Executive Summary / Key Takeaways

• Cardiff Oncology is strategically focused on addressing the significant unmet need in first-line RAS-mutated metastatic colorectal cancer (mCRC) with its lead asset, onvansertib, a differentiated PLK1 inhibitor.
• Onvansertib demonstrates a novel mechanism of action, synergizing with bevacizumab by targeting distinct nodes in the hypoxia pathway, providing a potential "1-2 punch" validated by preclinical and clinical data in bev-naïve patients.
• The recent completion of enrollment in the randomized Phase 2 CRDF-004 trial and encouraging initial data showing a dose-dependent objective response rate signal (up to 64% at 30mg) represent key operational and clinical milestones supporting the first-line strategy.
• A strengthened intellectual property portfolio, including patents covering onvansertib's use in bev-naïve mCRC, enhances the competitive moat ahead of potential registrational studies.
• With cash and investments of $79.9 million as of March 31, 2025, and projected runway into Q1 2027, the company has funding to reach critical data readouts and FDA discussions, though future capital will be required for potential Phase 3 and commercialization.

The Strategic Pivot: Targeting an Unmet Need in RAS-Mutated mCRC

Cardiff Oncology, Inc. is a clinical-stage biotechnology company dedicated to developing novel therapies for cancer by leveraging the inhibition of Polo-like Kinase 1 (PLK1). Founded in 1999 as Trovagene, Inc., the company's evolution reflects a persistent pursuit of high-impact oncology targets. A pivotal moment in its trajectory was the 2017 licensing of NMS-1286937, now known as onvansertib, an oral and highly selective PLK1 inhibitor that has become the cornerstone of its pipeline.

Initially, Cardiff focused on onvansertib in the second-line treatment of KRAS-mutated metastatic colorectal cancer (mCRC). However, emerging clinical data from its Phase 1b/2 trial (TROV-54) revealed a compelling signal, particularly in patients who had not previously received bevacizumab (bev-naïve). This observation, coupled with the discovery of a novel mechanism of action for onvansertib and supportive discussions with the FDA, prompted a "highly consequential decision" in 2023: to pivot the lead program to the first-line treatment of RAS-mutated mCRC.

This strategic shift targets a patient population of nearly 50,000 new diagnoses annually in the United States, a group that has seen no new therapeutic approvals in two decades. This significant unmet medical need, combined with the lack of competing clinical trials specifically for this first-line RAS-mutated population, positions Cardiff Oncology to potentially redefine the standard of care if onvansertib proves successful.

Onvansertib's Differentiated Technology: A Synergistic "1-2 Punch"

At the heart of Cardiff's strategy is onvansertib's unique technological profile. As a highly selective PLK1 inhibitor, onvansertib targets a well-validated oncology pathway. What differentiates it, particularly in the context of mCRC, is its newly discovered mechanism of action involving the hypoxia response pathway.

Tumors often become hypoxic as they grow, triggering survival mechanisms mediated by the HIF1 alpha protein. While bevacizumab, a standard-of-care anti-angiogenic agent, works by neutralizing VEGF-A (a downstream target of HIF1 alpha) to inhibit new blood vessel formation, onvansertib acts upstream by directly inhibiting HIF1 alpha. Preclinical data presented at AACR highlighted this synergy, demonstrating that onvansertib and bev hit two distinct nodes of the hypoxia pathway, providing a complementary "1-2 punch" to the tumor's ability to survive and grow in a low-oxygen environment.

This mechanistic rationale is supported by clinical observations. Data from the second-line TROV-54 trial showed that bev-naïve patients treated with onvansertib plus standard of care FOLFIRI/bev achieved an objective response rate (ORR) of 73% and median progression-free survival (mPFS) of 15 months. This significantly exceeded historical controls for standard of care alone (ORR 5-13%, mPFS 4.5-6.7 months). The randomized ONSEMBLE trial, though discontinued for new enrollment, provided independent validation, showing objective responses only in bev-naïve patients receiving onvansertib, with no responses in the bev-naïve control arm. This compelling evidence in bev-naïve patients formed the scientific and clinical basis for the pivot to the first-line setting, where all patients are, by definition, bev-naïve.

Beyond mCRC, preclinical studies suggest onvansertib's potential broad-spectrum activity. Data presented at AACR showed activity in RAS wild-type mCRC, including synergy with cetuximab. Further preclinical work indicates synergy with paclitaxel and ENHERTU in breast cancer models and with carboplatin, gemcitabine, and olaparib in ovarian cancer models, demonstrating the drug's potential to overcome resistance mechanisms in various tumor types. Positive data from an investigator-initiated trial combining onvansertib with paclitaxel in metastatic TNBC, presented at ASCO 2025, further supports this broader potential, showing a 40% ORR at the highest dose and a manageable safety profile.

Cardiff has actively protected this technological advantage, securing patents covering the method of using onvansertib in combination with bevacizumab for the treatment of bev-naïve mCRC patients, including both KRAS-mutated and RAS wild-type subtypes across all lines of therapy, with expected expiration no earlier than 2043. This intellectual property strengthens the company's competitive moat, particularly in the target first-line mCRC market.

Competitive Landscape and Positioning

Cardiff Oncology operates in a competitive oncology landscape dominated by large pharmaceutical companies with extensive resources and established market presence. Key competitors in the broader mCRC space include Amgen (AMGN) with therapies like Vectibix and a KRAS G12C inhibitor in the second-line, Merck (MRK) with its immunotherapy Keytruda, Bristol-Myers Squibb (BMY) with Opdivo, and AstraZeneca (AZN) with targeted therapies including KRAS inhibitors.

While these larger players have significant market share and financial strength (e.g., Amgen's 22% revenue growth and 25% net margin in 2024, Merck's 10% growth and 27% net margin), Cardiff's strategic focus on the first-line RAS-mutated mCRC population offers a distinct positioning. As management noted, there are currently no competing clinical trials specifically targeting this large, underserved first-line segment. Existing approved therapies from competitors either target different mutations (like Amgen's G12C, which addresses only ~4% of RAS mutations) or are primarily used in different settings or patient populations.

Cardiff's competitive advantage lies in onvansertib's unique mechanism and demonstrated synergy with bevacizumab, which is already a standard component of first-line mCRC treatment. This allows Cardiff to pursue an additive strategy, building upon existing standard of care rather than replacing it, which can be more appealing to physicians and patients. While larger competitors benefit from economies of scale, broader pipelines, and established infrastructure, Cardiff aims to leverage its innovation speed and clinical data to capture a significant niche market share. The success of this strategy hinges on demonstrating a clinically meaningful improvement over standard of care alone in the ongoing CRDF-004 trial and subsequent registrational studies.

Clinical Progress and Operational Execution

The strategic pivot culminated in the initiation of the CRDF-004 trial, a Phase 2, open-label, randomized multi-center study evaluating onvansertib in combination with standard of care (FOLFIRI or FOLFOX plus bevacizumab) versus standard of care alone in approximately 90 evaluable first-line RAS-mutated mCRC patients. A key operational achievement was the completion of patient enrollment in April 2025.

Initial data from CRDF-004, presented in December 2024, provided early validation for the first-line approach. The data showed a dose-dependent signal for objective response rate: 33% in the control arm, 50% in the onvansertib 20mg arm, and 64% in the onvansertib 30mg arm. Across all onvansertib-treated patients, the ORR was 57%. Importantly, the 30mg dose also showed deeper tumor responses. The combination was reported as well-tolerated with no major or unexpected toxicities, addressing a historical challenge for some earlier PLK1 inhibitors.

Management expects to release additional clinical data from CRDF-004 in the first half of 2025, aiming for a "more mature and substantive update." While PFS data is likely too early for this update, the focus will be on further solidifying the ORR signal and dose selection.

Cardiff's registrational strategy for onvansertib in mCRC involves a seamless Phase 3 trial (CRDF-5) with an interim ORR endpoint for potential accelerated approval, followed by PFS and lack of detriment on OS for full approval. This pathway has been agreed upon with the FDA and was recently validated by Pfizer's (PFE) successful accelerated approval for encorafenib in BRAF-mutated mCRC using a similar approach. The FDA meeting to discuss dose selection and finalize the CRDF-5 design is a critical gating factor for advancing to the registrational stage.

Financial Performance and Liquidity

As a clinical-stage biotechnology company, Cardiff Oncology's financial profile is characterized by net losses and negative operating cash flows, driven by significant investment in research and development. For the three months ended March 31, 2025, the company reported total revenues of $109 thousand, primarily from legacy royalty agreements unrelated to onvansertib, a decrease from $205 thousand in the same period of 2024.

Operating expenses increased substantially, rising from $11.1 million in Q1 2024 to $14.5 million in Q1 2025. This increase was primarily attributable to higher research and development costs ($10.5 million in Q1 2025 vs. $8.0 million in Q1 2024), driven by the ongoing CRDF-004 clinical trial and associated outside services. Selling, general, and administrative expenses also increased ($4.0 million in Q1 2025 vs. $3.1 million in Q1 2024), mainly due to professional fees for strategic advisory services. The net loss for Q1 2025 was $13.4 million, compared to $10.0 million for Q1 2024.

Cash used in operating activities for the three months ended March 31, 2025, was $12.8 million, an increase from $7.7 million in the prior-year period, reflecting the higher operating expenses.

As of March 31, 2025, Cardiff Oncology held $79.9 million in cash, cash equivalents, and short-term investments. This includes the net proceeds from a $40 million capital raise completed in December 2024, which was facilitated by the encouraging initial CRDF-004 data. Based on current projections and anticipated cash spend on ongoing clinical programs, management believes these resources are sufficient to fund operations into the first quarter of 2027. This provides runway through key upcoming data readouts and anticipated FDA interactions regarding the registrational path.

However, the company explicitly states that it expects to continue incurring losses and will require additional capital to further advance its clinical trial programs, particularly a potential Phase 3 study, and support commercialization efforts. The availability and terms of future funding are uncertain, and raising additional funds through equity issuance would likely result in further dilution for existing stockholders.

Risks and Challenges

Investing in a clinical-stage biotechnology company like Cardiff Oncology involves significant risks. The success of onvansertib is highly dependent on the outcome of ongoing and future clinical trials. While initial data from CRDF-004 is encouraging, there is no guarantee that subsequent data will be consistent or demonstrate statistically significant and clinically meaningful improvements sufficient for regulatory approval. Clinical trials are lengthy, expensive, and subject to numerous uncertainties, including patient enrollment, unexpected side effects, and trial design challenges.

Regulatory approval processes are stringent and can be unpredictable. Even with positive clinical data, there is no assurance that the FDA or other regulatory agencies will approve onvansertib for any indication. Delays or unfavorable outcomes in regulatory review could significantly impact the company's prospects.

The need for substantial additional capital beyond the current runway is a material risk. The costs of conducting a Phase 3 trial and building commercial capabilities are significant. Failure to raise sufficient funds on acceptable terms could force delays, reductions, or even termination of development programs. Any future equity financing would dilute current shareholders.

While the first-line RAS-mutated mCRC space currently lacks direct competing trials, the broader oncology market is highly competitive. Larger companies with greater resources could potentially develop or acquire competing therapies or strategies that impact onvansertib's market potential. The company's reliance on partnerships, such as with Pfizer Ignite for CRDF-004 execution, also introduces dependency risk.

Conclusion

Cardiff Oncology is strategically positioned to address a significant unmet need in first-line RAS-mutated metastatic colorectal cancer with its lead asset, onvansertib. The investment thesis is underpinned by onvansertib's differentiated mechanism of action, demonstrating preclinical and clinical synergy with bevacizumab in bev-naïve patients, and the promising initial data from the randomized Phase 2 CRDF-004 trial. The completion of enrollment in CRDF-004 represents a crucial operational milestone, setting the stage for more mature data readouts in the near term.

The company's intellectual property portfolio provides a layer of protection for its targeted strategy. With a cash runway extending into the first quarter of 2027, Cardiff has the financial resources to navigate upcoming clinical milestones and engage with the FDA regarding a potential registrational path.

However, significant risks remain, primarily centered on the successful outcome of clinical trials, the ability to secure regulatory approval, and the need for substantial future funding. The competitive landscape, while currently favorable in the specific first-line RAS-mutated niche, necessitates continued innovation and strong clinical differentiation. Investors should closely monitor the upcoming CRDF-004 data, the outcome of FDA discussions, and the company's plans for securing the capital required to advance onvansertib towards potential commercialization. The potential upside, if onvansertib successfully addresses this large, underserved patient population, remains compelling.