Second-Line Pembrolizumab Plus Gemcitabine, Vinorelbine, And Liposomal Doxorubicin Demonstrates Efficacy in R/R Classical Hodgkin Lymphoma

The combination of second-line pembrolizumab (Keytruda) plus gemcitabine, vinorelbine, and liposomal doxorubicin (GVD) can be a successful therapy to bridge patients with relapsed/refractory classical Hodgkin Lymphoma to high-dose therapy and autologous hematopoietic cell transplantation (HDT/AHCT), according to findings from a phase 2 study (NCT03618550).

Among the evaluable patients included in the study who received pembrolizumab/GVD, investigators reported an overall response rate (ORR) of 100% (95% CI, 91%-100%), including a complete response rate of 95% (95% CI, 82%-99%) . In total, 95% of evaluable patients (n = 36/38) went on to receive HDT/AHCT following 2 (n = 30) or 4 (n = 6) cycles of chemotherapy. Among these patients, 2 received pre-HDT/AHCT site radiation, while 13 (33%) received post-HDT/AHCT brentuximab vedotin (Adcetris) maintenance therapy. All 36 patients are in remission after a median post-transplant follow-up of 13.5 months (range, 2.66-27.06).

“This phase II study of [second-line therapy] SLT with pembrolizumab plus GVD for [relapsed/refractory classical Hodgkin lymphoma] showed high efficacy, good tolerability, and high rate of HDT/AHCT completion,” the study’s investigators wrote.

Investigators enrolled 39 patients on the study, 41% of whom had primary refractory disease and 38% had relapsed within the first year of completing frontline therapy. The most common frontline therapies included doxorubicin, bleomycin, vinblastine, and dacarbazine.

Patients were treated with 200 mg of intravenous pembrolizumab on day 1; 1000 mg/m2 of gemcitabine on days 1 and 8; 20 mg/m2 of vinorelbine on days 1 and 8; and 15 mg/m2 of liposomal doxorubicin on days 1 and 8. Additionally, growth factor support with pegfilgrastim (Neulasta) or an equivalent drug was administered on day 6 of each 21-day cycle.

A total of 38 of 39 patients were eligible for efficacy analysis, with 1 patient being excluded due to the presence of composite lymphoma. Among those eligible for response assessment, 92% (n = 35), achieved a CR after 2 cycles of treatment with pembrolizumab/GVD and 8% (n = 3) achieved partial response (PR). Additionally, 8 patients received 2 additional cycles of the pembrolizumab combination, including 3 who had an initial PR, and 4 patients with an initial CR that required a delay of HDT/AHCT due to COVID (n = 3) or personal reasons (n = 1). After 4 cycles of pembrolizumab/GVD, 1 patient’s response improved from a PR to a CR, 2 patients had a continued PR, and 4 patients had a sustained CR.

In total, 2 patients received pre-HDT/AHCT involved site radiation, 1 of whom had bulky disease and CR after 2 cycles of treatment with pembrolizumab/GVD, and another had a PR after 4 cycles of pembrolizumab/GVD. After undergoing HDT/AHCT, 33% of patients received either maintenance from brentuximab vedotin (n = 12), or brentuximab vedotin plus nivolumab (Opdivo; n = 1, on a clinical trial) for a median of 5 cycles (range, 1-11). Of the 2 patients who did not proceed with HDT/AHCT, 1 achieved a CR after 2 cycles of treatment and withdrew due to personal reasons and the other declined HDT/AHCT and received off-study pembrolizumab monotherapy. The second patient has been in remission for 16 months after completing treatment with pembrolizumab/GVD.

After a median follow-up at 13.5 months after HDT/AHCT, with all patients were alive and in remission. After treatment, 5 patients developed fluorodeoxyglucose-positron emission tomography-avid abnormalities, but biopsies did not demonstrate classical Hodgkin lymphoma.

In terms of safety, investigators did not report any dose limiting toxicities. Most patients had AEs of grade 1 or 2, although some grade 3 AEs included rash (n =1), elevated aspartate aminotransferase /alanine aminotransferase (n = 4), mucositis (n = 2), neutropenia (n = 4), and hyperthyroidism (n =1). All infusion reactions (n = 8) were related to treatment with liposomal doxorubicin. Reactions occurred with the first dose and improved with the additional administration diphenhydramine and slowing the rate of liposomal doxorubicin. Only 1 patient reported serious AEs and was admitted for nausea, vomiting, and diarrhea due to thyroiditis.

Additionally, immune-related AEs included hyperthyroidism (n = 5), transaminitis (n = 16), and rash (n = 19). Hyperthyroidism occurred during the first 2 cycles of treatment for 5 patients, 2 of whom recovered and 3 developed subsequent hypothyroidism but remained stable on levothyroxine (Synthroid). Those who had grade 3 events with transaminitis and rash were treated with steroids or treatments delays.

In total, 23% of patients (n =9), had a treatment delay lasting a median of 6 days. Reasons for delaying treatment included transaminitis (n = 4), rash (n = 1), mucositis (n = 1), neutropenia (n = 1), and upper respiratory infection (n = 2). Two patients had dose reductions, 1 had a 20% reduction of gemcitabine during cycle 2 on day 8 for transaminitis, and the other had a 25% reduction of GVD during cycle 4 of day 8 for grade 3 mucositis. No patient required delays or reductions more than once.

Reference

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. Published Online June 25, 2021. doi:10.1200/JCO.21.01056