Abstract 1102P
Background
The phase III IMspire150 study (NCT02908672) demonstrated that combination therapy with inhibitors of PD-L1 (atezolizumab [A]), BRAF (vemurafenib [V]), and MEK (cobimetinib [C]) improved investigator-assessed PFS vs placebo (P)+V+C (hazard ratio [HR] 0.78; 95% CI 0.63-0.97; log-rank P=0.025). An exploratory analysis was conducted to define efficacy outcomes in key prognostic subgroups defined by baseline PD-L1 and LDH status.
Methods
Treatment-naive patients (pts) with unresectable stage IIIc/IV melanoma (AJCC 7th ed), measurable disease by RECIST 1.1, and BRAF V600 mutation–positive tumors were randomized 1:1 to receive A+V+C or P+V+C. PD-L1 expression was assessed using the anti–PD-L1 antibody SP142 (Ventana Medical Systems). PD-L1 status was defined based on the proportion of PD-L1–expressing tumor-infiltrating cells as PD-L1+ (≥1%) or PD-L1– (<1%). LDH levels were defined as high (>ULN ) or normal/low (≤ULN).
Results
Treatment benefit, as assessed by PFS and duration of response (DOR), favored the A+V+C arm over the P+V+C arm in all subgroups. Median PFS for A+V+C in the PD-L1– and PD-L1+ subgroups was 15.2 mo and 14.8 mo, respectively, at 18 mo follow-up (Table). In pts with LDH ≤ULN at baseline, PFS and DOR benefit with A+V+C were greater for the PD-L1+ subgroup. Conversely, in pts with LDH >ULN, benefit with A+V+C was greater in the PD-L1– subgroup.
Conclusions
Pts with PD-L1– tumors, which generally benefit less from immunotherapy alone, appear to derive similar clinical benefit from A+V+C as pts with PD-L1+ tumors. This effect was more evident among pts with high LDH levels, which is a known poor prognostic factor in pts with melanoma. Analyses are ongoing to identify other subgroups that may benefit from A+C+V. Table: 1102P
| Subgroup | Median PFS, months, n | Median PFS, months, n | HR (95%CI) | Median DOR, months, n | Median DOR, months, n | HR (95%CI) |
| P+V+C | A+V+C | P+V+C | A+V+C | |||
| All | 10.6, 258 | 15.1, 256 | 0.77 (0.62-0.96) | 12.6, 160 | 21.0, 169 | 0.68 (0.50-0.91) |
| PD-L1– | 9.2, 86 | 15.2, 85 | 0.76 (0.53-1.10) | 11.1, 51 | 19.1, 56 | 0.78 (0.47-1.30) |
| PD-L1+ | 11.4, 158 | 14.8, 160 | 0.80 (0.60-1.06) | 13.1, 102 | 22.4, 105 | 0.59 (0.41-0.87) |
| PD-L1–, LDH >ULN | 5.6, 31 | 9.8, 27 | 0.53 (0.29-0.95) | 5.2, 15 | 13.4, 18 | 0.40 (0.17-0.95) |
| PD-L1+, LDH >ULN | 9.3, 49 | 6.3, 53 | 1.16 (0.75-1.80) | 12.9, 31 | 12.9, 27 | 0.94 (0.49-1.81) |
| PD-L1–, LDH ≤ULN | 11.9, 55 | 17.8, 58 | 0.93 (0.58-1.5) | 19.5, 36 | 21.2, 38 | 0.94 (0.49-1.79) |
| PD-L1+, LDH ≤ULN | 12.9, 109 | 22.7, 107 | 0.67 (0.46-0.96) | 13.1, 71 | N/A, 78 | 0.53 (0.34-0.85) |
Clinical trial identification
NCT02908672.
Editorial acknowledgement
Medical editorial assistance was provided by Apothecom and funded by F. Hoffmann-La Roche Ltd.
Legal entity responsible for the study
F. Hoffmann-La Roche Ltd.
Funding
F. Hoffmann-La Roche Ltd.
Disclosure
P.A. Ascierto: Advisory/Consultancy: BMS; Advisory/Consultancy: Roche-Genentech; Advisory/Consultancy: MSD; Advisory/Consultancy: Array; Advisory/Consultancy: Novartis; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Incyte; Advisory/Consultancy: Genmab; Advisory/Consultancy: NewLink Genetics; Advisory/Consultancy: MedImmune; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Syndax; Advisory/Consultancy: Sun Pharma; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Idera; Advisory/Consultancy: Ultimovacs; Advisory/Consultancy: Sandoz; Advisory/Consultancy: Immunocore; Advisory/Consultancy: 4SC; Advisory/Consultancy: Alkermes; Advisory/Consultancy: Italfarmaco. C. Robert: Advisory/Consultancy: BMS, Pierre Fabre, Novartis, Amgen, Merck, Roche, MSD, Sanofi, Biothera, Ultimovacs. K. Lewis: Advisory/Consultancy: Roche/Genentech. R. Gutzmer: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Non-remunerated activity/ies: BMS, Roche, Merck Serono, Amgen, Pierre Fabre, Sanofi Regeneron, MSD, Novartis; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: MSD; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Almirall Hermal, Pfizer, Sun Pharma, 4SC. H.J. Gogas: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: BMS, MSD; Travel/Accommodation/Expenses: Roche; Honoraria (self): Novartis; Advisory/Consultancy: Amgen; Honoraria (self), Travel/Accommodation/Expenses: Pierre Fabre. R.P. Pereira: Honoraria (self), Advisory/Consultancy: Roche. T. Eigentler: Honoraria (self), Advisory/Consultancy: Roche, MSD, BMS, Novartis, Leo Pharma, Sanofi. P. Rutkowski: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis, BMS, Pierre Fabre; Honoraria (self), Speaker Bureau/Expert testimony: Roche, MSD; Honoraria (self), Advisory/Consultancy: Blueprint Medicines. V. McNally: Full/Part-time employment: Roche Ltd. H. Forbes: Full/Part-time employment: Hoffmann-La Roche Limited. K. Shah, Y. Yan: Full/Part-time employment: Genentech. G. McArthur: Research grant/Funding (institution): Array Biopharma, Roche/Genentech. All other authors have declared no conflicts of interest.