Sotorasib for the treatment of locally advanced/metastatic non-small cell lung cancer

ABSTRACT

Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation is prognostic of poor survival for patients with non-small cell lung cancer (NSCLC). KRAS G12C mutations occur in 13% of NSCLC cases and despite the frequency of this mutation, advances in drug development against KRAS have historically been impeded due to the extremely high affinity of KRAS for guanosine triphosphate (GTP) and the lack of a binding pocket on the surface of KRAS that is suitable for drug binding. Sotorasib, a first-in-class, highly selective KRAS G12C inhibitor overcomes this issue by irreversibly binding in the switch-II pocket. Sotorasib was granted accelerated FDA approval for the treatment of KRASG12C-mutated locally advanced/metastatic NSCLC who have received at least one prior systemic therapy. This review summarizes the pharmacology, clinical efficacy, adverse effects, and clinical considerations of sotorasib.

Plain language summary: Sotorasib for the Treatment of Lung Cancer

Sotorasib is an oral targeted therapy option for the treatment of non-small cell lung cancer (NSCLC) with KRAS G12C mutations. KRAS G12C is a mutation of the KRAS protein that leads to uncontrollable cell growth of the cancer cells. This mutation is present in 13% of patients with NSCLC. Even though this mutation occurs frequently, it has taken some time for a drug to be developed that can target this mutation due to the unusual shape of KRAS G12C and a lack of suitable sites on it for drugs to attach. The review describes how sotorasib works, summarizes the data from clinical trials supporting its use, and information for providers to consider when prescribing this medication.

1. Introduction

Lung cancer is the third most common malignancy in the United States and the leading cause of cancer-related deaths [1]. It is classified into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) based upon histologic characteristics, with NSCLC comprising 80–85% of all lung cancer cases. [2]. Molecular biology and genomic discovery have led to the development of multiple therapeutic options for driver mutations in NSCLC, with a dramatic increase in U.S. Food and Drug Administration (FDA) approvals. Of the 207 new approvals for hematology/oncology indications between 1 May 2016, and 31 May 2021, 37 were for lung tumors [3]. Currently, the National Comprehensive Cancer Network (NCCN) Guidelines recommend at least 25 targeted therapies for treating advanced or metastatic NSCLC in which molecular abnormalities were detected [4].

The Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation is prognostic of poor survival for patients with NSCLC [4]. In NSCLC, KRAS mutations occur predominantly at codon 12, with the most common genotypes exhibiting as KRAS G12C (40%), KRAS G12V (19%), and G12D (15%) [5,6]. KRAS G12C mutations occur in approximately 13% of patients with adenocarcinoma of the lung and 3% of patients with squamous cell carcinoma of the lung [7,8]. In NSCLC, KRAS mutations are the most common targeted mutations in the North American population and are associated with cigarette smoking [4]. Despite the frequency of this mutation, advances in drug development against KRAS have historically been impeded due to the extremely high affinity of KRAS for guanosine triphosphate (GTP) and, the lack of a suitably identified orthosteric binding pocket on the surface of KRAS [9]. As a result, the design of small molecules that can compete with the GTP binding site on KRAS has been challenging. The discovery of a small pocket (P2) in KRASG12C spearheaded the development of small molecules directly inhibiting KRASG12C [10,11].

Sotorasib is a first-in-class, highly selective KRASG12C inhibitor for the treatment of locally advanced or metastatic NSCLC. Herein, we review sotorasib for the treatment of adult patients with KRAS G12C mutated locally advanced or metastatic NSCLC, who have received at least one prior systemic therapy.

2. Sotorasib mechanism and pre-clinical data

Sotorasib (AMG510) is a rationally developed acrylamide-containing pyridopyrimidine small molecule that specifically targets the KRASG12C mutation and inhibits unregulated activation of downstream KRAS oncogenic signaling pathways. Sotorasib demonstrates high in vivo potency and is distinguished mechanistically by its ability to covalently bind the cysteine residue at the heart of the highly oncogenic Gly12Cys KRAS mutant, thereby irreversibly inhibiting KRAS signaling (Figure 1) [12]. Mechanistically, the central quinazoline core of sotorasib binds the KRAS switch II pocket that normally binds GTP, while the acrylamide moiety covalently binds Cys12. This allows the isopropyl moiety to contact key residues that occupy a cryptic pocket of KRAS, which is otherwise not apparent in the absence of drug [12]. Together, these interactions prohibit the binding and catalysis of GTP, irreversibly locking the protein in an inactive GDP-bound state and thereby, permanently inhibiting KRAS function and downstream signals that drive oncogenic proliferation (Figure 1). Since the Cys12 site of action is absent in wild-type (i.e., normal) KRAS, sotorasib has decreased potential for off-target nonspecific effects that would homeostatically be mediated by KRAS.

Figure 1.

Mechanism of sotorasib-mediated inhibition of KRAS. GDP-bound KRAS is in the inactive state. Guanine-exchange factor activity driven by upstream regulators (e.g., receptor tyrosine kinases) facilitates exchange of GTP for GDP, activating KRAS and allowing it to regulate downstream cellular function including proliferation, migration, survival, and tumorigenesis, amongst others. The KRAS-G12C mutant exists in a perpetually active GTP-bound state allowing for unregulated KRAS activity. Sotorasib forms a covalent bond with the KRAS-Cys12 residue locking KRAS in the inactive GDP-bound state.

Functionally, sotorasib exhibits high potency in cellular assays, typically manifested in the range of 10–100 nM, depending on the functional outcome being measured (e.g., 68 nM EC50 at inhibiting phosphorylation of ERK1/2 kinases). In addition, compared to others in its chemical series that may have had more potent functional effects in vitro, sotorasib was selected as a developmental candidate based on its functional potency coupled with excellent aqueous solubility and membrane permeability, which facilitate rapid oral absorption and plasma exposure [12]. Perhaps most importantly, given its covalent-acting mechanism and the prevalence of the cysteine-proteome in human cell biology, a critically important feature is its selectivity for KRAS G12C compared to other cysteine-containing peptides. In this regard, of 6,451 unique cysteine-containing peptides that were profiled, the Cys12-containing peptide from KRAS G12C was the only covalently bound target of sotorasib, demonstrating near-exclusive selectivity of the agent for this target [13].

Pre-clinical xenograft studies were initially performed using MIA PaCa-2 T2 pancreatic epithelial carcinoma cells that also exhibit KRAS G12C mutagenicity and once-daily sotorasib treatment at 10, 30, 100 mg/kg was initiated when tumors were 170 mm³, resulting in 86% tumor growth inhibition, and 34% and 62% tumor regression from baseline, respectively [14]. In xenografts derived from human KRAS G12C SCLC and NSCLC, 100 mg/kg sotorasib significantly reduced tumor growth, while it had no effect on KRAS G12V mutated tumors, consistent with its cysteine-binding mechanism [13]. Interestingly, while sotorasib effectively prevented growth of tumor xenografts from KRAS G12C-driven NCI-H23 NSCLC cells, it was without significant effect in the H23ARC11 subclone that expresses amplification of MET and results in increases in KRAS-GTP, effectively driving sotorasib resistance [15]. Additionally, sotorasib susceptibility was restored in these xenografts upon addition of the MET inhibitor crizotinib or by MET knockdown, suggesting that inhibition of MET may be an option toward sotorasib resistance clinically [15].

3. Clinical data for sotorasib in KRAS G12C-mutated NSCLC and regulatory affairs

The safety and anti-tumor activity of sotorasib monotherapy was demonstrated in the first-in-human clinical trial of sotorasib. The Phase I trial was a multi-center, open-label trial conducted in several countries in North America, South America, Europe, Australia and Asia. A total of 129 patients were enrolled across multiple tumor types. Most of the patients had NSCLC (45.7%) followed by colorectal cancer (CRC) (32%). The drug was adequately tolerated across tumor types. In the subgroup of NSCLC, an objective response rate (ORR) of 32.2% (95% CI 20.62–45.64) was observed with a disease control rate (DCR) of 88.1% (95% CI 77.7–95.09). Whereas the ORR and DCR in the CRC cohort was 7.1% (95% CI 1.5–19.48) and 73.8% (95% CI 57.96–86.14) respectively. In the other cancers, an ORR of 14.3% (95% CI 57.96–86.14) and DCR of 75% (95% CI 55.13–89.31) was reported. The median progression free survival was 6.3 (0–14.9) months and 4.0 (0–11.1) months in the NSCLC and CRC cohorts.

The results of the phase I portion of the trial were reported a year after the promising results of the phase I arm. One hundred and twenty-six patients with locally advanced or metastatic KRAS G12C-mutated NSCLC whose cancers progressed after prior therapy with immune checkpoint inhibitors and/or platinum-based chemotherapy were enrolled. Patients with active, untreated brain metastases were excluded from the study. Twenty-one percent of patients had brain metastases. Sotorasib was given orally at 960 mg once daily and continued until disease progression or upon unacceptable toxicity. Of the 124 evaluable patients, the overall response rate (ORR) was 36% (95% confidence interval (CI): 28%-45%) and the observed disease control rate was 81% (95% CI: 73–87). The median duration of response (DOR) was 10 months (95% CI: 1.3 ± 11.1), median progression-free survival (PFS) was 6.3 months (95% CI: 5.3–8.2), and median overall survival (OS) was 12.5 months (95% CI: 10–18) [16]. At the median 2-year follow-up, the ORR was 41% (95% CI: 33–48) and the observed disease control rate was 84% (95% CI 77–89). The median DOR was 12.3 months (95% CI 7.1–15) [17]. In the exploratory analyses, the activity of sotorasib was observed in patients possessing co-mutations STK11 and KEAP. These results led to the accelerated approval of sotorasib for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic NSCLC who have received at least one prior systemic therapy.

At the time of accelerated FDA approval, the FDA required a post-marketing comparison of the approved 960 mg dose with a 240 mg dose to determine the optimal dose. The FDA Multi-Discipline Review did not consider 960 mg to be the optimal dose for a variety of reasons including: 1) there was no relationship between the administered dose and drug exposure at steady state, 2) there was no evidence of a relationship between dose and response rate, 3) gastrointestinal toxicities may be reduced at a lower dose, 4) preclinical data suggested that the minimal effective dose is 30–240 mg daily, and 5) the labeled dose requires patients to take eight tablets at a time, which is a significant pill burden [18].

In the phase I trials, the standard oral daily dose of 960 mg sotorasib yielded rapid absorption (Tmax of 2 h) with a peak plasma concentration of 7.5 µg/mL and 24 h AUC of 65.3 h • µg/mL [19]. Another study evaluated the absorption and metabolism of sotorasib. In healthy male volunteers given a single oral dose of 720 mg of [¹⁴C]-sotorasib, sotorasib exhibited rapid absorption with a median time to peak concentration (Tmax) of 0.75 h and peak plasma concentration (Cmax) of 6690 ng/mL. The mean terminal plasma half-life (T1/2) was 6.35 h, while radioactivity half-life was measured in the whole blood and plasma for 174 and 128 h, respectively [20]. The exposure of sotorasib is significantly enhanced when administered with a high-fat, high-calorie containing meal. Sotorasib is primarily excreted via fecal elimination (74%), with 53% of the dose excreted via this route as unchanged drug [20]. Following an oral dose, unchanged sotorasib and a single cysteine-conjugated primary metabolite (M10) were the only products found in the urine, and represented 1.6% and 1.5% of the dose, respectively [20]. In the plasma, sotorasib, the M10 metabolite, and a dealkylated metabolite (M24) that lacks the cysteine-alkylating group and is proposed to arise via CYP3A4 represent 22.2%, 31.6%, and 13.7% of each dose, respectively [20].

An open-label, phase 2, post-marketing study evaluated sotorasib at a dose of 960 mg versus 240 mg in the subset of Stage IV NSCLC patients whose tumors harbored KRAS G12C mutations and a serine/threonine kinase 11 (STK11) co-mutation, with a programmed death-ligand 1 (PD-L1) <1%. Sotorasib 960 mg (n = 104), as compared to 240 mg (n = 105), had a higher ORR (32.7% vs 24.8%), disease control response (DCR) (86.5% vs 81.9%) and an improved OS (median OS at 17.5 months was 13.0 months vs 11.7 months, HR 0.75 [95% CI: 0.53, 1.07]). Sotorasib 960 mg (n = 104), as compared to 240 mg (n = 104), was associated with a higher rate of grade ≥ 3 AEs (37% vs 20%); however, AEs were generally manageable at both doses with the recommended dose modifications [21]. Therefore, sotorasib 960 mg continues to be the FDA approved dose.

The confirmatory phase 3 trial, CodebreaK 200, randomized patients to either sotorasib or docetaxel, which was the standard of care (with or without ramucirumab) after progression on platinum-based chemotherapy and a programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor. CodeBreaK 200 was a randomized, open-label phase 3 trial at 148 centers in 22 countries. The average patient enrolled in this study was 64 years of age, Caucasian (83%), and enrolled from Europe (73%). Thirty-four percent of patients had CNS involvement. Most patients (98%) received both platinum-based chemotherapy and immunotherapy. Patients were randomly assigned to treatment with sotorasib 960 mg orally once daily (n = 171) or intravenous docetaxel 75 mg/m² once every 3 weeks (n = 174). Randomization was stratified by the number of previous lines of therapy in advance disease (1 vs 2 vs > 2), ethnicity (Asian vs non-Asian), and history of central nervous system (CNS) metastases (present or absent). The primary endpoint was PFS. After a median follow-up of 17.7 months, sotorasib significantly increased PFS (5.6 months [95% CI 4.3–7.8]) compared to docetaxel (4.5 months [95% CI 3.0–5.7]) (HR 0.66 [95% CI 0.51–0.86]; p = 0.0017). The overall response rate was significantly increased with sotorasib compared with docetaxel (28.1% [95% CI 21.5–35.4] vs 13.2% [8.6–19.2]; p < 0.001. The disease control rate was 82.5% (75.9–87.8) in the sotorasib group, compared with 60.3% (52.7–67.7) in the docetaxel group. Of the patients who responded, sotorasib was associated with a faster time to response (median 1.4 months vs 2.8 months) and longer duration of response (median 8.6 [7.1–18.0] months vs 6.8 [4.3–8.3] months) compared to docetaxel. Overall survival (OS) was not different between the two groups with a median OS of 10.6 months (95% CI 8.9–14.0) in the sotorasib arm versus 11.3 months (95% CI 9.0–14.9) in the docetaxel arm (HR 1.01 [95% CI 0.77–1.33]). In an exploratory analysis of patients with previous CNS disease, the median time to CNS recurrence was delayed with sotorasib compared to docetaxel (15.8 months [95% CI 9.7-not estimable] vs 10.5 months [5.6-not estimable]; HR 0.52 [95% CI 0.26–1.0]). Please see Table 1 for a list of sotorasib trials [23].

Table 1.

Sotorasib clinical trial results.

Clinical trial	Phase	Study Population	Intervention	Efficacy Endpoints	References
CodeBreaK 100 (n = 124)	I/II	LA/m KRAS G12C-mutated NSCLC, progression after prior therapy with immune checkpoint inhibitors and/or platinum-based chemotherapy	Sotorasib 960 mg PO daily	ORR 36% (95% CI: 28%-45%) DCR 81% (95% CI: 73–87) mDOR 10 mos (95% CI: 1.3–11.1) mPFS 6.3 mos (95% CI: 5.3-8.2) mOS 12.5 mos (95% CI: 10-18) Median 2-year follow-up ORR 41% (95% CI: 33-48) DCR 84% (95% CI: 77-89) mDOR 12.3 mos (95% CI: 7.1-15)	[7]
CodeBreaK 100 post-marketing study (n = 209)	II	Stage IV NSCLC patients, KRAS G12C mutation, STK11 co-mutation, PD-L1 < 1%, progression after previous platinum-based chemotherapy and a PD-1/PD-L1 inhibitor	Sotorasib 960 mg PO daily vs Sotorasib 240 mg PO daily	ORR: 32.7% vs 24.8% DCR: 86.5% vs 81.9% mOS: 13.0 mos vs 11.7 mos, HR 0.75 [95% CI: 0.53, 1.07]	[21]
CodeBreaK 101 (n = 58)	I	KRAS G12C-mutated advanced NSCLC	Sotorasib 960 mg once daily vs. Pembrolizumab plus carboplatin and pemetrexed x 4 cycles, maintenance with sotorasib or pembrolizumab with pemetrexed	1st line ORR: 65% (95% CI: 46.5-80.3) DCR: 100% mDOR: 9.1 mos (95% CI: 4.4-12.5) mPFS: 10.8 mos (95% CI: 5.4-NE) 2+ lines: ORR: 42% (95% CI: 20.3-66.5) DCR: 84% mDOR: NE mPFS: 8.3 mos (95% CI: 4.1-NE)	[22]
CodeBreaK 200 (n = 345)	III	LA/m KRAS G12C-mutated NSCLC, progression after prior therapy with immune checkpoint inhibitors and/or platinum-based chemotherapy	Sotorasib 960 mg PO daily vs. Docetaxel 75 mg/m2 once every 3 weeks (with or without ramucirumab)	mPFS 5.6 mos (95% CI: 4.3-7.8) vs 4.5 mos (95% CI: 3.0-5.7) (HR 0.66 [95% CI 0.51-0.86); p = 0.0017 ORR 28.1% [95% CI 21.5-35.4] vs 13.2% [8.6-19.2]; p < 0.001 DCR 82.5% vs. 60.3% (52.7-67.7) mTTR 1.4 mos vs 2.8 months mDOR: 8.6 [7.1-18.0] mos vs 6.8 [4.3-8.3] mos OS: 10.6 mos (95% CI 8.9-14.0) vs. 11.3 mos (95% CI 9.0-14.9)	[23]

LA/m=locally advanced/metastatic; KRAS=Kirsten rat sarcoma viral oncogene homolog; NSCLC=non-small cell lung cancer; ORR=overall response rate; DCR=disease control rate; mDOR=median duration of response; mPFS=median progression free survival; mOS=median overall survival; mTTR=median time to response; STK11=serine/threonine kinase 11; PD-L1=programmed death ligand 1; NE=not evaluable.

The underwhelming results of the CodebreaK 200 trial prompted the Oncologic Drugs Advisory Committee (ODAC) at the FDA to further assess the risk-benefit profile of sotorasib rather than voting on whether CodeBreaK 200 should be used to convert to traditional approval. Although the PFS endpoint met statistical significance, a 5-week PFS benefit was considered modest. In addition, there was no difference in overall survival. It is important to note that the study design was changedin consult with the FDA, based on the CodebreaK 100 trial results, to focus on the primary endpoint. Therefore, Amgen amended the study protocol to decrease the sample size to 330 patients. Due to this change, the power for overall survival was substantially decreased. Other points raised about the study conduct that could have impacted PFS endpoint included early crossover to the sotorasib arm prior to the assessment of disease progression by the blinded independent central review (BICR), early dropout in the docetaxel arm, and discrepancies in adherence to the imaging charter between the investigators and the BICR. Therefore, the ODAC voted that PFS per BICR of CodeBreaK 200 cannot be reliably interpreted. The ODAC determined that the PFS difference was small against single agent docetaxel and that there was no difference in overall survival between the two arms [24]. Finally, the ODAC expressed concern that potential bias was present due to the high rate of early dropouts/consent withdrawals on the docetaxel arm shortly after learning of treatment assignments. There is now a new post-marketing requirement for an additional confirmatory study to support full approval which needs to be completed no later than February 2028 [24].

4. Safety and tolerability of sotorasib

The safety and tolerability of sotorasib was studied in the CodeBreaK 100 and 200 trials. In CodeBreaK 100, 88 patients (69.8%) reported a treatment-related adverse event. The most frequent adverse events were diarrhea (31.7%), nausea (19.0%), increase in the alanine aminotransferase level (15.1%), increase in the aspartate aminotransferase level (15.1%), and fatigue (11.1%). Treatment-related adverse events led to dose modification and discontinuation of therapy in 22.2% and 7.1% of patients, respectively. Dose modifications occurred due to diarrhea (7.9%), increase in the aspartate aminotransferase level (7.9%), increase in the alanine aminotransferase level (7.1%), increase in the blood alkaline phosphatase level (2.4%), and nausea (2.4%) [7].

In CodeBreaK 200, sotorasib was well tolerated with fewer grade 3 or worse adverse events (n = 56 [33%] vs n = 61 [40%]) and serious treatment-related adverse events (n = 18 [11%] vs n = 34 [23%]) compared with docetaxel. The most common treatment-related adverse events with sotorasib were diarrhea (n = 20 [12%], alanine aminotransferase increase (n = 13 [8%]), and aspartate aminotransferase increase (n = 9 [5%]) [23]. These findings were comparable with data from the sotorasib expanded access protocol [25]. Dose interruptions, dose reductions, and trial regimen discontinuation occurred due to adverse events in 36%, 15%, and 10% of patients, respectively. The most common reason for discontinuation was hepatoxicity, which most frequently occurred in patients who were treated with sotorasib less than 2.6 months after the cessation of immunotherapy. There was a correlation between a long duration between immunotherapy cessation and initiation of sotorasib and a reduced incidence of grade 3 or greater hepatotoxicity. One patient (<1%) experienced a fatal adverse reaction (ILD) [23].

5. Clinical use

Sotorasib is the first FDA-approved KRAS inhibitor for patients with locally advanced/metastatic KRAS G12C-mutated NSCLC. Consistent with the current accelerated FDA approval, NCCN Guidelines recommend sotorasib for second-line treatment for KRAS G12C mutated patients after progression on first-line systemic therapy.⁵

The recommended starting dose of sotorasib is 960 mg by mouth daily. Sotorasib now comes in both 120 mg and 320 mg tablets to reduce pill burden (3 pills a day versus the original 8 pills a day). Proton-pump inhibitors and histamine-2 receptor blockers should be avoided to maximize absorption. If the use of antacids is unavoidable, sotorasib should be scheduled 4 hours before or 10 hours after antacids. Sotorasib is a substrate and moderate inducer of CYP3A4, so other medications should be screened for interactions and patients counseled to avoid grapefruit and grapefruit juice [26]. Since sotorasib may induce a pro-inflammatory response which can trigger hepatoxicity in patients who previously received immunotherapy, the timing of sotorasib after immunotherapy is an important clinical consideration [27].

Another important consideration is the use of sotorasib in patients with brain metastases. Although CodeBreaK 100 trial excluded patients with untreated brain metastases, a post-hoc analysis of the evaluable patients with stable brain metastases (n = 16) revealed that intracranial disease control was achieved in 14 of 16 patients (87.5%) [28,29]. In December 2022, adagrasib, an inhibitor of the RAS GTPase family, received accelerated FDA approval in for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic NSCLC who have received at least one prior systemic therapy based upon the KRYSTAL-1 trial. In this trial, patients with brain metastasis were prospectively enrolled. Of the 33 patients with evaluable brain metastases in the KRYSTAL-1 trial, the intracranial confirmed objective response rate was 33.3% (95% CI 18.0–51.8) and the median duration of intracranial response was 11.2 months (95% CI 2.99-not evaluable) [30]. Since both therapies are recommended by the NCCN Guidelines for use in this patient population, clinicians should make an individualized treatment decision based upon patient characteristics.

Adagrasib differs from sotorasib in its longer half-life (23 hours compared to 5 hours with sotorasib). Some providers may feel more comfortable prescribing adagrasib for patients with brain metastases, as patients with brain metastases were prospectively included in the KRYSALIS-1 trial. For patients that must be maintained on acid reducing agents, adagrasib may be preferred to sotorasib, as it was reformulated in a tablet form that does not depend on gastric acidity for absorption. Finally, the post-immunotherapy hepatotoxicity seen with sotorasib does not appear to be a class effect.

Patients who have an increased risk for nausea/vomiting/diarrhea may benefit from sotorasib as it has a lower incidence of nausea/vomiting than adagrasib. For patients with a cardiac history, sotorasib may be preferred as adagrasib is more likely to cause QTc prolongation. Patient medication histories should be evaluated as each drug has a differing CYP interaction profile. Noteably, adagrasib is a strong CYP3A4 inhibitor, which requires therapy modification of medications that are metabolized by CYP3A4 such as apixaban or rivaroxaban, which are often co-prescribed in cancer patients.

6. Current challenges and future directions

The approval of sotorasib in KRAS G12C mutated NSCLC was a landmark event that transformed the treatment paradigm of this subset of NSCLC. Yet, there is still a need for further development.

In contrast to the frontline use of targeted therapies in other driver mutations in advanced/metastatic NSCLC, such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), first-line therapy in KRAS G12C driven NSCLC remains chemotherapy/immunotherapy or immunotherapy alone (based upon PD-L1 status), while KRAS inhibitors are reserved for the second line setting [4]. This highlights the inferior response to the currently FDA approved KRAS G12C inhibitors compared to immunotherapeutic approaches. However, sotorasib with immunotherapy combination approaches were not successful due to unacceptable levels of toxicity. Sotorasib was combined with pembrolizumab or atezolizumab in KRASG12C inhibitor-naïve patients in the CodeBreak 100/101 trial. Patients experienced grade 3–4 hepatoxicity, which precluded efforts in that area going forward [31]. However, this same level of toxicity was not realized in the KRYSTAL-1 and KRYSTAL-7 trials investigating adagrasib and pembrolizumab thus far [32]. Therefore, there could still be a potential future for adagrasib in combination with immunotherapy in select patients.

Due to the positive results of CodeBreak 101 in the treatment-naïve population, CodeBreak 202 is currently ongoing. CodeBreak 202 is a phase 3 randomized study evaluating the efficacy of sotorasib versus pembrolizumab in combination with platinum doublet chemotherapy as a first-line treatment for PD-L1 negative, KRAS G12C-mutated advanced NSCLC. Seven hundred and fifty patients will be randomized to receive sotorasib 960 mg PO daily plus carboplatin and pemetrexed for up to four cycles followed by sotorasib 960 mg PO daily plus pemetrexed maintenance or pembrolizumab 200 mg IV plus caraboplatin and pemetrexed for up to four cycles followed by pembrolizumab 200 mg IV plus pemetrexed maintenance. Patients will be stratified by disease state, brain metastases, and region. The primary endpoint is PFS with secondary endpoints including ORR, OS, DCR, DOR, TTR, and safety. Intracranial PFS is an exploratory endpoint [33].

It is well established that a KEAP1 or STK11 co-mutation is a negative prognostic indicator as each is associated with poor outcomes to immunotherapy in the first-line setting, even more so than in patients with a KEAP1 or STK11 mutation alone. Both mutations are also associated with a significantly shorter mPFS and mOS to immunotherapy in this patient population/line of therapy [34]. Therefore, sotorasib is being studied in the first-line setting in CodeBreaK 201, a phase II, open-label global study to evaluate the safety and efficacy of sotorasib (960 mg or 240 mg) daily as first-line treatment in ~170 patients with KRAS G12C mutated, metastatic NSCLC with PD-L1 TPS < 1% and/or presence of STK11 mutation [35]. Estimated study completion is November 2024.

The presence of a co-mutation in tumor suppressors including TP53 and STK11 may affect treatment efficacy of first generation KRAS G12C inhibitors. Study results thus far have been inconclusive [7,23,36,37]. The LUNG MAP S1900E phase II, open-label trial utilizes comprehensive biomarker testing to prospectively understand the impact of co-mutations on the clinical activity of sotorasib in patients with KRAS G12C mutant NSCLC [38]. In this trial, patients with stage IV/recurrent KRAS G12C non-squamous NSCLC are assigned to one of three cohorts: 1) presence of TP53 co-mutation AND wild type STK11, KEAP1, NFE2L2, CUL3, 2) presence of STK11 co-mutation AND wild type TP53, KEAP1, NFE2L2, CUL3, 3) all patients not eligible for cohorts 1 and 2. Patients with asymptomatic untreated brain metastases are eligible. All patients received sotorasib 960 mg oral daily. Seventy-eight percent of accrual targets have been met as of 15 May 2023, and results are currently pending [38]. Please see Table 2 for a list of ongoing trials with sotorasib.

Table 2.

Ongoing clinical trials with sotorasib.

Clinical trial	Phase/Line of treatment	Description	Study Start Date	Anticipated enrollment	Anticipated completion date	Primary endpoint
NCT04933695 CodeBreaK 201	II/Frontline	Sotorasib 960 mg PO daily or 240 mg PO daily; Stage IV NSCLC, KRAS G1C mutation, PD-L1 < 1% and STK11 co-mutation	01/28/2022	42	11/2024	ORR
NCT05920356 CodeBreaK 202	III/Frontline	Sotorasib platinum doublet combination versus pembrolizumab platinum doublet combination in PD-L1 negative stage IIIB/IV NSCLC	11/16/2023	750	03/2031	PFS
NCT04185883 CodeBreak 101	I/II relapsed refractory	Multiple sotorasib combinations including: trametinib + panitumumab; afatinib; atezolizumab; palbocyclib; pembrolizumab; TNO155; AMG404; BI 1,701,963; everolimus	12/17/2019	1200	03/2028	DLT, TEAE, ORR
NCT05815173	I/relapsed refractory	Sotorasib plus ladrixin (interleukin‐8 receptors CXCR1 and CXCR inhibitor)	8/1/2023	40	08/2026	Incidence of DLTs; PFS
NCT06068153 AMBER	II/second line	Sotorasib plus lenvatinib	3/31/2024	47	09/2026	ORR
NCT05054725	II/relapsed refractory	Sotorasib and RMC-4630 (SHP2 inhibitor)	12/30/2021	47	03/2024	ORR
NCT05480865	I/relapsed refractory	Sotorasib and BBP-398 (SHP2 inhibitor)	7/6/2022	85	06/2025	Incidence and severity of AEs; ORR
NCT05118854	II/Neoadjuvant	Sotorasib in combination with cisplatin (or carboplatin) and pemetrexed chemotherapy for patients with surgically resectable stage IIA – IIIB	3/3/2022	27	10/2025	MPR

Development of acquired resistance to KRAS G12C-targeted therapies for patients with advanced NSCLC is inevitable. When acquired drug resistance emerges, multiple mechanisms are often implicated [39], including acquired KRAS alterations, bypass mechanisms and histologic transformation have been reported. New therapeutic strategies are needed to prevent or delay resistance. Ongoing clinical trials are investigating sotorasib in combination with platinum-pemetrexed chemotherapy [40] in treatment-naïve patients with KRAS G12C mutation positive NSCLC. In the SCARLET phase II study, thirty patients received sotorasib 960 mg once daily in combination with carboplatin AUC 5 and pemetrexed 500 mg/m² every 3 weeks for four cycles followed by sotorasib/pemetrexed maintenance. This combination has demonstrated a high ORR (88.9%), with promising PFS and acceptable safety profile.

Following the success of sotorasib and adagrasib there is now a rapidly growing landscape of novel KRAS targeted agents. Several KRASG12C inhibitors are in different phases of development (examples include: LY3537982 (Eli Lily), GDC-6036 (Genentech), D-1553 (InvestisBio), JDQ443 (Novartis Pharmaceuticals), JAB-21822 (Jacobio), RMC-6291 (Revolution Medicine). A comprehensive list of these agents in provided in Table 3. Additionally, other classes of KRAS inhibitors such as proteolysis-targeting chimeras (PROTACs) [41] are also being investigated. PROTACs are bifunctional molecules that bind to both the target and an E3-ligase protein, connected by a linker, degrading the protein of interest via the cellular proteasomal degradation machinery. KRAS G12C PROTACs in clinical development include ARS1620 [42] or MRTX849 [43].

Table 3.

Investigational KRAS G12C targeted therapies.

Drug	KRAS G12C On/Off	Trial	Phase	Sponsor
BBO-8520	On	NCT06343402	I	BridgeBio
BEBT-607	Off	NCT06117371	I	BeBetter Med Inc.
BI 1,823,911	Off	NCT04973163	I	Boehringer Ingelheim
BPI0421286	Off	–	I	Belta Pharmaceuticals
D3S 001	Off	NCT05410145	I	D3 Bio
Divarasib (GDC-6036)	Off	NCT04449874	I/II	Genentech
FMC-376	On	NCT06244771	I/II	Frontiers Medicine Co.
Garsorasib (D-1553)	Off	NCT05383898	I/II	InvestisBio
GEC-255	Off	NCT05768321	I	GenEros Biopharma
GFH925	Off	NCT05005234	I/II	Genfleet Threapeutics
GH35	Off	NCT05010694	I	Suzhou Genhouse Bio
Gleciracib (JAB-21822)	Off	NCT05002270	II	Jacobio Pharma
HBI-2438	Off	NCT05485974	I	Huyabio Intl
HS-10370	Off	NCT05367778	I	Jiangsu Hanosh Pharma
MK- 1084	Off	NCT05067283	I	Merck
Olomorasib (LY3537982)	Off	NCT04956640	I/II	Eli Lilly
Opnurasib JDQ443	Off	NCT05445843	I/II	Novartis
RMC-6291	On	NCT05462717	I	Revolution Medicine
SY-5933	Off	NCT06006793	I	Shouyao Holdings
YL-15293	Off	NCT05119933	I/ II	YL-Pharma
ZG-19018	On	NCT06237400	I/II	Zejing Pharmaceutical

Information from clinicaltrials.gov.

7. Conclusion

Sotorasib is a first-in-class KRAS G12C inhibitor that has shown significant survival benefits for patients with KRAS G12C-mutated metastatic NSCLC in the second-line setting. Sotorasib is well tolerated with the most common adverse events including diarrhea and hepatotoxicity. The presence of co-mutations and resistance mechanisms to sotorasib may limit its efficacy. Trials are currently ongoing.

Funding Statement

This paper was not funded.

Article Highlights

Sotorasib Mechanism and Pre-Clinical Data Sotorasib (AMG510) is a rationally developed acrylamide-containing pyridopyrimidine small molecule that specifically targets the KRASG12C mutation and inhibits unregulated activation of downstream KRAS oncogenic signaling pathways.  In xenografts derived from human KRAS G12C SCLC and NSCLC xenografts, 100mg/kg sotorasib significantly reduced tumor growth. Clinical Data for Sotorasib in KRAS G12C-Mutated NSCLC and Regulatory Affairs The phase I/II CodebreaK 100 study evaluated the safety and efficacy of sotorasib 960 mg by mouth daily in 126 patients in KRASG12C-mutated locally advanced/metastatic NSCLC who progressed on platinum-based therapy and a PD-1/PD-L1 inhibitor. The results of this study led to the accelerated approval of sotorasib for use in this patient population. The confirmatory phase III CodeBreak 200 study compared the safety and efficacy of sotorasib (n=171) to docetaxel (n=174) (previous standard of care) in the same patient population. Sotorasib significantly increased PFS and had a more favorable safety profile than docetaxel. Due to the modest PFS benefits and lack of OS seen in CodeBreak 200, the FDA required an additional confirmatory study prior to granting sotorasib full FDA approval. Safety and Tolerability of Sotorasib The most common treatment-related adverse events with sotorasib in the CodeBreak 200 trial were diarrhea (n=20 [12%], alanine aminotransferase increase (n=13 [8%]), and aspartate aminotransferase increase (n=9 [5%]), which was consistent with previous studies. Clinical Use Since both sotorasib and adagrasib are recommended by the NCCN Guidelines for use in this patient population, clinicians should make an individualized treatment decision based upon patient characteristics. Current Challenges and Future Directions Sotorasib is being studied in the first-line setting in CodeBreaK 201, a phase II, open-label global study to evaluate the safety and efficacy of sotorasib (960 mg or 240 mg) daily as first-line treatment in ~170 patients with KRAS-G12C mutated, metastatic NSCLC with PD-L1 TPS < 1% and/or presence of STK11 mutation. The LUNG MAP S1900E phase II, open-label trial utilizes comprehensive biomarker testing to prospectively understand the impact of co-mutations on the clinical activity of sotorasib in patients with KRAS-G12C mutant NSCLC. New therapeutic strategies are needed to prevent or delay resistance to sotorasib.

Disclosure statement

Jennifer W. Carlisle is on the Advisory Board for Sanofi; and receives institutional research funding from Amgen, AstraZeneca, Daiichi Sankyo, Parexel and Hutchmed. Nader H. Moniri is Co-founder of Channel Therapeutics, LLC; and is a consultant for Galt Pharmaceuticals; and Scientific Board of Advisors for Institute of Advanced Medical Research; and has received funding from NIH/NHLBI. Eziafa I. Oduah has received grant funding from Bristol Myers Squibb. Ticiana Leal is on the advisory board/consulting for Catalyst, OncoC4, Jazz Pharmaceuticals, Amgen, AstraZeneca, Pfizer, Regeneron, Janssen, Gilead, Genentech, Novartis, Novocure, Sanofi, Takeda, BMS and AbbVie. Jordyn Higgins is on the advisory board for OncoHost, Johnson and Johnson. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Author Contributions

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