On September 10, 2022 Cardiff Oncology, Inc. ( Nasdaq: CRDF), a clinical-stage biotechnology company leveraging PLK1 inhibition to develop novel therapies across a range of cancers, reported new preclinical and clinical data from its program in KRAS-mutated mCRC (Press release, Cardiff Oncology, SEP 10, 2022, View Source [SID1234619372]). The data are featured in two posters being presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022, which is taking place at the Paris Expo Porte de Versailles in Paris, France, and virtually.
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Poster 397P: Early Decreases in KRAS Mutant Allele Frequency (MAF) Predict Clinical Benefit to the PLK1 Inhibitor Onvansertib in Combination with FOLFIRI/bev in 2L Treatment of Metastatic Colorectal Carcinoma (mCRC)
Poster 397P includes updated data (data cut-off date: July 25, 2022), as well as the results of correlative biomarker analyses from a Phase 1b/2 clinical trial of onvansertib plus FOLFIRI/bevacizumab in second-line KRAS-mutated mCRC. Measures of clinical response were compared between subsets of patients defined as KRAS responders or non-responders. KRAS responders were defined as patients with a ≥90% decrease in KRAS mutant allele frequency (MAF) in circulating tumor DNA (ctDNA) after one treatment cycle.
"The data from this trial show onvansertib plus FOLFIRI and bevacizumab outperforming historical controls on multiple key endpoints and are highly encouraging," said Heinz-Josef Lenz, MD, FACP, professor of medicine at USC Norris Comprehensive Cancer Center and the trial’s principal investigator. "They suggest trial participants with various KRAS mutations experience durable clinical benefits and that the onvansertib-FOLFIRI combination is avoiding the mechanisms that typically drive rapid acquired resistance to the standard-of-care (SoC). This highlights onvansertib’s potential to fill a crucial gap in mCRC’s therapeutic paradigm, as there are currently limited options available for second line patients. In addition, the significant increases between response rates and progression-free survival in KRAS responders point to changes in MAF as a potential blood-based biomarker that could aid in treatment decisions."
Key data and conclusions presented in the poster include:
Overall response rate (ORR) and median progression-free survival (mPFS) reported in Phase 1b/2 trial substantially exceed those reported in historical control trials
ORR across all evaluable patients was 35%, with 17 of 48 evaluable patients achieving an objective response and responses have been observed across multiple KRAS variants
Median duration of response (mDoR) across all evaluable patients was 11.7 months (95% confidence interval (CI): 8.9 – not reached)
mPFS across all evaluable patients was 9.3 months (95% CI: 7.6 – 13.5)
Historical control trials of different drug combinations, including the standard-of-care (SOC) of FOLFIRI with bevacizumab, in similar patient populations have shown ORR and mPFS of 5 – 13% and ~4.5 – 5.7 months, respectively1-4
KRAS responders showed significantly greater ORR and mPFS compared to non-responders
ORR in KRAS responders vs. KRAS non-responders: 63.6% (14/22) vs. 8.7% (2/23) (p = 0.00014)
mPFS in KRAS responders vs. KRAS non-responders: 12.6 months vs. 6.0 months (p=0.019)
Poster 366P: The PLK1 Inhibitor Onvansertib Overcomes Irinotecan Resistance in RAS-mutated Metastatic Colorectal Cancer (mCRC) In Vivo and in Patients
Poster 366P includes findings (as of August 5, 2022) from Cardiff Oncology’s EAP of onvansertib in KRAS-mutated mCRC, as well as data from murine studies evaluating onvansertib in combination with irinotecan in 6 PDX models of irinotecan-resistant, RAS-mutated CRC. Clinical findings reported in the Expanded Access Program (EAP) were compared between KRAS responders and non-responders. To enroll in the EAP, a patient must have been ineligible for the Phase 1b/2 clinical trial having received prior treatment with irinotecan or failed or progressed on multiple prior lines of standard-of-care therapy. EAP patients are treated with the same treatment regimen (onvansertib 15 mg/m2 plus FOLFIRI and bevacizumab) and dosing schedule as patients in the Phase 1b/2 clinical trial.
Scott Kopetz, MD, PhD, FACP, professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center commented, "Currently available third-line or later treatment options for patients are severely limited, due in large part to the high prevalence of tumors that show resistance to irinotecan. Based on the findings being presented at ESMO (Free ESMO Whitepaper), combining onvansertib with the current SOC appears to be an innovative strategy that can overcome irinotecan resistance and address a broad and pressing unmet need. This hypothesis is further supported by onvansertib’s mechanism of action, which targets DNA damage repair pathways underlying resistance to irinotecan and other chemotherapeutic agents."
Key findings and conclusions presented in the poster include:
EAP patients with prior irinotecan treatment (43 out of a total of 51 EAP patients) showed clinical benefit following treatment with onvansertib plus FOLFIRI/bevacizumab
mPFS was 4.04 months (95% CI: 2.96 – 8.38); 6-month PFS rate was 37.3% (95% CI: 24.9 – 55.8)
Of EAP patients with prior irinotecan treatment, KRAS responders had significantly longer PFS compared to non-responders.
mPFS in KRAS responders vs. KRAS non-responders: 11.18 months vs. 3.25 months (p=0.0014)
The combination of onvansertib and irinotecan showed significantly greater anti-tumor activity compared to onvansertib monotherapy in 5 of 6 tested PDX models of irinotecan-resistant, RAS-mutated CRC.
The ESMO (Free ESMO Whitepaper) posters are currently available for viewing on the congress’s virtual platform and will also be presented by Drs. Lenz and Kopetz during Poster Sessions 8 and 7, respectively, on September 11, 2022. Following the congress, the posters will be available on the "Scientific Presentations" section of the Cardiff Oncology website at View Source
Clinical and Corporate Update Conference Call and Webcast
Cardiff Oncology will host a webcast and conference call to provide a clinical and corporate update to the investment community on Monday, September 12, 2022 at 4:30 PM ET. The event will feature discussions on the planned development pathway for onvansertib in KRAS-mutated metastatic colorectal cancer and updates on other development programs. In addition, company management will provide data updates from ongoing clinical trials. To access the call, please dial 1-877-407-9208 (domestic) or 1-201-493-6784 (international) and refer to conference ID 13731618. The conference call will also be webcast live and a link to the webcast can be accessed here. A replay of the webcast will be available by visiting the "Events" section of the Cardiff Oncology website after its conclusion.
About the Phase 1b/2 Trial of Onvansertib in the Second-Line Treatment of KRAS-mutated mCRC
This is a multi-center, single-arm, Phase 1b/2 trial of onvansertib in combination with standard-of-care FOLFIRI and Avastin (bevacizumab) to evaluate the safety and preliminary efficacy of the combination regimen in the second-line treatment of patients with KRAS-mutated mCRC. The trial, A Phase 1b/2 Study of Onvansertib (PCM-075) in Combination with FOLFIRI and Bevacizumab for Second–Line Treatment of Metastatic Colorectal Cancer in Patients with a KRAS Mutation, is enrolling patients with histologically confirmed metastatic and unresectable colorectal carcinoma harboring a KRAS mutation. Patients must also have experienced disease progression or treatment intolerance to first-line treatment with fluoropyrimidine and oxaliplatin (FOLFOX or CapeOx) with or without bevacizumab to be eligible. The trial is being conducted at the following cancer centers across the U.S.: USC Norris Comprehensive Cancer Center, The Mayo Clinic (Arizona, Rochester, and Jacksonville), Kansas University Medical Center (KUMC), CARTI Cancer Center and Inova Schar Cancer Institute. For more information on the trial, please visit NCT03829410.
About the EAP for Onvansertib in KRAS-mutated mCRC
Sometimes called "compassionate use", expanded access is a potential pathway for a patient with a serious or life-threatening disease to gain access to an investigational drug for treatment outside of a clinical trial, particularly when no comparable or satisfactory alternative therapy options are available. The Cardiff Oncology EAP in KRAS-mutated mCRC is using the same combination treatment regimen (onvansertib 15 mg/m2 + FOLFIRI and bevacizumab) and dosing schedule as the ongoing Phase 1b/2 clinical trial and is intended for patients that have progressed on prior therapy and do not meet the second line eligibility criteria for enrollment in the clinical trial. The program has reached capacity and is no longer open to enrollment.