Effect of Pembrolizumab (Pembro) Monotherapy Versus Brentuximab Vedotin (BV) on Patients (Pts) with Relapsed/Refractory Classical Hodgkin Lymphoma (R/R cHL): Exploratory Analysis of the Randomized, Phase 3 Keynote-204 Study By Prior Lines of Therapy

Introduction: The open-label, international, randomized, phase 3 KEYNOTE-204 (NCT02684292) study showed that in pts with R/R cHL, the PD-1 inhibitor pembro was superior to BV and demonstrated statistically significant, clinically meaningful improvement in PFS, with safety consistent with previous reports. This post hoc exploratory analysis of KEYNOTE-204 evaluated pembro vs BV by number of prior lines of therapy.

Methods: Eligible pts were aged ≥18 y, had measurable disease and ECOG PS 0 or 1, and were post−autologous stem cell transplant (auto-SCT) or ineligible for auto-SCT. Pts who were BV-naive or BV-exposed were also eligible. Pts were randomized 1:1 to pembro 200 mg IV Q3W or BV 1.8 mg/kg IV Q3W. Randomization was stratified by status after 1L therapy (primary refractory vs relapsed <12 mo vs relapsed ≥12 mo after end of 1L therapy) and prior auto-SCT (yes vs no). Pts in this exploratory analysis were evaluated by number of prior therapies before enrollment (1 and ≥2 prior therapies). Primary end points were PFS by blinded independent central review (BICR) per International Working Group (IWG) criteria, including clinical and imaging data after auto-SCT or allogeneic SCT (allo-SCT) and OS. Additional end points were PFS excluding clinical and imaging data after auto-SCT or allo-SCT (secondary PFS analysis), ORR and duration of response (DOR) by BICR per IWG, and safety.

Results: Of 304 randomized pts, 55 (pembro, 27; BV, 28) received 1 prior therapy and 249 (pembro, 124; BV, 125) received ≥2 prior therapies. For pts with 1 prior therapy, median (range) age was 49 y (22-84) and 22 pts (40.0%) were aged ≥65 y. No pts received prior auto-SCT and 18 (32.7%) had primary refractory disease. Auto-SCT ineligibility was due to chemorefractory disease for 21 pts (38.2%) and reasons not related to chemorefractory disease (eg, age, comorbidities) for 34 pts (61.8%). 23 pts (85.2%) and 25 pts (92.6%) in the pembro and BV groups, respectively, discontinued treatment; the most common reason was progressive disease. Median (range) time from randomization to data cutoff was 24.0 mo (18.7-34.8) for pembro and 23.6 mo (18.2-34.6) for BV. For the primary PFS analysis, median PFS was 16.4 mo for pembro and 8.4 mo for BV (HR 0.70; 95% CI 0.031-1.59); 12 mo PFS rates were 58.9% and 37.4%, respectively. For the secondary PFS analysis, median PFS was 11.7 mo for pembro and 8.3 mo for BV (HR 0.62; 95% CI 0.28-1.40). ORR was 66.7% for pembro and 53.6% for BV. Median (range) DOR for pembro was 20.7 mo (2.8-20.7) and 14.1 mo (0.0+ to 21.9) for BV. 7 pts (25.9%) and 9 pts (33.3%) in the pembro and BV groups, respectively, received subsequent auto-SCT; 1 pt in the BV group received subsequent allo-SCT. 21 pts (77.8%) on pembro and 20 (74.1%) on BV experienced a treatment-related adverse event (TRAE); most common were hyperthyroidism (22.2%) for pembro and peripheral neuropathy (22.2%) for BV. 1 (3.7%) and 8 (29.6%) of pts on pembro and BV, respectively, experienced grade 3-5 TRAEs. For pts with ≥2 prior therapies median (range) age was 34 y (18-83) and 27 (10.8%) pts were aged ≥65 y. 112 pts (45.0%) received prior auto-SCT and 105 (42.2%) had primary refractory disease. Median (range) time from randomization to data cutoff was 27.1 mo (18.8-42.0) for pembro and 27.6 (18.2-42.3) for BV. 87 (71.9%) and 121 (96.8%) in the pembro and BV groups discontinued; most common reason was progressive disease. For the primary PFS analysis, median PFS was 12.6 mo for pembro and 8.2 mo for BV (HR 0.66; 95% CI 0.47-0.92); 12-mo PFS rates were 52.8% and 35.3%, respectively. For the secondary PFS analysis, median PFS was 12.6 mo for pembro and 8.2 mo for BV (HR 0.63; 95% CI 0.45-0.88). ORR for pembro was 65.3% and 54.4% for BV. Median (range) DOR for pembro was 20.5 mo (0.0+ to 33.2+) and 11.2 mo (0.0+ to 33.9+) for BV. 23 (19.0%) and 25 (20.0%) pts in the pembro and BV groups, respectively, received subsequent auto-SCT; 14 (11.6 %) and 12 (9.6%) received subsequent allo-SCT. 89 pts (73.6%) on pembro and 97 (77.6%) on BV experienced a TRAE; most common were hypothyroidism (14.9%) for pembro and peripheral neuropathy (17.6%) for BV. 23.1% and 24.0% of pts on pembro and BV, respectively, experienced grade 3-5 TRAEs.

Conclusion: In pts with R/R cHL, pembro monotherapy resulted in an improvement in PFS and ORR vs BV in pts regardless of number of prior therapies. In particular, these data suggest that pembro monotherapy may be a promising option as 2L+ therapy for pts with R/R cHL ineligible for auto-SCT.