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VP4-2023: Sotorasib 960 mg versus 240 mg in pretreated KRAS G12C advanced NSCLC
Published: November 16, 2023
DOI: https://doi.org/10.1016/j.annonc.2023.10.790
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M.J. Hochmair, K. Vermaelen, G. Mountzios, ..., A. Curioni-Fontecedro
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Background
Sotorasib 960 mg daily is approved in pretreated KRAS G12C advanced NSCLC. Due to its non-linear pharmacokinetics (PK) and clinical responses seen at lower doses, we evaluated sotorasib 960 mg vs 240 mg in an open-label, phase 2, post-marketing study (NCT03600883).
Methods
Adults with KRAS G12C advanced NSCLC were randomized 1:1 to once daily sotorasib 960 mg or 240 mg. Eligibility criteria included prior PD-(L)1 inhibitor and/or platinum-based chemotherapy and ECOG PS ≤ 2. Primary endpoints were objective response rate (ORR) per RECIST 1.1 by BICR and safety. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and PK. Efficacy results are considered descriptive, with dosing to be assessed by totality of data.
Results
Baseline data of patients randomized to sotorasib 960 mg (n=104) or 240 mg (n=105) were similar. ORR/DCR were 32.7%/86.5% for 960 mg vs 24.8%/81.9% for 240 mg. The median PFS was 5.4 months (mo) for 960 mg vs 5.6 mo (HR for 960 mg/240 mg: 0.95 [95% CI: 0.67, 1.35]). With a median follow-up of 17.5 mo, median OS was 13.0 mo at 960 mg vs 11.7 mo at 240 mg (HR 0.75 [95% CI: 0.53, 1.07]). Geometric mean Cmax was 22% lower at 240 mg vs 960 mg. Treatment-related AEs (TRAEs) are reported in the table. Most common TRAEs (960 mg vs 240 mg) were diarrhea (35.6% vs 21.2%), nausea (15.4% vs 13.5%), elevated ALT (11.5% vs 13.5%), and elevated AST (10.6% vs 11.5%).
Table: VP4-2023 |
960 mg |
240 mg |
Efficacy* |
n=104 |
n=105 |
ORR, % (95% CI) |
32.7 (23.8, 42.6) |
24.8 (16.9, 34.1) |
DCR, % (95% CI) |
86.5 (78.5, 92.4) |
81.9 (73.2, 88.7) |
Median DOR, mo. (95% CI) |
13.8 (5.6, NE) |
12.5 (7.0, NE) |
Median PFS, mo. (95% CI) |
5.4 (4.2, 6.9) |
5.6 (4.1, 8.3) |
Median OS, mo. (95% CI) |
13.0 (10.7, 18.8) |
11.7 (9.5, 15.4) |
Safety† |
n=104 |
n=104 |
TRAEs, n (%) |
86 (82.7) |
64 (61.5) |
Grade ≥ 3 |
37 (35.6) |
20 (19.2) |
Serious |
14 (13.5) |
8 (7.7) |
Led to sotorasib discontinuation |
13 (12.5) |
10 (9.6) |
Led to sotorasib interruption/reduction‡ |
41 (39.4) |
23 (22.1) |
Fatal |
1 (1.0) |
0 (0.0) |
*Data cut: June 23, 2023. KM estimates for DOR, PFS, OS; †Data cut: January 18, 2023. Disease progression–related events excluded; ‡Dose reduced only in 960 mg group. | ||
Conclusions
Sotorasib 960 mg, as compared to 240 mg, had a higher ORR/DCR and an improved OS, with a higher rate of Grade ≥3 TRAEs. AEs were generally manageable at both doses with label-directed dose modifications. This is reinforced by the CodeBreaK 300 study in chemorefractory KRAS G12C mCRC where both doses of sotorasib (960 mg and 240 mg) with panitumumab showed statistically superior PFS over standard of care, with the 960 mg dose demonstrating a clinically superior benefit. Overall, sotorasib 960 mg daily provides a more favourable benefit-risk profile.
Clinical trial identification
NCT03600883.
Editorial acknowledgement: Medical writing support was provided by Advait A. Joshi of Cactus Life Sciences (part of Cactus Communications) and Maya Shehayeb of Amgen Inc. and funded by Amgen Inc.
Legal entity responsible for the study: Amgen Inc.
Funding: Amgen Inc.
