Novel KRAS p.G12C inhibitor Sotorasib from Amgen is the Frontrunner for First FDA Approval in Advanced Non-Small Cell Lung Cancer
The novel mutant KRAS p.G12C inhibitor sotorasib developed by Amgen (AMGN) has demonstrated a high response rate and prolonged progression-free survival in patients with relapsed KRAS p.G12C-mutated non-small cell lung cancer . Relapsed advanced non-small cell lung cancer is notoriously difficult to treat with poor response rates to subsequent therapies and few options for treatment strategies. Despite recent advances in frontline therapies, including immunotherapy, many patients continue to relapse, driving strong demand for improved second and third-line therapies.
Sotorasib is a first-in-class inhibitor that prevents the oncogenic activity of the particular mutant form of the KRAS with glycine 12 replaced by a cysteine. Targeting of mutated Kras has been a dream in cancer research for decades. This protein has long been considered undruggable when mutations change the glycine 12 residue, as this causes loss of function in GTPase activity. The mutant Kras without GTPase function results in constitutive downstream pro-growth signaling. This specific KRAS mutation produces a strong oncogenic driver in many types of cancer. Efforts to target signaling molecules downstream of Kras have not been effective at blocking this oncogenic signal due to Kras interaction with many different effectors. As most small molecules are inhibitors enzyme activity, targeting of loss-of-function mutant Kras has proven exceptionally challenging.
Sotorasib represents a breakthrough in medicinal chemistry based on the work of Dr. Kevan Shokat. This is achieved through an ingenious strategy of using cysteine-reactive compounds to covalently tether to cysteine 12 and situate in a cryptic pocket near the effector binding switch-II region . Unsurprisingly sotorasib was granted breakthrough therapy designation by the FDA in December 2020 for patients with KRAS p.G12C-mutant non-small cell lung cancer. This drug has specific activity for the G12C mutant form of Kras. Therefore, its anti-tumor activity will only be observed in tumors with this specific mutation. Despite this specific mutation niche, there is still a sizeable patient population as RAS is one of the most commonly mutated oncogenes across all cancer types, particularly solid tumors. Colorectal cancer for example is found to have KRAS oncogenic mutations in roughly 50% of cases . It is estimated that around 13% of lung adenocarcinomas harbor the KRAS G12C mutation. Success of KRAS p.G12C inhibition in one cancer type can serve as a strong indication for likely benefit in many other cancer types with the same mutation.
Patients in the Phase 1/2 CodeBreak 100 trial with KRAS p.G12C-mutated non-small cell lung cancer (NSCLC) were divided into two cohorts. The Phase 1 cohort of 59 patients demonstrated good bioavailability of sotorasib and an acceptable safety profile. Patients in this cohort also demonstrated an overall response rate of 32.2%, with a median duration of response of 10.9 months. The median progression-free survival was calculated at 6.3 months. Data from the Phase 2 registrational cohort presented at the International Association for the Study of Lung Cancer World Conference on Lung Cancer’s Presidential Symposium in January 2021 of 124 evaluable patients confirmed the Phase 1 results with an overall response rate of 37.1% (three complete responses and 43 partial responses), with a median duration of response of 10 months. Median progression-free survival was calculated at 6.8 months for this cohort. Given that these patients had heavily pre-treated NSCLC with a median of two prior treatments, in which cases the typical response rate is <20% and progression-free survival of <four months, the outcomes achieved by sotorasib offer potential for significant benefit for patients with tumors harboring the KRAS p.G12C mutation.
The safety profile for the sotorasib appears manageable with nine patients (7.1%) discontinuing treatment. Grade 3 treatment-related adverse events were reported in only 25 patients (19.8%). There were no treatment-related deaths.
Sotorasib is being evaluated in parallel in clinical trials for a variety of KRAS G12C-mutated solid tumor types, as well as in frontline treatment of KRAS p.G12C-mutated NSCLC.
Amgen filed a New Drug Application (NDA) with the FDA for sotorasib in non-small cell lung cancer on December 16, 2020. Other companies are concurrently developing similar KRAS p.G12C inhibitors, such as Mirati Therapeutic’s adagrasib, Johnson & Johnson’s JNJ-74699157, and the pan-Kras mutant inhibitor BI 1701963 from Boehringer Ingelheim. Adagrasib is currently in a Phase 1/2 trial for advanced solid tumors with KRAS p.G12C mutation. Interim data for this trial presented in October 2020 reported an overall response rate of 45% in the pooled Phase 1b and Phase 2 registrational cohorts (51 patients) with relapsed advanced non-small cell lung cancer. JNJ-74699157 is in a Phase 1/2 trial in advanced solid tumors harboring KRAS p.G12C. No results from this trial have yet been published. BI 1701963 is taking a slightly different strategy by treating as a monotherapy or in combination with trametinib. Trametinib is a MEK inhibitor, which functions as a primary downstream effector of Kras signaling. This combination offers to potentially augment the action of a pan-Kras inhibitor that may not be as potent against each individual mutant variant. BI 1701963 is currently in a Phase 1 trial in solid tumors with KRAS mutations. Primary objectives of this trial are to determine maximum tolerated dose (MTD), dose-limiting toxicity (DLT) evaluation, and objective response rate in an expansion cohort.
While clinical data for these inhibitors are still immature, there is clear potential for clinical outperformance of sotorasib by the competitors. However, sotorasib is positioned to be the first FDA approved KRAS p.G12C inhibitor and will obtain first market access.
Based on the safety and efficacy data from both Phase 1 and Phase 2 cohorts in the CodeBreak 100 trial, Biopharma Insights Group predicts an 81% probability of FDA approval of sotorasib for treatment of patients with relapsed advanced KRAS p.G12C non-small cell lung cancer.
This probability score is based on a quantitative statistical model built on clinical outcomes data from hundreds of clinical trials.
1. Chris Martin. Sotorasib Provides Durable Clinical Benefit for Patients with NSCLC and KRAS Mutations. Global News Wire. January 28, 2021. https://www.globenewswire.com/news-release/2021/01/28/2166217/0/en/Sotorasib-Provides-Durable-Clinical-Benefit-for-Patients-with-NSCLC-and-KRAS-Mutations.html
2. Lanman, B.A., et al. 2020. Discovery of a Covalent Inhibitor of KRASG12C (AMG 510) for the Treatment of Solid Tumors. J. Med. Chem., 63: 52-65.
3. Serebriiskii, I.G., et al. 2019. Comprehensive characterization of RAS mutations in colon and rectal cancers in old and young patients. Nat. Commun., 10: 3722.
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