Pembrolizumab monotherapy is an established treatment strategy for relapsed or refractory classical Hodgkin lymphoma. In combination with chemotherapy, the checkpoint inhibitor is also showing value in the front-line setting and further boosting outcomes in the relapsed setting, according to studies presented at the 2021 American Society of Hematology (ASH) Annual Meeting & Exposition.
Two studies1,2 evaluated pembrolizumab given sequentially or concurrently with doxorubicin, vinblastine, and dacarbazine (AVD) in previously untreated patients. A third study3 evaluated pembrolizumab plus ifosfamide, carboplatin, and etoposide (ICE) in relapsed or refractory disease. All of these studies showed that adding the checkpoint inhibitor to standard chemotherapy can improve outcomes.
Upfront: Sequential Pembrolizumab and AVD
A phase II trial investigated sequential pembrolizumab given for three cycles followed by AVD for four to six cycles in newly diagnosed patients.1 Outcomes after a median follow-up of 33 months, and correlative analyses, were presented by Pamela Allen, MD, MSc, of Winship Cancer Institute of Emory University, Atlanta.
Pamela Allen, MD, MSc
“Our study showed that previously untreated classical Hodgkin lymphoma is exquisitely sensitive to pembrolizumab and AVD. With extended follow-up, progression-free and overall survival rates were both 100%,” said Dr. Allen. “We also found no correlation between PD-1 pathway markers and the depth of response to the single-agent pembrolizumab lead-in.”
The study enrolled 30 newly diagnosed patients with early unfavorable and advanced-stage disease. In 47% of patients, B symptoms were present, 60% had advanced-stage disease, 33% had bulky disease, and 53% had extranodal involvement. The primary endpoint was complete metabolic response rate by positron-emission tomography/computed tomography (PET/CT) to three doses of pembrolizumab monotherapy.
Correlative studies analyzed genomic copy number alterations of chromosome 9p24.1 and PD-1 pathway expression (9p24.1 alterations increase PD-L1 and STAT expression). Investigators determined four categories of 9p24.1 alterations by fluorescence in situ hybridization (FISH), based on the target/control ratio and total copy numbers of the target per Hodgkin Reed-Sternberg cells; patients were categorized according to the highest level of the alteration.
“Many patients had a deep response to single-agent pembrolizumab, but it didn’t quite meet criteria for complete metabolic response. So, we defined a new one—near-complete metabolic response, which included patients with more than 90% decline in metabolic tumor volume,” she said.
Applying this criterion, by PET/CT, the investigators found 8 near-complete and 11 complete metabolic responses, for a total of 19 of 30 patients. And they found no correlation between clinical features and depth of response to single-agent pembrolizumab; however, bulky disease was significantly more common in patients with near-complete vs complete metabolic responses (75% vs 27%; P = .042).
“Impressively, with continued follow-up (median = 33.1 months), we continue to show 100% progression-free and overall survival, with not a single patient relapsing or dying of disease. We also had no patients dropping out due to toxicity,” Dr. Allen reported.
By FISH, all patients had some level of 9p24.1 alteration copy number gain for 50% and amplification for 50%. Median PD-L1 H score was 215, median PD-L2 H score was 20, and phosphorylated STAT3 H score was 300 (see explanation of H score below, in center column). No correlation was shown between PD-1 pathway markers and response. “Even low levels of PD-L1 expression resulted in favorable responses to pembrolizumab,” she said.
Upfront: Concurrent Pembrolizumab Plus AVD
“Although PD-1 inhibitors are very active in the relapsed or refractory setting, they do not appear to be curative in the majority of patients. Their activity and favorable safety profile make them ideal to combine with chemotherapy in the front-line setting,” said Ryan Lynch, MD, of the University of Washington/Fred Hutchinson Cancer Research Center, Seattle. Another advantage of treating patients in the upfront setting pertains to the “relatively intact host immunity and juxtaposition of malignant cells with T cells in the tumor microenvironment,” he added.
Ryan Lynch, MD
Dr. Lynch presented outcomes of newly diagnosed patients who received pembrolizumab concurrently with AVD.2 The results showed that concurrent pembrolizumab and AVD, without a pembrolizumab lead-in, was safe and effective, yielding a 96% progression-free survival rate at 1 year.
AVD was given at standard doses on days 1 and 15 of a 28-day cycle. Pembrolizumab was given at 200 mg IV starting on day 1 of cycle 1 and every 21 days thereafter. After PET2 response assessment, subjects could continue the combination for up to six total cycles as deemed appropriate. The primary endpoint was completion of at least two cycles by at least 85% of patients. The secondary endpoint was PET2 complete metabolic response (Deauville score of 1–3) after two cycles of pembrolizumab plus AVD.
Two cycles or more were completed by 29 patients. In this efficacy population, B symptoms were observed in 43%, and 50% had early-stage unfavorable disease.
“The study met its primary endpoint, as there were no treatment delays of longer than 21 days during the first two cycles,” Dr. Lynch said.
In 29 evaluable patients, PET/CT imaging after two cycles revealed complete metabolic responses in 19 and partial responses (Deauville score of 4) in 10, for a PET2 overall response rate of 100% and a complete metabolic response rate of 66%.
A total of 25 patients received two to four additional cycles of pembrolizumab plus AVD. Among the first group of partial responders, six converted to a complete response, two remained in partial response (with no evidence of disease progression), and one awaits end-of-treatment imaging. Of the 19 complete responders at PET2, complete responses were maintained; only one patient had progressive disease and underwent successful salvage therapy, making the end-of-treatment complete response rate 100%.
KEY POINTS
Expression score (range = 0–300) calculated as:
- 0 × % of nonstained tumor cells
- + 1 × % of weakly stained tumor cells
- + 2 × % of moderately stained tumor cells
After a median follow-up of 16.2 months, the 1-year progression-free survival rate was 96%, and 100% of patients were alive. “To date, no patients who interrupted or discontinued therapy due to an adverse event has had disease progression,” he added.
The main grade 3 or 4 toxicity was febrile neutropenia (17%), with other such toxicities occurring in up to 10% of patients. Six (20%) required interruption of pembrolizumab due to toxicity, primarily grade ≥ 2 transaminitis (83%), which was reversible. One patient had grade 4 transaminitis (possibly associated with high-dose cannabidiol oil). Other immune-related adverse events were mild, and all were successfully managed. Chemotherapy-related toxicities were as expected for AVD.
“Correlative studies performed on a limited sample of patients suggest that circulating tumor DNA (ctDNA) may help identify false-negative as well as false-positive PET scans,” Dr. Lynch further reported. He described one patient with stage IV disease at diagnosis who achieved a complete metabolic response after two treatment cycles but was Deauville 5 at the end of treatment and was found to have a biopsy-confirmed disease recurrence. Despite the negative interim PET scan, circulating tumor DNA (ctDNA) never cleared. Another patient with positive interim and end-of-treatment PET imaging had undetectable ctDNA after all cycles of treatment and has no evidence of disease at 15 months. Such cases suggest that ctDNA may be a more sensitive tool for detecting low levels of disease, he said.
“At this point, the utility of [fluorodeoxyglucose]-PET with PD-1 combinations is undefined. PET2 positivity is not associated with a high risk of disease relapse. Only 20% of patients with a positive end-of-treatment PET have developed recurrent disease,” he said. “We need more sensitive and specific [assessment] tools.”
Pembrolizumab Plus ICE in Relapsed Disease
In patients with relapsed or refractory disease, second-line treatment with pembrolizumab plus ICE resulted in complete metabolic responses in 88% of patients in a single-arm phase II multicenter study reported by Locke J. Bryan, MD, of the Georgia Cancer Center, Augusta.3 The complete metabolic rate after two cycles of pembrolizumab plus ICE was 86.5%, meeting the primary endpoint of improvement over historical outcomes ( ≥ 70% was expected).
As Dr. Bryan pointed out, the achievement of complete metabolic response assessed by PET/CT prior to autologous hematopoietic stem cell transplant (HSCT) predicts favorable progression-free survival and overall survival. Although the median follow-up in this study was short (27 months), these outcomes were “excellent,” he said, with 88.2% of patients progression-free and 95.1% alive.
Locke J. Bryan, MD
The regimen consisted of 21-day cycles of pembrolizumab at 200 mg intravenously on day 1 with standard ICE. Two cycles of pembrolizumab plus ICE were followed by stem cell mobilization and collection, after which one more cycle of pembrolizumab at 200 mg was administered. The primary endpoint was complete metabolic rate on PET/CT (PET2) imaging, defined as a Deauville score ≤ 3, by central review. An optional third cycle of pembrolizumab plus ICE was permitted for patients who achieved a complete metabolic response to allow for appropriate timing of the transplant.
In the study, 37 patients with relapsed or refractory classical Hodgkin lymphoma were treated. “I think it’s important to note that 39% of patients had primary refractory disease, another 32% had relapsed within 1 year, and 16% had bulky disease at enrollment, so certainly a high-risk group was treated on protocol,” he said.
Although PET2 responses showed that most patients (72%) had a Deauville score of 1 or 2, five patients (14%) had a Deauville score of 4, and two (5%) had a Deauville score of 5 (both shown not to be lymphoma).
Five patients received the optional third cycle of pembrolizumab plus ICE, with 35 of the 37 evaluable patients proceeding to autologous HSCT. Seven patients had radiation therapy as part of the conditioning regimen, and an additional four patients received consolidative radiotherapy following transplantation. The addition of pembrolizumab to ICE did not impair stem cell mobilization or engraftment.
Grade 3 or 4 adverse events occurred in 52.3% of patients, consisting of cytopenias, elevated liver enzymes, hyponatremia, hypophosphatemia, and fatigue. Five patients had severe adverse events attributed to pembrolizumab, including anemia, back pain, decreased ejection fraction, fever, and thrombocytopenia. No treatment was delayed because of an autoimmune event. Two patients died, none directly related to pembrolizumab plus AVD.
DISCLOSURE: Dr. Allen has served as a consultant to Kyowa Kirin, Secure Bio, ADC Therapeutics, MorphoSys, and Epizyme. Dr. Lynch has received research funding from Cyteir, Seagen, RAPT Therapeutics, Bayer, Incyte, Genentech, MorphoSys, TG Therapeutics, and Juno Therapeutics; and has served as a consultant to MorphoSys. Dr. Bryan reported no conflicts of interest.
REFERENCES
1. Allen P, Chen QC, Lu X, et al: Frontline treatment with single agent pembrolizumab followed by AVD chemotherapy for classic Hodgkin lymphoma: Updated results and correlative analysis. 2021 ASH Annual Meeting & Exhibition. Abstract 231. Presented December 11, 2021.
2. Lynch RC, Ujjani CS, Poh C, et al: Concurrent pembrolizumab with AVD for untreated classical Hodgkin lymphoma. 2021 ASH Annual Meeting & Exhibition. Abstract 233. Presented December 11, 2021.
3. Bryan L, Casulo C, Allen P, et al: Pembrolizumab added to ICE chemotherapy results in high complete metabolic response rates in relapsed/refractory classic Hodgkin lymphoma: A multi-institutional phase II trial. 2021 ASH Annual Meeting & Exhibition. Abstract 229. Presented December 11, 2021.
