Onvansertib Triplet Shows Promise in KRAS-Mutant Metastatic Colorectal Cancer

Daniel H. Ahn, DO

Daniel H. Ahn, DO

Patients with metastatic colorectal cancer (mCRC) treated with the combination of the investigational polo-like kinase 1 inhibitor, onvansertib, plus FOLFIRI (Irinotecan, Fluorouracil [5-FU], and folinic acid [leucovorin]), and bevacizumab (Avastin) had a 100% clinical benefit rate at 8 weeks by radiographic response in a phase Ib study presented at the 2020 Gastrointestinal Cancers Symposium.

Data from the efficacy assessment also show that at 16 weeks, 100% of patients had a confirmed tumor decrease and additional tumor regression by radiographic scan. One of the patients had a partial response (PR) to the combination, and 4 patients had stable disease (SD). Additionally, 25% of the patients evaluated at 16 weeks (n = 3) had tumor decrease, 1 of whom has since proceeded to curative surgery. Within the first cycle of treatment, 5 out of 6 patients withKRASmutations developed undetectableKRASmutant levels. 

More than 2 patients in the study experienced adverse events (AEs), according to the safety assessment. Most of the AEs were grade 1 or 2, with the exception of grade 3/4 abdominal pain, and neutropenia. The most common grade 1/2 AEs were fatigue (88%), nausea (50%), and stomach pain (38%). Overall, the investigators concluded that the combination was tolerable in patients withKRAS-mutant mCRC.

The phase Ib study is in the second dose escalation with one more dose escalation to go. Once the phase II portion of the study initiates, the primary end point of the study will be objective response rate, and the secondary end points will include the number of participants with a complete response, a PR, SD, progression-free survival, and the number of participants with a reduction inKRASallelic burden on liquid biopsies.

In an interview withTargeted Oncology, Daniel H. Ahn, DO, internist/oncologist at the Mayo Clinic, discussed the phase Ib/II study of onvansertib plus FOLFIRI and bevacizumab for the treatment of patients with mCRC with a KRASmutation. He also predicts how the findings of this study may impact the treatment landscape for CRC.

TARGETED ONCOLOGY: Can you provide background on this study? What was the overall goal?

Ahn:KRASmutations are prevalent in patients with mCRC. As we know from previously published data, patients with KRASexon 2 mutation amount to greater than 40%, and the others are exon 3 and 4. KRASmutations are associated with poor prognosis and anti-EGFR resistance, and they cannot receive agents such as cetuximab (Erbitux) or panitumumab (Vectibix). The poor prognostic indications highlight the need for new targeted agents against patients with KRASalterations.

Trovagene has been able to generate a lot of data showing that FOLFIRI backbone with onvansertib can create a synergistic effect.

TARGETED ONCOLOGY: What was the rationale for this study?

Ahn:Onvansertib is a first-in-class third-generation, oral, highly-selective adenosine triphosphate inhibitor of the serine/threonine enzyme, and based on preclinical studies, it has been shown that the combination of this agent with irinotecan has synergistic effects against cells with KRASmutations. This preclinical data provided the rationale for the study, specifically with the chemotherapy regimen, FOLFIRI, plus bevacizumab, which is the standard first- or second-line therapy in patients with KRAS-mutated mCRC in combination with this investigational agent.

TARGETED ONCOLOGY: What promising signals were observed in this study?

Ahn:The preliminary results from the study are interesting because this is a phase Ib dose-escalation trial looking at the standard chemotherapy regimen FOLFIRI plus bevacizumab in combination with onvansertib. What we noticed is that when we looked at some of the correlative work, including capturing circulating tumor DNA (ctDNA), which demonstrated a decrease in percentage ofKRAS-mutated circulating tumor DNA. These were the patients that were treated with the investigational agents in combination with chemotherapy and bevacizumab. Not only did we see evidence of radiographic response, but we also saw evidence of a decrease in theirKRAS-mutated ctDNA.

TARGETED ONCOLOGY: How can these findings impact the treatment landscape for mCRC?

Ahn:While I understand the limitations of early preclinical data, what these data suggest is that onvansertib may truly affect KRAS-mutant mCRC in patients, a disease [in which] we know there are no targeted agents that can [reach] allKRASgene alterations. There are some early clinical data trials looking at specific KRAS clones targeting specificKRASmutations, specifically KRASG12C. There are no approved agents that are pan RAS inhibitors.

If this treatment does prove to be effective in the phase II study, it could eventually go on to a phase III study and eventually become a new standard of care patients withKRAS-mutated CRC. This therapy may not only be effective in CRC but also in other diseases whereKRASalterations are prevalent.

Reference:

Barsi A, Lenz HJ, Samuelz E. et al. A Phase 1b/2 Study of Onvansertib in Combination with FOLFIRI and Bevacizumab for Second Line Treatment of Metastatic Colorectal Cancer in Patients with a KRAS Mutation.J Clin Oncol. 2020;38(suppl