Poster Presentation Clinical Oncology Society of Australia Annual Scientific Meeting 2024

Efficacy and safety of olomorasib (LY3537982), a second-generation KRAS G12C inhibitor (G12Ci), in combination with pembrolizumab in patients with KRAS G12C-mutant advanced NSCLC (#258)

Timothy F. Burns 1 , Konstantin Dragnev 2 , Yutaka Fujiwara 3 , Yonina R. Murciano-Goroff 4 , Dae Ho Lee 5 , Antoine Hollebecque 6 , Takafumi Koyama 7 , Philippe Cassier 8 , Antoine Italiano 9 , Rebecca S. Heist 10 , Ji-Youn Han 11 , Dustin Deming 12 , Alexander Spira 13 , Joshua Sabari 14 , Michael J. Chisamore 15 , Aaron Fink 16 , Aaron Chen 16 , Melinda D. Willard 16 , Geoffrey R. Oxnard 16 , Natraj Reddy Ammakkanavar 17 , Aarohan Pruthi 18
  1. Department of Medicine, Division of Hematology Oncology, University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, United States
  2. Department of Hematology/Oncology, Norris Cotton Cancer Center Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA
  3. Aichi Cancer Center Hospital, Aichi, Japan
  4. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York , USA
  5. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
  6. Gustave Roussy, Villejuif, France
  7. Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan
  8. Department of Medical Oncology, Centre Léon Bérard, Lyon, France
  9. Early Phase Trials Unit, Institut Bergonié, Bordeaux, France
  10. Massachusetts General Hospital, Boston, MA, USA
  11. Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
  12. Carbone Cancer Center, University of Wisconsin, Madison, WI, USA
  13. Virginia Cancer Specialists, Fairfax, Farifax, VA, USA
  14. NYU Langone Health – Perlmutter & Long Island, New York, USA
  15. Merck & Co., Inc., Rahway, NJ, USA
  16. Loxo@Lilly, Stamford, Stamford, CT, USA
  17. Community Health Network, Indianapolis, IN, USA, Indianapolis
  18. Eli Lilly, Indianapolis, IN, USA

Aim: Immunotherapy (IO), the established cornerstone of first-line treatment for KRAS-mutant NSCLC, has suboptimal outcomes. Here, we study pembrolizumab+olomorasib, a second-generation inhibitor of GDP-bound KRAS G12C, in NSCLC patients treated on LOXO-RAS-20001, a phase 1/2 study of olomorasib in KRAS G12C-mutant solid tumors (NCT04956640).

 

Methods: Patients with advanced KRAS G12C-mutant NSCLC (tissue/plasma) in any treatment line were eligible. Antitumor activity was studied in all patients who had ≥1, or had discontinued before the first, post-baseline response assessment.

 

Results: As of 30Oct2023, 50 eligible patients received 50-150mg BID PO olomorasib + 200mg Q3W pembrolizumab. During escalation, 2/6 patients treated at 150mg BID developed grade ³3 LFTs, precluding further evaluation of this dose. In 44 patients (50/100mg BID), TRAEs ≥15% (related to olomorasib and/or pembrolizumab) were diarrhea (30%), ALT increased (20%), AST increased (18%); grade 3 TRAEs ≥10% were diarrhea (16%); pneumonitis was seen in 3 patients (grades 2/3/4). Due to TRAEs: 14% of pts had olomorasib dose reduction; dose hold in 27% (olomorasib) and 18% (pembrolizumab); 9% discontinued olomorasib or pembrolizumab; 9% discontinued both. 27 patients remain on treatment, and 17 discontinued treatment (10 due to PD, 4 due to AE). Among 30 efficacy evaluable KRAS G12Ci-naïve patients (60% IO/60% chemotherapy pre-treated) (median follow-up: 6 months [95% CI, 4-7]), ORR was 63% (15 PR/4 unconfirmed PR pending/ongoing; 95% CI, 44-80); DCR was 93% (28/30; 95% CI, 78-99); median PFS was not estimable (95% CI, 5-NE); ORR was 75% (9/12) in PD-L1 ≥50%, 56% (10/18) in PD-L1 <50%/unknown (3 patients PD-L1 unavailable). In 9 first-line patients, ORR was 78% (6 PR/1 unconfirmed PR pending/ongoing; 95% CI, 40-97); DCR was 100%.

 

Conclusion: Olomorasib (50/100mg BID) + pembrolizumab demonstrated favorable safety and antitumor activity in KRAS G12C-mutant advanced NSCLC. A global, registrational study investigating this combination in first-line NSCLC is currently enrolling (SUNRAY-01/NCT06119581).