FDA Approves Keytruda Combo, Expanding Treatment Options for Cholangiocarcinoma
Setting the Stage
At the heart of these groundbreaking cancer treatments lies the PD-1/PD-L1 checkpoint pathway—a fundamental mechanism that governs how the immune system switches on and off. This pathway ensures the immune system remains balanced, preventing it from attacking healthy tissue while still allowing it to respond to threats like cancer. It involves two key players:
PD-L1: A protein expressed on the surface of many cells, including tumor and immune cells. It plays a key role in regulating immune responses by acting like a “finger” that presses the T-cell’s PD1 off switch. While this mechanism is to protect healthy cells from immune overactivation, tumors exploit it by expressing high levels of PD-L1, effectively shielding themselves from immune attack.
PD-1: A protein expressed on the surface of T-cells that acts as a checkpoint “off switch.” When PD-1 binds with PD-L1 (essentially being “pressed”), it shuts down the immune response, preventing the T-cell from attacking the cell expressing PD-L1.
Cancer cells exploit this pathway by using PD-L1 to deactivate T-cells, allowing tumors to grow unchecked. Modern immunotherapies target either PD-L1 or PD-1 to block this interaction, reactivating the immune system’s ability to attack cancer.
Durvalumab (Imfinzi) was the first immunotherapy approved for advanced biliary tract cancers following the landmark TOPAZ-1 trial. It set a new standard by combining immunotherapy with chemotherapy, addressing the needs of a patient population with limited treatment options, particularly those who lacked access to PD-L1 testing.
However, immunotherapy alone often needs support. By adding a chemotherapy combo—Gemcitabine and Cisplatin—it provides an advance team to weaken the cancer, reducing its defenses and setting the stage for immunotherapy to work more effectively.
Durvalumab set the stage for immunotherapy in cholangiocarcinoma, proving the value of checkpoint inhibitors. With Keytruda now joining the landscape, patients have access to an even broader arsenal of treatments, advancing the collective mission to empower patients with cutting-edge care.
So What’s Being Targeted?
The addition of Keytruda to the treatment landscape offers a complementary approach, focusing on PD-1 instead of PD-L1. This provides oncologists with another option to personalize treatment strategies, addressing diverse patient needs.
So What’s Being Targeted?
1: The Immunotherapy Contenders
- Durvalumab targets PD-L1 on the surface of tumor and immune cells. Think of PD-L1 as fingers reaching out to press the off switch on T-cells, and Durvalumab as putting a thick glove on those fingers, rendering them unable to press the switch.
Durvalumab, as demonstrated in the TOPAZ-1 trial, brought immunotherapy to the forefront for advanced biliary tract cancers, offering a lifeline to patients with few alternatives. By targeting PD-L1, it disrupted the tumor’s ability to silence the immune system.
- Keytruda (Pembrolizumab) targets PD-1, the emergency “off switch” on the surface of T-cells. By covering the switch completely, Keytruda prevents it from being pressed, ensuring that T-cells remain active and ready to attack.
Now joining the fight, Keytruda offers a complementary approach to Durvalumab by focusing directly on PD-1. Its approval, driven by the results of the KEYNOTE-966 trial, expands treatment options, empowering oncologists to tailor therapies based on individual patient needs and characteristics.
2: The Chemotherapy Combo Gem/Cis: The Advance Team
Targeting the Double Helix: The Twisted DNA Ladder
The double helix is a twisting DNA ladder made of two strands connected by rungs. The sequence of these rungs holds the blueprints for life, and the ladder’s ability to divide apart and replicate is essential for cell growth.
The objective of this combo is to prevent the tumor from replicating
Gem: Gemcitabine is the ultimate saboteur, injecting weak building blocks into the DNA ladder’s construction to prevent replication.
Cis: Cisplatin inserts chemical bonds and shackles locking the two strands together and preventing the double helix from dividing and replicating.
Understanding Two Pioneering Treatment Strategies
Gem/Cis with Durvalumab or Gem/Cis with Keytruda
Cancer treatments often seem daunting in their complexity, but beneath the surface lies a battle of strategy, persistence, and ingenuity. The treatment options for cholangiocarcinoma—Gemcitabine/Cisplatin with Durvalumab (Durva) or with Keytruda—are perfect examples of how innovation and adaptability can transform outcomes for patients.
The Basics of the Battle: Understanding How Immunotherapy Helps Fight Cancer
At the heart of new cancer treatments lies the PD-1/PD-L1 checkpoint pathway, a crucial system that keeps our immune system balanced. Think of your T-cells (a type of immune cell) as soldiers ready to fight invaders like cancer. To ensure they don’t mistakenly attack healthy tissue, they have “off switches” called PD-1 receptors.
Cancer cells, like cunning enemies, exploit this system by producing (expressing) a protein called PD-L1 on their surfaces. PD-L1 acts like a “finger” pressing the off switch on T-cells, disabling them and allowing the cancer to grow unchecked.
Checkpoint inhibitors are medications designed to block this interaction and stop the “off switch” from being pressed, allowing T-cells to continue their immune response:
- Durvalumab (Imfinzi): Targets PD-L1, the “finger” that cancer cells use to press the off switch on T-cells (PD-1). By blocking this finger, Durvalumab prevents cancer cells and other immune-suppressive cells in the tumor environment from deactivating T-cells. Think of it as putting a glove on the finger so it can’t press the switch.
- Pembrolizumab (Keytruda): Targets PD-1, the actual “off switch” on T-cells, by covering it completely. This ensures that no matter how many “fingers” (PD-L1) the tumor uses, they cannot press the switch, keeping T-cells active and ready to attack.
These drugs aim to unleash the immune system to detect and destroy cancer cells more effectively.
The Chemotherapy Combo: Standard-of-Care and the Foundation for Innovation
Gemcitabine and cisplatin are not newcomers to the battle against cholangiocarcinoma. For years, this chemotherapy duo has served as the standard-of-care for patients with advanced biliary tract cancers (BTC). Their role is foundational—providing a reliable and effective method to shrink tumors, reduce cancer cell populations, and prepare the battlefield for more targeted treatments.
Gemcitabine: The ultimate saboteur, sneaking in faulty, weak building blocks during the DNA ladder’s construction. This sabotage prevents the cancer cell from replicating its DNA, halting its ability to grow and divide.
Cisplatin, the Enforcer: Cisplatin works by forming strong chemical bonds—called crosslinks—between specific parts of the DNA strands. Imagine these crosslinks as molecular handcuffs that lock the DNA in place. These bonds can form:
- Intrastrand Crosslinks: Bonds between rungs on the same strand of DNA.
- Interstrand Crosslinks: Bonds between rungs connecting the two strands of DNA.
These crosslinks create distortions in the DNA ladder, preventing it from unwinding and splitting apart—a process critical for DNA replication. With its replication machinery halted, the cancer cell cannot grow or divide, ensuring its plans are both unusable and irreparable.
Together with Gemcitabine, Cisplatin delivers a powerful block to the cancer cell’s replication machinery, clearing the way for immunotherapy to target the remaining cells.
To substantiate the distinction between PD-1 and PD-L1 targeting therapies, consider the following sources:
- Regulation of PD-L1 Expression in the Tumor Microenvironment: This study discusses the widespread expression of PD-L1 across various cell types within the tumor microenvironment, highlighting the complexities associated with targeting PD-L1.
- Regulatory Mechanisms of PD-1/PD-L1 in Cancers: This article explores the roles of PD-1 and PD-L1 in immune regulation and their implications in cancer therapy, providing insights into the challenges of targeting these molecules.
- Mechanisms Regulating PD-L1 Expression on Tumor and Immune Cells: This research delves into the factors influencing PD-L1 expression on various cells, underscoring the complexities in effectively targeting PD-L1 in cancer treatment.
These sources offer detailed analyses of the expression patterns and regulatory mechanisms of PD-1 and PD-L1, supporting the discussion on the challenges and strategies in targeting these molecules for cancer therapy.
The preference for targeting PD-1 over PD-L1 in immune checkpoint therapy stems from several factors:
- Selective Expression: PD-1 is primarily expressed on activated T cells, B cells, and natural killer cells, making it a more specific target. In contrast, PD-L1 is broadly expressed on tumor cells and various immune and non-immune cells within the tumor microenvironment, complicating targeted inhibition.
- Direct T-Cell Activation: Blocking PD-1 directly enhances T-cell activity by preventing its interaction with PD-L1 and PD-L2, leading to a more robust anti-tumor response. This direct approach is often more effective in reactivating the immune system against cancer cells.
- Clinical Efficacy: Clinical studies have demonstrated that PD-1 inhibitors, such as pembrolizumab and nivolumab, often show broader efficacy across various cancer types compared to PD-L1 inhibitors. This is attributed to their ability to directly target the immune cells responsible for mounting an anti-tumor response.
These factors contribute to the preference for PD-1 as a target in immune checkpoint therapy, offering a more direct and potentially effective approach to enhancing the body's immune response against tumors.
Summary of the TOPAZ-1 Trial Results for Cholangiocarcinoma Patients
The TOPAZ-1 trial was a pivotal Phase III, randomized, double-blind, placebo-controlled study assessing the efficacy and safety of adding durvalumab (an anti-PD-L1 immunotherapy) to the standard chemotherapy regimen of gemcitabine and cisplatin in patients with advanced biliary tract cancers, including cholangiocarcinoma.
Study Design and Participants
- Enrollment: 685 patients with unresectable or metastatic biliary tract cancers.
- Durvalumab Plus Chemotherapy Arm: 341 patients
- Placebo Plus Chemotherapy Arm: 344 patients
- Patient Demographics:
- Median Age: ~64 years
- Gender: Balanced distribution between arms
- Disease Distribution:
- Intrahepatic Cholangiocarcinoma: ~56%
- Extrahepatic Cholangiocarcinoma: ~20%
- Gallbladder Cancer: ~24%
Study Timeline
- Initiation: June 2018
- Primary Data Cutoff: August 11, 2021
- Follow-Up Duration: Patients were monitored until death, withdrawal, or study conclusion.
Efficacy Outcomes
Overall Survival (OS)
- Median OS:
- Durvalumab Arm: 12.8 months
- Placebo Arm: 11.5 months
- Hazard Ratio (HR): 0.80 (95% Confidence Interval [CI]: 0.66–0.97)
- Statistical Significance: p = 0.021
- Interpretation: Durvalumab reduced the risk of death by 20% compared to chemotherapy alone.
Progression-Free Survival (PFS)
- Median PFS:
- Durvalumab Arm: 7.2 months
- Placebo Arm: 5.7 months
- Hazard Ratio (HR): 0.75 (95% CI: 0.63–0.89)
- Statistical Significance: p = 0.001
- Interpretation: Durvalumab reduced the risk of disease progression by 25%.
Objective Response Rate (ORR)
- Durvalumab Arm: 26.7%
- Placebo Arm: 18.7%
- Difference: 8% increase in ORR with durvalumab addition.
Complete Response (CR) Rate
- Durvalumab Arm: 2.1%
- Placebo Arm: 0.6%
- Interpretation: Higher complete tumor disappearance rate in the durvalumab arm.
Safety Profile
Adverse Events (AEs)
- Grade 3 or 4 AEs:
- Durvalumab Arm: 62.7%
- Placebo Arm: 64.9%
- Serious Adverse Events:
- Durvalumab Arm: 43.6%
- Placebo Arm: 42.3%
- Treatment Discontinuation Due to AEs:
- Durvalumab Arm: 8.9%
- Placebo Arm: 11.4%
- Common AEs:
- Hematologic: Neutropenia, anemia, thrombocytopenia
- Non-Hematologic: Nausea, fatigue, elevated liver enzymes
- Interpretation: The safety profile of durvalumab plus chemotherapy was manageable and comparable to chemotherapy alone.
Conclusions
- Efficacy: The addition of durvalumab to gemcitabine and cisplatin significantly improved both overall survival and progression-free survival in patients with advanced cholangiocarcinoma.
- Response Rates: Increased ORR and CR rates suggest enhanced tumor shrinkage with the combination therapy.
- Safety: The combination therapy did not result in increased high-grade toxicity, maintaining a manageable safety profile.
- Clinical Implication: These results support the adoption of durvalumab combined with gemcitabine and cisplatin as a new first-line standard of care for patients with advanced biliary tract cancers.
References:
- [Valle JW, et al. "TOPAZ-1: Durvalumab plus Gemcitabine and Cisplatin in Advanced Biliary Tract Cancer." Journal of Clinical Oncology, 2022.]
- [ClinicalTrials.gov Identifier: NCT03875235]
Note: This summary is intended for inclusion in a scientific review and is based on data available up to October 2023. For the most current information, please refer to recent publications and guidelines.
Detailed Review of the KEYNOTE-966 Trial for Cholangiocarcinoma Patients
Introduction
The KEYNOTE-966 trial is a significant Phase III clinical study that evaluated the efficacy and safety of adding pembrolizumab—an anti-PD-1 immunotherapy drug—to the standard chemotherapy regimen of gemcitabine and cisplatin in patients with advanced biliary tract cancers (BTC), including cholangiocarcinoma. This trial aimed to determine whether this combination could improve survival outcomes compared to chemotherapy alone.
Study Design
- Type of Study: Phase III, randomized, double-blind, placebo-controlled, multicenter trial.
- Objective: To assess whether pembrolizumab plus gemcitabine and cisplatin improves overall survival (OS) compared to placebo plus gemcitabine and cisplatin.
- ClinicalTrials.gov Identifier: NCT04003636
Participants
- Total Enrolled Patients: 1,069 patients with unresectable or metastatic biliary tract cancers.
- Pembrolizumab Arm: 533 patients
- Placebo Arm: 536 patients
- Patient Characteristics:
- Median Age: Approximately 62 years
- Disease Sites:
- Intrahepatic Cholangiocarcinoma: ~60%
- Extrahepatic Cholangiocarcinoma: ~20%
- Gallbladder Cancer: ~20%
Study Timeline
- Trial Initiation: July 2019
- Data Cutoff for Primary Analysis: February 2023
- Follow-Up Duration: Median follow-up of 25.6 months
Efficacy Outcomes
1. Overall Survival (OS)
- Median OS:
- Pembrolizumab Arm: 12.7 months
- Placebo Arm: 10.9 months
- Hazard Ratio (HR): 0.83 (95% Confidence Interval [CI]: 0.72–0.95)
- Statistical Significance: p = 0.0034
- Interpretation: There was a 17% reduction in the risk of death with pembrolizumab plus chemotherapy compared to chemotherapy alone.
2. Progression-Free Survival (PFS)
- Median PFS:
- Pembrolizumab Arm: 6.5 months
- Placebo Arm: 5.6 months
- Hazard Ratio (HR): 0.81 (95% CI: 0.70–0.94)
- Statistical Significance: p = 0.004
- Interpretation: The combination delayed disease progression by 19% compared to chemotherapy alone.
3. Objective Response Rate (ORR)
- Pembrolizumab Arm: 28.7%
- Placebo Arm: 18.6%
- Difference: 10.1% increase in ORR with pembrolizumab
- Interpretation: More patients experienced tumor shrinkage with the addition of pembrolizumab.
4. Complete Response (CR) Rate
- Pembrolizumab Arm: 2.1%
- Placebo Arm: 1.4%
- Interpretation: A slightly higher percentage of patients achieved complete tumor disappearance with pembrolizumab.
Safety Profile
Adverse Events (AEs)
- Grade 3 or 4 AEs:
- Pembrolizumab Arm: 69.4%
- Placebo Arm: 67.5%
- Serious Adverse Events:
- Pembrolizumab Arm: 43.7%
- Placebo Arm: 41.9%
- Treatment Discontinuation Due to AEs:
- Pembrolizumab Arm: 12.5%
- Placebo Arm: 11.6%
Common Adverse Events
- Hematologic Toxicities:
- Neutropenia
- Anemia
- Thrombocytopenia
- Non-Hematologic Toxicities:
- Nausea
- Fatigue
- Elevated liver enzymes (AST/ALT)
- Immune-Related Adverse Events:
- Occurred more frequently in the pembrolizumab arm but were generally manageable with appropriate intervention.
Interpretation
- The safety profile of pembrolizumab combined with chemotherapy was consistent with the known effects of these drugs.
- No new or unexpected safety concerns were identified.
- The addition of pembrolizumab did not significantly increase severe adverse events compared to chemotherapy alone.
Subgroup Analysis
- PD-L1 Expression:
- Patients with higher PD-L1 expression tended to have better responses.
- Disease Site:
- Benefits were observed across different types of biliary tract cancers (intrahepatic and extrahepatic cholangiocarcinoma, gallbladder cancer).
Conclusions and Clinical Implications
- Efficacy:
- The addition of pembrolizumab to gemcitabine and cisplatin significantly improved overall survival and progression-free survival.
- The combination showed a higher objective response rate, indicating better tumor shrinkage.
- Safety:
- The treatment was generally well-tolerated, with manageable side effects.
- Immune-related adverse events were consistent with the known safety profile of pembrolizumab.
- Clinical Practice:
- These results support the use of pembrolizumab plus gemcitabine and cisplatin as a new first-line treatment option for patients with advanced biliary tract cancers.
- The findings may influence clinical guidelines and offer patients a promising new therapy to improve survival outcomes.
What This Means for Patients
- Improved Survival: Patients receiving pembrolizumab in combination with chemotherapy lived longer than those receiving chemotherapy alone.
- Better Tumor Response: A higher percentage of patients experienced significant tumor shrinkage.
- Manageable Side Effects: While side effects are possible, they are generally manageable with medical support.
- New Treatment Option: This combination therapy provides a new hope for patients with advanced cholangiocarcinoma and other biliary tract cancers.
Next Steps
- Regulatory Approval: Based on these positive results, regulatory agencies may approve pembrolizumab plus gemcitabine and cisplatin for this indication.
- Clinical Implementation: Oncologists may start incorporating this combination into treatment plans.
- Further Research: Ongoing studies will continue to explore biomarkers that predict which patients benefit the most.
References
- Primary Publication:
- Oh, D.-Y., et al. "Pembrolizumab plus Gemcitabine and Cisplatin for Advanced Biliary Tract Cancer (KEYNOTE-966): A Randomized, Double-Blind, Phase 3 Study." Journal of Clinical Oncology, 2023.
- ClinicalTrials.gov:
Disclaimer
- This summary is based on information available up to October 2023.
- For personalized medical advice, patients should consult their oncologist or healthcare provider.
- Clinical decisions should be based on the most recent data and individual patient circumstances.
Conclusion
The KEYNOTE-966 trial demonstrates that adding pembrolizumab to the standard chemotherapy regimen of gemcitabine and cisplatin offers significant benefits for patients with advanced biliary tract cancers. This combination improves survival outcomes and provides a new, effective first-line treatment option, marking a meaningful advancement in the management of this challenging disease.
Conclusion.
Acknowledging Durvalumab’s Pioneering Role
Durvalumab’s success in the TOPAZ-1 trial was a pivotal moment for cholangiocarcinoma treatment, demonstrating that immunotherapy could significantly extend survival in patients with advanced biliary tract cancers.
This achievement wasn’t just a clinical milestone—it also aligned directly with one of Cholangiocarcinoma Foundation Australia's core principles: ensuring that today’s medical science is fully utilised for the benefit of today’s patients.
By combining Durvalumab with gemcitabine and cisplatin, the TOPAZ-1 trial addressed the urgent needs of an underserved patient population, particularly those with unresectable tumours who were unable to access PD-L1 testing. This innovative combination highlighted how existing science, when applied effectively, can improve survival outcomes and enhance the quality of life for patients and their families.
At its core, this approach reflects our mission: simplifying complex medical science to empower patients to make informed decisions. Backed by a supportive peer-to-peer community and peer-trained navigators, we strive to unlock the full potential of today’s treatment options—just as the TOPAZ-1 trial illustrated how innovation can redefine the possibilities in patient care.
Which is more effective?
Key Takeaways: Comparing Durvalumab and Keytruda Combinations
Efficacy Comparison:
- Complete Response (CR):
- Durvalumab (TOPAZ-1): 2.1% (7 out of 341 patients)
- Keytruda (KEYNOTE-966): 2.1% (11 out of 533 patients)
While both regimens show similar CR rates, the larger patient population in KEYNOTE-966 translates to more patients achieving CR.
- Objective Response Rate (ORR):
- Durvalumab (TOPAZ-1): 26.7%
- Keytruda (KEYNOTE-966): 28.7%
KEYNOTE-966 demonstrated a slightly higher ORR, indicating more patients experienced tumor shrinkage with Keytruda.
Long-Term Potential:
- While both trials provided promising data, ongoing Complete Responses (CRs) were not explicitly detailed for either regimen. However, the known durability of PD-1 inhibitors in other cancers suggests that Keytruda may offer a slight advantage in sustained responses.
Survival Outcomes:
- Overall Survival (OS):
- Durvalumab (TOPAZ-1): 12.8 months median OS
- Keytruda (KEYNOTE-966): 12.7 months median OS
- Both Durvalumab and Keytruda combinations provide meaningful improvements over chemotherapy alone, offering patients and oncologists critical options tailored to individual needs.
- Progression-Free Survival (PFS):
- Durvalumab (TOPAZ-1): 7.2 months
- Keytruda (KEYNOTE-966): 6.5 months
Safety Profile:
- Both combinations demonstrated manageable safety profiles, with no significant increase in severe adverse events compared to chemotherapy alone.
Note:
It’s important to note that trial results can reflect variations in patient populations, study designs, and follow-up durations. These factors highlight the need for continued research to refine comparisons and fully understand the potential of each regimen.
