Pembrolizumab Plus Lenvatinib Breakthroughs: KEYNOTE-581 Trial

• Pembrolizumab plus Lenvatinib, individually known for their robust anti-cancer mechanisms, when combined, show significant promise in treating advanced renal cell carcinoma.

• The KEYNOTE-581 trial revealed significant improvements in survival outcomes with pembrolizumab/lenvatinib, demonstrating its potential as a first-line treatment for advanced renal cell carcinoma.

• However, potential immune-mediated adverse reactions and other complications linked to this treatment combination require careful monitoring and management.

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• The promising results of this study also hint at potential applications of this drug combination for other types of cancer, but more extensive research is needed.

• Despite the potential side effects, the combination of pembrolizumab and lenvatinib signals a promising step forward in the ongoing quest for more effective cancer treatments.

Renal cell carcinoma (RCC), a type of kidney cancer, represents a significant challenge in oncology.

It is the most common type of kidney cancer, accounting for about 90% of all kidney cancers.

RCC can be asymptomatic in the early stages, often diagnosed by accident during routine examinations, and it’s known for its resistance to radiation therapy and chemotherapy.

Advanced Renal Cell Carcinoma refers to stages III and IV of the disease, where the cancer has spread beyond the kidneys, either to nearby lymph nodes or distant parts of the body.

Pembrolizumab (trade name KEYTRUDA®) and lenvatinib (trade name LENVIMA®) are two potent drugs indicated for the treatment of several types of cancers. Pembrolizumab, an immunotherapy, is a PD-1 inhibitor used in numerous cancers including melanoma, non-small cell lung cancer, and head and neck squamous cell carcinoma, among others. Lenvatinib, a multi-kinase inhibitor, is used in treating thyroid cancer and hepatocellular carcinoma.

Recently, a combination of pembrolizumab and lenvatinib has shown promise for use in advanced renal cell carcinoma.

This dual regimen capitalizes on the strengths of both drugs, potentially offering a significant survival benefit for patients.

The pembrolizumab/lenvatinib regimen brings a revolutionary approach to oncology treatment.

Lenvatinib targets multiple tyrosine kinases involved in angiogenesis, while pembrolizumab amplifies the body’s immune response against tumor cells. Together, they may enhance the effectiveness of cancer treatment, potentially improving outcomes for patients with advanced RCC.

Introduction to the KEYNOTE-581 Trial

The KEYNOTE-581 trial, a pivotal Phase 3 trial, was conducted to study the efficacy of pembrolizumab plus lenvatinib as a first-line treatment for patients with advanced RCC.

The trial demonstrated a long-term, durable survival benefit of this combined treatment, reducing the risk of death by 21% versus the commonly used drug, sunitinib. This discovery marks a significant milestone in the treatment of advanced RCC, potentially setting a new standard of care.

In the upcoming sections, we will delve deeper into the world of advanced RCC, pembrolizumab and lenvatinib, exploring their mechanisms, side effects, the comprehensive findings of the KEYNOTE-581 trial, and much more.

Understanding KEYTRUDA and Lenvima Treatment in Advanced Renal Cell Carcinoma

KEYTRUDA (pembrolizumab) is an immunotherapy that falls under a category of drugs known as checkpoint inhibitors:

• It works by blocking a protein called programmed death-1 (PD-1) present on the surface of immune cells.

• By inhibiting PD-1, pembrolizumab enables T cells – the soldiers of our immune system – to recognize and attack cancer cells more effectively.

• This mechanism of action has proven to be a significant step forward in cancer therapy, offering benefits in various cancer types.

Lenvima (lenvatinib) is a targeted therapy classified as a tyrosine kinase inhibitor:

• It works by blocking several enzymes (kinases) that promote cellular growth and angiogenesis (formation of new blood vessels).

• By inhibiting these enzymes, lenvatinib can slow the growth of cancer cells and cut off their blood supply, thereby limiting their ability to multiply and survive.

The Synergistic Impact of Pembrolizumab/Lenvatinib Combination

The combination of pembrolizumab plus lenvatinib has shown a synergistic effect in the treatment of advanced RCC.

The rationale behind this combination lies in their different but complementary modes of action.

While lenvatinib curbs the growth and blood supply of the tumor, pembrolizumab aids the immune system in recognizing and attacking the cancer cells.

This approach enhances the overall effect, potentially leading to better outcomes for patients.

FDA Approval Status of Pembrolizumab for RCC and Kidney Cancer

As of 2023, pembrolizumab has been FDA approved for use in numerous cancer types, including advanced RCC. The combination treatment of pembrolizumab/lenvatinib for advanced renal cell carcinoma was recently evaluated in the KEYNOTE-581 trial.

This trial’s positive results indicate a potential new standard of care for this cancer type, but specific FDA approval for this combination in RCC is still pending as of my last update in September 2021.

Mechanism of Action of Lenvatinib plus Pembrolizumab

• Pembrolizumab (KEYTRUDA) is an immune checkpoint inhibitor that works by blocking the protein PD-1 (Programmed Death-1), which is present on the surface of the body’s immune cells, known as T cells. Cancer cells often manipulate the PD-1 pathway to escape immune detection.

However, by blocking PD-1, pembrolizumab allows the T cells to recognize these cancer cells and destroy them, effectively restoring the body’s natural anti-cancer immune response.

• Lenvatinib (LENVIMA), on the other hand, belongs to a class of drugs known as tyrosine kinase inhibitors (TKIs). It works by blocking certain proteins (kinases) that promote cell proliferation and angiogenesis, the formation of new blood vessels that tumors need to grow and spread.

By inhibiting these key proteins, lenvatinib disrupts the cancer cells’ growth and their ability to form new blood vessels, starving the tumor of the nutrients it requires to survive and grow.

Combined Mechanism of Lenvatinib Plus Pembrolizumab

When used together, lenvatinib and pembrolizumab work in synergy to combat cancer more effectively.

The combination of these two drugs – one boosting the immune system’s ability to attack cancer cells and the other disrupting the cancer cells’ growth and ability to form blood vessels – forms a powerful and multifaceted approach in treating advanced renal cell carcinoma.

The lenvatinib/pembrolizumab combination not only inhibits cancer growth but also creates an environment within the tumor that makes it easier for the immune system to do its job.

By blocking angiogenesis, lenvatinib can make tumors more susceptible to the effects of pembrolizumab, making this combination particularly effective.

KEYNOTE-581 Trial: A Pivotal Phase 3 Study

The KEYNOTE-581/CLEAR (Study 307) trial is a pivotal Phase 3 clinical study that aimed to evaluate the efficacy and safety of the combination of pembrolizumab and lenvatinib as a first-line treatment for patients with advanced renal cell carcinoma (RCC).

This study marks a significant milestone in the search for effective therapeutic options for patients with RCC, the most common form of kidney cancer in adults.

In the KEYNOTE-581 trial, patients with RCC were randomized into three groups: one group received pembrolizumab plus lenvatinib, the second group received sunitinib (a standard treatment for RCC), and the third group received lenvatinib plus everolimus (an immunosuppressive drug).

The main objective was to evaluate the effectiveness of lenvatinib plus pembrolizumab in prolonging progression-free survival and overall survival compared to sunitinib.

Key Findings from the KEYNOTE-581 Trial

Efficacy Results

After four years of follow-up, the results revealed that pembrolizumab in combination with lenvatinib significantly improved progression-free survival and overall survival among patients compared to the sunitinib group.

The pembrolizumab/lenvatinib group demonstrated a 21% reduction in the risk of death compared to those who were administered sunitinib.

Safety and Tolerability

The safety profile of the pembrolizumab plus lenvatinib combination was consistent with the known safety profiles of each drug alone.

However, some patients experienced severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis.

Long-Term, Durable Survival Benefit

Beyond its efficacy, the combination of pembrolizumab and lenvatinib also demonstrated long-term, durable survival benefits.

These findings underscore the potential of this combination therapy to provide patients with advanced RCC with a new first-line treatment option.

Overall Survival of Pembrolizumab and Lenvatinib in RCC

Taken together, these data from the KEYNOTE-581 trial support the use of pembrolizumab and lenvatinib as a first-line treatment option for patients with advanced RCC.

The promising survival benefit, coupled with the manageable safety profile, positions this combination as a potential game-changer in the RCC treatment landscape.

Side Effects of Lenvatinib Plus Pembrolizumab

As with any medical treatment, the use of lenvatinib and pembrolizumab can lead to side effects.

The combination of lenvatinib and pembrolizumab, like many cancer treatments, is associated with several common side effects. These generally include:

• Fatigue

• Musculoskeletal pain

• Hypertension

• Diarrhea

• Decreased appetite

• Weight loss

• Nausea

While common side effects are often manageable, the lenvatinib/pembrolizumab combination can also lead to severe side effects. The KEYNOTE-581 trial reported severe or life-threatening infusion-related reactions, including:

• Hypersensitivity

• Anaphylaxis (in 0.2% of patients receiving the treatment)

• Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) were another area of concern, with fatal and other serious complications reported in patients who received allogeneic HSCT before or after anti-PD-1/PD-L1 treatments.

This highlights the need for careful patient management and close monitoring during treatment with these agents.

Furthermore, the trial found that in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. This indicates that the use of pembrolizumab in this combination is not recommended outside of controlled trials.

Lastly, embryofetal toxicity is a potential risk.

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman.

Management of Side Effects

The management of side effects associated with lenvatinib and pembrolizumab involves monitoring for signs and symptoms, slowing the rate of infusion for Grade 1 or Grade 2 reactions, and discontinuing treatment for Grade 3 or 4 reactions.

In the case of allogeneic HSCT complications, careful follow-up is required to promptly intervene if evidence of complications appears.

Pregnancy should be verified prior to starting treatment, and effective contraception is recommended during treatment and for 4 months after the last dose.

KEYTRUDA and Lenvima: Duration of Treatment

When treating patients with advanced renal cell carcinoma using the combination of KEYTRUDA and Lenvima, the duration of treatment becomes a crucial aspect to consider.

The duration of treatment with pembrolizumab and lenvatinib depends on several factors. The most significant are:

• The patient’s overall health

• The stage and progression of the cancer

• The patient’s response to the treatment

Adverse reactions also play a critical role in determining the duration of treatment.

Furthermore, the National Cancer Institute notes that immunotherapies such as pembrolizumab can sometimes result in delayed responses, implying that the treatment may need to be continued for a longer period even if immediate changes are not visible.

This is the reason why the exact duration of treatment with pembrolizumab and lenvatinib can vary, but it’s typically administered until the patient achieves a complete response, or until the patient experiences disease progression or unacceptable toxicity.

In the KEYNOTE-581 trial, the benefits of pembrolizumab/lenvatinib treatment in terms of survival were observed after four years of follow-up:

• Throughout the treatment period, the progress of the patient must be closely monitored.

• Regular follow-ups and assessments are essential to evaluate the effectiveness of the treatment and to monitor for any adverse reactions.

• This constant evaluation helps to determine whether the treatment should be continued, adjusted, or stopped.

Patients are often subjected to scans and other tests to track the size of the tumors and to detect any new ones. Monitoring the levels of certain biomarkers in the blood can also provide important clues about how the patient is responding to the treatment.

Interview with Corina Dutcus, M.D.

To offer our readers a deeper and more personalized perspective on the transformative impact of KEYTRUDA and LENVIMA in the treatment of advanced renal cell carcinoma, we have a special addition to our blog. We invite you to watch an engaging and insightful video interview with Corina Dutcus, M.D.:

 

 

Immune-Mediated Adverse Reactions and Other Complications

While the combination of pembrolizumab and lenvatinib has shown significant promise in the treatment of advanced renal cell carcinoma, it is essential to understand the possible complications associated with this therapy.

Immune-mediated adverse reactions are a unique category of side effects that can occur when taking immune checkpoint inhibitors like pembrolizumab.

These reactions occur when the immune system, once activated by the drug, starts attacking normal cells in the body, causing inflammation and potentially serious damage to certain organs.

Specific Adverse Reactions

The combination of pembrolizumab/lenvatinib, although effective, can lead to several immune-mediated adverse reactions, including:

• Colitis (inflammation of the colon)

• Hepatitis (inflammation of the liver)

• Endocrinopathies (hormonal disorders)

• Nephritis (inflammation of the kidneys)

Infusion-Related Reactions

Infusion-related reactions, which can range from mild to severe, have been reported in a small percentage of patients receiving pembrolizumab. These reactions include:

• Hypersensitivity

• Anaphylaxis

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Patients who undergo allogeneic HSCT before or after treatment with pembrolizumab can experience fatal and other serious complications, including:

• Hyperacute graft-versus-host disease (GVHD)

• Acute and chronic GVHD

• Hepatic veno-occlusive disease

Conclusion

As we delve into the arena of cancer therapeutics, the groundbreaking efficacy of pembrolizumab/lenvatinib combination for advanced renal cell carcinoma shines brightly. This game-changing approach, backed by the compelling results of the KEYNOTE-581 trial, has the potential to reshape the landscape of kidney cancer treatment.

The combination of KEYTRUDA (pembrolizumab) and LENVIMA (lenvatinib), two powerful drugs, each with a unique mechanism of action, demonstrated significantly improved survival outcomes in patients with advanced renal cell carcinoma.

Importantly, the therapeutic benefits were achieved without an unacceptable increase in toxicity, rendering this combination a promising first-line treatment option for these patients.

The journey towards finding effective cancer treatment is long and complex.

Yet, the promising results from the KEYNOTE-581 trial underscore the importance of innovative treatment combinations and provide hope for improved outcomes for patients with advanced renal cell carcinoma.