and safety results in heavily pretreated adult patients with R/R cHL, as presented by Carmelo Carlo-Stella.5 The primary endpoint was ORR as assessed by a central review and secondary endpoints included duration of response (DOR), PFS, and safety. ORR was 70.1% (82/117) with a CR of 33.3% (39/117). Patients who received prior hematopoietic stem cell transplantation achieved a higher ORR of 74% than those who had not (63%). There was an overall median DOR of 13.7 months in all responders, 14.5 months for patients with CR, and 7.9 months in those with partial response (PR). The median PFS in all treated patients was 9.1 months, with a median follow-up of 10.7 months, and the PFS for patients with CR and PR was 15.8 months and 9 months, respectively.
For safety, all-grade treatment-emergent adverse events (TEAEs) occurred in ≥25% patients, including fatigue (38.5%), maculopapular rash (32.5%), pyrexia (29.9%), nausea (27.4%), and rashes (26.5%). Grade ≥3 TEAEs, observed in ≥5% patients, included thrombocytopenia (9.4%), anemia (8.5%), hypophosphatemia (7.7%), maculopapular rash (6.8%), and lymphopenia (5.1%). The pyrrolobenzodiazepine-associated TEAEs at any grade and Grade ≥3 were skin/nail reactions (any grade, 74.4%; Grade ≥3, 20.5%), hepatobiliary test abnormalities (any grade, 29.1%; Grade ≥3, 36.8%), and edema/effusion (any grade, 17.1%; Grade ≥3, 0).
Serious TEAEs and fatal TEAEs occurred in 46 patients (39.3%) and four patients (3.4%), respectively. There were instances of immune-related TEAEs in 38 patients (32.5%), with ten patients (8.5%) experiencing Grade ≥3 immune-related AEs. This included two patients each (1.7%) for diabetic ketoacidosis/Type 1 diabetes, drug-induced liver injury, and tubulointerstitial nephritis; and one patient each (0.9%) for aplastic anemia, autoimmune hemolytic anemia or hepatitis, and lichenoid keratosis.
GBS was closely investigated given its previous occurrence in the phase I study. Overall, eight patients (6.8%) experienced GBS; four patients fully recovered, three patients experienced ongoing GBS that reduced to Grade 1, and one patient died from sepsis.
Anti-PD-1 checkpoint inhibitors, such as nivolumab, have proven highly efficacious in clinical trials and have therefore been FDA approved for the treatment of patients with R/R cHL; however, patients often develop progressive disease. Local RT has been shown to induce systemic antitumor activity through an immune-mediated effect called the abscopal response, which could be amplified by the association of an anti-PD-1 blockade.6 Therefore, it has been postulated that nivolumab and RT in combination could work together to produce an antitumor effect. Paul Bröckelmann6 presented an interim analysis of the phase II AERN trial, evaluating the efficacy and safety of nivolumab and RT in patients who relapse following anti-PD-1 treatment.
The primary endpoint of the study was the abscopal response rate (ARR) at first interim restaging, after 4–6 nivolumab infusions + 20 Gy local RT. The secondary endpoints included the overall ARR, ORR, PFS, DOR, OS, and safety. In nine evaluable patients at the first interim restaging, ARR was 56% and the primary endpoint was met, meaning that enrolment could continue. CR was not observed, but five patients achieved a PR (ORR, 56%). Most patients experienced a substantial reduction in the tumor burden, with a median sum of the products of the longest perpendicular diameter reduction of −57.44% (−81.2 to −10.36) from baseline. The 1-year PFS was 42.3% with a median observation time of 15.5 months.
Overall, the treatment was well tolerated, with most toxicities being Grade 1/2. The most common event was skin related (55%). There was only one Grade ≥3 toxicity (gastrointestinal mucositis), and no Grade 4/5 toxicities were observed.
The four studies highlighted above demonstrate the promising therapeutic options for the future of cHL treatment, both in the frontline setting and for patients with R/R cHL.
For frontline treatment, pembrolizumab in combination with COPDAC-28 for pediatric patients produced a high PET-negative response and a favorable safety profile. In adult patients with advanced stage cHL, BV + AVD showed a significant OS benefit over the standard ABVD, with a substantial reduction in the risk of death, and adverse events were manageable.
With a high ORR in heavily pretreated and highly R/R patients with cHL after BV and PD1 failure, camidanlumab tesirine demonstrated durable efficacy and, despite the continued incidence of GBS, no new safety signals were observed. Treatment with nivolumab and RT led to an overall ARR and ORR of 56% in patients with R/R cHL and was well tolerated.
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