XL092: A New Era in Metastatic Colorectal Cancer Treatment

1. XL092 is a promising multi-kinase inhibitor (MKI) designed to disrupt critical signaling pathways in cancer cells, making them more vulnerable to treatment.

2. Metastatic Colorectal Cancer (mCRC) continues to pose a significant therapeutic challenge, especially for patients with non-MSI-H phenotype. The ongoing STELLAR-303 study aims to address this issue with a novel combination therapy.

3. STELLAR-303 is a landmark study that tests the combination of XL092 and atezolizumab against regorafenib in mCRC patients, potentially changing the treatment standard for this patient population.

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4. The innovation in cancer treatments, as seen in XL092 and other novel therapies, underscores the rapid evolution of oncology and the continuous search for more effective, tolerable treatments.

5. Lastly, it is crucial to stay informed and connected with the latest findings in the field. The interview with Dr. J. Randolph Hecht, an expert in gastrointestinal oncology, offers deep insights into these advanced treatment strategies.

Metastatic colorectal cancer (mCRC) continues to be a significant health challenge worldwide. Despite advancements in treatment methods, the prognosis for patients with mCRC remains poor, with a 5-year survival rate of only 14% according to the American Cancer Society.

Current treatment options such as regorafenib or trifluridine-tipiracil offer limited benefits, emphasizing the urgent need for innovative therapeutic approaches.

One such promising avenue of research involves the use of novel multi-kinase inhibitors (MKIs) in combination with immune checkpoint inhibitor (ICI) therapies. This article will delve into an ongoing phase 3 clinical trial named STELLAR-303, which is assessing the efficacy and safety of a combination of XL092 and atezolizumab versus regorafenib in patients with previously treated RAS wild-type or RAS mutant mCRC.

XL092 is a novel MKI, developed with a focus on targeting MET, VEGFR2, and the TAM kinases AXL and MER.

This new therapeutic agent, characterized by a relatively short half-life (~21 hours), is favorable for once-daily (QD) dosing and dose modification to manage tolerability.

On the other hand, atezolizumab is an immune checkpoint inhibitor that has shown encouraging results when combined with VEGFR2 MKIs in early phase trials.

In-Depth Look at XL092

XL092 is a novel therapeutic compound that has emerged as a potential game-changer in the treatment of metastatic colorectal cancer.

This compound belongs to a class of drugs known as multi-kinase inhibitors (MKIs).

MKIs, such as XL092, are molecules that can inhibit the activity of a range of kinases.

Kinases are proteins that play a critical role in several cellular processes, including cell growth, differentiation, and apoptosis. Some kinases are implicated in cancer development, making them promising targets for cancer therapies.

XL092 specifically targets:

• MET

• VEGFR2

And the TAM kinases:

• AXL

• MER

These proteins play key roles in tumor growth, angiogenesis (formation of new blood vessels), and the immune response to cancer. By inhibiting these proteins, XL092 disrupts the pathways that drive tumor progression and helps make cancer cells more vulnerable to the immune system:

1. MET Inhibition: MET is a receptor tyrosine kinase that, when activated, promotes cell proliferation and survival. Overactivity of the MET pathway has been linked to various types of cancer, including colorectal cancer. By inhibiting MET, XL092 aims to curtail tumor growth.

2. VEGFR2 Inhibition: VEGFR2 is another receptor tyrosine kinase. It primarily acts to promote angiogenesis, which is critical for tumor growth and metastasis. Inhibiting VEGFR2 aims to starve the tumor of the blood supply it needs to grow.

3. TAM Kinase Inhibition: TAM kinases, consisting of TYRO3, AXL, and MER, have been implicated in the survival, growth, and metastasis of several types of cancer. They are also involved in suppressing the immune response against tumors. Inhibition of TAM kinases by XL092 could, therefore, not only limit tumor progression but also enhance the immune system’s ability to fight the cancer.

Half-Life and Dosing of XL092

The half-life of a drug refers to the time it takes for the concentration of the drug in the body to reduce by half. The half-life of XL092 is about 21 hours, which is relatively short for MKIs.

This characteristic allows for once-daily (QD) dosing and eases the management of any side effects through dose modifications.

In the ongoing STELLAR-303 trial, XL092 is administered at a dose of 100 mg orally once daily. This dosage is being tested in combination with atezolizumab, an immune checkpoint inhibitor, in the treatment of mCRC.

The potential of XL092 extends beyond its action as an MKI.

Its synergistic effect with immune checkpoint inhibitors may provide a new avenue for improved treatment outcomes in mCRC. This therapeutic strategy is currently under evaluation in the STELLAR-303 study, which we will discuss in more detail in the following sections.

Overall, XL092 offers a promising step forward in the pursuit of more effective treatment options for patients with mCRC.

The Reality of Metastatic Colorectal Cancer

Understanding the context and complexity of metastatic colorectal cancer (mCRC) provides crucial insights into the promise of new therapies like XL092.

Colorectal cancer is the third most common cancer worldwide and the second leading cause of cancer-related deaths.

The prognosis worsens significantly once the disease progresses to a metastatic stage, where it spreads beyond the primary site to other parts of the body. According to the American Cancer Society, the 5-year survival rate for mCRC is a dismal 14%.

Patients with mCRC often progress after front-line chemotherapy, leaving them with limited treatment options.

Currently, regorafenib and trifluridine-tipiracil are approved for patients in the third- or later-line setting, but these drugs offer limited survival benefit.

Microsatellite Instability and mCRC

One of the reasons mCRC is challenging to treat is the heterogeneity of the disease.

For instance, about 5% of mCRC patients exhibit a phenotype known as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

These patients can benefit from immune checkpoint inhibitor (ICI) therapy, but unfortunately, the majority of mCRC patients do not fall into this category.

RAS Status and mCRC

Another crucial factor that influences mCRC treatment is RAS status. RAS is a family of genes that, when mutated, can drive the development of cancer. Data from phase 1/2 trials suggest that ICIs in combination with VEGFR2 MKIs have shown encouraging activity in mCRC, particularly in patients with RAS wild-type (wt) disease, as opposed to mutant (mut) disease.

XL092 and Atezolizumab

In the search for more effective treatments for metastatic colorectal cancer (mCRC), novel therapies like XL092 and atezolizumab have emerged as hopeful contenders.

As previously discussed, XL092 is a novel multi-kinase inhibitor (MKI) that targets MET, VEGFR2, and the TAM kinases AXL and MER. This unique mechanism of action potentially enables it to inhibit multiple pathways involved in tumor growth and angiogenesis, which is the formation of new blood vessels.

Let’s also keep in mind that:

• XL092’s relatively short half-life (~21 hours) is favorable for once-daily (QD) dosing and dose modification to manage tolerability, making it an attractive therapeutic option.

• Atezolizumab is an immune checkpoint inhibitor (ICI) that blocks the protein PD-L1. PD-L1 is often overexpressed in cancer cells, allowing them to “hide” from the immune system.

• By blocking PD-L1, atezolizumab allows the immune system to recognize and attack cancer cells more effectively.

The idea behind combining XL092 and atezolizumab is based on a strategic, two-pronged attack against cancer.

• While XL092 aims to inhibit tumor growth and angiogenesis.

• Atezolizumab is designed to boost the immune system‘s ability to recognize and destroy cancer cells.

In addition to their individual actions, these two drugs might work together in a synergistic manner.

MKIs like XL092 can normalize tumor vasculature, potentially enhancing the delivery and effectiveness of ICIs like atezolizumab.

Moreover, some studies suggest that MKIs can influence the tumor microenvironment in a way that makes it more receptive to the actions of ICIs. This may lead to a greater therapeutic benefit, particularly in patients with RAS wild-type mCRC, as suggested by data from phase 1/2 trials.

The STELLAR-303 Study: Design and Methodology

The STELLAR-303 study is a critical trial that aims to validate the potential of XL092 and atezolizumab as a new treatment option for patients with metastatic colorectal cancer (mCRC).

Initiated as a global, open-label, randomized phase 3 study, STELLAR-303 has a primary objective to evaluate the efficacy of XL092 in combination with atezolizumab versus regorafenib in patients with previously treated mCRC. This clinical trial involves two arms:

• One receiving XL092 and atezolizumab

• The other receiving regorafenib

Eligibility Criteria

To ensure the reliability and validity of the study, rigorous eligibility criteria have been set. Patients are required to be:

• At least 18 years old

• Have measurable mCRC per RECIST v1.1

• Be documented not to have MSI-H or dMMR disease

• Have an ECOG performance status of 0–1 with adequate organ function.

• RAS and MSI/dMMR status must be determined by a tissue-based analysis

• Patients must have progressed during or after or be intolerant to standard-of-care treatments for mCRC

• Prior regorafenib, trifluridine/tipiracil, or PD-L1/PD-1 ICIs are not allowed

The Randomization Process

• Randomization is 1:1, stratified by geographic region (Asia vs other)

• RAS status (wild-type vs mutant)

• Presence of liver metastases (yes/no)

In the XL092 + atezolizumab arm, patients receive XL092 100 mg orally once daily (PO QD) + atezolizumab 1200 mg intravenously every three weeks (IV Q3W).

The comparator arm receives regorafenib 160 mg orally once daily (21 days of a 28-day cycle).

Study Endpoints and Goals

• STELLAR-303 has a broad range of objectives, with the primary endpoint being the overall survival in the RAS wild-type population.

• Additional efficacy endpoints include:

  • Progression-free survival

  • Objective response rate

  • Duration of response per RECIST v1.1

The study also plans to evaluate safety, quality of life, changes in biomarkers, pharmacokinetics, immunogenicity of atezolizumab, and healthcare utilization. All these factors combined will provide a comprehensive understanding of the potential benefits and risks of this novel treatment approach.

Study Size and Duration

The study aims to enroll around 600 patients, with 400 being RAS wild-type and 200 being RAS mutant. It is expected to continue for approximately 26 months after the first subject is randomized.

The methodology of the STELLAR-303 study is designed with precision and a broad scope, aligning with the principles of good clinical practice and ethical guidelines as provided by World Health Organization and the International Council for Harmonisation.

As the study is ongoing, the final outcomes are yet to be revealed. However, the design and approach of the STELLAR-303 trial clearly highlight the commitment of researchers to explore innovative ways to improve the treatment landscape for mCRC.

Expected Outcomes and Measures

While the results of the STELLAR-303 study are highly anticipated, it is essential to understand what specific outcomes and measures are expected from the trial.

As highlighted earlier, the primary endpoint of the STELLAR-303 study is to evaluate the overall survival of patients in the RAS wild-type population. The researchers hope to ascertain whether the use of XL092 and atezolizumab can significantly improve the lifespan of these patients compared to those who receive the standard care treatment, regorafenib.

The secondary endpoints or measures include:

• Progression-free survival (PFS): This measures the length of time during and after the treatment of the disease in which a patient lives with the disease but it does not get worse.

• Objective response rate (ORR): This quantifies the percentage of patients whose cancer shrinks or disappears after treatment.

• Duration of response (DoR): This gauges how long the tumor continues to respond to treatment without the cancer growing or spreading.

As we wait for the study’s conclusion, it’s crucial to note that the results will require careful interpretation by professionals in the field. Even if the study reaches its primary endpoint, the researchers will need to consider the balance of benefits and risks, including any potential side effects.

As we look forward to the culmination of the STELLAR-303 study, the medical community is hopeful that the results will bring us one step closer to enhancing the treatment landscape for patients with mCRC.

Potential Implications

As we edge closer to the conclusion of the STELLAR-303 study, the potential implications of this trial are of immense significance to both the medical community and patients suffering from metastatic colorectal cancer (mCRC).

The promise of XL092 and atezolizumab lies not just in their potential to extend the life expectancy of mCRC patients but also in transforming the therapeutic landscape for this type of cancer.

1. Potential to Improve Patient Outcomes

A significant implication of the study is the potential to improve patient outcomes.

Current treatments for mCRC, like chemotherapy or targeted therapies, often come with their own set of challenges, including severe side effects and limited efficacy.

If XL092 and atezolizumab prove to be effective, they may offer a new avenue of hope for mCRC patients by extending survival rates and improving quality of life.

2. Transformation of the Treatment Landscape

If successful, the study could mark a pivotal shift in the treatment landscape for mCRC.

The combination therapy of XL092 and atezolizumab could become a new standard of care for mCRC, adding another tool in the oncologist’s arsenal for combating this aggressive disease.

This would provide more options for physicians when designing a patient’s treatment plan.

3. Potential Implications for Other Cancers

The promise of XL092 and atezolizumab extends beyond mCRC.

Given that XL092 targets multiple kinases and atezolizumab is an immune checkpoint inhibitor, their combined effectiveness might hold implications for other types of cancers as well.

It opens the possibility of exploring their efficacy in treating other forms of cancer, further expanding their potential impact.

4. Financial Impact

The development of new cancer treatments often carries substantial financial implications.

If XL092 and atezolizumab prove to be effective, it could lead to significant financial gains for the pharmaceutical companies involved.

This success could encourage more investment in cancer research, leading to the development of more effective therapies in the future. At the same time, it’s crucial to consider the cost to patients and healthcare systems.

Looking Ahead

As we await the results of the STELLAR-303 study, it is crucial to approach the potential outcomes with a balanced perspective.

While there is indeed hope, it is equally important to understand that the development of new drugs is a complex process with no guaranteed results.

Yet, every study brings us closer to understanding the intricacies of cancer and finding new ways to combat it.

Expert Commentary: Interview with J. Randolph Hecht, MD

To delve even deeper into the subject of XL092 and atezolizumab, we highly recommend watching an insightful video interview with J. Randolph Hecht MD from the American Society of Clinical Oncology (ASCO) 2023 event. As a leading expert in the field of gastrointestinal oncology, Dr. Hecht shares his expert commentary and thoughts on the potential of this combination therapy in the fight against metastatic colorectal cancer. His perspectives can offer unique insights into the implications of the STELLAR-303 study and the future of cancer treatment. Watch the video interview here:

Conclusion

In conclusion, the landscape of metastatic colorectal cancer treatment is shifting. The advent of therapies like XL092, used in combination with immune checkpoint inhibitors like atezolizumab, may herald a new dawn for patients who previously had limited options.

The STELLAR-303 study is not just an isolated clinical trial; it represents a beacon of hope for the vast majority of mCRC patients who don’t possess the MSI-H phenotype.

These are complex therapies working to unravel an even more complex disease.

However, the core takeaway here is the progress being made, the potential for significantly improved patient outcomes, and the relentless pursuit of finding more effective treatment options.

While we await the results of the STELLAR-303 study with bated breath, we can certainly say that the field of oncology is a testament to human innovation and resilience. The study stands at the intersection of targeted therapy and immunotherapy, leveraging the strengths of both to strike cancer harder and smarter.

External Links and References:

A Study of XL092 as Single-Agent and Combination Therapy in Subjects With Solid Tumors (STELLAR-001): https://clinicaltrials.gov/study/NCT03845166

Clinical Trials Using Zanzalintinib: https://www.cancer.gov/research/participate/clinical-trials/intervention/zanzalintinib

Internal Links on OncologyTube:

Colorectal Cancer Treatment: The STELLAR-303 Phase 3 Trial of XL092 in Combination with Atezolizumab