PharmaShots Interview: Cardiff Oncology's Mark Erlander Shares Insight on the P-I Data of Onvansertib for Metastatic Colorectal Cancer

In an interview with PharmaShots, Mark Erlander, CEO of Cardiff Oncology shared his views on the data presented at the ASCO-GI Conference, P-Ib results of Onvansertib, what these results meant for the patients with this aggressive type of mCRC, and the company's other ongoing programs for Onvansertib, including metastatic castration-resistant prostate cancer and AML

Shots:

The data presented at ASCO-GI showed that Onvansertib has the potential to improve outcomes for patients with the notoriously difficult-to-treat KRAS-mutated mCRC
The results, from a P-Ib trial, showed that 83% of evaluable patients achieved clinical benefit and 75% of patients experienced tumor shrinkage
EAP is intended for patients that have progressed on prior therapy and do not meet the eligibility criteria for enrollment in the clinical trial. Requests for expanded access to Onvansertib must be made by the US-licensed, treating physician

Tuba: Discuss the key points of the poster presented at ASCO-GI.

Mark: The Phase 1b data, presented at ASCO-GI show a significant percentage of patients experienced tumor shrinkage, achieved clinical benefit, and demonstrated a durable response, with two-thirds of the patients have been on treatment for at least six months, as Daniel H. Ahn, D.O., lead investigator, and medical oncologist, Mayo Clinic Cancer Center, Arizona, has noted. Key highlights from the poster are as follows:

Efficacy:

Of the 12 evaluable patients as of the ASCO-GI data cut-off date, 5 (42%) achieved a partial response (PR); 4 patients had a confirmed PR; 1 patient went on to curative surgery; 1 patient with a non-confirmed PR went off study due to an unrelated event prior to their 16-week confirmatory scan
Time to achieving a PR ranges from 2 to 6 months in patients on treatment
8 (67%) showed durable responses of >6 months with a range from 6.1 to 13.7 months

Biomarker Analyses:

10 of 12 patients had a KRAS variant detected by ddPCR at baseline (all had a KRAS mutation detected by NGS)
Clinical responses were observed across different KRAS variants, including the 3 most common in CRC
The greatest decreases in KRAS mutant allelic frequency (MAF) after 1 cycle of treatment were observed in patients achieving a PR (ranging from -78% to -100%), while the 2 patients who progressed showed a more modest reduction in KRAS MAF (-55% and -26%)
Patients with PR and stable disease (SD) tended to have lower on-treatment KRAS MAF than patients with early progressive disease (PD)

Safety:

Onvansertib in combination with FOLFIRI/bevacizumab is safe and well-tolerated with only 9% of all adverse events (AEs) being grade 3 or 4
Grade 4 adverse events were attributed to the 5-FU bolus component of the combination regimen, which was eliminated in subsequent cycles of treatment per protocol and institutional guidelines
The only G3/G4 AEs reported in =2 patients were neutropenia (n=8), which were managed by dose delay, growth factor therapy, and/or discontinuation of the 5-FU bolus; no patients went off trial due to neutropenia
No major or unexpected toxicities were attributed to onvansertib

Source: Cardiff Oncology

Tuba: Can we have design of P-Ib/II study evaluating Onvansertib in patients with KRAS-mutated metastatic colorectal cancer?

Mark: It is a multi-center, open-label 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, will enroll up to 44 patients with a KRAS mutation and histologically confirmed metastatic and unresectable disease. In addition, eligible patients must have failed treatment with, or be intolerant to, FOLFOX (fluoropyrimidine and oxaliplatin) with or without bevacizumab.

P-Ib, was a dose escalation study at 12mg, 15mg and 18mg/m2 in successive cohorts of 3 patients and dose limiting toxicities evaluated during the first cycle (28 days). P-II is an expansion of the cohort at the recommended phase II dose (RP2D) of 15mg/m2.

For more information on the trial, please visit https://clinicaltrials.gov/ct2/show/NCT03829410.

Tuba: Give a glance at Expanded Access Program (EAP) for Onvansertib in KRAS-mutated mCRC.

Mark: Our expanded access program (EAP) in KRAS-mutated mCRC is using the same combination treatment regimen (onvansertib 15 mg/m2 + FOLFIRI/bevacizumab) and dosing schedule as the ongoing Phase Ib/II clinical trial. Our EAP however, is intended for patients that have progressed on prior therapy and do not meet the eligibility criteria for enrollment in the clinical trial. Requests for expanded access to onvansertib must be made by the U.S. licensed, treating physician.

We were encouraged by the initial findings from our EAP which reported that 6 (66%) of the first 9 patients treated have shown tumor shrinkage and remain on treatment to-date with durable responses lasting an average of 6 months. Additionally, five different KRAS mutation subtypes were represented (G12A, G12C, G12V, G13D, A146T).

Tuba: What these results (P-Ib and EAP data) could mean for patients with this aggressive type of mCRC?

Mark: The results from our P-1b data highlight the promise of onvansertib plus standard-of-care as an effective second-line treatment for patients with the KRAS-mutated mCRC. Furthermore, our EAP has been very well received by clinicians and patients who would otherwise not have access to onvansertib because they don't meet the strict eligibility criteria for our trial.

The initial observations are reassuring as we continue to see a duration of response that is consistent with the data from our clinical trial. The key difference in the patients enrolled in our EAP is that several had received and progressed on prior FOLFIRI-based treatment and with the addition of onvansertib we are seeing tumor shrinkage and durable stable disease.

Tuba: Discuss the working of Onvansertib. How it is helpful for patients with KRAS-Mutated mCRC?

Mark: Onvansertib targets KRAS mutations through downstream effects on tumor cell division. Our rationale for Onvansertib + FOLFIRI / bevacizumab in KRAS-Mutated Metastatic CRC is as follows:

Synthetic Lethality

CRC tumor cells harboring KRAS mutation are more vulnerable to cell death with PLK1 inhibition1
KRAS-mutated cells are more sensitive to onvansertib than KRAS wild-type isogenic cells2

Source: Cardiff Oncology

Synergy

Onvansertib + irinotecan (the 'IRI' in FOLFIRI) and onvansertib + 5-FU are synergistic in KRAS mutated CRC cell lines3
Combinations demonstrated significantly greater tumor growth inhibition than either drug alone

1Luo J, Elledge SJ, Cell 2009;

2Cardiff Oncology, Investigator Brochure, 2019;

3Cardiff Oncology Data on File, 2020

Tuba: What are the different clinical programs in which the company is evaluating Onvansertib?

Mark: Ovansertib is being evaluating in several different clinical programs, including:

Tuba: When can we expect the initiation of P-III & P-II study of Onvansertib in mCRPC and mCRC respectively?

Mark: We are actively recruiting for our P-II studies of onvansertib in mCRC and mCRPC. The study completion dates, respectively, will be dependent upon rate of accrual and enrollment among other things. To learn more about these clinical trials, please visit www.clinicaltrials.gov # NCT03829410 for our P-II study of onvansertib in participants with KRAS-mutated mCRC and # NCT03414034 for our P-II study of onvansertib in participants with mCRPC.

Tuba: Are you looking for collaborations to advance Onvansertib in other cancer indications? If yes, how can one contact you?

Mark: Interested parties can send an email to bd@cardiffoncology.com

Tuba: As Cardiff Oncology licensed onvansertib from Nerviano Medical Sciences. Is there any plan to license more molecules in order to expand your pipeline?

Mark: We continue to opportunistically evaluate other compounds with the potential to license.

Tuba: What does Cardiff Oncology think, how digital health is transforming oncology care?

Mark: Cardiff Oncology is a clinical-stage company, but we are seeing digital health come into play further down the line. Telemedicine, for example, is helping to increase access to care, particularly for patients in remote areas where the nearest cancer treatment center may be many miles away. New digital health tools such as AI and data analytics are showing the potential to help oncology care providers better understand the patient experience, which in turn may improve care.

Main Image Source: Parkway Cancer Centre

About Author:

Dr. Erlander has served as a Director since June 2020 and has served as our Chief Executive Officer since May 2020, and formerly as the Chief Scientific Officer from March 2013 to May 2020.