Although historically considered to be undruggable, the KRAS G12C mutation has since emerged as an actionable alteration in the field of non–small cell lung cancer.
Although historically considered to be undruggable, the KRAS G12C mutation has since emerged as an actionable alteration in the field of non–small cell lung cancer (NSCLC), Bob T. Li, MD, said in a presentation during the 15th Annual New York Lung Cancers Symposium, and several therapeutics are under examination, such as sotorasib (AMG 510) and adagrasib (MRTX849).1
“For decades [KRAS] has been considered undruggable because of its structural biology being so spheric, smooth, and round. There is also a total lack of drug-minding pockets,” said Li. “There is no key approach to KRAS as there is with EGFR, ALK, and other oncogene drivers.”
KRAS is considered to be the most mutated oncogene in human cancers (80%), and it has long been associated with poor prognoses in patients with lung cancer.2 It was determined through a retrospective analysis in 2014 that a KRAS mutation is a prognostic factor for disease-free survival (DFS) and overall survival (OS) outcomes, underscoring the need to develop drugs that target the oncogene.3
Years of research around KRAS pegged the DFS rate for patients with the KRAS mutation as 28.5 months (95% CI 16.8-40.2) compared with a median that was not reached in patient with KRAS wild-type disease (Log-rank P = .006). In addition, patients with KRAS mutations had a significantly lower OS rate at 24 months of (72.9% ± 4.8) versus 79.6% (± 4.2) for patients with KRAS wildtype (Log-rank P = .041).3
To treat patients with KRAS mutation in the past, oncologists have utilized chemotherapy, immunotherapy, and a combination of both. According to David A. Erberhard, MD, PhD, et al, who observed patients with KRAS mutation in the early 2000s, the mutation is prognostic of response to erlotinib (Tarceva) and a chemotherapy regimen of carboplatin plus paclitaxel.4
The issue currently present in the treatment paradigm for KRAS-mutant lung cancers is the absence of approved targeted therapies. Recent research is aiming to fill in this unmet need.1
Drugging the undruggable KRAS G12C mutation has been demonstrated is multiple early-phase clinical trials. Collectively, the studies show that targeting KRAS potentially improves different efficacy outcomes for patients with KRAS-mutant non–small cell lung cancer (NSCLC).1
The first-in-class KRAS G12C inhibitor, sotorasib (formerly AMG 510), has shown promise in the phase 1/2 CodeBreak 100 clinical trial (NCT03600883) across tumor types. Topline results revealed a satisfactory objective response rate (ORR) of 32.2% in heavily pretreated patients with KRAS G12C–mutant NSCLC.5
Li highlighted a European Society of Medical Oncology (ESMO) Virtual Annual Congress 2020 presentation, which provided further information about this trial. The study enrolled 59 patients
with locally advanced and unresectable or metastatic NSCLC with KRAS G12C mutations who have received no prior standard therapies and have no active brain metastases. The total study population included 129 patients with various KRAS G12C–mutant locally advanced or metastatic malignancies. The primary end point was safety, and the secondary end points were pharmacokinetics (PK), ORR, duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and duration of stable disease (SD).
Dosing with sotorasib in this study started at 180 mg. The dose was escalated from the low dose to 360 mg, 720 mg, followed by 960 mg. Three patients in the study received the 180-mg dose, 16 patients were treated with sotorasib 360 mg, 6 patients were given 720 mg, and 34 patients received the 960-mg dose.
Patients were followed on treatment with sotorasib for a median of 11.7 months (range, 4.8-21.2). At the time of data cutoff, 14 patients were continuing therapy, 35 had disease progression, 5 had died.
When evaluating for the primary end point, investigators did not discover any dose-limiting toxicities or treatment-related deaths. Treatment-related adverse events (TRAEs) were observed in 66.1% of the overall population. TRAEs were grade 3/4 in severity in 18.6% of patients, respectively.
The most common TRAEs were diarrhea (25.4%), alanine transferase (ALT) increased (20.3), and aspartate transferase (AST) increased (20.3). The most common grade 3 TRAEs included ALT increased (10.2%), diarrhea (5.1%), AST increased (5.1%), and alkaline phosphatase increase (3.4%). These TRAEs were reversible, and all but one patient safely resumed sotorasib.
Tumor burden at data cutoff compared with baseline measurements showed a reduction after treatment with sotorasib in 71.2% of patients. The ORR of 32.2% (95% CI, 20.6%-45.6%) consisted of all partial responses (PRs), and 55.9% of patients had SD. Contrarily, progressive disease was observed in 8.5% of the population. The overall DCR was 88.1% (95% CI, 77.1%-95.1%).
Of the patients who had a response to sotorasib, the median DOR was 10.9 months (range, 1.1+ to 13.6), and the median duration of SD was 4.0 months (range, 1.4 to 10.9+). The median PFS was 6.3 months (range, 0.0+ to 14.9).
Aside from CodeBreak 100, targeting KRAS in NSCLC is an area of active research, especially involving sotorasib.1 Currently the phase 3 multicenter CodeBreak 200 clinical trial (NCT04303780) of sotorasib in combination with docetaxel is recruiting patients with locally advanced and unresectable or metastatic NSCLC with KRAS G12C mutations who are aged 18 years with an ECOG performance status of at least 1 and who are previously treated. The primary end point of the study is PFS, and the secondary end points include OS, ORR, patient-reported outcomes, quality of life, DOR, time to response, DCR, and safety.
In a phase 1/2 multi-expansion cohort clinical trial (KRYSTAL-1, NCT03785249), adagrasib was evaluated in patients with advanced solid tumors harboring KRAS G12C mutations.6
From the phase 1 dose-escalation portion of the study, it was determined that the maximum tolerated dose (MTD) of adagrasib was 600 mg twice daily. The agent was administered at the 600-mg level as monotherapy to 18 patients with NSCLC in the phase 1b segment of the study. The agent was also administered in combination with either pembrolizumab (Keytruda), afatinib (Gilotrif), or cetuximab (Erbitux) in various expansion cohorts. The phase 1 coprimary end points were safety, MTD, PK, and the recommended phase 2 dose.
The phase 2 segment of KRYSTAL-1 looked at adagrasib monotherapy in 61 patients with NSCLC, who were evaluated for the primary end point of ORR per RECIST 1.1, as well as the secondary end point of safety.
Eligibility criteria for this phase 1/2 trial noted that patients must have a solid tumor with a KRAS G12C mutation, unresectable or metastatic disease, treated or stable brain metastases, and patients must have progressed on or after treatment with a PD-1/PD-L1 inhibitor after or in combination with chemotherapy for patients with NSCLC.
In prior animal models, adagrasib demonstrated favorable PK with Cave of 2.63 μg/μL, which was 2.5-fold above the target threshold for full dose interval. After this preclinical research, the agent also demonstrated tolerable safety and early efficacy.
Pooled data on responses to adagrasib showed an ORR of 43% in the 14 evaluable patients treated with the single agent in the phase 1/1b segments, which included PRs in 43% and SD in 57%, for a DCR of 100%. And amongst all patients treated at the recommended phase 2 dose with adagrasib monotherapy across all segments of the trial, the ORR was 45% with PRs in 45% and SD in 51%, for a DCR of 96%. With a median duration of treatment of 8.2 months (range, 1.4-13.1+), Li pointed out that compared with baseline, adagrasib led to a decrease in patients’ tumor burden.
As of the data cutoff for these pooled data, 83% of patients who responded have not progressed and remain on the study. In addition, 65% are still receiving adagrasib.
Treatment with adagrasib in KRYTAL-1 led to TRAEs of any grade in 85% of the population, as well as grade 3/4 TRAEs in 30% and grade 5 TRAEs in 2%. The most common any-grade TRAEs were nausea (54%), diarrhea (51%), vomiting (35%), and fatigue (32%). The most common grade 3/4 event was fatigue, which occurred in 6% of patients. The grade 5 events included pneumonitis in 1 patient and cardiac failure in 1 patient. It was noted that 7.3% of TRAEs led to discontinuation of adagrasib treatment.
These existing data around targeting KRAS are just the beginning of what is in store for the field. Upcoming trials exploring KRAS inhibition include phase 1 studies of investigational agents JNJ-74699157 and GDC-6036 as treatment of patients with KRAS G12C mutations, and a phase 1 study of BI 1701963 as treatment of patients with pan-KRAS mutations.