The KRAS Dilemma in Pancreatic Cancer: Unveiling the Potential of Sotorasib

Article by: Shreyas Paregaonkar

Introduction:

Pancreatic cancer is associated with poor prognosis, high incidence of mortality, and a low 5-year overall survival. Late diagnosis is an important factor that contributes to the poor prognosis of pancreatic cancer patients. Oncogenic driver genes like KRAS, CDKN2A, SMAD4 and TP53 are also involved in the proliferation and metastasis of pancreatic cancer. The presence of somatic KRAS mutations in most low-grade pancreatic intraepithelial neoplasias suggests that KRAS mutation is one of the earliest alterations in pancreatic tumorigenesis. Therefore, targeted therapy for KRAS mutation has considerable prospects in pancreatic ductal adenocarcinoma (PDAC) treatment. According to a study by Bannoura et al. KRAS-targeted therapy has been a challenge [2]. This could be attributed to the challenge involving the development of small molecule inhibitors specifically targeting all KRAS mutations owing to the scarcity of appropriate pockets within the protein structure. Apart from a nucleotide-binding pocket, there is a limited presence of well-defined pockets, which could potentially be deep hydrophobic pockets or allosteric regulatory pockets, along with the protein's strong affinity for GTP. Thereby, studies have focused on alternative mechanisms for indirect inhibition either by inhibiting KRAS activation or downstream pathway inhibition. Small molecule inhibitors for specific KRAS mutations have also been developed and one such inhibitor is AMG150 (Sotorasib) which targets the KRAS G12C mutation. Sotorasib is currently under investigation for KRAS G12C mutated solid tumors and is approved by the US FDA for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer.

KRAS in PDAC and the G12C mutation: 

The KRAS protein functions as a molecular switch that regulates proliferation by switching between a guanosine diphosphate (GDP)-bound inactive form and a guanosine triphosphate (GTP)-bound active form. This makes it capable of engaging downstream effector proteins to induce a pro-proliferative response. The regulated recycling of the two forms is impaired by the G12C mutation by disrupting the association of GTPase-activating proteins (GAPs), leading to the accumulation of the pro-proliferative form. The KRAS G12C mutation is one of the most common oncogenic alterations in human cancer coming across various tumors, including lung, colon, and pancreatic cancer. Particularly in pancreatic cancer, KRAS mutations are nearly ubiquitous, with up to 52% of pancreatic ductal adenocarcinomas (PDACs) harboring KRAS mutations (COSMIC accessed on 09/05/2022) [7]. Of these, the G12C mutation accounts for approximately 2-5% of all KRAS mutations in PDAC. 

Studies have shown that patients with PDAC harboring KRAS mutations, including G12C, have worse survival outcomes compared to those without KRAS mutations. One study by Itonaga et al. assessed the prognosis of the KRAS mutations in PDAC patients who had received chemotherapy and found that the progression-free survival (PFS) and overall survival (OS) was significantly longer in the patients with KRAS wildtype [3]. The progression-free survival was 6.9 months and 5.3 months for the KRAS wildtype and KRAS mutant group respectively while the overall survival was 19.9 months and 11.8 months for the wildtype and the mutant group respectively. Despite the poor prognosis indicated by KRAS G12C mutation in pancreatic cancer, it has emerged as a promising therapeutic target for Sotorasib, an FDA-approved drug for KRAS G12C mutated non-small cell lung cancer. Currently, clinical trials are underway to explore Sotorasib treatment of pancreatic cancer as preclinical studies have shown that KRAS G12C inhibition can lead to significant tumor growth inhibition and improved survival in mouse models of PDAC. 

Sotorasib Mechanism of action:

Sotorasib is a small molecule inhibitor that targets the KRAS G12C mutation selectively. The KRAS G12C mutation results in a change in the amino acid at position 12 from glycine (G) to cysteine (C), which creates a cysteine residue in the KRAS protein. The Sotorasib molecule exploits a previously unrecognized H95/Y96/Q99 cryptic pocket which is present only in GDP-KRAS G12C [6]. The drug binds irreversibly to induce a conformational change in the mutated protein and locks it in an inactive state. This conformational change prevents the protein from interacting with downstream signaling pathways that are necessary for cell growth and proliferation, ultimately leading to the inhibition of cancer cell growth. The irreversible binding of Sotorasib to KRAS G12C is important because it allows for sustained inhibition of the protein, even when the concentration of Sotorasib is low. It is worth noting that Sotorasib only targets the KRAS G12C mutation and is not effective against other KRAS mutations.

Accelerated approval of Sotorasib for KRAS G12C mutated NSCLC:

Sotorasib was approved based upon the results of CodeBreaK 100, a global, multicenter, multicohort, dose escalation and dose expansion trial that enrolled 427 patients with advanced KRAS G12C-mutated solid tumors, including 250 patients with NSCLC [4]. All the patients had received at least one prior systemic therapy except in the treatment naÏve NSCLC cohort. The primary endpoint of the trial was the overall response rate (ORR) determined by the blinded independent central review (BICR) and the secondary endpoint was the duration of response (DOR). The primary efficacy analysis included only 124 patients with KRAS G12C mutated NSCLC patients. The BICR determined ORR in the primary efficacy population was 36%. The median duration of response was 10 months with a DOR >6 months for 58% of the responders. The results of this clinical trial were the basis for the accelerated approval of Sotorasib (Brand name: LUMAKRAS) for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC).

Multiarm exploration of Sotorasib activity - the NCT03600883 trial:

The NCT03600883 trial had a number of publications of which two studies in particular explored the application of Sotorasib therapy for PDAC.

Hong, D. S et al. reported a multicenter, open-label, phase I trial that examined the efficacy of Sotorasib in KRAS G12C mutated patients with solid tumors [5]. The primary endpoint was safety and additional secondary endpoints included were objective response, duration of response, disease control, progression-free survival and duration of stable disease. A total of 129 patients were included in the trial comprising 59 with NSCLC, 42 with colorectal cancer, and 28 with other tumor types. Among the NSCLC patients, 19 had a confirmed partial response, and 33 had stable disease. Among 25 patients with colorectal cancer, 12 had a confirmed objective response. Among the other tumor types, 4 patients with pancreatic cancer, endometrial cancer, appendiceal cancer and melanoma had a response. No dose-limiting toxic effects were observed. None of the treatment-related adverse events lead to death. The study concluded that Sotorasib had promising anticancer activity against the KRAS G12C mutated heavily pretreated advanced solid tumors patients with no dose-limiting side effects even in the extended treatments.   

In another study Strickler, J. H et al. reported a phase I/II trial which examined the efficacy of Sotorasib in advanced KRAS G12C mutant pancreatic cancer patients who had been treated with at least one previous systemic therapy [1]. The main aim of the phase I portion of the trial was to determine the recommended dose and the primary endpoint of the phase II portion was to determine the centrally confirmed objective response rate which was defined as the complete or partial response. A total of 38 patients pooled from phase I and phase II were treated with Sotorasib. Objective response (21%) was confirmed by 8 patients.. The progression-free survival and the overall survival were reported as 4 months and 16 months respectively. An adverse event was reported by 16 patients, while 6 patients reported grade 3 adverse events. None of the patients had a fatal adverse event or an event leading to discontinuation of the treatment. The trial concluded that Sotorasib had an acceptable safety profile along with anticancer activity in patients with KRAS p.G12C-mutated advanced pancreatic cancer who had received previous treatment.

Conclusion:

Pancreatic cancer is a lethal malignancy with a poor prognosis and minimal benefit with cytotoxic inhibitors. Although progress is made in targeting the downstream effectors, and systemic treatments, the prognosis of the patients has not been improved significantly. A lot is yet to be studied about the resistance mechanisms to KRAS mutant or downstream pathway inhibitors. The development of the KRAS G12C inhibitors has given new hope for the targeted treatments in KRAS mutant PDAC patients. Recently, Sotorasib is recommended in the National Comprehensive Cancer Network (NCCN) guideline for PDAC (version 1.2023) as subsequent therapy for locally advanced/metastatic KRAS G12C positive PDAC patients which is useful in certain circumstances. In spite of these advances, the benefit of KRAS G12C inhibitors in PDAC patients with the KRAS mutation is restricted to a certain degree. KRAS G12C only accounts for a small subgroup of the total KRAS mutations in PDAC with KRAS G12D and G12V being the most abundant. Along with G12C inhibitors, the ongoing work to develop other inhibitors for KRAS and the new combinations may potentially provide promising new therapeutic approaches to PDAC.

References: 

1. Strickler, John H., et al. “Sotorasib in KRAS p.G12C–Mutated Advanced Pancreatic Cancer.” New England Journal of Medicine, vol. 388, no. 1, Massachusetts Medical Society, Jan. 2023, pp. 33–43. Crossref, https://doi.org/10.1056/nejmoa2208470.
2. Bannoura, Sahar F., et al. “Targeting KRAS in Pancreatic Cancer: New Drugs on the Horizon.” Cancer and Metastasis Reviews, vol. 40, no. 3, Springer Science and Business Media LLC, Sept. 2021, pp. 819–35. Crossref, https://doi.org/10.1007/s10555-021-09990-2.
3. Itonaga, Masahiro, et al. “Kras Gene Analysis Using Liquid-Based Cytology Specimens Predicts Therapeutic Responses and Prognosis in Patients With Pancreatic Cancer.” Cancers, vol. 14, no. 3, MDPI AG, Jan. 2022, p. 551. Crossref, https://doi.org/10.3390/cancers14030551.
4. Nakajima, Erica C., et al. “FDA Approval Summary: Sotorasib for KRAS G12C-Mutated Metastatic NSCLC.” Clinical Cancer Research, vol. 28, no. 8, American Association for Cancer Research (AACR), Dec. 2021, pp. 1482–86. Crossref, https://doi.org/10.1158/1078-0432.ccr-21-3074.
5. Hong, David S., et al. “KRASG12C Inhibition With Sotorasib in Advanced Solid Tumors.” New England Journal of Medicine, vol. 383, no. 13, Massachusetts Medical Society, Sept. 2020, pp. 1207–17. Crossref, https://doi.org/10.1056/nejmoa1917239.
6. Lanman, Brian A., et al. “Discovery of a Covalent Inhibitor of KRASG12C (AMG 510) for the Treatment of Solid Tumors.” Journal of Medicinal Chemistry, vol. 63, no. 1, American Chemical Society (ACS), Dec. 2019, pp. 52–65. Crossref, https://doi.org/10.1021/acs.jmedchem.9b01180.
7. Tate, John G., et al. “COSMIC: The Catalogue of Somatic Mutations in Cancer.” Nucleic Acids Research, vol. 47, no. D1, Oxford UP (OUP), Oct. 2018, pp. D941–47. Crossref, https://doi.org/10.1093/nar/gky1015.

Illustration compiled from Macrovector via Freepik, and Wikimedia