Garsorasib Results Add to the Growing Group of KRASG12C Inhibitors in NSCLC

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Early results with garsorasib (D-1553) showed the potential for the oral KRASG12C inhibitor in patients with advanced non–small cell lung cancer (NSCLC) and provided the rationale to move ahead to a phase 2 trial, according to data published in the Journal of Thoracic Oncology.¹

In a multicenter, open-label phase 1 dose-escalation and dose-expansion study (NCT05383898) 79 patients were treated with the covalent KRASG12C inhibitor orally once daily doses of 600 mg, 800 mg, 1200 mg, and then 400 mg or 600 mg twice a day. In the dose expansion portion of the study all patients were given 600 mg of garsorasib twice a day. Primary end points of the study were safety evaluated in 75 patients and efficacy evaluated in 74 eligible patients.¹

Most patients had treatment-related adverse events (TRAEs) of any grade, with 38% reporting grade 3 or 4 TRAEs. Grade 3/4 TRAEs led to 31.6% of patients needing a dose interruption or reduction to manage toxicities, however, 1.3% had to discontinue treatment altogether, which suggested to researchers the monotherapy was tolerable. Further, when comparing the toxicity profile of garsorasib to the other currently approved KRASG12C inhibitors, adagrasib (Krazai) and sotorasib (Lumakras),^2,3 these therapies have similar AEs. Further, all noted KRASG12C inhibitors still show higher rates of toxicity when combining with immunotherapy. High rates of hepatoxicity were seen with both sotorasib and garsorasib in combination therapy at a rate of 60%-80% grade 3 or 4 hepatoxicity events, suggesting further research is needed to avoid the 50% rate of discontinuation that was later seen with sotorasib, according to Aurora Norman, MD, and Alex A. Adjei, MD, PhD who wrote an accompanying editorial in the Journal of Thoracic Oncolgoy.⁴

The authors also noted that the AE profile of garsorasib was similar to sotorasib, suggesting a phase 2 study of garsorasib could reveal similar AEs to those of sotorasib in the phase 2 CodeBreaK100 trial (NCT03600883).5 Treatment related AEs occurred in 69.8% of patients with grade 3 events occurring in 19.8% of patients compared with 0.8% experiencing grade 4 AEs. The most common treatment-related AE of any grade was diarrhea (31.7%), nausea (19.0%), and alanine aminotransferase increase (15.1%).

On the phase 1 study conducted by Li et al, 38% of patients had a grade 3 or 4 adverse event (AE) which led to a dose interruption or reduction in 31.6% of patients. Still, they observed just 1.3% of patients needed to discontinue treatment due to any of the treatment-related AEs, which for indicated overall tolerability to the researchers. They also noted that among the study group, patients that received an anti PD-L1 inhibitor 90 days prior to the study treatment made up 82.4% of grade 3 to 4 hepatoxicity, among a subgroup of patients given prior PD-L1 therapy.¹

In this study, 6 patients also had intracranial (IC) disease with stable and evaluable brain metastases at baseline. These patients had an IC overall response rate of 17% and IC DCR of 100%.¹ When compared to the phase 1/2 KRYSTAL-1 trial (NCT03785249), which looked at the efficacy of adagarsib in patients with NSCLC, subgroup of patients with brain metastases had an IC ORR of 33% and DCR of 85%, however, the KYRSTAL-1 trial subgroup looked at 33 patients, which researchers concluded powered some of these differences.⁶

Efficacy results on this study also showed a potential stronger initial response with garsorasib with an objective response rate (ORR) of 40.5% and disease control rate (DCR) of 91.9%. Median progression-free survival (PFS) on the dose escalation portion of the study was 8.2 months while the median duration of response (DOR) was observed to be 7.1 months, after a median follow up of 8.8 months. In the recommended phase 2 dose portion of the study 62 patients were given 600 mg of garsorasib twice a day and had a median PFS of 7.6 months and DOR of 6.9 months.¹

“Despite the development of KRASG12C small molecule inhibitors, KRAS is distinct from mutations such as EGFR or ALK in that its targeted agents are currently approved for use in the second rather than front line,” explained Norman and Adiei, a medical oncologist at the Mayo Clinic in Rochester, Minnesota, and Chair of the Taussig Cancer Institute at the Cleveland Clinic in Cleveland, Ohio, respectively.⁴

Garsorasib presents another option to pursue, but still in heavily pretreated patients. In this study, 69.6% of patients had refractory disease or were intolerant to prior PD-L1 treatment, while 93.7% of patients were resistant to platinum-containing chemotherapy and 68.4% were resistant to both.1 Active phase 2 trials of garsorasib are ongoing, but the initial results of this trial have led researches to caution that there is not yet an efficacy or toxicity advantage garsorasib has compared with other KRAS G12C inhibitors.⁴

_Reference:

_{1. Li Z, Song Z, Zhao Y, et al. D-1553 (Garsorasib), a Potent and Selective Inhibitor of KRASG12C in Patients With NSCLC: Phase 1 Study Results. J Thorac Oncol. 2023 Jul;18(7):940-951. doi:10.1016/j.jtho.2023.03.015}

_{2. FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC. FDA. December 12, 2022. Accessed: July 24, 2023. https://tinyurl.com/3kpvvmet}

_{3. FDA. FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC. May 28, 2023. Accessed: July 24, 2023.https://tinyurl.com/mw95s4am}

_{4. Norman A, Adjei AA. Expanding the KRASG12C Inhibitor Class: What Do We Need Next? J Thorac Oncol. 2023 Jul;18(7):844-846. doi:10.1016/j.jtho.2023.04.010}

_{5. Skoulidis F, Li BT, Dy GK, et al. Sotorasib for Lung Cancers with KRAS p.G12C Mutation. N Engl J Med. 2021 Jun 24;384(25):2371-2381. doi:10.1056/NEJMoa2103695}

_{6. Negrao MV, Spira AI, Heist RS, et al. Intracranial Efficacy of Adagrasib in Patients From the KRYSTAL-1 Trial With KRASG12C-Mutated Non-Small-Cell Lung Cancer Who Have Untreated CNS Metastases. J Clin Oncol. 2023 Jun 16:JCO2300046. doi:10.1200/JCO.23.00046}