Changing Trial Design When Stepping Up From Second-Line To First-Line Treatment
A conversation with Fairooz F. Kabbinavar, MD, FACP, chief medical officer, Cardiff Oncology
It’s not every day that sponsors switch midstream from studying a therapy as a second-line treatment to a first-line treatment. But that’s what Cardiff Oncology is pursuing after promising early data from its CRDF-004 trial of onvansertib targeting KRAS-mutated metastatic colorectal cancer (mCRC).
In this Q&A, Chief Medical Officer Fairooz F. Kabbinavar, MD, FACP, brings us closer to the moment when the decision was made and explains how conversations with consultants and the FDA made it possible to pursue.
Clinical Leader: Cardiff Oncology announced its transition from second-line to first-line treatment of RAS-mutated metastatic colorectal cancer for the CRDF-004 trial after conducting a data review and consultation with the FDA. Take us back to some of the early conversations about going down this path. What did you learn from the data review?
Our clinical program targeting KRAS-mutated metastatic colorectal cancer (mCRC) in the second-line setting was initiated in 2019. This Phase 1b/2 trial was designed to evaluate our drug candidate, onvansertib, in combination with the standard of care (FOLFIRI chemotherapy and bevacizumab) in a second-line setting in patients who had failed an Oxaliplatin regimen in the first-line setting. As the trial data matured, we discovered an unexpected finding that a certain subgroup of patients had a strong positive response to the combination therapy of FOLFIRI + bev + onvansertib.
Specifically, the patients on our Phase 1b/2 second-line trial who had not received bevacizumab as part of their prior first-line therapy (we refer to them as “bev naïve” patients) had a remarkable 73% objective response rate (ORR) and 15-month median progression-free survival (mPFS), comparing favorably against historical controls that report an ORR of approximately 25% with a seven- to eight-month mPFS. Such high levels of efficacy have never been previously observed in second-line mCRC.
This clinical finding was the first clue that onvansertib could play an important role in RAS-mutated mCRC therapy, and we then performed a series of preclinical experiments (an example of reverse translational science) to understand the potential mechanism of action of onvansertib that produced these results. In the end, we found strong evidence to support our hypothesis that there is a synergistic effect of the onvansertib and bevacizumab combination that inhibits angiogenesis, which is the process of recruiting new blood vessels to support the growth of tumors.
And at what point did Cardiff consult the FDA about taking onvansertib from a second-line to first-line therapy?
After a substantial in-depth internal review, and discussion with many mCRC experts, we presented our clinical findings and the data supporting our hypothesis about onvansertib’s mechanism of action at a meeting with the FDA in June of 2023. At that meeting, we received their encouragement and support to transition to the first-line RAS-mutated mCRC setting because in this setting all mCRC patients are bev-naïve and this is where the data suggests onvansertib has the biggest opportunity to be most effective for the largest mCRC patient population. And these patients have a significant unmet need for new therapies given no new treatments for first-line mCRC have been approved for nearly 20 years and none targeting the RAS-mutated mCRC population ever!
At the meeting with the FDA, we also received feedback and support for our proposed clinical development plan in first-line RAS-mutated mCRC. Our plan starts with our dose-confirmation trial (CRDF-004), which we are currently enrolling at sites across the U.S., and from which we expect to provide an initial look at data in the second half of 2024. The CRDF-004 trial will be followed by a registrational Phase 3 trial that we have discussed with the FDA, and which has the potential to provide both accelerated and full approval in one trial.
What was that exchange like, and what were some of the questions asked and answered?
Our interaction with the FDA, both through a written process in advance of the meeting and during the discussion at the meeting, was extremely collegial and collaborative. We discussed the implications of our clinical and preclinical data and the options for a first-line and second-line development strategy.
The FDA also was very supportive of our request to move to a first-line treatment. From the outset, we have been working closely with them to ensure the CRDF-004 trial, and subsequent data, are sufficient to put us in a position for a Phase 3 trial that could lead to an accelerated approval of onvansertib in RAS mutated mCRC.
Generally, or specific to this circumstance, what are some risks in deciding to switch midcourse from second-line to first-line treatment?
Because our existing clinical data are from second-line patients, there is always the risk that first-line patients may respond differently to treatment given prior lines of therapy can alter tumor genetics. However, our decision to shift from second-line to first-line RAS-mutated mCRC was based on the totality of our clinical data, and our preclinical data identifying a new mechanism of action that explains our clinical findings. While all development programs involve risk, we believe our decision follows our data signals and puts us on the strongest possible path to success.
What does moving to a first-line treatment mean for patients?
Quite simply, if our CRDF-004 first-line trial generates efficacy data similar to our previous second-line trial, it means patients may have a more effective first-line treatment compared to the current SOC for a challenging disease. We estimate there are 48,000 newly diagnosed patients in the U.S. annually in the first-line RAS-mutated mCRC setting who could benefit from an improved treatment regimen. And currently, our CRDF-004 trial is the only clinical trial focused on this patient population.
And what about other stakeholders? How does this move benefit the company?
Moving onvansertib to first-line RAS-mutated mCRC allows us to target a large patient population backed by solid data from our previous trial. If our CRDF-004 trial generates supportive data, we strongly believe our company’s stakeholders would view this favorably due to the benefit we would be providing to patients.
Tell us about the relationship with Pfizer under the Ignite program. What does the program entail and how has it been beneficial to Cardiff and the pursuit of onvansertib?
Pfizer became a shareholder in our company in November 2021. As they saw the development of the full data package discussed earlier, Pfizer proposed that we consider using Pfizer Ignite to provide the clinical execution of the CRDF-004 trial, meaning they provide the services that would otherwise be provided by our CRO conducting the trial. Before Pfizer Ignite will work with a company like Cardiff Oncology, they first determine if the program is of strategic interest to Pfizer, so we believe this relationship signals Pfizer’s support for our clinical program, including our shift to the first-line setting of RAS-mutated mCRC.
About The Author:
Fairooz F. Kabbinavar, MD, FACP, joined Cardiff Oncology as chief medical officer in 2023. He is responsible for oversight of all clinical programs related to its lead asset, onvansertib. Following a 25-year academic career at UCLA as a medical oncologist, where he served as the lead investigator for two practice-changing trials that led to the approval of bevacizumab (Avastin) in metastatic colorectal cancer (mCRC), he joined Genentech as a principal medical director, where he led the small cell lung cancer (SCLC) registrational study and head and neck cancer programs. Subsequently, he led clinical development programs at Tocagen, PUMA Biotechnology, and HUYABIO International. Dr. Kabbinavar is a Harvard- and UCLA-trained academic oncologist and was a full professor of medicine and medical oncology. He also was awarded the Meinhardt Family Endowed Chair in cancer research. Dr. Kabbinavar has participated in over 100 clinical trials, has published over 100 peer-reviewed research papers, and authored more than 150 abstracts.