Data from an ongoing Phase Ib/II clinical trial of onvansertib, also known as NMS-1286937 and PCM-075, in combination with FOLFIRI* and bevacizumab (Avastin®; Genentech/Roche) for second-line treatment of KRAS-mutated metastatic colorectal cancer (mCRC) were featured in a poster presentation at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO-GI) in San Francisco on Saturday, January 25th, 2020.
The presented data demonstrated the pan-KRAS inhibitory effect of onvansertib.
Five patients participating in this study were evaluable for efficacy assessment demonstrated a significant reduction in their KRAS mutational burden as measured by a simple blood test, which was subsequently confirmed by tumor regression visible on radiographic scans.
Three patients had a >25% tumor shrinkage and one patient is now eligible for curative surgery, a clinically meaningful achievement, which is considered to be unprecedented in this patient population with only a 5% response to standard-of-care.
In the Ib dose-escalation phase of the trial, the 1st dose level (onvansertib 12 mg/m2) was cleared for safety. The 2nd dose level (onvansertib 15 mg/m2) fully enrolled without dose-limiting toxicities (DLT) in two patients treated to-date. In addition:
- Radiographic scans performed at 8 weeks showed tumor decrease and clinical benefit in 100% (n=5) of evaluable patients treated with onvansertib 12 mg/m2 (n=5); 1 patient achieved Partial Response (PR), 4 patients achieved Stable Disease (SD).
- Radiographic responses were confirmed at 16 weeks with further tumor shrinkage in all patients; 3 patients had a >25% decrease; 1 patient is proceeding to curative surgery
- Five different KRAS mutant variants were detected in 6 patients, which represents >90% of KRAS mutations in CRC; all five KRAS variants decreased within the 1st cycle of treatment (onvansertib dose levels 12 and 15 mg/m2)
- At dose level 1 (onvansertib 12 mg/m2), 4 patients had detectable KRAS mutant ctDNA at baseline; in all 4 patients KRAS was undetectable within the 1st cycle of treatment; this preceded subsequent tumor shrinkage observed with radiographic scans, supporting the predictive value of liquid biopsy
- At dose level 2 (onvansertib 15 mg/m2), the 2 patients treated to-date had detectable KRAS mutant ctDNA at baseline; in 1 patient KRAS was undetectable within the 1st cycle of treatment; radiographic scans will be performed at 8 weeks.
Onvansertib: Investigational drug
Onvansertib, an investigational agent being developed by Trovagene **, a clinical-stage, Precision Cancer Medicine™ oncology therapeutics company, is a first-in-class, third-generation, oral and highly-selective adenosine triphosphate (ATP) competitive inhibitor of the serine/threonine polo-like-kinase 1 (PLK1) enzyme.
PLK1, which is over-expressed in multiple cancers including leukemias, lymphomas and solid tumors, has been identified as having synthetic lethality, which means that KRAS-mutated tumors have a higher sensitivity to PLK1 inhibition compared with KRAS wild-type cells.
The novel trial drug was tested against more than 260 kinases with the PLK1 isoform (not PLK2 or PLK3) being the only active target with an IC50 of 2nM. The agent is orally administered and has a 24-hour half-life with only mild-to-moderate side effects reported.
Researchers involved in the development of onvansertib believe that only targeting PLK1 and having a favorable safety and tolerability profile, along with an improved dose/scheduling regimen will significantly improve on the outcome observed in previous studies with a former panPLK inhibitor in AML.
In preclinical studies, onvansertib has demonstrated synergy with numerous chemotherapeutic and targeted therapeutics used to treat leukemia, lymphoma and solid tumors, including irinotecan, FLT3, and HDAC inhibitors, taxanes and cytotoxins.
They believe that the combination of onvansertib with other anti-cancer agents has the potential to improve clinical efficacy in acute myeloid leukemia (AML), metastatic castration-resistant prostate cancer (mCRPC), non-Hodgkin lymphoma (NHL), colorectal cancer and triple-negative breast cancer (TNBC), as well as other types of cancer.
Based on the available data the researchers believe that onvansertib may provide an answer to effectively “drugging” the once thought-to-be “undruggable” KRAS mutation. 
Early trial results
“Early results from the onvansertib Phase Ib/II trial are very exciting and encouraging,” said Daniel Ahn, the study’s principal investigator at the Mayo Clinic Cancer Center.
“Regardless of the specific KRAS mutation, we are seeing decreases in the mutational burden and tumor regression in all of our patients. This is indicative of onvansertib’s effect as a pan-KRAS inhibitor,” Ahn added.
Another investigator involved in the trial, Tanios Bekaii-Saab, leader of the Gastrointestinal Cancer Program at the Mayo Clinic Cancer Center, noted: “Successfully treating patients in the second-line setting has been quite challenging to-date, with a relatively low response rate and poor prognosis.”
“The combination of onvansertib plus standard-of-care FOLFIRI/bevacizumab offers promise as being both safe and effective,” Bekaii-Saab added.
KRAS, a major oncogene
The KRAS gene, identified over 30 years ago as a proto-oncogene, is one of the most frequently mutated oncogenes in human cancer.
The gene, which is part of a signaling pathway known as the RAS/MAPK pathway, provides instructions for making a protein called K-Ras and relays signals from outside the cell to the cell’s nucleus. These signals instruct the cell to grow and divide (proliferate) or to mature and take on specialized functions (differentiate).
The K-Ras protein is a GTPase, which means it converts a molecule called GTP into another molecule called GDP. In this way, the K-Ras protein acts like a switch that is turned on and off by the GTP and GDP molecules. To transmit signals, it must be turned on by attaching (binding) to a molecule of GTP. The K-Ras protein is turned off (inactivated) when it converts the GTP to GDP. When the protein is bound to GDP, it does not relay signals to the cell’s nucleus. 
When mutated the KRAS gene, which has long been recognized as a major oncogene, is responsible for some of the most common and deadly carcinomas, including lung, colorectal, and pancreatic cancers. Approximately 50% of mCRC patients have the KRAS mutation.
The efficacy of current second-line therapy in terms of survival prolongation and response remains very limited, especially in patients diagnosed with colorectal cancer, where there is only a 5% response rate.
KRAS and KRAS mutations
One type of KRAS mutation, KRASG12C, is responsible for nearly 44% of all known KRAS mutations. G12C, a single point mutation with a glycine-to-cysteine substitution at codon 12, favors the activated state of KRAS and amplifies the signaling pathways that lead to oncogenesis.
Researchers have observed that KRASG12C is particularly prevalent in non-small cell lung cancer (NSCLC), which makes up about 85% of all lung cancer cases in the United States. Approximately 14% of Americans with NSCLC have a KRASG12C mutation. Each year about 23,000 patients in the United States are being diagnosed with a KRASG12C NSCLC. This mutation is also found in 8% of patients with colorectal and pancreatic cancer. Collectively, KRASG12C mutations affect a patient population with a worldwide annual incidence of greater than 100,000 individuals.
However, despite the high unmet medical need, attempts to inhibit KRAS have proven difficult. Some scientists have tried to find surface targets on the protein where drugs could get a foothold to disrupt unchecked cell growth, while other developments have resulted in non-selective KRAS inhibitors, binding to both mutated and wild-type (non-mutated) KRAS, which can block the normal function of wild-type KRAS.
In addition to Trovagene‘s onvansertib, Amgen and Mirati, have produced some potentially promising early clinical results in developing drug candidates addressing specific KRAS mutations.
For example, Mirati’s investigational drug candidate MRTX849, an optimized KRASG12C inhibitor, is designed to stop some of the most complex and aggressive cancers in their tracks. MRTX849, a potent, highly selective, oral therapy, designed to maximizes inhibition by irreversibly locking the KRAS molecule in its inactive state, thereby preventing tumor cell growth which results in tumor cell death, is in phase I/II clinical development in both NSCLC and colorectal cancer. 
Researchers at Amgen are also developing a novel KRASG12C inhibitor. Their extensive compound screening and structure-based design resulted in the development of AMG 510, which irreversibly binds to KRASG12C protein and permanently locks it in an inactive state, leading to inhibition of tumor cell growth in KRASG12C driven tumors. In preclinical development, AMG 510 has demonstrated favorable potency and selectivity, and induced regression in mice bearing KRASG12C mutated tumors.
* FOLFIRI is a chemotherapeutic regimen consisting of leucovorin calcium (calcium folinate), 5-fluorouracil, and irinotecan.
** Trovagene licensed onvansertib from Nerviano Medical Sciences (NMS), the largest oncology-focused research and development company in Italy.
Onvansertib in Combination With Abiraterone and Prednisone in Adult Patients With Metastatic Castration-Resistant Prostate Cancer – NCT03414034
Onvansertib in Combination With FOLFIRI and Bevacizumab for Second Line Treatment of Metastatic Colorectal Cancer Patients With a Kras Mutation – NCT03829410
Onvansertib in Combination With Either Low-dose Cytarabine or Decitabine in Adult Patients With Acute Myeloid Leukemia (AML) – NCT03303339.
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