PD-1 Inhibitor Improves Outcomes in NHL Subtype

Treatment with PD-1 inhibitor toripalimab along with radiation therapy improves outcomes in patients with stage I/II extranodal NK/T cell lymphoma who don't achieve a complete response to initial chemotherapy, while pretreatment mutational profiles offer clues as to which patients may respond to such anti-PD-1 treatments, according to studies presented at the European Society of Medical Oncology (ESMO) Congress 2023.

"We found that toripalimab combined with radiotherapy is safe and has promising efficacy for stage I/II extranodal NK/T cell lymphoma [patients] who have poor response after previous standard chemotherapy," said first author Ming Jiang, MD, of the department of medical oncology, Cancer Center, West China School of Medicine/West China Hospital of Sichuan University, Chengdu, China.

"This combined strategy can not only improve patient efficacy but also avoid unnecessary medication, and is worth further exploration," she said in a presentation at ESMO on Oct. 27 in Madrid. The current standard of care for extranodal NK/T cell lymphoma, a subtype of non-Hodgkin lymphoma, is L-asparaginase or pegaspargase-based multi-agent chemotherapy combined with radiotherapy.

However, for patients who fail to respond to first-line treatment, the prognosis is poor: The median progression-free survival of those patients is approximately 4.5 months, with a median overall survival of about 6.4 months, Dr. Jiang explained.

"There is a need to establish a better first-line treatment for this group of patients," she said.

In the prospective, single-arm, multicenter phase 2 study, Dr. Jiang and her colleagues enrolled patients with stage 1 and 2 extranodal NK/T cell lymphoma who had failed to achieve a complete response following 2-3 cycles of multi-agent chemotherapy.

Of the patients, eight (36.4%) had partial response, eight (36.2%) had stable disease, and six (27.2%) had progressive disease after the chemotherapy.

The patients were treated with toripalimab at 240 mg, once every 3 weeks, plus radiotherapy at a dose of 56 Gy, sequentially with or without two to four cycles of chemotherapy.

Patients who did not have disease progression were then continued with toripalimab for 1 year or until disease progression or intolerable toxicity.

The 22 patients had a median age of 45 (range 26-64) and 14 were male. Most were stage 1 (77.3%; 17) and the remaining were stage 2, while 81% had primary tumor invasion.

For the primary endpoint, at 3 months following radiotherapy, the overall response rate was 90.9%, with 17 patients (77.3%) having a complete response, 3 (13.6%) a partial response, and 2 (9.1%) having progressive disease.

Eight who had responded to previous chemotherapy received two additional chemotherapy cycles after completion of radiotherapy, while the others were treated with toripalimab alone.

With a median follow-up of 23 months (range 3-78), the 2-year progression-free survival was 81.6%, and overall survival was 95.0%.

Two of three patients with a partial response had a recurrence after radiotherapy at 5 and 10 months; one of the complete-response patients had a recurrence at 60 months, and two patients with progressive disease died at 9 months after radiotherapy.

In terms of safety, the most common adverse events during and after radiotherapy included oral mucositis and hypothyroidism. No adverse events of grade 3 or higher were reported.

Dr. Jiang speculated that "radiotherapy could synergize PD-1 inhibitors," and she urged that "optimal radiotherapy and PD-1 inhibitor administration plans should be further explored."

Genetic factors

Additional research presented in that ESMO session offered insights into the genetic factors that may play key roles in either response or resistance to anti-PD-1 therapy in peripheral T cell lymphoma (PTCL), of which extranodal NK/T cell lymphoma is a subtype.

The findings are from a genetic analysis of a phase 2 trial that demonstrated benefits the PD-1 inhibitor geptanolimab in patients with PTCL who failed initial chemotherapy.

Specifically, geptanolimab treatment was associated with an objective response rate of 40.4%, a complete response rate of 14.6%, and partial response rate of 25.8%.

Of 44 patients who had been treated with geptanolimab and had next-generation sequencing genetic data available, PD-L1 expression was found to be significantly elevated among those who had a complete or partial response, whereas PD-L1 expression was lower among those who had disease progression, which is consistent with previous research suggesting that low PD-L1 expression is linked to poorer response to anti-PD-1 therapies.

Tumor mutation burden did not exhibit significant prognostic value. However, the authors noted that this may be confounded by variation across PTCL subtypes.

Among other key findings were that JAK3 and EZH2 mutations, which are among the top genes frequently mutated in PTCL and extranodal NK/T cell lymphoma, were consistently associated with low PD-L1 expression (P < .05) and shorter progression-free survival (HR 5.97; P = .027, JAK3, and HR 4.76; P = .027 EZH2).

"Notably, we found JAK3 mutations, which are vital and prevalent in PTCL, reduced PD-L1 levels in vivo and in vitro, which are of great clinical and biological sense," said the study's first author, Ning Lou, MD, of the Cancer Hospital Chinese Academy of Medical Sciences & Peking Union Medical College, in Beijing.

Commenting on the study, discussant Olivier Casasnovas, MD, PhD, of the department of hematology, University Hospital Francois Mitterrand in Dijon, France, said that the findings are especially notable in relation to extranodal NK/T cell lymphoma.

"The clinical relevance of anti PD1 is mainly observed in relapsing/recurrent extranodal NK/T cell lymphoma, and much less in other T-cell lymphoma subtypes," he told this news organization.

"So identifying molecular events associated with the chance of response to a PD1 blocker in relapsing extranodal NK/T cell lymphoma is important as PD1-blockers are recommended to treat [those] patients," Dr. Casasnovas added.

Furthermore, "the interest of next-generation sequencing to identify JAK3 mutations associated with low level of PDL1 expression and weak response to anti PD1 blockers is important as JAK3 mutated tumors are potentially targetable by JAK inhibitors such as tofacitinib," he said.

"Obviously this assumption has to be tested in clinical trials but it's an interesting lead."

The research on toripalimab additionally shows that "the combination of radiotherapy and PD1 blockers provides a high response rate in patients who are nonresponders to asparaginase-based chemotherapy on the basis of PET evaluation and could be a new option for optimizing the first line treatment of extranodal NK/T cell lymphoma patients," Dr. Casasnovas added.

The authors and Dr. Casasnovas had no disclosures to report.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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Cite this: PD-1 Inhibitor Improves Outcomes in NHL Subtype - Medscape - Nov 01, 2023.