Sotorasib (AMG510), an experimental small molecule that selectively and irreversibly inhibits KRASG12C *, demonstrated a manageable safety profile and preliminary antitumor activity that was durable in patients with heavily pre-treated non-small cell lung cancer (NSCLC) harboring a KRAS p.G12C mutation.
The early-stage clinical trial results of the investigational drug, being developed by Amgen, were presented during the ESMO Virtual Congress 2020 with analysis accompanied by an editorial published simultaneously The New England Journal of Medicine. .
The most frequently mutated oncogene
KRAS is the most frequently mutated oncogene in human cancers. It encodes a guanosine triphosphatase (GTPase) that cycles between active guanosine triphosphate (GTP)–bound and inactive guanosine diphosphate (GDP)–bound states to regulate signal transduction. GTP binding to KRAS promotes binding of effectors to trigger signal transduction pathways including the RAF–MEK–ERK (MAPK) pathway.
KRAS mutations play a role in some of the most common cancers, including lung, colorectal, and pancreatic cancers, and are often associated with resistance to targeted therapies and poor outcomes.
Available data showed that one specific KRAS mutation, KRASG12C is responsible for accounts for nearly 44% of all KRAS mutations. This mutation is particularly prevalent in non-small cell lung cancer (NSCLC), which makes up about 85% of all lung cancer cases in the United States. According to the American Cancer Society, approximately 13% of all Americans diagnosed with NSCLC have the KRASG12C mutation, and each year 23,000 patients are diagnosed with NSCLC with this mutation. KRASG12C is also found in 1 to 3% of patients diagnosed with colorectal and pancreatic cancer.
However, despite more than three decades of development effort and the availability of clinically approved inhibitors of MEK, BRAF, and EGFR for a subset of cancer types, no selective KRAS inhibitor has been approved, resulting in a major unmet medical need among patients diagnosed with cancers harboring KRASG12C.
Now, for the first time, a novel, investigational drug may offer a glimmer of hope to patients diagnosed with cancers harboring KRASG12C. According to findings presented by David S. Hong M.D. Deputy Chair, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, a phase I clinical trial of the investigational drug reported the durability of clinical benefit and biomarker data following sotorasib treatment of patients with NSCLC.
The phase I, multicenter, open-label trial of sotorasib enrolled patients with advanced solid tumors harboring the KRAS p.G12C mutation. The trial included a dose-escalation and expansion cohorts.
As part of the clinical trial, sotorasib was administered orally once daily, with planned dose levels for the escalation cohorts (1 through 4) included 180 mg, 360 mg, 720 mg, and 960 mg, with two to four patients receiving treatment in each cohort. Each treatment cycle was 21 days.
Administration of the investigational drug continued until the occurrence of progressive disease, development of unacceptable side effects, withdrawal of consent, or end of the study. The investigators used a two-parameter Bayesian logistics-regression model to guide dose escalation.
The study permitted intrapatient dose escalations for cohorts 1 through 3, and additional patients could be enrolled in a particular cohort once a dose for that cohort was deemed safe. The expansion cohort opened once the recommended phase 2 dose had been determined.
The primary endpoint of the study was safety and key secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and progression-free survival (PFS). KRAS p.G12C mutant allele frequency (MAF) and PD-L1 level were also evaluated.
Patients eligible for study inclusion had tumors with the KRAS p.G12C mutation and had received prior systemic anticancer treatment. As of the data cut-off of June 1, 2020, 59 patients with NSCLC were enrolled; of these 35 (59.3%) patients were female with a median age of 68.0 years (range, 49 to 83). A total of 44 (74.6%) patients had received ≥2 previous lines of treatment and 30 (50.8%) patients had received ≥3 prior lines.
The safety analysis uncovered no dose-limiting toxicities or fatal treatment-related adverse events; 5 (8.5%) patients discontinued due to adverse events of any cause.
Regarding the secondary efficacy endpoints, with a median follow-up of 11.7 (range, 4.8 to 21.2) months, the ORR in the overall population was 32.2% (95% confidence interval [CI] 20.6–45.6). The median DoR was 10.9 (range, 1.1+ to 13.6) months, with 10 of 19 responding patients remaining in response at data cut-off. The DCR was 88.1% (95% Cl, 77.1–95.1). Five (8.5%) patients had progressive disease (PD). Among 34 patients treated with the 960 mg daily dose, the ORR and DCR were 35.3% and 91.2%, respectively.
Median PFS for all 59 patients was 6.3 (range, 0.0+ to 14.9) months. At data cut-off, 14 (23.7%) patients remained on study without disease progression and 26 (44.1%) had died.
Biomarkers predictive of resistance to sotorasib were not identified in the small biomarker analysis. Among 32 (54.2%) patients with KRAS p.G12C MAF data available for biomarker analysis, there were 9 partial response (PR),19 stable diseases (SD), and 2 PD.
No significant association between KRAS p.G12C MAF and response was determined (Wilcoxon p = 1 for PR versus SD).
PD-L1 data were available for 18 (30.5%) patients, with 4 patients achieving PR, 12 achieving SD, and 1 PD. The one patient with PD had a TPS of 75%, and there was no significant association between PD-L1 level and response (Wilcoxon p = 0.73 for PR versus SD).
According to the investigators, patients with heavily pre-treated NSCLC demonstrated durable responses to sotorasib, with the majority of patients achieving disease control leading to a median PFS of 6.3 months. The current limited dataset suggests that neither KRAS p.G12C MAF nor PD-L1 expression level from tissue specimen predicts response to sotorasib.
This study was funded by Amgen.
* G12C is a single point mutation with a glycine-to-cysteine substitution at codon 12. This substitution favors the activated state of KRAS, amplifying signaling pathways that lead to oncogenesis.
AMG 510 (pINN) Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101) – NCT04185883
 1257O – Hong DS, Bang Y-J, Barlesi F, et al. Durability of clinical benefit and biomarkers in patients (pts) with advanced non-small cell lung cancer (NSCLC) treated with AMG 510 (sotorasib). ESMO Virtual Congress 2020.
 Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, Falchooket GS, al. KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors. N Engl J Med. 2020 Sep 20. DOI: 10.1056/NEJMoa191723 [Article]
 LoRusso PM, and Sebolt-Leopold JS. One Step at a Time — Clinical Evidence that KRAS Is Indeed Druggable. N Engl J Med. 2020 Sep 20. DOI: 10.1056/NEJMe2026372 [Article]
 Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, Gaida K, Holt T, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019 Nov;575(7781):217-223. doi: 10.1038/s41586-019-1694-1. Epub 2019 Oct 30. PMID: 31666701.
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