CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: April 17, 2023
Expiration: April 16, 2024
Background for Advanced-Stage cHL
To set the stage for the 2 studies in cHL that we will discuss next, I would like to mention the results from the randomized phase III ECHELON-1 trial evaluating brentuximab vedotin, a CD30-targeted antibody–drug conjugate, in combination with AVD vs doxorubicin/bleomycin/vinblastine/dacarbazine (ABVD) in previously untreated patients with stage III or IV cHL.42,43 In ECHELON-1, brentuximab vedotin plus AVD demonstrated a survival advantage vs ABVD, with a 6-year PFS rate of 82.3% vs 74.5% (HR: 0.68; 95% CI: 0.53-0.86) and a 6-year OS rate of 93.9% vs 89.4% (HR: 0.59; 95% CI: 0.40-0.88; P = .009).
We also recently completed accrual to the S1826 trial, which is a randomized trial comparing the brentuximab vedotin plus AVD regimen with nivolumab plus AVD (NCT03907488).
SGN35-027: Phase II Study of Frontline Brentuximab Vedotin/Nivolumab + Doxorubicin/Dacarbazine for Advanced-Stage cHL
Peter Martin, MD:
SGN35-027 is a multipart phase II trial of brentuximab vedotin in combination with doxorubicin and dacarbazine plus vinblastine or nivolumab for newly diagnosed patients with advanced-stage cHL (NCT03646123). In Part B, patients with treatment-naive stage II bulky mediastinal disease or stage III/IV cHL received brentuximab vedotin/nivolumab in combination with doxorubicin/dacarbazine (AN + AD). Of interest, Part B of the trial is a natural continuation to the ECHELON-1 trial regimen of brentuximab vedotin plus AVD, with the addition of nivolumab to increase efficacy but the removal of vinblastine to decrease risk of AEs—namely, neuropathy, neutropenia, and infection seen with brentuximab vedotin plus AVD.44
At ASH 2022, Lee and colleagues45 reported the efficacy and safety results from part B of SGN35-027.
SGN35-027: Baseline Characteristics
Peter Martin, MD:
In total, 57 patients were enrolled on part B of the phase II SGN35-027 trial. The median age was 35 years (range: 19-78), and the majority of patients were White (88%); 18% of patients had stage III cHL, 51% had stage IV cHL, and 48% had extranodal disease.
SGN35-027: Efficacy
Peter Martin, MD:
Although these results are from a single arm phase II trial, the clinical outcomes are pleasantly surprising and encouraging considering the patient population.
The ORR and CR rates (primary endpoint) with AN + AD were 93% and 88%, respectively, with a 12-month PFS rate of 95% in patients with advanced stage cHL. At the time of the report, 95% and 94% of patients had a DoR and duration of CR of ≥12 months, respectively. The median DoR and median duration of CR were both not reached.
SGN35-027: Safety
Peter Martin, MD:
The most important question when evaluating any new regimen is whether the benefits outweigh the risks. As mentioned, the exclusion of vinblastine has the potential to reduce peripheral neuropathy, neutropenia, and infections. Of note, a significantly lower proportion of patients on the SGN35-027 trial experienced neutropenia (all grade: 11%; grade ≥3: 9%) as compared with the ECHELON-1 trial, where the rates of any-grade and grade ≥3 neutropenia were 58% and 54%, respectively, in patients receiving bretuximab vedotin plus AVD.42,45
The rate of peripheral sensory neuropathy seen with AN + AD was still pretty significant, with 44% and 4% experiencing all-grade and grade ≥3 peripheral sensory neuropathy, respectively. However, these rates are lower than those seen with brentuximab vedotin plus AVD in the ECHELON-1 trial (all grade: 67%; grade ≥3: 11%).
Other grade ≥3 AEs seen with the AN + AD regimen on the SGN35-027 trial included fatigue (4%), increased alanine aminotransferase (12%), increased aspartate aminotransferase (4%), and pyrexia (4%). No febrile neutropenia or grade 5 AEs were observed.
AEs that are usually observed with immune checkpoint inhibitors, such as colitis and pneumonitis, are uncommon with this regimen, but they still occur. Pneumonitis may be particularly problematic and may end up being a major concern in the long term.
SGN35-027: Safety (cont'd)
SGN35-027: Clinical Implications
Peter Martin, MD:
Overall, AN + AD generated promising efficacy data and was associated with a reasonably well-tolerated safety profile. However, we need to continue to monitor some of the immune mediated AEs over time.
John M. Burke, MD:
I totally agree. In my clinical experience of treating some of the patients on this trial, I observed the emergence of nivolumab related immune mediated AEs that we are not used to seeing with typical induction regimens for cHL.
From the response rates observed with the AN + AD regimen, it is difficult to decipher whether one regimen is better than another because the response rates are so high with all available regimens. If this combination is going to move forward, a randomized trial where one of the arms is the AN + AD regimen will be needed. I do not know whether such a trial is forthcoming or planned, but I think a lot of people are waiting for the results of the National Cancer Institute’s phase III S1826 trial evaluating AVD plus nivolumab or brentuximab vedotin in newly diagnosed stage III-IV cHL (NCT03907488) to decide on the best control arm for future trials.
It is incredibly interesting that no febrile neutropenia was reported with the AN + AD regimen. It appears the tradeoff with AN + AD compared with brentuximab vedotin plus AVD is that, although the regimen results in some immune mediated AEs, it also results in a reduction of some of the other AEs related to conventional chemotherapy. As I mentioned, we ultimately will need a randomized clinical trial to determine the optimal treatment approach for these patients.
Extended Follow-up With BV + AVD in Untreated, Early-Stage, Unfavorable-Risk cHL
Peter Martin, MD:
Shifting gears away from advanced cHL, the second trial in cHL we will discuss is in early-stage, unfavorable-risk cHL.
In this open-label pilot study, patients with previously untreated early stage, unfavorable risk cHL received the same brentuximab vedotin plus AVD regimen used in the ECHELON 1 trial.42,46 After 4 cycles of brentuximab vedotin plus AVD, patients were stratified by the results of a PET/CT scan. Those with PET/CT-negative disease were enrolled on 1 of 4 sequential cohorts, which I will describe momentarily. Patients with PET/CT-positive disease who had a positive biopsy were taken off study. However, those with a negative biopsy were enrolled on 1 of the 4 sequential cohorts.
Patients on cohorts 1 and 2 had ≥1 unfavorable risk factor but varied in their level of bulky disease. Patients on cohort 1 had either >1/3 mediastinal mass ratio or disease bulk ≥10 cm by CT, and those in cohort 2 had disease bulk >7 cm in maximal transverse diameter (MTD) or maximal coronal diameter (MCD). Besides tumor bulk, the unfavorable risk factors for cohorts 1 and 2 included erythrocyte sedimentation rate (ESR) ≥50 mm/h or ESR ≥30 mm/h in patients with B symptoms, extranodal involvement, >2 lymph node sites, or infradiaphragmatic disease. All patients on cohorts 3 and 4 had disease bulk >7 cm in MTD or MCD.
Patients on cohort 1 received 30 Gy involved-site radiation therapy (ISRT), whereas those in cohort 2 received 20 Gy ISRT. For patients on cohort 3, radiation was administered to the consolidation volume post induction rather than to the original involved sites. Hence, patients on cohort 3 received 30 Gy consolidation volume radiotherapy, which represents a smaller or more focused dose of radiation. Patients on cohort 4 did not receive any radiation therapy. In essence, across the 4 patient cohorts, radiation was administered in a de-escalating dose manner.
The extended efficacy results of this study after a median follow-up of 4.6 years were presented at ASH 2022.46
BV + AVD in Early cHL: Baseline Characteristics
Peter Martin, MD:
In the overall population of 117 patients, the median age was 32 years, and 98% of patients had stage II disease. Except for cohort 4, in which only 11 (38%) of the patients were males, the remaining cohorts included 50% to 59% males. The main difference in the unfavorable risk factors among patients on the 4 cohorts was the bulk of the disease, and 23 (77%), 20 (69%), 29 (100%), and 29 (100%) of the patients on cohorts 1, 2, 3, and 4, respectively, had MTD or MCD of the largest mass >7 cm. In the overall patient population, 52% had elevated ESR, 39% had B symptoms, and 21% had extranodal involvement. In addition, for 56% of the patients, >2 lymph node sites were involved. Only 3.4% of the patients had infradiaphragmatic disease.
BV + AVD in Early cHL: PFS by Cohort
Peter Martin, MD:
Overall, patients on all of the 4 cohorts appear to have done quite well. After a median follow-up of 4.6 years, the 4- year PFS rates were 93.1%, 96.6%, 89.7%, and 92.5% for cohorts, 1, 2, 3, and 4, respectively. The median PFS has not yet been reached in any of the cohorts.
BV + AVD in Early cHL: PFS by Baseline MTV and PET2
Peter Martin, MD:
Of interest and unexpectedly, the baseline metabolic tumor volume (MTV) was associated with PFS outcome, as was PET scan after 2 cycles of chemotherapy (PET2) status. The 4-year PFS rate for patients with a low baseline MTV was 100%, whereas that for patients with a high baseline MTV was 91%. Among patients who achieved PET2 negativity, the 4-year PFS rate was 95% compared with 79% for patients with PET2-positive disease.
BV + AVD in Early cHL: PFS by Combined MTV/PET2 and Relapse Status
Peter Martin, MD:
The lowest 4-year PFS rate of 60% was achieved in patients with PET2-positive disease who had a high baseline MTV. Of note, the 4-year PFS rate among patients with a high MTV who achieved PET2 negativity was 95%, which is nearly as high as that for patients with low baseline MTV. For all patients with low baseline MTV regardless of PET2 status, the 4-year PFS rate was 100%. Among this group of patients, it is important to note that those who were PET2 positive may have had false positive PET scans.
Only 4 patients experienced disease progression: 2 patients with MTV-high/PET2-negative disease and 2 patients with MTV-high/PET2-positive cHL. Both patients with MTV-high/PET2-negative disease received salvage therapy and went on to ASCT, whereas both patients with MTV-high/PET2-positive disease received salvage therapy followed by radiation and ASCT.
BV + AVD in Early cHL: Clinical Implications
Peter Martin, MD:
Reducing the amount of radiation received is always a consideration in the management of patients with early-stage cHL, so I think this is an interesting trial. Clearly, there are newer ways to deliver radiation beyond what has been done in the past. Really, this trial is the first to evaluate radiation therapy in a systematic way, and it makes sense to try to add one of the newer agents, such as brentuximab vedotin, to the AVD regimen to see if it is possible to exclude bleomycin in the combination to reduce the pulmonary toxicity and improve outcomes.
Overall, the brentuximab vedotin plus AVD regimen appeared to produce promising efficacy data. Of importance, however, these data are from a small trial in a population of patients who generally do very well anyway. Therefore, it is going to take larger studies and randomized trials to see what we should be doing differently for patients with early stage, unfavorable-risk cHL.
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