In the first of a 2-part article series, Kartik Konduri, MD, discusses the data behind the use of adagrasib and sotorasib for patients with advanced non–small cell lung cancer harboring a KRAS G12C mutation.
Targeted OncologyTM:What do the National Comprehensive Cancer Network (NCCN) guidelines suggest for a patient like this?
KARTIK KONDOURI, MD: The NCCN recommends obtaining molecular testing for all patients before an administration of a first-line therapy, particularly an immune checkpoint inhibitor [ICI] therapy.1 Although PD-L1 expression can be elevated…on patients with an oncogenic driver, the oncogenic driver should take precedence over treatment for the PD-L1 marker.
[This is] because there are many circumstances when the PD-L1 marker might be high in those patients who have actionable genomic alterations, but nevertheless, it does not suggest significant improvement in outcomes with PD-L1 therapy. Patients with a PD-L1 expression greater than 1% with a targetable variance should receive first-line targeted therapy for that oncogene, and not a first-line ICI, because there's higher yields of response rates for the targeted therapy.
How has NGS impacted treatment for these patients?
[My center] participated in the MYLUNG Consortium, [which looked at biomarker testing rates in the community setting], but NGS testing is still woefully on the low side.2 We seem to not have made a dent yet, but hopefully, we'll continue to make a dent as MYLUNG-2 [NCT05885698] shows that there is an improvement in this consideration.3
For the overall population [of patients (n = 3474) compared with nonsquamous (n = 2820) patients], only 37% of patients were getting evaluations, and a retrospective evaluation suggested that these patients [. But in a single institution study with 335 patients, 79% received more than one biomarker test. [However,] there's at least 11% of patients in that study, in the single institution, that did not receive any testing at all. So, it's not that this doesn't happen in the larger institutions, it does happen, but that's the battle to overcome.
What studies investigate the use of adagrasib (Krazati) for patients with KRAS G12C-mutated NSCLC?
The phase 2 KYRSTAL-1 study [NCT03785249] is of adagrasib and it had the key eligibility criteria…of prior treatment with a PD-L1 inhibitor in combination with chemotherapy.4 If they had central nervous system [CNS] metastases, they were treated [with the study dose]. [For those with] stable CNS, the dosing is 600 mg twice a day before meals [n = 116]. The study objectives were objective response rate [ORR] and secondary end points included duration of response [DOR], progression-free survival [PFS], overall survival [OS], and safety.
Most of these patients [had] metastatic disease [88%]. A proportion of these patients, 10.3% and 12%, are on their third and fourth-line of therapy, respectively; but most of them only received 1 prior first-line therapy.5 Then there were people with CNS metastases [20.78%], but most of them had to be stable.
ORR was [found to be] 48%...and some [patients] had deep responses happening. The median DOR was 8.5 months [range, 6.2-13.8]. Median PFS was 6.5 months, and the best overall response was 1 patient who had a complete response [CR] at the time they evaluated therapy.
Median OS was 12.6 months…. They did have a post-hoc analysis,5 best intracranial tumor change from baseline, and that was [looking at] 33 patients who had previously been treated with 27 out of 33 [given radiation therapy prior to adagrasib]. Most of them were treated within 3 months of their study. The median intracranial PFS was 5.4 months, and the median duration of intracranial response was 11.2 months. That means those responding patients had a relatively decent time on the drug when responding. This includes patients who were untreated, too—6 of those patients were untreated in that scenario…. [For] the untreated patients there was a response, which suggests that there was intracranial efficacy.
What were the adverse events (AEs) seen with this drug?
These AEs are natural—we have almost come to expect it from tyrosine kinase inhibitors [TKIs] to a certain extent, but I will [say] that nausea [69% all grades, 4.3% grade 3/4] is a rampant concern that people have at the full dose of adagrasib. What happens is, once you have a dose reduction, nausea starts getting significantly better in those considerations. There's [many other AEs too], as you would expect, including diarrhea [70%], constipation [22%], fatigue [59%], and some edema [32%]. Renal impairment [36%] can happen as well, and then…interstitial lung disease [ILD] is known to happen, although grade 3 and 4 ILDs are relatively rare…with 1 fatality reported on the [prescribing information].
Which study introduced the use of sotorasib (Lumakras) to treat these patients?
CodeBreaK 100 [NCT03600883] is the sotorasib trial.6 CodeBreak 100 was a single-arm study with orally-administered sotorasib at 960 mg daily until [disease] progression. The primary end point was ORR and secondary end points were DOR, time to response [TTR], PFS, and OS. [Patients with] no more than 3 prior lines of therapy were allowed, and treatment beyond progressive disease [PD] was allowed if certain criteria were met, but brain metastasis had to be stable and treated.
In their evaluation, 96.8% of these patients were metastatic, and if you look at previous lines of therapy, there were 22.2% of these patients who previously had 3 lines [of therapy]. So, some of these patients were heavily pretreated; 89.7% had platinum-based chemotherapy and 81% had checkpoint inhibitors [along with chemotherapy].
In their efficacy evaluation, the ORR was 37.1%. Best response of CR in full [was seen in 4 patients] and there were deep responses. Median OS was 12.5 months, median PFS was 6.8 months, [and median DOR was 11.1 months].
They did have a post-hoc analysis in Codebreak-100…[for patients with] stable brain metastases with target and non-target stable brain metastases defined by Response Assessment in Neuro-Oncology criteria. [Moreover], 9.2% had a baseline of 1 or more on treatment-evaluable brain scan, and responses were seen in the target and non-target CNS lesions group [n = 3], with 1 patient having stable disease and 2 [patients with] progressive disease. In the only non-target CNS [lesions group] with 13 patients, 2 had a CR and 11 had stable disease.
What were the AEs and long-term outcomes on this trial?
The considerations for AEs, as one could expect, [were mostly] diarrhea [42%] and nausea [26%]. There were also considerations for issues with liver enzymes [25%], some dyspnea issues [16%], and pneumonia [12%].
The 2-year ORR was 41% [95% CI, 33.3%-48.4%] when we follow them through, and stable disease was 43%.7 Median DOR was 12.3 months [95% CI, 7.1-15.0], and nothing was more surprising on this. So, the 2-year outcomes showed a 6.3-month median PFS, but the median OS was still at approximately 12.5 months—however, the confidence interval [for OS] is adequate, at approximately 32.5%.
1. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer. Version 1.2023. Accessed June 29, 2023. http://bit.ly/42MaCpG
2. Robert NJ, Espirito JL, Chen L, et al. Biomarker testing and tissue journey among patients with metastatic non-small cell lung cancer receiving first-line therapy in The US Oncology Network. Lung Cancer. 2022;166:197-204. doi:10.1016/j.lungcan.2022.03.004
3. Aggarwal C, Marmarellis E, Hwang W, et al. Association of comprehensive molecular genotyping and overall survival in patients with advanced non-squamous non-small cell lung cancer. J clin Oncol. 2022;40(16):9022-9022. doi:10.1200/JCO.2022.40.16_suppl.9022
4. Spira A, Riely G, Gadgeel S, et al. KRYSTAL-1: Activity and safety of adagrasib (MRTX849) in patients with advanced/metastatic non–small cell lung cancer (NSCLC) harboring a KRASG12C mutation. 2022;40(16):9002-9002. doi:10.1200/JCO.2022.40.16_suppl.9002
5. Jänne PA, Riely GJ, Gadgeel SM, et al. Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRASG12C Mutation. N Engl J Med. 2022;387(2):120-131. doi:10.1056/NEJMoa2204619.
6. Skouldis F, Li B, Govindan R, et al. Overall survival and exploratory subgroup analyses from the phase 2 CodeBreaK 100 trial evaluating sotorasib in pretreated KRAS p.G12C mutated non-small cell lung cancer. J Clin Oncol. 2022;39(15):9003-9003. doi:10.1200/JCO.2021.39.15_suppl.9003
7. Dy GK, Govindan R, Velcheti V, et al. Long-Term Outcomes and Molecular Correlates of Sotorasib Efficacy in Patients With Pretreated KRAS G12C-Mutated Non-Small-Cell Lung Cancer: 2-Year Analysis of CodeBreaK 100. J Clin Oncol. 2023;41(18):3311-3317. doi:10.1200/JCO.22.02524