Lenvatinib (len) plus pembrolizumab (pembro) for patients (pts) with advanced melanoma and confirmed progression on a PD-1 or PD-L1 inhibitor: Updated findings of LEAP-004.
Authors: Arance Ana Maria , de la Cruz-Merino Luis , Petrella Teresa M. , Jamal Rahima , Ny Lars , Carneiro Ana , Berrocal Alfonso , Marquez-Rodas Ivan , Spreafico Anna , Atkinson Victoria , Svedman Fernanda Costa , Mant Andrew , Smith Alan D. , Chen Ke , Diede Scott J. , Krepler Clemens , Long Georgina V. 
Published: June 2021

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Background: Initial results of the open-label, single-arm, phase 2 LEAP-004 study (NCT03776136) showed that len and pembro in combination had promising efficacy and manageable safety in pts with unresectable stage III-IV melanoma and confirmed PD on a PD-(L)1 inhibitor given alone or in combination. ORR was 21.4% with a 6.3-mo median DOR; ORR was 31.0% in patients with PD on prior anti–PD-1 + anti–CTLA-4. We present updated data from LEAP-004 and additional ORR subgroup analyses. Methods: Eligible pts with PD confirmed per iRECIST within 12 wk of the last dose of a PD-(L)1 inhibitor given alone or with anti–CTLA-4 or other therapies for ≥2 doses received len 20 mg/d once daily plus ≤35 doses of pembro 200 mg Q3W until PD or unacceptable toxicity. Primary end point is ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary end points are PFS and DOR per RECIST v1.1 by BICR, OS, and safety. ORR was calculated for pts with PD on prior anti–PD-1 + anti–CTLA-4, pts whose only prior anti–PD-(L)1 was in the adjuvant setting, pts with primary resistance (ie, best response of SD or PD to prior anti–PD-(L)1 in the advanced setting) and pts with secondary resistance (ie, PD following best response of CR or PR on prior anti–PD-(L)1 in the advanced setting). Results: 103 pts were enrolled. Median age was 63 y, 68.0% of pts had stage M1c/M1d disease, 55.3% had LDH > ULN (20.4% ≥2 × ULN), 58.3% received ≥2 prior treatments, 94.2% received therapy for advanced disease, and 32.0% received BRAF ± MEK inhibition. With median study follow-up of 15.3 mo (range 12.1-19.0), 17.5% of pts were still receiving study drug. ORR by BICR remained 21.4% (95% CI 13.9-30.5), although the number of CRs increased from 2 to 3. DCR was 66.0%. Median DOR increased to 8.2 mo, and the KM estimate of DOR ≥9 mo was 37.2%. ORR was 33.3% in pts with PD on prior anti–PD-1 + anti–CTLA-4 (n = 30), 18.2% in pts whose only prior anti–PD-1/L1 was in the adjuvant setting (n = 11), 22.6% in pts with primary resistance (n = 62), and 22.7% in pts with secondary resistance (n = 22). Median (95% CI) PFS and OS in the total population were 4.2 mo (3.8-7.1) and 14.0 mo (95% CI 10.8-NR); 12-mo PFS and OS estimates were 17.8% and 54.5%. Incidence of treatment-related AEs was as follows: 96.1% any grade, 45.6% grade 3-4, 1.0% grade 5 (decreased platelet count), 7.8% led to discontinuation of len and/or pembro, and 56.3% led to len dose reduction. Conclusions: The combination of len and pembro continues to show clinically meaningful, durable responses in pts with advanced MEL with confirmed progression on a prior PD-(L)1 inhibitor, including those with PD on anti–PD-1 + anti–CTLA-4 therapy, and regardless of primary or secondary resistance to prior anti–PD-(L)1 therapy. The safety profile was consistent with prior studies of len + pembro. These data support len + pembro as a potential regimen for this population of high unmet need. Clinical trial information: NCT03776136.