Intracranial Activity Observed With Sotorasib in KRAS G12C+ NSCLC Brain Metastases

Updated results from the phase 1/2 CodeBreaK 100 trial show that treatment with sotorasib (Lumakras), achieved systemic durable anticancer activity with intracranial complete responses and continued intracranial stabilization in patients with KRAS G12C–mutated non–small cell lung cancer (NSCLC) and stable brain metastases previously treated with radiation or surgery, according to a presentation given during the 2021 World Conference on Lung Cancer.¹

At a median follow-up of 12 months, sotorasib led to a confirmed objective response rate (ORR) per RECIST v1.1 criteria of 25% in patients with NSCLC and baseline brain metastases compared with 42% in patients with NSCLC without baseline brain metastases. The disease control rates (DCRs) were 77.5% vs 84.1%, respectively.

Additionally, the median progression-free survival (PFS) was 5.3 months (95% CI, 2.7-9.3) in patients with brain metastases compared with 6.7 months (95% CI, 5.3-8.2) in patients without brain metastases. The median overall survival (OS) was 8.3 months (95% CI, 7.3-12.5) vs 13.6 months (95% CI, 10.0-not evaluable), respectively.

Notably, the intracranial disease control rate was 88% (n = 14) among 16 patients with evaluable brain metastases.

Sotorasib is a first-in-class, selective, irreversible small molecule inhibitor of KRAS G12C that received accelerated approval from the FDA on May 28, 2021, for the treatment of patients with KRAS G12C–mutated locally advanced or metastatic NSCLC, as determined by an FDA-approved test, who have received at least 1 prior systemic therapy.^1,2

The regulatory decision was based on findings from the CodeBreaK 100 trial (NCT0360088), in which sotorasib induced an ORR of 37.1%, a median PFS of 6.8 months, and a median OS of 12.5 months in this patient population.³

Up to 50% of patients with NSCLC will develop brain metastases. This population has poor outcomes and represents an area of unmet need. The current standard of care for patients with NSCLC and brain metastases is docetaxel plus ramucirumab (Cyramza), which is associated with a median PFS of approximately 3 to 5 months.⁴

Patients with active brain metastases were excluded from the CodeBreaK 100 trial; however, patients with stable, asymptomatic brain metastases were eligible for inclusion.

The study enrolled patients with locally advanced or metastatic NSCLC who harbored a KRAS p.G12C mutation as assessed by central testing of tumor biopsies and had progressed on prior standard therapies. Patients received a 960-mg oral dose of sotorasib daily until disease progression.

The primary end point of the study was ORR per RECIST v1.1 criteria by blinded-independent central review. Key secondary end points included duration of response, DCR, time to response, PFS, OS, and safety.

In the post-hoc analysis, investigators retrospectively evaluated responses to sotorasib in target and non-target stable brain metastases. Target lesions were defined as measurable lesions suitable for accurate repeated measurements, whereas non-target lesions were defined as lesions too small for accurate repeated measurements.

In patients with baseline brain metastases (n = 40), the median age was 67 (range, 46-83), and 98% of patients (n = 39) were current or former smokers. Most patients had an ECOG performance status (PS) of 1 (n = 30; 75%), three metastatic sites (n = 11; 27%), and had received 1 prior line of systemic anticancer therapy (n = 16; 40%). Regarding local therapies for the brain, 65% of patients (n = 26) received prior radiotherapy, 20% (n = 8) underwent surgery, and 12% (n = 5) underwent radiotherapy and surgery.

In patients without baseline brain metastases (n = 134), the median age was 65 (range, 37-86), and 90% of patients (n = 121) were current or former smokers. Most patients had an ECOG PS of 1 (n = 95; 71%), one metastatic site (n = 60; 45%), and had received 1 prior line of systemic anticancer therapy (n = 55; 41%). Regarding local therapies for the brain, 1% of patients (n = 2) received prior radiotherapy and 1% (n = 1) underwent surgery. Of note, these local therapies may have been historic and led to sufficient removal of the brain metastasis so that the patient did not have a confirmed brain metastasis at baseline during the time of enrollment.

Additional findings from the study demonstrated that the median tumor reduction rate was 27% in patients with brain metastases compared with 40% in patients without brain metastases.

Central Response Assessment in Neuro-Oncology (RANO) analysis demonstrated that 9.2% (n = 16) of patients had baseline scans, as well as at least 1 on-treatment evaluable scan, which confirmed that 9 patients had 1 lesion, 2 patients had 4 lesions, and 5 patients had 5 or more lesions.

In patients with target and non-target central nervous system (CNS) lesions (n = 3), no patients achieved a complete response (CR), 33% (n = 1) achieved stable disease (SD) and 67% (n = 2) had progressive disease (PD). In patients with only non-target CNS lesions (n = 13), 15% (n = 2) achieved a CR, 85% (n = 11) achieved SD, and no patients had PD. In all evaluable patients with brain metastases (n = 16), 13% (n = 2) achieved a CR, 75% (n = 12) achieved SD, and 13% (n = 2) had PD.

Regarding safety, 20% (n = 8) of patients with baseline brain metastases reported grade 3 treatment-related adverse effects (TRAEs) with sotorasib compared with 19% (n = 26) of patients without baseline brain metastases. Zero patients vs 2 patients (1.5%) reported grade 4 TRAEs, respectively. No grade 5 TRAEs occurred in either arm.

The ongoing phase 1/2 CodeBreaK 101 trial (NCT04185883) is evaluating sotorasib in patients with KRAS G12C–mutated advanced solid tumors and active untreated brain metastases.¹

_References

_{1. Ramalingam SS, Skoulidis F, Govindan R, et al. Efficacy of sotorasib in KRAS p.G12C-mutated NSCLC with stable brain metastases: a post-hoc analysis of CodeBreaK100. Presented at: 2021 World Conference on Lung Cancer; September 8-14, 2021. Virtual. Abstract P52.03.}

_{2. FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC. News release. FDA. May 28, 2021. Accessed September 8, 2021. https://bit.ly/3jqh0Qk}

_{3. Skoulidis F, Li BT, Dy GK, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med. 2021;384(25):2371-2381. doi:10.1056/NEJMoa2103695}

_{4. Furuya N, Ito K, Sakaguchi T, et al. The impact of EGFR mutation status and brain metastasis for non-small cell lung cancer treated with ramucirumab plus docetaxel. Oncology. 2020;98(9):661-668. doi:10.1159/000507050}