Advanced Angiosarcoma (AS) is a rare and aggressive form of cancer that forms in the lining of blood vessels and lymph vessels. Characterized by rapid growth and high potential for metastasis, this disease presents unique challenges to medical professionals and patients alike.
As per the American Cancer Society, angiosarcoma accounts for only a small fraction of all sarcomas, yet its impact is significant.
The journey of treating advanced angiosarcoma remains full of obstacles.
One of this obstacles is the limited amount of treatment options, especially after taxane chemotherapy. Taxanes, a class of drugs commonly used in the treatment of many cancers, may initially be effective for angiosarcoma patients.
However, the disease often returns, leading to a scenario where alternative treatment options are sorely needed.
Furthermore, while there have been significant strides in cancer treatment over the years, sarcomas, including angiosarcoma, have demonstrated less benefit from immunotherapy than many other cancers.
This is primarily due to the diverse nature of sarcomas, requiring more personalized treatment approaches.
Immunotherapy has been a revolutionary approach in the fight against cancer.
By harnessing the power of the body’s immune system, it provides a new strategy for attacking cancer cells.
However, not all forms of cancer respond to immunotherapy equally.
For example, cutaneous angiosarcomas, which form on the skin and are often linked to a high UV damage signature, might respond differently to immunotherapy than other types of angiosarcoma.
According to a study published in the Journal of Clinical Oncology, cutaneous angiosarcomas have shown promise in responding to immunotherapy, while the same cannot be said with certainty for other types of angiosarcomas.
Understanding Cabozantinib and Nivolumab
Cabozantinib: A Multikinase Inhibitor
Cabozantinib, sold under the brand name Cometriq, is a medication used to treat certain types of cancer, including medullary thyroid cancer and renal cell carcinoma.
It is classified as a multikinase inhibitor that works by blocking the action of an abnormal protein that signals cancer cells to multiply.
This helps to slow down the growth and spread of cancer cells. As described by the American Cancer Society, targeted therapies like Cabozantinib provide a more precise way of attacking cancer cells.
Cabozantinib is believed to have additional benefits regarding treating angiosarcoma.
Specifically, it may alter PD-1 expression in regulatory T cells, essentially tweaking the immune response in a way that could make immunotherapy more effective.
Nivolumab: A Powerful Immunotherapy Drug
Nivolumab, sold under the brand name Opdivo, is a type of immunotherapy drug known as a checkpoint inhibitor.
It works by blocking the action of a protein called PD-1 on immune cells. This “unleashes” the immune system, allowing it to attack cancer cells more effectively.
As noted by the National Cancer Institute, checkpoint inhibitors like Nivolumab have transformed the treatment of many types of cancer.
The Power of Combination: Cabozantinib plus Nivolumab
What makes the combination of Cabozantinib and Nivolumab so promising?
It’s the potential synergy between these two drugs.
While Cabozantinib can alter PD-1 expression in regulatory T cells, Nivolumab blocks the action of PD-1, allowing the immune system to attack the cancer cells more vigorously.
This combined action can create an immune-permissive environment that enhances the body’s ability to fight angiosarcoma.
Extended Follow-up Supports First-Line Use of Nivolumab Plus Cabozantinib in Advanced Angiosarcoma
In the fight against advanced angiosarcoma, it is crucial to explore every possible treatment avenue.
As such, the first-line use of combination therapy involving Nivolumab and Cabozantinib has come into the limelight following encouraging results from recent studies. Specially in the study: “a multicenter phase II study of cabozantinib plus nivolumab for patients (pts) with advanced angiosarcoma (AS) previously treated with a taxane”.
An Extended Look at the Use of Combination Therapy
Extended follow-up studies are vital in evaluating the effectiveness and safety of treatment regimens over time.
They provide a long-term perspective, which is especially important when considering the treatment of a relentless and aggressive disease like advanced angiosarcoma.
The treatment of advanced angiosarcoma with Nivolumab plus Cabozantinib has been subject to such scrutiny.
The results have shown promising effectiveness and tolerability.
In fact, extended follow-up data support using Nivolumab and Cabozantinib as a first-line treatment for patients with advanced angiosarcoma.
These results were presented at major cancer conferences and are making waves in the field of oncology.
Promising Results from the Front Line
In a recent phase II study published in ClinicalTrials.gov, the combination of Cabozantinib plus Nivolumab demonstrated significant anti-tumor activity in taxane-pretreated angiosarcoma patients.
This comes as a breakthrough for many patients who have limited treatment options after taxane chemotherapy.
The study reported that primary disease sites were diverse, including cutaneous (scalp/face), liver, breast, among others.
Remarkably, the combination therapy was effective across these different angiosarcoma subtypes, reinforcing its potential as a first-line treatment for advanced angiosarcoma.
The primary endpoint was met with 72% of the first 18 evaluable patients experiencing an objective response, indicating a reduction in their tumor size. Median progression-free survival was 9.6 months, and overall survival was 20.5 months.
These figures, taken together, underline the promising potential of this joint treatment approach in managing advanced angiosarcoma.
Tolerability and Safety of the Combination Therapy
Equally important to the effectiveness of a treatment is its safety profile. Here, the combination of Nivolumab and Cabozantinib shines.
In the study “A multicenter phase II study of cabozantinib plus nivolumab for patients (pts) with advanced angiosarcoma (AS) previously treated with a taxane”, the most common treatment-related adverse event was grade 3 hypertension, with no grade 4/5 treatment-related adverse events reported.
These findings support the tolerability of this combination therapy in the long-term treatment of advanced angiosarcoma patients.
Moreover, the National Institute of Cancer has listed both Nivolumab and Cabozantinib as approved drugs for the treatment of specific types of cancer, further emphasizing their well-established safety profiles.
Trial Design, Oversight, and Treatments
Scientific discoveries and advances don’t just happen overnight.
They are the result of carefully designed, meticulously conducted, and thoroughly reviewed studies.
This is precisely the case with the multicenter phase II study examining the efficacy of cabozantinib plus nivolumab in patients with advanced angiosarcoma.
Understanding the Trial Design
The study was designed as an open-label, multi-arm trial.
The study cohort included patients with locally advanced or metastatic angiosarcoma who had previously been treated with a taxane. Eligible patients received cabozantinib (40 mg orally, daily) and nivolumab (480 mg intravenously every four weeks).
The study design incorporated a Simon 2-stage approach, a commonly used design in phase II oncology trials.
It offers greater efficiency and ethical advantages by allowing for early termination of the study if the drug or combination shows insufficient activity.
Unwavering Trial Oversight
This important study was conducted under stringent oversight to ensure the highest level of patient safety and the validity of the findings. Independent committees performed regular reviews of the study, providing unbiased analysis of the data.
The Treatment in Detail
The key components of this study were the drugs cabozantinib plus nivolumab.
As mentioned earlier, eligible patients received 40 mg of cabozantinib orally on a daily basis, along with 480 mg of nivolumab administered intravenously every four weeks.
Treatment was allowed beyond progressive disease in the first 12 weeks, though the PD response was censored at 12 weeks.
The treatment-related adverse events were also carefully monitored, with hypertension being the most common adverse event reported.
The absence of any Grade 4/5 treatment-related adverse events reaffirms the tolerability of the combination therapy.
Impact on Quality of Life
When discussing cancer treatments, the conversation usually revolves around efficacy, survival rates, and side effects.
While these factors are crucially important, it’s equally essential to address the impact of this treatment on patients’ quality of life.
After all, cancer treatments should not only aim to prolong life but also enhance its quality.
Understanding Quality of Life in Cancer Care
Quality of life (QoL) in cancer care refers to the patient’s overall wellbeing, considering:
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Physical health
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Psychological state
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Level of independence
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Social relationships
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Personal beliefs
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Relationship to salient features in the environment
It is an essential parameter that helps us understand the broader impact of the disease and its treatment on patients’ lives.
A key part of this is Patient-Reported Outcomes (PROs), which allow patients to provide direct, timely insights about how they feel and function.
Cabozantinib Plus Nivolumab and Quality of Life
As per the multicenter phase II study, the cabozantinib plus nivolumab combination has shown significant anti-tumor activity, suggesting potential improvements in the quality of life for patients with advanced angiosarcoma.
While specific details related to QoL in this trial were not included in the initial results, it’s important to note that the treatment regimen was generally well-tolerated by patients.
This aspect is paramount because a treatment that’s hard to tolerate can significantly reduce a patient’s quality of life.
Another encouraging observation was the absence of any Grade 4/5 treatment-related adverse events, which suggests that severe side effects are unlikely to drastically impact patients’ QoL.
Ongoing studies will further assess QoL parameters among patients receiving this combination therapy.
With the positive initial outcomes, we can remain hopeful about its positive implications for patients quality of life.
It’s worth noting that maintaining or improving QoL requires a holistic approach that extends beyond medication.
In this regard, support groups can play a vital role.
The combination of cabozantinib plus nivolumab presents a promising treatment that might not only prolong survival but also improve the quality of life of angiosarcoma patients.
# VI. Approval Status and Classification of Cabozantinib and Nivolumab
Both cabozantinib and nivolumab have proven instrumental in the battle against various forms of cancer.
However, each medication falls into a distinct category and holds different approval statuses for different cancers.
Is Nivolumab and Cabozantinib Approved for RCC?
Renal cell carcinoma (RCC) represents the most common type of kidney cancer.
In the fight against this disease, both cabozantinib and nivolumab have earned the green light from health authorities.
The U.S. Food and Drug Administration (FDA) granted approval to nivolumab in 2015 for patients with advanced RCC who had received prior anti-angiogenic therapy.
This decision followed clinical trials showing a higher overall survival rate in patients treated with nivolumab compared to a standard treatment.
Cabozantinib, meanwhile, received FDA approval in 2016 for the treatment of advanced RCC in patients who have received prior anti-angiogenic therapy. Cabozantinib demonstrated improved rates of progression-free survival, overall survival, and objective response rates compared to a standard treatment.
Is Cabozantinib Chemotherapy or Immunotherapy?
To classify these medications, we need to understand how they act in the body:
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Cabozantinib is considered a targeted therapy, not a traditional chemotherapy or an immunotherapy. It’s specifically a tyrosine kinase inhibitor, which works by blocking certain proteins that contribute to tumor growth and cancer progression. By doing so, it inhibits the growth and spread of cancer cells.
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Nivolumab, on the other hand, falls under the umbrella of immunotherapy. It’s a type of drug known as a checkpoint inhibitor. These drugs essentially “take the brakes off” the immune system, enabling it to attack cancer cells more effectively.
While both drugs have their respective roles and classifications, their combined use is showing promising results in the treatment of advanced angiosarcoma, opening up new avenues in the fight against this aggressive form of cancer.
Evaluating the Success of Cabozantinib and Nivolumab
The effective management of any cancer treatment protocol often hinges on a lot of factors, with survival and success rates topping the list.
Let’s examine the performance of cabozantinib plus nivolumab in this context.
What is the Survival Rate for Cabozantinib?
The survival rate for cabozantinib tends to vary depending on the specific type of cancer it’s used to treat.
It’s essential to remember that survival rates are typically reported as median values, representing the middle value of a dataset, not the average.
This measure provides a more accurate representation given the wide range of individual experiences with cancer.
In the context of renal cell carcinoma (RCC), for instance, a pivotal study published in The Lancet demonstrated that patients treated with cabozantinib had a median overall survival of 21.4 months, compared to 16.5 months for patients treated with a standard therapy.
What is the Success Rate of Nivolumab for Cancer?
Similarly to cabozantinib, nivolumab’s success rate differs according to the type of cancer it’s employed against. In RCC, a CheckMate 025 study published in the New England Journal of Medicine showed a significant improvement in overall survival in patients treated with nivolumab compared to a standard treatment.
It’s crucial to note that success rates are contingent on multiple factors such as the type and stage of the cancer, the patient’s overall health, and whether the cancer has spread to other parts of the body.
Cabozantinib and Nivolumab in Advanced Angiosarcoma
As mentioned in our examination of the multicenter phase II study, the combination of cabozantinib and nivolumab has shown promise in the treatment of advanced angiosarcoma, a particularly aggressive form of cancer.
The overall response rate was 62%, with a median progression-free survival of 9.6 months and overall survival of 20.5 months.
These results suggest a considerable improvement over existing therapies, bringing new hope to patients with this challenging disease.
While survival and success rates provide a crucial measure of a treatment’s effectiveness, they don’t capture the entire picture.
Each patient’s experience with cancer is unique, and the ideal treatment plan should be personalized to the individual’s needs and circumstances.
This nuanced approach forms the bedrock of personalized medicine, an approach increasingly embraced in oncology.
A Breakthrough Discovery Presented at ASCO 2023 with Gary Schwartz, MD
Angiosarcoma, a rare form of cancer affecting only one in a million people annually in the US, may have a new, promising treatment, according to Gary Schwartz, MD, in a recent interview during the ASCO 2023 conference.
Dr. Schwartz is the co-chair of the Experimental Therapeutics Rare Cancer Committee, which has been instrumental in developing this innovative approach.
In the realm of sarcoma treatment, chemotherapy has been the traditional approach.
Taxol, Doxorubicin, and Toxil have demonstrated effectiveness, but the benefits are relatively small, with a short duration of benefit. Dr. Schwartz explains, “even with chemotherapy, the benefits are relatively small. And the duration of benefit over are still short.”
About five years ago, a new direction was taken.
The experimental therapeutics committee started a study using an immune therapy checkpoint, nivolumab. This drug has already been approved for use in melanoma and many other solid tumors.
However, its effectiveness in sarcoma treatment remained a question.
The study, published in Lancet Oncology, showed that nivolumab had a significant benefit in treating angiosarcoma, although the response rate was still modest, around 10-12%.
Adding a second targeted checkpoint therapy, Ipilimumab, slightly raised the response rate to about 20-25%. However, the combination led to increased toxicity, including diarrhea, colitis, and other inflammatory reactions.
Looking for ways to improve the response rate without increasing toxicity, the team turned to Cabozantinib, a broad-based receptor tyrosine kinase inhibitor (RTKI). “We wanted to ask the question, what would happen if we tested this now with a second agent, especially for people who had failed chemotherapy, and we elected to combine it with a drug called Cabozantinib,” said Dr. Schwartz.
In this new trial, researchers looked at patients who had failed Taxol treatment.
These individuals were then given the combination of nivolumab plus Cabozantinib. The hope was that this approach would further enhance immunogenicity for patients with angiosarcoma.
Dr. Schwartz described the results as “exceptional.”
The primary goal of the study was to see at least four responses in the 22 patients treated on the trial. However, they saw 13 responses – a staggering 59% response rate. This included two complete responses in patients with metastatic disease that disappeared with the combination of Nivolumab and Cabozantinib. “That’s pretty exceptional,” Schwartz said. “For any clinical trial, we really were surprise.”
The median progression-free survival in the trial was about 9.6 months, and the overall survival hasn’t been met as most patients are still alive.
Despite the success of the trial, some patients did not respond to the treatment.
A significant area of ongoing research is to identify biomarkers predictive of response in sarcoma. “Can we tell upfront, is there a biomarker we could test?” Schwartz asked, hoping to refine treatment approaches in the future.
Nonetheless, the takeaway from ASCO 2023 is encouraging.
A new combination therapy that shows an exceptional response rate and clinical benefit ratio of 73% may indicate a new treatment paradigm for patients with angiosarcoma.
Schwartz finished with a hopeful note: “We now have a new combination that, we think, could very well indicate a new treatment paradigm for patients with this cancer.”
Angiosarcoma is a rare form of cancer, with around 200 new cases in the United States each year Dr. Gary Schwartz, co-chair of the Experimental Therapeutics Rare Cancer Committee, says that “most medical oncologists may not even see an angiosarcoma during their academic or medical practice in the United States”.
Therefore, understanding and managing angiosarcoma presents a unique challenge due to its rarity.
Chemotherapies including Taxol, Doxorubicin, and Toxil have been effective in treating angiosarcoma, albeit with modest benefits, “even with chemotherapy, the benefits are relatively small. And the duration of benefit over are still short,” says Schwartz.
Around five years ago, the committee explored immunotherapy as a potential treatment option for sarcomas, starting a study using an immune therapy checkpoint called nivolumab.
The results showed promise, but the response rate was modest (10-12%).
Seeking to improve upon these results, the group decided to combine nivolumab with an RTK inhibitor called Cabozantinib, a broad-based inhibitor that targets VGFR 2 among others, and has been shown pre-clinically to have its own immunological effect.
This combination was tested in patients who had failed chemotherapy, specifically in the Taxol refractory population.
The primary aim of the trial was to observe four responses in the 22 patients treated on the trial. The results surpassed expectations, with 13 responders, marking a 59% response rate. “That exceeded anything we thought,” said Schwartz, “we’ve never seen this before”.
Among the 13 responders were two complete responses, cases where metastatic disease completely disappeared.
This was coupled with several cases of stable disease, bringing the total clinical benefit ratio to 73%. Importantly, many responses were durable, with patients remaining on treatment for up to two years.
Schwartz finds these results especially exciting given that the response rate and clinical benefit ratio were higher than expected. This combination therapy could signal a new treatment paradigm for patients with angiosarcoma.
The study also confirmed that this therapy combination was effective in both angiosarcomas of the head and neck, as well as in other sites.
The treatments were well-tolerated, with toxicities similar to what you would get with these drugs by themselves.
Schwartz pointed out the ongoing challenge in oncology is to find a predictive biomarker, a test that can indicate upfront if the patient will respond to the treatment. This could guide treatment choices and avoid unnecessary drug administration.
While the search for a predictive biomarker in sarcoma treatment continues, the promising results of the nivolumab and Cabozantinib combination therapy offer hope for patients with angiosarcoma.
Schwartz concludes, “we now have a new combination that, we think, could very well indicate a new treatment paradigm for patients with this cancer. And that’s the excitement we have.”
If you want to check Gary Schwartz, MD interview and more information from his study “A multicenter phase II study of cabozantinib + nivolumab for patients (pts) with advanced angiosarcoma (AS) previously treated with a taxane”:
Conclusion
Angiosarcoma, a rare but aggressive form of cancer, has proven challenging to treat effectively.
However, the 2023 ASCO meeting brings promising news to the field.
The combination of the immunotherapy drug nivolumab and the receptor tyrosine kinase inhibitor Cabozantinib has emerged as a potential game-changer in angiosarcoma treatment.
Key Takeaways:
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The Necessity for New Treatments: Traditional chemotherapy agents have had limited success in treating angiosarcoma, with modest response rates and short durations of benefit. The disease’s rarity and aggressive nature emphasize the urgent need for more effective treatments.
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Immunotherapy & RTKI – A Promising Combination: The joint use of nivolumab and Cabozantinib has shown surprisingly positive results in clinical trials. Achieving a response rate of 59% in the Taxol refractory population, this combination therapy far exceeded initial expectations.
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Impressive Clinical Benefits: With a clinical benefit ratio of 73%, the nivolumab-Cabozantinib combination represents a significant step forward in angiosarcoma treatment. The therapy was also effective in angiosarcomas of various sites and generally well-tolerated.
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Predictive Biomarkers – The Future Direction: The search for a predictive biomarker in sarcoma treatment continues, which could allow clinicians to determine upfront who will respond to a given treatment. This could guide treatment decisions and reduce unnecessary drug administration.
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A New Treatment Paradigm: Despite the need for further research and optimization, the results of the combination therapy trial suggest we might be on the cusp of a new treatment paradigm for angiosarcoma.
In summary, while the battle against angiosarcoma is far from over, the developments presented at ASCO 2023 provide significant hope for patients and clinicians alike.
The potent combination of nivolumab and Cabozantinib offers a ray of light in an otherwise challenging landscape, heralding a new era in the treatment of this rare cancer.
The task now is to build on this success, optimizing treatment and identifying predictive biomarkers to ensure that the right patients receive the right treatment at the right time.