Idée - Oncology - # Frontline and Salvage Treatments for Esophageal and Gastric Cancers

Emerging Biomarkers and Targeted Therapies for Esophageal and Gastric Cancers: Insights from Leading Oncologists

Q: How can clinicians best balance the trade-offs between toxicity and efficacy when selecting frontline regimens for esophageal and gastric cancer patients?

Clinicians face a critical challenge in balancing toxicity and efficacy when selecting frontline regimens for esophageal and gastric cancer patients. The choice of treatment often hinges on the patient's performance status, comorbidities, and the specific characteristics of the cancer. For instance, regimens like FLOT (5-FU/leucovorin/oxaliplatin/docetaxel) may offer improved efficacy over traditional chemoradiation approaches like CROSS but come with a higher risk of toxicity. To navigate this trade-off, clinicians should adopt a patient-centered approach that includes thorough assessments of the patient's overall health, weight loss, and ability to tolerate intensive chemotherapy. Regular monitoring for adverse effects and being prepared to adjust dosages or switch to less toxic regimens, such as FOLFOX (leucovorin, fluorouracil, and oxaliplatin), can help mitigate toxicity while still aiming for effective disease control. Additionally, incorporating biomarkers such as PD-L1 expression can guide the use of immunotherapy, potentially enhancing efficacy without significantly increasing toxicity. Ultimately, the goal is to tailor treatment plans that maximize therapeutic benefits while minimizing harm, ensuring that patients receive the most appropriate care based on their individual circumstances.

Q: What are the potential challenges in implementing a biomarker-driven approach in the real-world setting, and how can they be addressed?

Implementing a biomarker-driven approach in the real-world setting presents several challenges. One significant hurdle is the variability in access to biomarker testing, which can differ based on institutional resources, geographic location, and healthcare policies. Additionally, the turnaround time for biomarker results can delay treatment decisions, potentially impacting patient outcomes. Another challenge is the interpretation of biomarker results, particularly when different assays and cutoffs are used across studies. For example, the PD-L1 combined positive score (CPS) has varying thresholds for determining eligibility for immunotherapy, which can lead to confusion in clinical practice. To address these challenges, healthcare systems should prioritize the integration of standardized biomarker testing protocols and ensure that all patients have access to timely testing. Education and training for oncologists on the interpretation of biomarker results and their implications for treatment decisions are also essential. Furthermore, fostering collaboration between academic institutions and community practices can help disseminate knowledge and best practices, ultimately leading to more consistent and effective implementation of biomarker-driven strategies in esophageal and gastric cancer care.

Q: What novel combination strategies, beyond chemotherapy and targeted therapies, hold promise for improving outcomes in esophageal and gastric cancers?

Novel combination strategies that extend beyond traditional chemotherapy and targeted therapies are emerging as promising avenues for improving outcomes in esophageal and gastric cancers. One such strategy involves the use of antibody-drug conjugates (ADCs), which combine the specificity of monoclonal antibodies with the cytotoxicity of chemotherapy. For instance, trastuzumab deruxtecan is being explored in clinical trials for HER2-positive gastric cancer, potentially offering enhanced efficacy with a more favorable toxicity profile. Another innovative approach is the combination of immunotherapy with chemotherapy, as seen in trials like KEYNOTE-811, which evaluates the addition of pembrolizumab to FOLFOX and trastuzumab for HER2-positive patients. This strategy aims to leverage the synergistic effects of immune checkpoint inhibitors alongside conventional treatments, potentially leading to improved response rates and survival outcomes. Additionally, the exploration of bispecific antibodies and T-cell engagers, which can simultaneously target multiple antigens, is gaining traction. These agents may provide a more effective means of overcoming tumor heterogeneity and resistance mechanisms. Finally, the integration of novel biomarkers, such as claudin-18.2, into treatment algorithms can guide the selection of appropriate therapies, including ADCs and other investigational agents. As research continues to evolve, these combination strategies hold the potential to significantly enhance the therapeutic landscape for patients with esophageal and gastric cancers, ultimately leading to better clinical outcomes.

Concepts de base

Oncologists are exploring new biomarker-driven approaches, combination therapies, and sequencing strategies to improve outcomes for patients with esophageal and gastric cancers.

Résumé

The discussion covers several key topics in the management of esophageal and gastric cancers:

Adoption of the ESOPEC trial data: The oncologists agree that the FLOT (5-FU/leucovorin/oxaliplatin/docetaxel) regimen will likely become the preferred neoadjuvant approach over the CROSS (chemoradiation) regimen for patients with locally advanced esophageal adenocarcinoma. However, they note the need to carefully select patients who can tolerate the FLOT regimen.
Role of PD-L1 testing: PD-L1 testing is now routinely performed, as it guides decisions on incorporating immunotherapy. There is a trend towards a binary approach, where patients with any PD-L1 positivity may be considered for checkpoint inhibitors.
Emerging frontline trials: The oncologists are exploring novel triplet chemotherapy regimens, such as FOLFIRINOX, as potential alternatives to FLOT or FOLFOX in the frontline setting. These trials also incorporate targeted therapies and immunotherapy.
Second-line and beyond: For patients who progress after frontline therapy, the oncologists discuss the potential role of emerging targeted agents, such as antibody-drug conjugates (ADCs) and claudin-18.2 inhibitors, in addition to the standard ramucirumab plus paclitaxel.
Surgical considerations: The oncologists acknowledge that a subset of patients with oligometastatic disease may benefit from surgical resection, but emphasize the need for careful patient selection and a window of systemic therapy prior to considering surgery.

Overall, the discussion highlights the rapidly evolving landscape of esophageal and gastric cancer management, with a focus on personalized, biomarker-driven approaches and combination strategies to improve patient outcomes.

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Citations

"We test PD-L1 in nearly everybody, knowing that even in the patients with locally advanced data, half of the time their disease comes back, even with the best treatment, such as FLOT."
"Our thought process was starting with upfront triplet, with a more effective and possibly less toxic regimen, such as FOLFIRINOX as opposed to FLOT or DCF (docetaxel, cisplatin, and 5-fluorouracil). Maybe that's a better approach."
"There are a lot of different claudin-targeting approaches these days. I actually googled it and there are maybe 50, 60 clinical trials with different claudin 18.2–targeting drugs."

Idées clés tirées de

Episode 5: Emerging Biomarkers and Therapies for Esophageal Cancer

by Samuel J. Kl... à www.medscape.com 09-26-2024

https://www.medscape.com/viewarticle/999886

Episode 5: Emerging Biomarkers and Therapies for Esophageal Cancer

Questions plus approfondies

How can clinicians best balance the trade-offs between toxicity and efficacy when selecting frontline regimens for esophageal and gastric cancer patients?

Clinicians face a critical challenge in balancing toxicity and efficacy when selecting frontline regimens for esophageal and gastric cancer patients. The choice of treatment often hinges on the patient's performance status, comorbidities, and the specific characteristics of the cancer. For instance, regimens like FLOT (5-FU/leucovorin/oxaliplatin/docetaxel) may offer improved efficacy over traditional chemoradiation approaches like CROSS but come with a higher risk of toxicity.
To navigate this trade-off, clinicians should adopt a patient-centered approach that includes thorough assessments of the patient's overall health, weight loss, and ability to tolerate intensive chemotherapy. Regular monitoring for adverse effects and being prepared to adjust dosages or switch to less toxic regimens, such as FOLFOX (leucovorin, fluorouracil, and oxaliplatin), can help mitigate toxicity while still aiming for effective disease control. Additionally, incorporating biomarkers such as PD-L1 expression can guide the use of immunotherapy, potentially enhancing efficacy without significantly increasing toxicity. Ultimately, the goal is to tailor treatment plans that maximize therapeutic benefits while minimizing harm, ensuring that patients receive the most appropriate care based on their individual circumstances.

What are the potential challenges in implementing a biomarker-driven approach in the real-world setting, and how can they be addressed?

Implementing a biomarker-driven approach in the real-world setting presents several challenges. One significant hurdle is the variability in access to biomarker testing, which can differ based on institutional resources, geographic location, and healthcare policies. Additionally, the turnaround time for biomarker results can delay treatment decisions, potentially impacting patient outcomes.
Another challenge is the interpretation of biomarker results, particularly when different assays and cutoffs are used across studies. For example, the PD-L1 combined positive score (CPS) has varying thresholds for determining eligibility for immunotherapy, which can lead to confusion in clinical practice.
To address these challenges, healthcare systems should prioritize the integration of standardized biomarker testing protocols and ensure that all patients have access to timely testing. Education and training for oncologists on the interpretation of biomarker results and their implications for treatment decisions are also essential. Furthermore, fostering collaboration between academic institutions and community practices can help disseminate knowledge and best practices, ultimately leading to more consistent and effective implementation of biomarker-driven strategies in esophageal and gastric cancer care.

What novel combination strategies, beyond chemotherapy and targeted therapies, hold promise for improving outcomes in esophageal and gastric cancers?

Novel combination strategies that extend beyond traditional chemotherapy and targeted therapies are emerging as promising avenues for improving outcomes in esophageal and gastric cancers. One such strategy involves the use of antibody-drug conjugates (ADCs), which combine the specificity of monoclonal antibodies with the cytotoxicity of chemotherapy. For instance, trastuzumab deruxtecan is being explored in clinical trials for HER2-positive gastric cancer, potentially offering enhanced efficacy with a more favorable toxicity profile.
Another innovative approach is the combination of immunotherapy with chemotherapy, as seen in trials like KEYNOTE-811, which evaluates the addition of pembrolizumab to FOLFOX and trastuzumab for HER2-positive patients. This strategy aims to leverage the synergistic effects of immune checkpoint inhibitors alongside conventional treatments, potentially leading to improved response rates and survival outcomes.
Additionally, the exploration of bispecific antibodies and T-cell engagers, which can simultaneously target multiple antigens, is gaining traction. These agents may provide a more effective means of overcoming tumor heterogeneity and resistance mechanisms.
Finally, the integration of novel biomarkers, such as claudin-18.2, into treatment algorithms can guide the selection of appropriate therapies, including ADCs and other investigational agents. As research continues to evolve, these combination strategies hold the potential to significantly enhance the therapeutic landscape for patients with esophageal and gastric cancers, ultimately leading to better clinical outcomes.