Cardiff Oncology, Inc. (NASDAQ:CRDF) is gearing up to report results from its phase 2 randomized CRDF-004 study, which is using its drug onvansertib + chemotherapy [Folfiri] + bevacizumab [Avastin] for the treatment of RAS-mutated metastatic colorectal cancer [mCRC] patients. This combination therapy of onvansertib is being compared to the current 1st-line standard of care [SOC] therapy chemotherapy + bevacizumab. The company is currently conducting this phase 2 randomized CRDF-004 study with Pfizer (PFE). Cardiff had seen such great results from its prior phase 1b/2 TROV-054 trial in targeting 2nd-line RAS-mutated mCRC patients [along with positive data from its ONSEMBLE study], that it, along with Pfizer, decided to push forward towards targeting these 1st-line patients with a new treatment option.
Why is this program important to look at now? That's because it is gearing up to report preliminary data from the CRDF-004 study in the 2nd half of 2024. This is a highly promising target because Folfiri + bevacizumab remains as the remaining champ for 1st-line and 2nd-line RAS-mutated mCRC patients. Having said that, the FDA agreed that the next randomized study CRDF-005 study, pending the meeting of the primary endpoint with statistical significance, would quality onvansertib for an Accelerated Approval pathway.
There was a slight setback in the ongoing trial using onvansertib in combination with SOC to target 1st-line pancreatic ductal adenocarcinoma [PDAC] patients, but for a good reason. It was because a new SOC option was approved and thus, the path forward is to establish this new option together with onvansertib. With 2nd half of 2024 data from the ongoing CRDF-004 study targeting patients with RAS-mutant mCRC, plus the continued advancement of the PDAC drug development program, I believe that investors could benefit with any potential gains made.
Onvansertib Has Chance At Accelerated Approval With Next Registrational Trial
The main reason to bring up Cardiff Oncology is that its lead drug onvansertib has considerable potential for Accelerated approval for the treatment of patients with RAS-mutant metastatic colorectal cancer [mCRC]. The ongoing phase 2 CRDF-004 study, is using the combination of this drug together with the current SOC Folfiri + bevacizumab for the treatment of this patient population.
Before going over this mid-stage trial, plus any catalysts to come out of this program, I believe it is first important to note what this cancer is and what the possible market opportunity for it could be. Colorectal cancer is a type of cancer of the colon that develops with polyps on the inner lining becoming malignant. The good news for these patients is that there are tests typically done to catch precancerous polyps and then remove them. However, if these polyps are left untreated, they could become malignant and spread to other parts of a person's body. Thus, this is where the term metastatic comes in, which is that the cancer has already metastasized and spread to other organs.
The global colorectal cancer market is expected to reach $30.09 billion by 2033. This is a big market opportunity, but it is critical to note that this biotech is specifically targeting mCRC patients with the RAS mutation. It is said that about half or 50% of these patients will have this RAS mutation type. With current SOC still not being a targeted therapy because it is chemotherapy + bevacizumab [anti-VEGF inhibitor], new treatment options are definitely needed.
The thing is that Cardiff Oncology, along with its partner Pfizer, are currently testing the use of this drug for the treatment of these RAS-mutant mCRC patients. That is, onvansertib is being added to SOC therapy Folfiri + bevacizumab for the treatment of these 1st-line RAS-mutant patients. This drug combination is being explored in the ongoing phase 2 CRDF-004 study, which has already randomized a total of 90 patients and is still enrolling. The arms of the study to be tested for this mid-stage study are as follows:
- 20 mg of onvansertib + SOC [Folfiri + bevacizumab]
- 30 mg of onvansertib + SOC
- SOC alone.
The primary endpoint of this trial will be the overall response rate [ORR] as measured by RECIST v1.1 by an independent central review. In essence, a person will be considered to have an ORR if they achieve either a complete response [CR] or partial response [PR] to treatment. This is to be evaluated over a two-year period.
The ability for this company to start such a study goes back to positive data achieved from two prior studies. These two studies were phase 1b/2 TROV-054 and phase 2 ONSEMBLE. The former study being a single-arm one and then the latter being a double-blind randomized study. Based on talks with its partner Pfizer, this was the basis for starting the new randomized phase 2 CRDF-004 study. Why would the company start an entirely new mid-stage study? That's because the original plan was to only target 2nd-line RAS-mutant mCRC patients. However, there were several key factors that changed its path forward toward the targeting of these 1st-line patients. They are as follows:
- Positive data released from the phase 1b/2 TROV-054 study
- Good results shown from the phase 2 ONSEMBLE randomized study
- Potential to offer a new mechanism of action for 1st-line patients
- FDA recommendation that it would be better to target 1st-line patients
- No new approved therapy for 1st-line RAS-mutant mCRC in over 20 years.
Regarding the bullet point above, I want to focus on prior data from the phase 1b/2 ONSEMBLE study. It was noted during this randomized trial that patients given onvansertib + SOC achieved an ORR of 73%, versus only 25% for patients given SOC alone. The drug combination produced a median progression-free survival [mPFS] rate of 15 months, versus only 8 months for the patients who took SOC. This is highly substantial data, especially in light of current SOC not being as effective. This, along with talks held with the FDA, pushed the company away from 2nd-line and to attempt the targeting of 1st-line RAS-mutant mCRC patients.
Having said all of this, there is a catalyst for investors to look forward to. It is expected that data from the phase 2 CRDF-004 trial, using onvansertib in combination with Folfiri + bevacizumab for the treatment of patients with RAS-mutant mCRC, is expected in the 2nd half of 2024. There is considerable promise with this program, but it is a bit of a wait. Why is that? That's because this specific randomized study is an exploratory one. Thus, the data to be released will look at initial efficacy, along with what optimized dose would be best for it to move forward with.
Speaking of moving forward, the FDA Type C meeting held in June 2023, stated that another randomized study to be known as CRDF-005 would be able to handle both types of approval pathways. The first, which could be an Accelerated Approval pathway, would be based on the primary endpoint of objective response rate [ORR] being met with the onvansertib combination. However, on the other hand, the other efficacy endpoints of Progression-free survival [PFS] and overall-survival [OS] would serve as the basis for Full FDA approval.
Financials
According to the 10-Q SEC Filing, Cardiff Oncology had cash, cash equivalents and short-term investments of $60.3 million as of June 30th of 2024. It believes that it has enough cash runway, or cash on hand to fund its operations, through the end of Q3 of 2025. This is not enough cash runway, and this is evidenced by the fact that it had to raise some cash during a certain period. From July 1st of 2024 through August 6th of 2024, it raised gross proceeds of $2.3 million from the sale of 900,000 shares of its common stock. Plus, it is going to need to start looking at enacting another cash raise soon.
Where it might raise cash is either before or after the release of data expected from the phase 2 CRDF-004 study in the 2nd half of 2024. Total cash burn during Q2 of 2024 was $12.7 million. This is further broken down to $9.49 in Research & Development expenses and $3.21 in selling, general & administrative expenses.
Risks To Business
There are several risks that investors should be aware of before investing in Cardiff Oncology. The first risk to consider would be regarding the release of preliminary data from the phase 2 CRDF-004 study, which is using onvansertib + Folfiri + bevacizumab for the treatment of RAS-mutant mCRC patients. Such data is expected at some point before the end of this year and there is no assurance that the data from it will be positive, nor that the efficacy endpoints will be met with statistical significance.
The second risk to consider would be regarding the expected registrational study, to be known as CRDF-005. The thing is that there is no assurance that this late-stage study will be initiated. Why is that? That's because if poor data is established in the prior CRDF-004 study, then it will not be initiated. Even if this study is initiated, there is no guarantee that the Accelerated Approval or Full Approval endpoints will be positive or warrant the ability to file for regulatory approval. Lastly, if the company receives FDA Accelerated Approval for onvansertib for this RAS-mutant mCRC patient population because of meeting ORR, it is possible that it could be pulled off the market years later. This would be because to maintain this drug on the market, plus convert such Accelerated Approval to a “Full” approval, it would have to meet the other required endpoints of PFS and OS.
The third risk to consider would be in terms of the new investigator-initiated trial that is expected to begin soon. That is, a new phase 2 trial using onvansertib in combination with Nalirifox to treat patients with 1st-line PDAC. There is no assurance that combining PLK1 inhibitor together with this other drug will result in positive data being achieved, nor that it will be enough to warrant further investment towards another study. Again, the premise for dropping the prior study is because Gemzar and Abraxane are no longer SOC therapy for these patients. Nalirifox is now the new 1st-line targeted therapy established as SOC for them.
The fourth and final risk to consider would be the financial position that it is in. That's because, as it noted above, it believes that it has enough cash on hand to fund its operations through Q3 of 2025. This means it is likely going to need to raise cash in the coming months. Again, it could choose to do this either before or after the release of data from the CRDF-004 study data, to be released in the 2nd half of 2024.
Conclusion
Cardiff Oncology is gearing up for a major data readout in the 2nd half of 2024. This is a huge inflection point because it will determine if onvansertib being added to current SOC folfiri + bevacizumab is superior to SOC alone for RAS-mutant mCRC patients. This remains to be seen, but the importance of this study goes beyond only the targeting of this population. That's because if this drug ends up working well here, then it could drive the company to move towards the targeting of other RAS-mutant solid tumors. For instance, it would target all RAS-mutant types of a solid tumor.
In the case of mCRC patients, it would target 52% of RAS mutated ones, whereas a KRAS G12C inhibitor drug would only address 4% of these patients. Other such solid tumor types in its pipeline to be explored with onvansertib could be PDAC as noted above, plus small cell lung cancer [SCLC] and triple-negative breast cancer [TNBC]. I think a good thing about this company is that it is gearing up for the next study to be done with this program. That is, CRDF-005 could potentially be used for an Accelerated Approval pathway of onvansertib for RAS-mutated mCRC patients upon successful completion. If it obtains such early approval for these mCRC patients, it would be huge for both the company itself and for patients who have not seen another approved therapy for them in 20 years.
This article is published by Terry Chrisomalis, who runs the Biotech Analysis Central pharmaceutical service on Seeking Alpha Marketplace. If you like what you read here and would like to subscribe to, I'm currently offering a two-week free trial period for subscribers to take advantage of. My service offers a deep-dive analysis of many pharmaceutical companies. The Biotech Analysis Central SA marketplace is $49 per month, but for those who sign up for the yearly plan will be able to take advantage of a 33.50% discount price of $399 per year.
