The MEK/ERK pathway is activated in many tumors and important for melanoma transformation and progression. Clinical activity observed with the MEK1/2 inhibitor PIM in a phase 1 trial in pts with melanoma, a population with an unmet medical need, triggered this phase 2 trial.
In a multicenter, open-label phase 2 trial (EudraCT 2012-002669-37), pts with previously untreated unresectable stage IIIc/IV cutaneous NRAS melanoma were randomized (2:1) to receive PIM (60mg PO BID) or DTIC (1000mg/m2 IV q3w) in 21-day cycles. DTIC-treated pts could switch to PIM at progression. Key endpoints were progression-free survival (PFS, primary endpoint; investigator-read), objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety.
194 pts were randomized (intent-to-treat [ITT] set); 41/64 pts in DTIC arm switched to PIM after progression. Baseline characteristics were similar in the arms. Median PFS was significantly longer with PIM than with DTIC (13.0 vs 6.9 weeks; hazard ratio (HR) = 0.59, 95% confidence interval [CI] 0.42-0.83; p = 0.0022). The table shows efficacy outcomes.
Efficacy outcomes in the PIM and DTIC treatment arms (ITT)
|Efficacy endpoint||PIM (n = 130)||DTIC (n = 64)|
|Median PFSab, weeks (HR [95% CI])||13.0||6.9|
|0.59 [0.42-0.83], p = 0.0022|
|Median PFSc, weeks (HR [95% CI])||12.7||6.4|
|0.65 [0.45-0.94], p = 0.0195|
|Median OS, months (HR [95% CI])||8.9||10.6|
|ORRa, % (OR [95% CI])||26.9||14.1|
|2.24 [1.00-4.98], p = 0.0453|
|ORRc,% (OR [95% CI])||23.1||14.1|
|1.83 [0.81-4.13], p = 0.1430|
|DCRa, % (OR [95% CI])||33.1||15.6|
|2.65 [1.23-5.69], p = 0.0106|
|DCRc, % (OR [95% CI])||37.7||26.6|
|1.68 [0.87-3.26], p = 0.1235|
aInvestigator read; bPrimary endpoint; cBlinded independent read.
OR, odds ratioThe most common (% pts) adverse events (AEs)/drug-related AEs in the PIM arm were diarrhea (82.3/70.8), elevated creatine kinase (CPK) (68.5/68.5), peripheral edema (46.2/38.5) and serous retinal detachment (44.6/44.6); % pts with grade ≥3/drug-related grade ≥3 of these AEs were 6.2/3.8, 33.8/33.1, 2.3/2.3 and 3.1/3.1, respectively. Ocular AEs in PIM pts were reversible (>92%), mild to moderate (>95%) and did not impact on visual acuity (in >91%). Most (>90%) cases of CPK increase were asymptomatic, transient and reversible laboratory findings.
The primary objective of significant PFS improvement in the PIM arm was achieved. Consistent trend in favor of the PIM arm for PFS, ORR and DCR was seen, but no difference in OS. The safety profile of PIM was consistent with previous studies with no new safety signals.
Clinical trial identification
Legal entity responsible for the study
C. Lebbe: Member of advisory board for: Roche Novartis Bristol-Myers Squibb MSD. T. Lesimple: Research grants: Roche Advisory board member: Roche Novartis MSD. W. Kruit: Advisory Board Member: Novartis MSD Bristol-Myers Squibb. F. de Braud: Advisory board member for: Boehringer Ingelheim, Philogen, Novartis, Novartis Oncology, IRIS, GlaxoSmithKline, MSD, Bristol-Myers Squibb, Merck Serono, Eli Lilly, Servier, Tiziana Life Sciences. C. Garbe: Advisory board member for: Amgen Bristol-Myers Squibb MSD Novartis Leo Pharma Research funding from: Bristol-Myers Squibb Novartis Roche. C. Loquai: Advisory board member for: Roche Bristol-Myers Squibb Novartis Amgen MSD Speakers honoraria from Roche, Bristol-Myers Squibb, Novartis, MSD Travel reimbursement from Roche, Bristol-Myers Squibb, Novartis, MSD, Amgen. V. Ferraresi: Research funding: Bristol-Myers Squibb Roche GlaxoSmithKlein Merck. C. Robert: Advisory board member for: Amgen Bristol-Myers Squibb Novartis Merck Roche. R. Isaacs: On board of directors for: Australia New Zealand Breast Cancer Clinical Trials Group. E. Espinosa: Advisory Board Member: Bristol-Myers Squibb Merck Novartis Roche Research funding from: Bristol-Myers Squibb Merck Novartis Roche. A. Schueler, A. Markivskyy: Employed by Merck KGaA. B. Dreno: Member of advisory board for: Roche GlaxoSmithKlein Novartis Bristol-Myers Squibb. All other authors have declared no conflicts of interest.