Favezelimab Plus Pembrolizumab Continues to Elicit Antitumor Activity in R/R Classical Hodgkin Lymphoma

The combination of favezelimab (MK-4280) and pembrolizumab (Keytruda) continued to demonstrate a manageable safety profile and antitumor activity in patients with relapsed/refractory classical Hodgkin lymphoma, irrespective of whether they received prior anti–PD-1 therapy, according to updated data from the dose-expansion portion of the phase 1/2 MK-4280-003 trial (NCT03598608) presented at the 17th AnnualInternational Conference on Malignant Lymphoma.¹

At a median follow-up of 31.5 months (range, 24.0-43.2), patients in cohort 1 (n = 30) who were naïve to anti-PD-1 therapy experienced an overall response rate (ORR) of 80% (95% CI, 61%-92%). Thirty-three percent of patients had a complete response (CR), 47% had a partial response (PR), 10% had stable disease (SD), and 10% had progressive disease (PD).

Among patients who received prior anti–PD-1 therapy in cohort 2 (n = 34), the ORR was 29% (95% CI, 15%-48%) at a median follow-up of 35.3 months (range, 15.0-49.4). Nine percent of patients had a CR, 21% had a PR, 35% had SD, 21% had PD, and 15% of patients had no response assessment at data cutoff.

In cohort 1, all patients experienced an all-cause adverse effect (AE), and 90% of patients experienced a treatment-related AE (TRAE). Thirty percent of patients had grade 3/4 TRAEs, and 17% had serious TRAEs. Seventeen percent of patients discontinued treatment due to TRAEs.

In cohort 2, at least 1 all-cause AE occurred in all patients, and 82% of patients experienced an any-grade TRAE. Eighteen percent of patients had grade 3/4 TRAEs, 18% had serious TRAEs, and 18% of patients discontinued treatment due to TRAEs. No deaths due to TRAEs were reported in either arm.

“With 6 months of additional follow-up, the combination of favezelimab plus pembrolizumab continued to demonstrate manageable safety and sustained antitumor activity in patients with anti–PD-1-naïve and anti–PD-1-refractory relapsed/refractory classical Hodgkin lymphoma,” lead study author David Lavie, MD, of Hadassah Medical Center in Jerusalem, Israel, and colleagues, wrote in a poster presentation of the data.

Although PD-1 inhibitors, such as pembrolizumab, have an established role in the treatment of patients with relapsed/refractory Hodgkin lymphoma, improving outcomes for this patient population remains a clinical goal. Dual blockade of PD-1 and LAG-3 has demonstrated activity in other histologies, and the MK-4280-003 trial of pembrolizumab and favezelimab aimed to investigate this approach in classical Hodgkin lymphoma.

Initial results from the study showed that patients with relapsed/refractory Hodgkin lymphoma treated at the recommended phase 2 dose of 800 mg favezelimab plus 200 mg pembrolizumab every 3 weeks (n = 29) achieved an ORR of 31% (95% CI, 15%-51%) at a median follow-up of 16.5 months.²

The study enrolled patients at least 18 years of age with relapsed/refractory classical Hodgkin lymphoma who underwent autologous stem cell transplant (ASCT), had no response to salvage chemotherapy, or were ineligible for ASCT. All patients were required to have an ECOG performance status of 0 or 1. Cohort 1 included patients who received no prior anti–PD-1 therapy. Cohort 2 enrolled patients who had progressive disease within 12 weeks of their last dose of anti–PD-1 therapy.¹

Part 1 of the trial consisted of a safety lead-in phase, where patients from cohorts 1 to 4 (n = 21) were treated with 200 mg of intravenous (IV) pembrolizumab plus 200 mg or 800 mg of IV favezelimab once every 3 weeks. Upon the determination of the RP2D of favezelimab, patients in the part 2, dose-expansion portion of the study received 200 mg of IV pembrolizumab plus 800 mg of IV favezelimab once every 3 weeks for up to 35 cycles.

The primary end point was safety. ORR per International Working Group (IWG) 2007 criteria was a secondary end point. Duration of response (DOR) and progression-free survival (PFS) per IWG 2007 criteria, as well as overall survival (OS), served as exploratory end points.

The median age in cohort 1 was 40.5 years, 57% of patients were male, and 83% were White. Moreover, 53% of patients had an ECOG performance status of 0, 67% received at least 3 prior lines of therapy, and 47% of patients underwent prior ASCT.

As of data cutoff, 13 patients completed 35 cycles of treatment, 16 discontinued, and 1 was ongoing on the study treatment. Following discontinuation of treatment or completion of study, 5 patients (17%) received allogeneic hematopoietic stem cell transplant.

In cohort 2, the median age was 37.5 years, 47% of patients were male, and 91% were White. Additionally, 62% of patients had an ECOG performance status of 0. Moreover, 82% of patients had received at least 5 prior lines of therapy, and 74% had undergone prior ASCT

Eight patients in cohort 2 completed 35 cycles of treatment, 26 discontinued, and none were ongoing. Two patients (6%) underwent an allogeneic hematopoietic stem cell transplant after treatment discontinuation or completion.

Additional data showed the median DOR for patients in cohort 1 was 17.0 months (range, 2.6-30.2), and the median DOR for cohort 2 was 21.9 months (0.0+ to 26.1+). The estimated 24-month DOR rate was 47% in cohort 1 and 17% in cohort 2.

The median PFS was 19.4 months (95% CI, 9.0-28.5) and 9.7 months (95% CI, 5.1-14.7) in cohort 1 and cohort 2, respectively. The estimated 24-month PFS rates were 46% and 21%, respectively.

Moreover, the median OS was not reached (NR; 95% CI, NR-NR) in cohort 1 and 34.3 months (95% CI, 25.7-NR) in cohort 2. The estimated 24-month OS rates were 93% and 76% in cohorts 1 and 2, respectively.

The most common any-grade TRAEs reported in at least 5% of patients in cohort 1 included hypothyroidism (27%), infusion-related reaction (23%), fatigue (20%), headache (17%), pruritus (17%), chills (13%), pyrexia (13%), arthralgia (10%), hyperthyroidism (10%), myalgia (10%), nausea (10%), rash (10%), maculopapular rash (10%), abdominal pain (7%), increased blood creatine phosphokinase (7%), constipation (7%), decreased appetite (7%), diarrhea (7%), muscular weakness (7%), and decreased weight (7%).

In cohort 2, the most common any-grade TRAEs reported in at least 5% of patients included hypothyroidism (18%), nausea (18%), fatigue (15%), arthralgia (12%), diarrhea (12%), headache (12%), infusion-related reactions (9%), pyrexia (9%), rash (9%), alopecia (6%), chills (6%), dry skin (6%), hyperthyroidism (6%), hyponatremia (6%), lymphopenia (6%), pruritis (6%), and thrombocytopenia (6%).

“This combination warrants further research in patients with relapsed/refractory classical Hodgkin lymphoma,” Lavie concluded.

References

1. Lavie D, Johnson N, Borchmann P, et al. An Open-Label Phase 1/2 Study of Favezelimab Plus Pembrolizumab in Patients With Relapsed/ Refractory Classical Hodgkin Lymphoma With/Without Previous Anti–PD-1 Treatment. Presented at: 17th International Conference on Malignant Lymphoma; June 13-17, 2023. Lugano, Switzerland. Abstract 263.
2. Timmerman J, Lavie D, Johnson NA, et al. Favezelimab (anti–LAG-3) plus pembrolizumab in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) after anti–PD-1 treatment: an open-label phase 1/2 study. J Clin Oncol. 2022;40(suppl 16):7545. doi:10.1200/JCO.2022.40.16_suppl.7545