Sugemalimab Monotherapy Has Clinical Benefit in NK/T-Cell Lymphoma

The PD-L1 inhibitor sugemalimab produced durable responses with a tolerable safety profile in patients with relapsed/refractory natural killer (NK)/T-cell lymphoma, according to findings from a preplanned primary analysis of the multicenter, single-arm, phase 2 GEMSTONE-201 trial (NCT03595657).

At a median follow-up of 18.7 months, the overall response rate (ORR) as assessed by an independent radiologic review committee (IRRC) was 44.9% (n = 35; 95% CI, 33.6%-56.6%; P < .0001) with sugemalimab, including 35.9% of patients (n = 28) with a best response of complete response (CR) and 9.0% of patients (n = 7) with a best response of partial response (PR).¹ Additionally, 10.3% (n = 8) and 32.1% (n = 25) of patients achieved stable disease (SD) and progressive disease (PD) as their best response, respectively. Best response was unknown in 1 patient and not applicable (NA) in 11.5% of patients (n = 9). The IRRC-assessed median time to response was 2.8 months (range, 1.4-11.1), and the disease control rate (DCR) was 55.1% (n = 43; 95% CI, 43.4%-66.4%).

“Sugemalimab showed potent, durable antitumor activity and a manageable safety profile in the largest study of an immune checkpoint inhibitor in patients with relapsed/refractory extranodal NK/T-cell lymphoma, representing a promising treatment option for patients with this rare and aggressive disease,” wrote lead study author Huiqiang Huang, MD, of Sun Yat-sen University Cancer Center in Guangzhou, China, and coauthors, in a paper published in the Journal of Clinical Oncology.

In 2020, the FDA granted a breakthrough therapy designation to sugemalimab for adult patients with relapsed/refractory extranodal NK/T-cell lymphoma, based on prior findings in 38 evaluable patients from GEMSTONE-201. These patients achieved an ORR of 44.7%, including a CR rate of 31.6%.²

Patients aged 18 to 75 years with histologically confirmed nasal and nonnasal extranodal NK/T-cell lymphoma who had relapsed after or were refractory to asparaginase-based chemotherapy or chemoradiotherapy were eligible to enroll in GEMSTONE-201.¹ All enrolled patients had at least 1 lesion measurable or evaluable per 2014 Lugano classification. Patients needed to provide immunohistochemically stained tumor tissue sections and their corresponding pathologic reports or unstained tumor tissue sections or tissue block for central pathology review. Additionally, patients needed to have an ECOG performance score (PS) of 0 or 1, a life expectancy of at least 12 weeks, and adequate organ function.

Patients were excluded if they had aggressive NK-cell leukemia or hemophagocytic lymphohistiocytosis or primary or secondary disease involvement in the central nervous system. Patients could not have received prior treatment with PD-1, PD-L1, or CTLA-4 inhibitors; or had prior chemotherapy, biological therapy, immunotherapy, or underwent major surgery within 28 days, or radiotherapy within 90 days, allogeneic hematopoietic stem cell transplant (HSCT) within 5 years, or autologous HSCT within 90 days before the first sugemalimab dose. Patients were also excluded if they had an autoimmune disease requiring systemic treatment in the 2 years prior to beginning the study treatment or if they had received systemic immunosuppressive agents in the 14 days before the first sugemalimab dose.

Patients at 16 centers in China received 1200 mg of sugemalimab intravenously once every 3 weeks in 21-day cycles for a maximum of 24 months or until disease progression, death, intolerable toxicity, or withdrawal of consent. Patients could continue to receive sugemalimab after their first disease progression at the investigator’s discretion.

The primary end point of this trial was IRRC-assessed ORR per the 2014 Lugano classification. Among the key secondary end points were investigator-assessed ORR; IRRC- and investigator-assessed CR rate and duration of response (DOR); and safety.

At a data cutoff date of February 23, 2022, 80 patients had enrolled in the trial. The efficacy analysis population included all patients treated with sugemalimab who had extranodal NK/T-cell lymphoma confirmed by central pathology (investigator-assessed efficacy, n = 79; IRRC-assessed efficacy, n = 78). The safety analysis population included all patients who received at least 1 dose of sugemalimab (n = 80). Of these patients, 72.5% (n = 58) discontinued treatment because of progressive disease (41.3%), adverse effects (AE; 13.8%), patient withdrawal (10.0%), deterioration of symptoms without progression (6.3%), and death (1.3%).

Patients had a median age of 48.0 years (range, 29.0-74.0), and 73.8% (n = 59) of patients had an ECOG PS of 1. At baseline, 11.3% (n = 9), 21.3% (n = 17), and 67.5% (n = 54) of patients had stage I, II, and IV disease, respectively. Additionally, 51.3% (n = 41), 27.5% (n = 22), and 21.3% (n = 17) of patients had received 1, 2, and at least 3 prior lines of systemic therapy, respectively.

The investigator-assessed ORR was 45.6% (95% CI, 34.3%-57.2%; P < .0001), with 30.4% (n = 24), 15.2% (n = 12), 5.1% (n = 4), and 35.4% (n = 28) achieving CR, PR, SD, and PD as their best responses, respectively. One patient had an unknown best response, and best response assessment was NA in 12.7% of patients (n = 10). The median time to response was 2.8 months (range, 1.4-8.0), and the DCR was 50.6% (n = 40; 95% CI, 39.1%-62.1%).

The IRRC- and investigator-assessed ORRs were 95.7% in concordance with each other, and both ORRs were generally consistent across prespecified patient subgroups. Additionally, in the IRRC ORR assessment, 5 patients changed from SD or PR to a best response of CR.

In the IRRC assessment, the median DOR was not reached (NR; 95% CI, 19.7-NR). The respective 6-, 12-, and 18-month DOR rates were 91.3% (95% CI, 75.5%-97.1%), 82.5% (95% CI, 62.0%-92.6%), and 82.5% (95% CI, 62.0%-92.6%).

The investigator-assessed median DOR was NR (95% CI, 13.9-NR), and the respective 6-, 12-, and 18-month DOR rates were 76.9% (95% CI, 59.0%-87.8%), 72.7% (95% CI, 53.5%-84.9%), and 67.5% (95% CI, 46.8%-81.6%).

The median OS was NR (95% CI, 14.0-NR). The respective 6-, 12-, and 18-month OS rates were 79.2% (95% CI, 68.3%-86.7%), 67.5% (95% CI, 55.4%-77.0%), and 57.9% (95% CI, 44.9%-68.9%).

Two patients had detectable antidrug antibodies at baseline, and 4 patients had detectable antidrug antibodies after baseline. Additionally, neutralizing antibodies were detected in 1 patient after baseline.

In total, 96.3% of patients (n = 77) experienced at least 1 treatment-emergent AE (TEAE), and 40.0% of patients (n = 32) experienced TEAEs of grade 3 or higher.

Additionally, 78.8% of patients (n = 63) experienced at least 1 treatment-related AE (TRAE), with 16.3% of patients (n = 13) having grade 3 or 4 TRAEs. The most common TRAEs were decreased white blood cell counts (grade 1-2, 21.3%; grade ≥ 3, 1.3%), hypothyroidism (17.5%; 1.3%), decreased neutrophil counts (15.0%; 1.3%), increased aspartate transferase (12.5%; 2.5%), pyrexia (grade 1-2, 15.0%), rash (11.3%; 1.3%), increased alanine transaminase (10.0%; 1.3%), and increased blood thyroid stimulating hormone (grade 1-2, 11.3%).

Additionally, 23.8% of patients (n = 19) experienced serious AEs. In total, 7.5% (n = 6) of the serious AEs were considered related to the treatment: pyrexia, which occurred in 2 patients; and sinus node dysfunction, abnormal hepatic function, pneumonia, and myositis, which occurred in 1 patient each. All serious AEs except 1 sinus node dysfunction event were resolved by the data cutoff date without sequelae. Infusion-related reactions occurred in 5.0% of patients (n = 4).

A total of 31.3% of patients (n = 25) had AEs of special interest, which were grade 3 or higher in 2 patients. These included hypothyroidism (18.8%), skin adverse reactions (11.3%), and hyperthyroidism (7.5%).

Overall, 13.8% of patients (n = 11) discontinued sugemalimab because of TEAEs, 6.3% (n = 5) of which were considered related to the treatment. These TRAEs included increased blood bilirubin in 2 patients and cellulitis orbital, pyrexia, and facial nerve disorder in 1 patient each.

Five patients died because of AEs that the investigator did not attribute to sugemalimab. Two patients died from unknown causes, and 1 patient each died from upper gastrointestinal hemorrhage, hemophagocytic lymphohistiocytosis, and septic shock.

“Our safety findings were consistent with the expected safety profile of this drug class and with previous reports of sugemalimab in advanced non–small cell lung cancer and other solid tumors,” the study authors concluded.

A phase 3 clinical trial (NCT05700448) is planned to determine the efficacy and safety of sugemalimab plus pegaspargase, gemcitabine, and oxaliplatin vs placebo plus the chemotherapy regimen in patients with relapsed/refractory extranodal NK/T-cell lymphoma.³

References

1. Huang H, Tao R, Hao S, et al. Sugemalimab monotherapy for patients with relapsed or refractory extranodal natural killer/T-cell lymphoma (GEMSTONE-201): results from a single-arm, multicenter, phase 2 study. J Clin Oncol. Published online March 30, 2023. doi:10.1200/JCO.22.02367
2. CStone Pharmaceuticals announced FDA granted breakthrough therapy designation to anti-PD-L1 antibody sugemalimab for the treatment of adult patients with R/R ENKTL. News Release. CStone Pharmaceuticals. October 22, 2020. Accessed April 14, 2023. https://www.cstonepharma.com/en/html/news/2480.html
3. Study of sugemalimab (or placebo) plus PGemOx regimen in participants with extranodal NK/T-cell lymphoma. ClinicalTrials.gov. Updated January 26, 2023. Accessed April 14, 2023. https://clinicaltrials.gov/ct2/show/NCT05700448