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Anti-PD-1 Drugs Impress as Frontline Therapy for Early, Unfavorable Hodgkin's

— 3-year PFS of 99%, OS of 100% with nivolumab-chemo, high response rate with pembrolizumab

Ƶ MedicalToday

NEW ORLEANS -- Patients with early unfavorable-risk Hodgkin lymphoma had near-perfect 3-year survival outcomes following concurrent or sequential treatment with nivolumab (Opdivo) and chemotherapy, a prospective phase II study showed.

After a median follow-up of 40 months, the 3-year progression-free survival (PFS) rate was 99% and the 3-year overall survival (OS) rate was 100%. No secondary malignancies had been reported, and no new safety signals had emerged. Global quality of life improved or did not deteriorate during follow-up, reported Paul J. Bröckelmann, MD, of the University of Cologne in Germany.

"The efficacy is outstanding in this setting, and especially patients who are given a PR [partial response] do not seem to have disease activity and convert to a CR [complete response] during follow-up," Bröckelmann said during the American Society of Hematology annual meeting. "We are happy to report ... that most toxicities are temporary and of grade 1 and 2."

"We need to take all of this together and [ask whether] all of our patients need anti-PD-1 blockade plus a nearly full course of chemo and radiotherapy," he added. "This is what we want to address in the upcoming trial, looking at individualized immunotherapy in early-stage unfavorable Hodgkin lymphoma."

A second study involving untreated early-stage unfavorable-risk or advanced classic Hodgkin lymphoma treated with pembrolizumab (Keytruda) and chemotherapy showed a PET-negative (Deauville 1-3) rate of 84% in an analysis of the first 50 patients in an ongoing trial. Treatment-related adverse events (TRAEs) were mostly grade 1/2 and more often related to the chemotherapy, reported Ranjana H. Advani, MD, of Stanford Cancer Center in California.

Bröckelmann reported updated results from the multicenter phase II , conducted in Germany. A preliminary report published 2 years ago showed that all but two of 105 evaluable patients responded to nivolumab administered concurrently or sequentially with AVD (doxorubicin, vinblastine, and dacarbazine) chemotherapy. The update focused on PFS, OS, and toxicity and was published simultaneously in the .

The trial involved a total of 109 patients with early unfavorable classic Hodgkin lymphoma. The patients were randomly assigned to four cycles of concurrent or sequential nivolumab and AVD, followed by involved-site radiotherapy. The previously reported primary analysis showed that more than 90% of patients in each treatment arm achieved a CR by the end of treatment. Bröckelmann said no additional survival events occurred during follow-up.

The patients randomized to concurrent therapy had a 3-year PFS rate of 100%. The sequential group had a 3-year PFS rate of 98%. Both groups had a 3-year OS rate of 100%.

Minimizing Toxicity

During follow-up, three-fourths of patients had at least one adverse event (AE), most of which were grade 1/2. No patients had grade >1 cardiac events, and 95% of patients had a normal left ventricular ejection fraction. Grade 3 adverse events (AEs) occurred in 9% of patients in both arms combined (no grade 4 AEs). Only 5% of patients required corticosteroids, and a fourth of the patients required long-term non-steroid medication for AEs. At last follow-up visit, no patients required corticosteroids, and 15% remained on non-steroid medications.

Hypothyroidism was the most common grade 2 AE (21%) and also the most common nivolumab-related AE, requiring long-term medication in a majority of cases. Women accounted for almost 90% of the patients who developed hypothyroidism.

The follow-up study to NIVAHL, called , will use the PD-1 inhibitor tislelizumab, and treatment will be driven by PET imaging. All patients will begin with two doses of tislelizumab. Patients who achieve PET-negative status at the point will receive four additional doses of the PD-1 inhibitor. Those who are not PET negative will receive four doses of tislelizumab plus chemotherapy. Involved-site radiotherapy will be reserved for patients who remain PET positive after chemotherapy.

"We want to try to get rid of most of the chemotherapy in this setting," Bröckelmann said during the discussion that followed his talk. "We have striking early responses clinically, but also with our correlative studies, to single-agent anti-PD-1, and histologic remission is observed and also reversion of the peripheral immune landscape. We feel confident that two doses of tislelizumab can actually induce some sort of complete remission. This is the rapidly and excellently responding patient population where we can try to de-escalate."

PET-Adapted Pembrolizumab-Chemo

Advani reported preliminary findings from the study, which involved a mix of patients with newly diagnosed, early unfavorable, and advanced-stage classic Hodgkin lymphoma. Treatment consisted of pembrolizumab followed by AVD. A of the regimen showed that the median PFS or OS had yet to be reached after a median follow-up of 33 months. No disease progression or deaths had occurred, and no patient discontinued early because of toxicity.

The ongoing KEYNOTE-C11 is evaluating a PET-adapted regimen of sequential therapy with the PD-1 inhibitor plus chemotherapy, followed by pembrolizumab consolidation in early-stage unfavorable or advanced-stage classic Hodgkin lymphoma. Radiotherapy is omitted in all cases. Investigators have enrolled a total of 146 patients, and Advani presented results from a prespecified interim futility analysis involving the first 50 patients enrolled and treated.

All patients received pembrolizumab and AVD chemotherapy, followed by a PET scan. Patients who were PET negative received additional AVD. PET-positive patients received escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine [Oncovin], procarbazine, and prednisone) chemotherapy. All patients received pembrolizumab consolidation therapy. The 50 patients included in the interim analysis had completed all chemotherapy, 47 treated only with AVD and three who received BEACOPP.

The 146-patient study population consisted of 62 with early unfavorable disease and 84 with advanced disease, including 32 patients with bulky disease at diagnosis.

Seven of the 50 patients had PET-positive results at the end of treatment, and 42 had negative findings. The remaining patient had discontinued.

During initial pembrolizumab, 80% of the 146 patients experienced AEs: 64% had TRAEs, 12% had grade ≥3 TRAEs, and 5% discontinued because of TRAEs. Among 116 patients who received AVD, 76% had AEs of any grade, 64% had TRAEs, 54% had grade ≥3 TRAEs, and no patients discontinued.

The most common pembrolizumab-related AEs were pyrexia, pruritus, elevated alanine transaminase levels, and hyperthyroidism. Most of the AEs were grade 1/2. The most common AEs during AVD were nausea, decreased neutrophil count, and neutropenia.

"Mid-treatment, this PET-adapted regimen showed promising antitumor activity and no safety concerns," said Advani. "Per study design, patients are continuing with planned therapy. Pembrolizumab induction followed by chemotherapy may be an effective treatment option in patients with newly diagnosed, early unfavorable, or advanced-stage classic Hodgkin lymphoma."

  • author['full_name']

    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined Ƶ in 2007.

Disclosures

The NIVAHL study was sponsored by the University of Cologne and supported by Bristol Myers Squibb.

Bröckelmann disclosed relationships with BeiGene, Bristol Myers Squibb, Celgene, Merck Sharp & Dohme, and Takeda.

KEYNOTE-C11 is supported by Merck.

Advani disclosed relationships with ADC Therapeutics, Cyteir, Daiichi Sankyo, Gilead Sciences, Merck, Regeneron, Roche, Seattle Genetics, Bristol Myers Squibb, Epizyme, Incyte, and Sanofi.

Primary Source

American Society of Hematology

Bröckelmann PJ, et al "Nivolumab and AVD in early-stage unfavorable Hodgkin lymphoma: Follow-up from the GHSG phase II NIVAHL trial" ASH 2022; Abstract 729.

Secondary Source

American Society of Hematology

Advani RH, et al "Pembrolizumab and chemotherapy in newly diagnosed, early unfavorable or advanced-stage classic Hodgkin lymphoma: The phase II KEYNOTE-C11 study" ASH 2022; Abstract 731.