Executive Summary / Key Takeaways

• Cardiff Oncology (NASDAQ: CRDF) is strategically focused on addressing the significant unmet medical need in first-line RAS-mutated metastatic colorectal cancer (mCRC) with its lead asset, onvansertib, a highly differentiated PLK1 inhibitor. This patient population has seen no new therapies in two decades, presenting a substantial market opportunity.
• Onvansertib's unique mechanism of action, directly inhibiting HIF1 alpha and demonstrating strong synergy with bevacizumab, combined with its favorable safety profile, distinguishes it from prior PLK1 inhibitors and provides a strong scientific rationale for its efficacy in bevacizumab-naïve patients.
• Recent positive data from the CRDF-004 Phase 2 trial (N=110) showed a 49% confirmed Objective Response Rate (ORR) in the 30mg onvansertib arm versus 30% in the control arm, representing a compelling 19% improvement. Early Progression-Free Survival (PFS) data also trended favorably, supporting advancement to a registrational Phase 3 trial.
• The company maintains a solid financial position with cash and short-term investments of $71.0 million as of June 30, 2025, providing a projected cash runway into the first quarter of 2027, well beyond the critical CRDF-004 data readout.
• While significant clinical and regulatory hurdles remain, including dose selection and final trial design discussions with the FDA, onvansertib's mutation-agnostic approach within RAS-mutated mCRC and the validated regulatory pathway (as demonstrated by Pfizer (PFE)'s BREAKWATER trial) position Cardiff Oncology for a potentially transformative impact in this underserved indication.

The Unmet Need in RAS-Mutated mCRC

Cardiff Oncology, Inc. is a clinical-stage biotechnology company dedicated to developing novel therapies for various cancers, primarily leveraging its lead asset, onvansertib. The company's journey, which began as Trovagene, Inc. in 1999 and rebranded to Cardiff Oncology in 2012, has culminated in a focused strategy on first-line RAS-mutated metastatic colorectal cancer (mCRC). This strategic pivot, initiated in 2023, was driven by compelling early clinical signals and a deeper understanding of onvansertib's mechanism of action.

The decision to target first-line RAS-mutated mCRC addresses a critical and long-standing unmet medical need. This patient population, representing nearly 50,000 new diagnoses annually in the United States, has not seen a new approved therapy in over two decades. The current standard of care (SoC) for these patients consists solely of chemotherapy combined with bevacizumab (bev), a regimen that has remained unchanged for an extended period. This stagnant treatment landscape underscores the immense potential for a novel, effective therapy like onvansertib to redefine patient outcomes.

Onvansertib: A Differentiated Technological Approach

At the heart of Cardiff Oncology's investment thesis is onvansertib, an oral, highly selective Polo-like Kinase 1 (PLK1) inhibitor. This drug candidate stands out due to its precision and favorable safety profile, which are crucial differentiators from earlier PLK1 inhibitors that encountered toxicity issues in clinical development. Onvansertib exhibits high potency and selectivity against the PLK1 enzyme with an IC50 of 2nM, while showing negligible activity (IC50 > 500 nM) against other PLK members (PLK2, PLK3) and a broad panel of 63 other kinases. This specificity is paramount, as it minimizes off-target effects that plagued previous PLK1 inhibitors.

The drug's oral bioavailability offers ease and flexibility of dosing, enhancing patient convenience. Crucially, onvansertib has demonstrated a favorable safety profile across over 380 patients in multiple clinical trials, with a manageable toxicity profile where myelosuppression, neutropenia, or leukopenia are the most common, yet typically resolved without treatment discontinuation. This robust safety record is a significant competitive advantage, enabling its combination with aggressive chemotherapy regimens.

Beyond its selectivity and safety, onvansertib's novel mechanism of action provides a strong scientific foundation for its efficacy, particularly in combination with bevacizumab. Research has revealed that onvansertib plays a role in the hypoxia response pathway by directly inhibiting HIF1 alpha. This is complementary to bevacizumab, which neutralizes VEGF-A. By delivering "two separate hits on the tumor angiogenic pathway and its survival mechanisms," onvansertib and bevacizumab create a synergistic effect, explaining the robust clinical signals observed in bevacizumab-naïve patients. This dual-pronged attack on tumor survival pathways forms a core part of the company's competitive moat.

Cardiff Oncology is also actively exploring new intellectual property opportunities stemming from its discoveries. A second patent (U.S. patent No. 12.26M) was issued in April 2025, specifically covering the method of using onvansertib in combination with bevacizumab for the treatment of mCRC in bevacizumab-naïve patients, with protection extending until at least 2043. This patent further solidifies the company's market position and long-term potential.

Clinical Validation and Strategic Momentum

Cardiff Oncology's strategic pivot to first-line mCRC is strongly supported by a series of clinical data readouts. The initial signal emerged from the TROV-054 Phase 1b/2 trial in second-line KRAS-mutated mCRC, which completed enrollment in October 2022. Data from this trial, presented in August 2023, showed an Objective Response Rate (ORR) of 29% across all evaluable patients and a median Progression-Free Survival (mPFS) of 9.3 months. Notably, a subgroup of bevacizumab-naïve patients (n=15) achieved a remarkable 73% ORR and 15 months mPFS, significantly exceeding historical controls (5-13% ORR and 4.5-6.7 months mPFS). This compelling signal in bevacizumab-naïve patients was a key driver for the shift to first-line.

Further validation came from the ONSEMBLE (CRDF-003) trial, an independent, randomized study in second-line mCRC that, despite being discontinued to focus on first-line, provided crucial insights. The ONSEMBLE data confirmed that objective responses were observed exclusively in bevacizumab-naïve patients receiving onvansertib plus standard of care, with no responses in the control arm. This randomized evidence underscored onvansertib's critical role in the observed robust responses.

The company's flagship CRDF-004 Phase 2 randomized trial in first-line RAS-mutated mCRC completed enrollment of approximately 90 evaluable patients in April 2025. The latest data, released on July 29, 2025, from an intent-to-treat population of 110 patients, is highly encouraging. The 30mg onvansertib dose arm demonstrated a 49% confirmed ORR, a substantial 19% improvement over the 30% confirmed ORR in the control arm. Early PFS data also showed a favorable trend for the 30mg dose, and onvansertib continued to be well-tolerated with a dose-dependent response observed across all efficacy endpoints, including early tumor shrinkage and depth of response.

This positive data positions Cardiff Oncology to engage in discussions with the FDA regarding its registrational CRDF-005 trial. The company's regulatory strategy is reinforced by the precedent set by Pfizer's BREAKWATER trial for encorafenib in BRAF-mutated mCRC, which achieved accelerated approval based on ORR from an interim analysis, followed by full approval based on PFS. This pathway aligns directly with Cardiff Oncology's agreed-upon registrational plans, providing a clear roadmap for onvansertib. The company aims to finalize a single optimal dose (from the 20mg and 30mg arms) with the FDA, which will be the gating factor for initiating the registrational trial.

Expanding Horizons: Pipeline Optionality Beyond mCRC

While first-line RAS-mutated mCRC is the primary focus, Cardiff Oncology is prudently exploring onvansertib's broader potential across other challenging cancer indications, providing valuable pipeline optionality. In metastatic pancreatic ductal adenocarcinoma (mPDAC), the company is supporting an investigator-initiated Phase 1b/2 trial combining onvansertib with the newly approved first-line standard of care, NALIRIFOX. This strategic shift from a previously planned regimen leverages onvansertib's known synergy and tolerability with most of NALIRIFOX's components.

In small cell lung cancer (SCLC), a Phase 2 investigator-initiated trial of onvansertib monotherapy has shown promising early signals, with a 57% disease control rate among the first seven patients. Preclinical data further supports a combination strategy with paclitaxel, demonstrating synergistic inhibition of tumor proliferation and high effectiveness in cisplatin-sensitive and resistant models. Similarly, in metastatic triple-negative breast cancer (mTNBC), a Phase 1b investigator-initiated trial of onvansertib plus paclitaxel yielded positive results at ASCO in June 2025, showing a 40% ORR at the recommended Phase 2 dose in heavily pretreated patients, further validating preclinical synergy.

Beyond these clinical programs, preclinical research highlights onvansertib's broad spectrum activity. In RAS wild-type mCRC, it demonstrated robust antitumor activity as a single agent and enhanced efficacy when combined with cetuximab, inducing tumor stasis or regression in 90% of patient-derived xenograft models. In ovarian cancer, preclinical data showed onvansertib's ability to overcome resistance to PARP inhibitors like olaparib and synergy with carboplatin and gemcitabine in platinum-resistant models. The company is also exploring combinations with Antibody-Drug Conjugates (ADCs). These diverse preclinical findings suggest significant future clinical development opportunities, underscoring onvansertib's versatility and potential impact across multiple tumor types.

Financial Health and Investment in Innovation

As a clinical-stage biotechnology company, Cardiff Oncology's financial performance reflects its heavy investment in research and development. For the six months ended June 30, 2025, the company reported a net loss of $27.377 million, an increase from $21.789 million in the prior year period. This rise is primarily attributable to increased R&D expenses, which grew by $4.6 million to $22.057 million, driven by the CRDF-004 trial and strategic hires. Selling, general, and administrative expenses also increased by $1.0 million to $7.332 million due to new stock option grants and professional fees. Royalty revenues, derived from unrelated intellectual property licenses, remained negligible at $0.230 million for the six-month period.

Despite these operating losses, Cardiff Oncology maintains a robust liquidity position. As of June 30, 2025, the company held $71.0 million in cash, cash equivalents, and short-term investments. This includes the net proceeds from a successful $40 million capital raise completed in December 2024 with institutional investors. The company's cash used in operating activities for the six months ended June 30, 2025, was $21.122 million, with a quarterly cash burn of approximately $10.3 million in Q4 2024. Management projects that its current capital resources are sufficient to fund operations into the first quarter of 2027, extending well beyond the recent CRDF-004 data readout and providing crucial financial stability through upcoming regulatory discussions. While the company anticipates requiring additional capital in the future to advance its clinical programs, it maintains a shelf registration statement as a standard practice for financial flexibility, acknowledging the potential for future stockholder dilution.

Navigating the Competitive Landscape

Cardiff Oncology operates in the highly competitive oncology market, but its strategic focus on first-line RAS-mutated mCRC positions it uniquely. Unlike larger, diversified pharmaceutical companies such as Bristol-Myers Squibb (BMY), Merck (MRK), Pfizer, Amgen (AMGN), and Gilead Sciences (GILD), Cardiff Oncology is a specialized, clinical-stage player. These larger competitors typically exhibit stronger revenue growth, higher profitability margins, and more robust cash flow generation from their established product portfolios. Their extensive resources allow for broader R&D pipelines, global commercialization infrastructures, and greater strategic adaptability.

However, Cardiff Oncology's competitive advantage lies in its agility and the differentiated nature of onvansertib. The company's lead asset, with its high selectivity for PLK1 and a favorable safety profile, addresses a critical historical challenge for this class of inhibitors. Furthermore, onvansertib's novel mechanism of action, directly inhibiting HIF1 alpha, offers a complementary and synergistic approach when combined with bevacizumab, providing a "two separate hits" strategy on tumor angiogenesis. This scientific rationale underpins the compelling clinical data observed in bevacizumab-naïve patients.

Crucially, Cardiff Oncology faces no direct competing clinical trials in its specific target population of first-line RAS-mutated mCRC. While other companies are developing therapies for RAS-mutated cancers, such as KRAS G12C inhibitors (e.g., Amgen's drug), these are primarily in the second-line setting and target a very small subset (around 4%) of the broader RAS-mutated patient population. Onvansertib's mutation-agnostic approach within RAS-mutated mCRC offers a unique advantage over these more narrowly focused therapies. This lack of direct competition in its primary indication, combined with its proprietary technology and patent protection until at least 2043, creates a significant market opportunity for Cardiff Oncology. The company's partnership with Pfizer Ignite for clinical execution further enhances its operational capabilities, leveraging a larger partner's resources while maintaining its focused development strategy.

Conclusion

Cardiff Oncology stands at a pivotal juncture, poised to potentially redefine the treatment paradigm for first-line RAS-mutated metastatic colorectal cancer. The company's strategic pivot to this underserved indication, driven by onvansertib's differentiated PLK1 inhibition, novel HIF1 alpha mechanism, and compelling synergistic activity with bevacizumab, represents a high-conviction play. The recent positive data from the CRDF-004 trial, demonstrating a significant improvement in ORR and favorable PFS trends, provides strong clinical validation for this approach.

While the path forward involves critical regulatory discussions regarding dose selection and the design of the registrational CRDF-005 trial, the established regulatory precedent set by Pfizer's BREAKWATER trial offers a clear and validated pathway for accelerated approval. Supported by a solid cash runway into 2027 and a pipeline of promising preclinical and investigator-initiated programs, Cardiff Oncology is well-positioned to advance onvansertib through late-stage development. The company's ability to execute on its registrational strategy and successfully bring this much-needed therapy to market will be the ultimate determinant of its long-term value for investors.