The new drug sotorasib reduces tumor size and shows promise in improving survival among patients with lung tumors caused by a specific DNA mutation, according to results of a global phase 2 clinical trial.
The drug is designed to shut down the effects of the mutation, which is found in about 13% of patients with lung adenocarcinoma, a common type of non-small-cell lung cancer.
The Food and Drug Administration approved sotorasib May 28 as a targeted therapy for patients with non-small-cell lung cancer whose tumors express a specific mutation – called G12C – in the KRAS gene and who have undergone at least one previous therapy for their cancer.
Non-small-cell lung cancer makes up over 80% of all lung cancers. More than 200,000 new cases of non-small-cell lung cancer are diagnosed annually in the United States.
The study, led by researchers at Washington University School of Medicine in St. Louis, Perlmutter Cancer Center at NYU Langone Health in New York, MD Anderson Cancer Center in Houston, and Memorial Sloan Kettering Cancer Center in New York, will be presented June 4 at the annual meeting of the American Society of Clinical Oncology and published the same day in The New England Journal of Medicine.
Sotorasib, also known by the brand name Lumakras, is made by Amgen, which funded the trial.
“This is a group of patients whose tumors have been difficult to treat and for whom we did not have targeted therapies,” said co-senior author and medical oncologist Ramaswamy Govindan, MD, the Anheuser Busch Endowed Chair in Medical Oncology at Washington University.
“The new drug is addressing an unmet need for these patients, targeting the most common mutation that we can go after. We’re also continuing to investigate this drug in combination with other experimental drugs to see if we can further improve responses and survival.”
The study involved 126 patients with non-small-cell lung cancer that had a specific mutation in the KRAS gene. A single DNA error swaps out an important protein building block, placing a cysteine where a glycine should be.
Tumors with the mutation manufacture a version of the KRAS protein that is almost constantly active, driving tumor growth. Sotorasib, taken daily by mouth, blocks tumor growth by trapping the KRAS protein in its inactive form.
Most patients in the trial previously had been treated with standard chemotherapy along with an immunotherapy drug that targets a protein called PD-1. To evaluate this new therapy, all patients enrolled in the study were treated with sotorasib; phase 2 trials evaluating safety and effectiveness often do not include a placebo group.
The drug caused at least some tumor shrinkage in 102 out of 126 patients (82%). About 37% of the patients’ tumors reduced in size at least 30%. In contrast, response rates to standard therapy in these patients range from 6% to 20%.
Forty-two patients’ tumors (34%) showed a partial response to the therapy, meaning the tumor shrank substantially and its growth was controlled for a period of time; and four patients (3%) showed a complete response that left no evidence of disease. For tumors that shrank, the tumor size was reduced by about 60%, on average.
The effects of sotorasib lasted an average of 11 months, and the drug also showed progression-free survival – meaning the tumor did not continue growing during this time – of almost seven months.
In contrast, patients with this lung cancer who receive standard therapy have an average progression-free survival of two to four months. The average overall survival for all patients in the trial was 12 ½ months.
“We are hopeful that this approach will be a new option for patients with lung cancer driven by this specific type of KRAS gene alteration,” said Govindan, who treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.
“KRAS gene alterations have long been considered not amenable for targeted therapies. A number of combination regimens are being tested here at the Siteman Cancer Center and at other leading cancer centers around the world. This highlights work that Washington University has excelled at over the past few decades—studying the genomic alterations in tumors with the goal of identifying treatment targets. This early cancer genome research is now coming full circle to help our patients.”
Govindan and his team have led pioneering studies to define genomic alterations in lung cancer, including making key contributions to The Cancer Genome Atlas, a national effort supported by the National Institutes of Health (NIH).
“The excitement surrounding this trial result is that sotorasib is now the first targeted therapy for lung cancer patients with KRAS mutations,” said co-corresponding author Vamsidhar Velcheti, MD, of NYU Langone Health. “KRAS-targeted treatments, decades in the making, are urgently needed for these patients with limited treatment options.”
About 7% of patients stopped sotorasib treatment because of severe side effects, but no side effects were life-threatening, and no patient died as a result of the treatment. The drug caused adverse events severe enough to require a reduced dose of the drug in about 22% of patients.
Almost 70% of patients experienced side effects of some kind related to the drug; the most common were diarrhea, fatigue, nausea and increased liver enzyme levels, the latter an indicator of liver damage.
“Sotorasib showed clinically significant benefit without any new safety concerns in patients with this specific form of KRAS mutant lung cancer,” Govindan said. “Moving forward, our team will seek to inform the development of combination therapies featuring sotorasib and other emerging drugs, and to determine which best fit the mix of mutations in each patient’s cancer cells.”
The researchers currently are conducting a phase 3 clinical trial comparing the effectiveness of sotorasib with a chemotherapy drug called docetaxel in 345 patients who have non-small-cell lung cancer and this specific KRAS mutation.
Cancer is one of the leading causes of death worldwide, accounting for an estimated 9.6 million deaths in 2018, with lung and colorectal cancers being the two most common causes of cancer-related deaths [1,2]. Despite the significant improvements in survival outcomes with the advent of targeted therapies and immunotherapy, the majority of patients with advanced/metastatic solid tumors will eventually progress on systemic treatment and die of disease [2,3].
The RAS proto-oncogene has been identified as a main driver of tumorigenesis in human cancers . Different solid tumors are correlated with mutations in certain isoforms of RAS, with Kirsten RAS (KRAS) being the most frequently mutated isoform . The frequency of KRAS mutation in the most common lethal solid tumors has led to several investigations in search of effective therapeutic approaches targeting KRAS. Historically,
KRAS has been acknowledged as “undruggable”, largely because the RAS proteins do not appear to present suitable pockets to which small inhibitory molecules can bind . However, over the last years, novel molecules targeting KRAS have shown promising results, suggesting that this paradigm is potentially changing with a future positive impact on therapeutic strategy .
In this review, we describe the role of KRAS mutation across different solid tumors. We also provide data on novel KRAS inhibitors currently under development and an updated overview of ongoing research in this field. The referenced papers were selected through a PubMed search performed on 11 March 2021 with the following searching terms: KRAS and non-small cell lung cancer (NSCLC), or colorectal cancer (CRC), or pancreatic cancer, or low-grade serous ovarian carcinoma (LGSOC), or endometrial cancer (EC).
Oral presentation, abstracts, and posters presented at the American Society of Clinical Oncology (ASCO) 2020 and the European Society for Medical Oncology (ESMO) 2020 annual meetings were retrieved for preliminary data of KRAS inhibitors currently under investigation. Clinicaltrials.gov (accessed on 4 May 2021) was searched to identify ongoing clinical trials of KRAS inhibitors in solid tumors.
KRAS Mutation in Solid Tumors
RAS family proteins are encoded by the highly homologous genes HRAS, NRAS, KRAS4A, and KRAS4B, of which activating mutations are involved in ~25% of all human cancers . Most mutations affect the KRAS isoform (~86%), which is predominant in NSCLC, CRC, pancreatic ductal adenocarcinoma (PDAC), LGSOC, and EC.
KRAS protein is a small guanosine triphosphate (GTPase) which connects cell mem- brane growth factor receptors to intracellular signaling pathways and transcription factors, thus playing a major role in many cellular processes . RAS proteins are made of two func- tional domains, a G domain which binds to GTP, and a membrane-targeting domain; only after KRAS is effectively attached to the cell membrane can it be activated by binding to GTP.
nce KRAS is bound to GTP, it activates more than 80 downstream signaling pathways, such as the mitogen-activated protein kinase (MAPK)–MAPK kinase (MEK), phosphoinosi- tide 3-kinase (PI3K)–AKT–mechanistic target of rapamycin (mTOR), and rapidly acceler- ated fibrosarcoma (RAF)–MEK–extracellular signal-regulated kinase (ERK) . KRAS also activates several transcription factors, such as ELK, JUN, and MYC, promoting crucial processes involved in cell differentiation, proliferation, transformation, and survival .
Mutation in KRAS impairs the intrinsic activity of GTPase, and prevents GTPase-activating proteins (GAPs) from converting GTP to guanosine diphosphate (GDP) . KRAS is thus permanently bound to GTP and activates downstream signaling pathways and nuclear transcription factors, leading to sustained cell proliferation and survival.
Beyond this sustained replication property, KRAS mutation also mediates autocrine effects and crosstalk with several components in the tumor microenvironment (TME), promoting inflammation and evading the immune response [11,12]. Tumor cells expressing mutated KRAS induce the production of cytokines, chemokines, and growth factors, medi- ating the remodeling of surrounding stroma cells .
Moreover, oncogenic KRAS interacts with other mutated oncogenes and tumor suppressor genes, inducing a pro-inflammatory immunosuppressive stroma, which contributes to immune evasion and tumor progres- sion . Figure 1 summarizes the most important signaling effector pathways activated by KRAS.
For this reason, much research has focused on targeting upstream or downstream proteins in the same pathways, specifically RAS modulators or mediators of RAS-specific synthetic lethality . However, this approach has often turned out to be unsuccessful due to the multiple intrinsic parallel escape mechanisms of RAS pathways [13,14]. The use of KRAS as a therapeutic target in different types of solid tumors is discussed in the further sections.
Non-Small Cell Lung Cancer
Role of KRAS
KRAS mutations are very frequent in NSCLC, especially in smokers; they are detected in approximately 30% of adenocarcinoma in Western countries [15,16]. KRAS G12C (glycine 12 to cysteine) mutation accounts for ~50% of all KRAS mutations, and is detected in approximately 11–16% of patients with lung adenocarcinoma. Other frequently observed mutations include KRAS G12V and KRAS G12D .
Schleffer et al. demonstrated that co-occurring mutations in the tumor protein p53 gene (TP53) (39.4%), serine/threonine kinase 11 gene (STK11) (19.8%), kelch like ECH associated protein 1 gene (KEAP1) (12.9%), ATM serine/threonine kinase gene (ATM) (11.9%), MNNG HOS transforming gene (MET) amplifications (15.4%), erb-b2 receptor tyrosine kinase 2 gene (ERBB2) amplifications (13.8%, exclusively in G12C), EGFR (1.2%), and BRAF (1.2%) are detected in KRAS mutated NSCLC .
KRAS mutation seems to be an independent negative prognostic factor for survival in NSCLC . Goulding et al. performed a systematic review and meta-analysis demonstrating that KRAS mutational status could be associated with poor prognosis for survival and response outcomes in advanced NSCLC patients .
Several studies have investigated the prognostic role of KRAS mutation in patients receiving immune-checkpoint inhibitors. However, to date the role of KRAS during immunotherapy is not well established. Results from a meta-analysis by Kim et al. demon- strated that immunotherapy compared to chemotherapy significantly improved OS in pretreated patients with mutated KRAS NSCLC but not in those with wild-type KRAS .
On the contrary, results from a retrospective study involving 530 previously treated NSCLC patients treated with nivolumab showed that KRAS status was not a reliable predictor of im- munotherapy efficacy in terms of response and survival rates . Chengming et al. demon- strated that mutated KRAS NSCLC showed an inflammatory phenotype with adaptive immune resistance, characterized by an increased proportion of CD8+ tumor-infiltrating lymphocytes (TILs) and high tumor mutational burden (TMB) .
An exploratory analysis of patients randomized to first line pembrolizumab vs. platinum-based chemotherapy in the KEYNOTE-042 trial, showed that patients with KRAS G12C mutation had higher programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) and TMB, compared with KRAS wild-type patients. Based on the efficacy results of immunotherapy regardless of KRAS mutational status in this trial, the authors suggested that a pembrolizumab-based treatment can be considered a valuable comparator for clinical trials of first line KRAS targeted therapy in KRAS mutated NSCLC .
This putative immune sensitizing feature of KRAS mutation can be partly impaired by the concomitant presence of other mutations, as loss or alteration of serine-threonine kinase 11 (STK11)/liver kinase B1 (LKB1), which acts as a genomic driver of primary resistance to immune-checkpoint inhibitors [25,26].
In the past, several trials have investigated the inhibition of KRAS downstream signaling pathways, including RAF/MEK/ERK and PI3K/AKT/mTOR pathways, with disappointing overall results. This approach probably failed due to the many alternative feedback mechanisms modulating these pathways . Despite promising findings from a phase II study, results from the phase III SELECT-1 trial demonstrated that the MEK inhibitor selumetinib in combination with docetaxel did not improve progression-free survival (PFS) compared to chemotherapy alone in 510 KRAS mutated NSCLC patients (median PFS 3.9 months vs. 2.8 months, p = 0.44) [28,29].
The MEK1/MEK2 inhibitor trametinib did not improve PFS and response rates (RR) compared with docetaxel in 121 KRAS mutated NSCLC patients . In the phase II study BASALT-1, Vansteenkiste et al. investigated the pan-PI3K inhibitor buparlisib in PI3K pathway-activated, relapsed NSCLC patients. The trial stopped early due to futility at the first interim analysis .
Recently, several inhibitors targeting KRAS G12C with similar covalent binding mech- anisms have been investigated in clinical trials. Adagrasib (MRTX849) is a potent and selective KRAS G12C inhibitor that demonstrated a significant anti-tumor efficacy in all evaluated KRAS G12C mutated cancer models . The administration of adagrasib, at a dose of 600 mg orally twice a day, has been investigated in the multi-cohort, phase I/II KRYSTAL-1 study (NCT03785249), in 110 patients with advanced solid tumors, includ- ing 79 NSCLC patients with KRAS G12C mutation, who had progressed after previous standard treatments.
Preliminary efficacy and safety results of adagrasinb in the cohort of NSCLC patients were presented during the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Therapeutic in 2020: among 51 NSCLC patients evaluable for re- sponse, objective response rate (ORR) was 45% and disease control rate (DCR) was 96% . Adagrasib demonstrated a manageable safety profile, the most common grade 3 or greater treatment-emergent adverse events (TEAEs) included nausea, diarrhea, vomiting, fatigue, and elevations of aminotransferase levels .
Sotorasib (AMG 510) is an oral KRAS G12C inhibitor that permanently blocks KRAS G12C in an inactive GDP-bound state. In preclinical analyses, this small molecule demon- strated the ability to promote tumor regression and improve the efficacy of chemotherapy and targeted agents. Furthermore, sotorasib in combination with immune checkpoint in- hibitors demonstrated tumor regression in mice models . CodeBreak 100 (NCT03600883) is a phase I/II study evaluating sotorasib in patients with advanced solid tumors harboring KRAS G12C mutation, who progressed after previous standard treatments. Recently, Hong et al. published the results of the phase I study with 129 patients enrolled .
The primary endpoint was safety, while key secondary endpoints included pharmacokinetics (PK), ORR, DCR, duration of response (DoR), and PFS. Sotorasib demonstrated notable anti-tumor activity across all 56 NSCLC patients enrolled in the trial . ORR was 32% and DCR was 88%. The median time to response was 1.4 months and the median DoR was 10.9 months. The median PFS for NSCLC patients was 6.3 months.
Tumor shrinkage was described in 71% of patients at the first week-6 assessment. Sotorasib showed a favorable safety profile, with no dose-limiting toxic effects or treatment-related deaths reported. Any grade treatment-related adverse events (TRAEs) occurred in 56% of enrolled patients, and only two patients (1.6%) experienced serious adverse events. The most common adverse events described were diarrhea, fatigue, nausea, vomiting, and elevations of aminotransferase levels .
During the 2020 World Conference on Lung Cancer (WCLC), results from the phase II CodeBreak 100 study, enrolling 126 advanced NSCLC patients, were presented. Forty- six patients experienced a confirmed response, resulting in an ORR of 37% and DCR of 80%. The median time to objective response was 1.4 months, and the median DoR was 10 months. The median PFS was 6.8 months. TRAEs of any grade were described in 70% of patients, leading to discontinuation in 9 (7.1%) patients. The most frequently reported grade 3 TRAEs were alanine aminotransferase increase (6.3%), aspartate aminotransferase increase (5.6%), and diarrhea (4.0%). There were no treatment-related deaths.
The randomized, phase III CodeBreak 200 trial (NCT04303780), comparing sotorasib WITH docetaxel in advanced NSCLC patients with KRAS G12C mutation who have pro- gressed after platinum-based doublet chemotherapy and checkpoint inhibitor, is currently recruiting . Table 1 shows the characteristics of ongoing clinical trials of KRAS mutated tumors (direct KRAS targeting), while Table 2 shows ongoing clinical trials of drugs target- ing KRAS pathways. Details on the mechanisms of action of novel therapeutic compounds are reported in Table 3.
reference link :https://doi.org/10.3390/ pharmaceutics13050653
More information: Skoulidis F, Li BT, Dy GK, Price TJ, Falchook GS, Wolf J, Italiano A, Schuler M, Borghaei H, Barlesi F, Kato T, Curioni-Fontecedro A, Sacher A, Spira A, Ramalingam SS, Takahashi T, Besse B, Anderson A, Ang A, Tran Q, Mather O, Henary H, Ngarmchamnanrith G, Friberg G, Velcheti V, Govindan R. Sotorasib for lung cancers with KRAS p.G12C mutations (CodeBreak 100). The New England Journal of Medicine. June 4, 2021.