By. Allen Wilbanks
Today, the focus is on the ALINA trial, a phase three study comparing Alectinib versus chemotherapy as adjuvant therapy for patients with stage 1B to 3A ALK-positive non-small cell lung cancer. Presented in 2023, the trial results are discussed by Josina Reddy, MD. The significance of the phase 3 ALINA results lies in the 76% reduction in the risk of disease recurrence or death with Alectinib compared to platinum-based chemotherapy in ALK-positive early-stage non-small cell lung cancer.
Josina Reddy, MD, explains that the ALINA trial enrolled patients with early-stage lung cancer that could be surgically removed, specifically focusing on ALK-positive lung cancer. The trial aimed to address the high risk of recurrence in these patients. The randomized study revealed that Alectinib led to a substantial 76% reduction in the risk of cancer recurrence and death.
The discussion then turns to the observation of a statistically significant and clinically meaningful improvement in central nervous system disease-free survival (DFS) with Alectinib. Josina Reddy, MD, emphasizes the impact of lung cancer spreading to the brain and highlights Alectinib's ability to penetrate the brain, resulting in a 78% decrease in recurrences in the brain.
The role of comprehensive biomarker testing is underscored, emphasizing its importance in securing a personalized diagnosis for ALK-positive non-small cell lung cancer. Josina Reddy, MD, explains that understanding different biomarkers is crucial for treatment decisions, and comprehensive testing enables informed discussions about available treatment options.
Concerning the safety and tolerability of Alectinib, Josina Reddy, MD, notes that the findings in the ALINA study align with the extensive data from the metastatic setting. The two-year treatment duration in the study did not yield any notable differences in safety and tolerability compared to previous trials in the metastatic setting.
With the ALINA study potentially impacting the management of early-stage ALK-positive lung cancer, Josina Reddy, MD, expresses the data's significance. Efforts are underway to discuss the findings with health authorities globally, aiming to bring Alectinib to patients in this setting. Josina Reddy, MD, expresses optimism about ongoing advancements in lung cancer treatment and acknowledges the commitment to improving outcomes for patients in the early stages with a chance of cure.
By. Nicolas Rigard, MD
In this interview, Nicolas Girard, MD, a medical doctor and professor of respiratory medicine at Versailles, St. Quentin University, and the head of the Curie-Montsouris Thorax Institute, discusses the PAPILLON study. The interview, conducted by Alan from OncologyTube, explores the comparison between Amivantamab plus chemotherapy and chemotherapy alone as the first-line treatment for EGFR Exon 20 insertion-mutated advanced non-small cell lung cancer.
Nicolas Girard, MD, provides an overview of the study's primary endpoint, progression-free survival (PFS), emphasizing the reduction in the risk of disease progression and the extension of median PFS with the Amivantamab plus chemotherapy combination. Nicolas Girard, MD, highlights the clinical benefits observed in terms of long-term efficacy, as reflected in PFS2 data and overall survival data.
The discussion touches upon the implications of these PFS results for the treatment landscape of patients with EGFR Exon 20 insertion-mutated advanced non-small cell lung cancer. Nicolas Girard, MD, underscores the role of Amivantamab plus chemotherapy as a new standard of care, supported by the absence of comparable clinical data with other treatments.
The interview further explores the strategic considerations in the treatment approach, comparing the combination upfront with a sequential approach of chemotherapy followed by Amivantamab. Nicolas Girard, MD, emphasizes the benefits of initiating the combination upfront based on PFS2 data and interim overall survival data.
The safety and tolerability of Amivantamab combined with chemotherapy are addressed, with Nicolas Girard, MD, providing an assessment of manageable side effects, including hematological and digestive issues. Nicolas Girard, MD, emphasizes the importance of proactive management and early identification of side effects.
The option for patients in the chemotherapy arm to crossover to Amivantamab monotherapy upon progression is discussed in the context of real-world clinical practice. Nicolas Girard, MD, points out that, in the current landscape, many patients are already receiving targeted agents against Exon 20 in the second-line setting, making the study's crossover design relevant to the ongoing treatment strategies for these patients.
In conclusion, Nicolas Girard, MD's expertise and insights in this interview contribute to understanding the findings of the PAPILLON study and the potential impact on the standard of care for patients with EGFR Exon 20 insertion-mutated advanced non-small cell lung cancer.
At the European Society for Medical Oncology (ESMO) 2023 Congress in Madrid, Spain, Dr. Joaquim Bellmunt, MD, PhD, from Harvard Medical School in Boston, MA, shared insights on advancements in renal cancer during a dedicated session. Discussing first-line treatment options, Dr. Bellmunt highlighted the four established choices, including combinations of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors. In an interview, he touched upon the critical analysis of which patients are best suited for each treatment strategy.
During the session, Dr. Bellmunt delved into the Phase III CONTACT-02 trial (NCT04446117) focusing on prostate cancer. The trial evaluated the efficacy of a combination therapy involving immunotherapy (atezolizumab) and a tyrosine kinase inhibitor (cabozantinib). Notably, this approach demonstrated results, representing a development in the field of prostate cancer treatment. Dr. Bellmunt emphasized that these findings, although preliminary and currently available only through press release, indicate the potential for a new treatment option in metastatic castration-resistant prostate cancer.
This session provided a platform to discuss and analyze the evolving landscape of cancer treatment, specifically in renal and prostate cancers, shedding light on innovative strategies that may shape the future of patient care.
Crispin Hiley, PhD, from the UCL Cancer Institute in London, UK, discusses developments in second-line treatment for EGFR mutation-positive lung cancer patients at the European Society for Medical Oncology (ESMO) 2023 Congress in Madrid, Spain. Crispin Hiley, PhD, acknowledges progress in addressing the needs of patients who have progressed on osimertinib or third-generation tyrosine kinase inhibitors (TKIs).
In an interview, Crispin Hiley, PhD, talks about studies on second-line EGFR mutation-positive lung cancer and the challenges faced by patients advancing on tyrosine kinase inhibitors. He acknowledges the existing unmet need, especially for those not suitable for metastasis-directed therapy, and mentions the strides made in developing a second-line systemic combination.
Crispin Hiley, PhD, reflects on the common scenario in clinics where patients with EGFR mutation-positive lung cancer progress on existing treatments like osimertinib. While metastasis-directed therapy, such as stereotactic radiotherapy, has proven beneficial for some, he notes that there remain patients whose progression doesn't respond to such approaches. The development of an effective second-line systemic combination is seen as a significant advance, particularly for patients progressing on standard or emerging therapies in the first line. Crispin Hiley, PhD, emphasizes the importance of this breakthrough in the treatment of EGFR mutation-positive lung cancer.
At ESMO this year, Mansoor Raza Mizra, MD, a figure in gynecologic oncology, shared insights on developments in the field. The focus began with cervical cancer, where three phase three randomized trials showed results. The Interlace trial, conducted in the neoadjuvant setting for locally advanced cervical cancer, demonstrated outcomes in both progression-free survival (PFS) and overall survival (OS). Another trial, exploring Cho radiation with or without pisab concomitant and maintenance in locally advanced cervical cancer, showed an increase in PFS, with a trend in OS, though data maturity is awaited. The third trial, targeting second-line cervical cancer patients who had progressed on PRI Platinum pxel plus minus B therapy, demonstrated differences in both PFS and OS with toota vtin.
Turning to endometrial cancer, Mansoor Raza Mizra, MD, discussed the results of the Duo trial, investigating the addition of immune checkpoint inhibitors to chemotherapy in stage 3, 4, and first relapse patients. The trial, randomizing patients to receive chemotherapy plus or minus a parp inhibitor, yielded outcomes. Further analysis is needed to discern patient benefits in the UMC with parp inhibitors, but the overall intention-to-treat population showed results. Additionally, the results of the Tal trial (enot and7) in the same population with chemotherapy plus or minus at isisa demonstrated positivity in both primary endpoints, progression-free survival in dmmr population, and overall progression of survival in the intention-to-treat population. However, the benefit was not observed in the subgroup of mmrp.
Unfortunately, in ovarian cancer, a negative trial of immune checkpoint inhibitors emerged, indicating a trend in the data that such inhibitors may not be effective in this type of cancer. Mansoor Raza Mizra, MD, acknowledged the need to await the maturity of other trials to determine if checkpoint inhibitors have any role in treating ovarian cancer. In conclusion, Mansoor Raza Mizra, MD, highlighted the strides made in cervical and endometrial cancers, emphasizing the impact of recent trials on patient care in these areas.
In a significant development in the field of oncology, Nicolas Girard, MD, played a role in the approval of Amivantamab for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertions. The approval specifically targets individuals who have experienced disease progression during or after platinum-based chemotherapy, representing an advancement in therapeutic options.
The approval stems from a phase 3 international randomized trial overseen by Dr. Nicolas Girard and colleagues. In this trial, 308 patients with advanced NSCLC and EGFR exon 20 insertions, previously untreated with systemic therapy, were assigned in a 1:1 ratio to receive intravenous Amivantamab plus chemotherapy (Amivantamab–chemotherapy) or chemotherapy alone. The primary outcome assessed was progression-free survival, as determined by blinded independent central review.
The results of the trial were impressive. Patients in the Amivantamab–chemotherapy group exhibited significantly longer progression-free survival compared to those in the chemotherapy-alone group. The median progression-free survival was 11.4 months for the Amivantamab–chemotherapy group, as opposed to 6.7 months for the chemotherapy-alone group. The hazard ratio for disease progression or death was 0.40, with a 95% confidence interval of 0.30 to 0.53, underlining the clinical benefit of the combination therapy.
At the 18-month mark, progression-free survival rates further underscored the superiority of Amivantamab–chemotherapy, with 31% of patients in this group compared to 3% in the chemotherapy-alone group. Additionally, a complete or partial response at data cutoff was reported in 73% of the Amivantamab–chemotherapy group and 47% of the chemotherapy-alone group (rate ratio, 1.50; 95% CI, 1.32 to 1.68; P<0.001).
An interim overall survival analysis, with 33% maturity, indicated a favorable trend in favor of Amivantamab–chemotherapy, with a hazard ratio for death of 0.67 (95% CI, 0.42 to 1.09; P=0.11).
The predominant adverse events associated with Amivantamab–chemotherapy were reversible hematologic and EGFR-related toxic effects. While 7% of patients discontinued Amivantamab due to adverse reactions, the overall efficacy and safety profile demonstrated the potential of this treatment approach.
In conclusion, under the leadership of Dr. Nicolas Girard, MD, the utilization of Amivantamab–chemotherapy has emerged as a first-line treatment for patients with advanced NSCLC bearing EGFR exon 20 insertions. This study heralds a new era in the management of this subset of lung cancer patients, offering a significantly improved therapeutic option that promises both enhanced efficacy and a manageable safety profile.
By. Aaron E. Lisberg, MD,
During ESMO 2023, Aaron E. Lisberg, MD, delivered a presentation on the results from the TROPION-Lung01 study, focusing on the clinical question of second-line chemotherapy for advanced metastatic non-small cell lung cancer compared to docetaxel.
The study investigated a novel antibody-drug conjugate targeting TROPION-Lung01, Datopotamab deruxtecan, in a head-to-head comparison with docetaxel. Approximately 300 patients were enrolled and randomized at a one-to-one ratio, regardless of histology or the presence of targetable mutations. The trial had dual primary endpoints—progression-free survival (PFS) and overall survival (OS).
Dr. Lisberg's presentation concentrated on the PFS final analysis in the intention-to-treat population. The data showed a statistically significant benefit across all patients, with a hazard ratio of 0.75. Patients treated with Datopotamab deruxtecan exhibited a median PFS of 4.4 months, compared to 3.7 months in the docetaxel group. However, a closer examination uncovered a notable divergence in benefits based on histology. Non-squamous patients exhibited a hazard ratio of 0.63, translating to nearly two months longer median PFS and nearly three times the objective response rate. In contrast, squamous patients did not experience a similar improvement.
The other primary endpoint, OS, exhibited a trend favoring Datopotamab deruxtecan at the interim analysis, with the most significant benefit observed in non-squamous patients who also demonstrated the greatest PFS advantage.
In addition to efficacy, Dr. Lisberg emphasized the importance of safety data, noting a superior safety profile for Datopotamab deruxtecan compared to docetaxel. The incidence of treatment-related adverse events, especially those of grade three or higher, was lower with Datopotamab deruxtecan, indicating improved patient tolerability. Although practitioners should be aware of unique toxicities such as mucositis and stomatitis, these were generally low-grade and well-managed. The presentation acknowledged the association of DxD-class drugs with interstitial lung disease, but the rates observed were deemed manageable, emphasizing Datopotamab deruxtecan as a viable option for patients with metastatic non-small cell lung cancer, particularly in the non-squamous population, after progression on chemotherapy and other targeted therapies.
In this interview, Peter Schmid, FRCP, MD, PhD, from Barts Cancer Institute, London, UK, delves into the compelling 5-year follow-up data emanating from the Phase III KEYNOTE-522 (NCT03036488) trial. The trial was designed to investigate the efficacy of combining pembrolizumab with chemotherapy as neoadjuvant therapy and pembrolizumab as adjuvant therapy in patients grappling with the challenges of triple-negative breast cancer.
The previously reported findings from the trial had already indicated noteworthy and statistically significant improvements in both pathological complete response (pCR) and event-free survival (EFS) with the administration of the pembrolizumab regimen. Building upon these promising results, the 5-year follow-up data, presented at the European Society for Medical Oncology (ESMO) 2023 Congress in Madrid, Spain, serve to validate and fortify the robustness of these earlier outcomes.
The 60-month EFS rates, a pivotal marker of the treatment's long-term impact, were unveiled, showcasing a substantial advantage in the pembrolizumab and chemotherapy arm with rates reaching 81.3%, compared to 72.3% in the chemotherapy and placebo arm. What makes these results particularly compelling is the consistency of the observed benefit across pre-specified subgroups, affirming the broad applicability and efficacy of the pembrolizumab-based approach.
The remarkable 37% reduction in the risk of recurrence over the 5-year period positions pembrolizumab as a promising and enduring component in the therapeutic arsenal against triple-negative breast cancer.
The interview not only elucidates the scientific and clinical implications of the 5-year follow-up data but also underscores the potential paradigm shift these results signify in the management of triple-negative breast cancer. As a beacon of progress in the field, the study sets the stage for further exploration and refinement of immunotherapeutic strategies in the ongoing pursuit of improved outcomes for patients facing this challenging malignancy.
Professor Funda Meric-Bernstam presented pivotal findings at the ESMO Congress 2023, shedding light on the latest developments in the realm of cancer treatment. The focal point of her presentation was the noteworthy LBA34 - Trastuzumab deruxtecan (T-DXd) for HER2-expressing solid tumors. These insights emanated from the primary analysis of the DESTINY-PanTumor02 (DP-02) study, offering a comprehensive examination of T-DXd's efficacy in a diverse cohort of patients.
The study, designed to address the therapeutic potential of T-DXd, specifically targeted patients with HER2 expression who had undergone prior treatment. Professor Meric-Bernstam's discourse encompassed the enrollment of patients expressing HER2 at levels of 2+ or 3+, spanning seven distinct cohorts representing various disease types. A pan-tumor cohort was also included in this comprehensive investigation.
Key parameters under scrutiny included the objective response rate, duration of response, progression-free survival, and overall survival. The results unveiled a notable 37% objective response rate across all cohorts, with particular emphasis on elevated response rates among gynecological patients and those with HER2 expression at 3+. Durable responses were a hallmark of T-DXd, demonstrated by a median response duration of 11 months in the overall cohort and an impressive 22 months in the HER2 3+ subgroup.
In addition to the efficacy findings, Professor Meric-Bernstam discussed safety outcomes, which were in line with expectations for T-DXd. Approximately 40.8% of patients experienced grade 3 or higher adverse events, predominantly drug-related. Despite this, the study highlighted the potential of T-DXd in the landscape of HER2-expressing tumor types, suggesting a tumor-agnostic application.
The results unveiled at the ESMO Congress 2023 underscored the promising role of T-DXd in providing meaningful clinical benefits for patients with pretreated HER2-expressing solid tumors. Professor Funda Meric-Bernstam's comprehensive overview offered a significant contribution to advancing our understanding of T-DXd's potential impact on cancer treatment paradigms.
Lisa Yen, MD, the Director of Programs and Outreach at ESMO 2023 in Madrid, is alongside Dr. Jennifer Chan, the Principal Investigator of the Alliance Phase Three Study. This study, known as the Cabinet Study, explores Cabozantinib's efficacy compared to a placebo in Advanced Neuroendocrine Tumors after prior therapy. Dr. Chan recently revealed the trial's outcomes, demonstrating the effectiveness of Cabozantinib in both cohorts of patients. The results showed an improvement in progression-free survival for those receiving Cabozantinib compared to the placebo group, with no new safety concerns. The observed side effects aligned with Cabozantinib's known safety profile.
The trial included two patient cohorts: one with extra-pancreatic NETs and the other with pancreatic NETs. About 20% of the extra-pancreatic NET patients had lung neuroendocrine tumors, while more patients had GI neuroendocrine tumors, and some had tumors of unknown primary origin.
The data revealed encouraging outcomes, suggesting that cabozantinib holds significant promise in managing NET, expanding the arsenal of viable treatments for patients facing these challenging conditions. This potential effectiveness extends hope to the NET patient community, raising the prospect of another FDA-approved oral medication becoming accessible in the foreseeable future. This development is particularly significant given the limited therapeutic options available for NET patients, especially for those with advanced or metastatic forms of the disease.
The CABINET trial findings not only highlight the potential of cabozantinib as an effective therapeutic avenue for NET but also hint at its applicability across different stages of the disease. The introduction of another FDA-approved oral treatment could revolutionize the landscape of care for NET patients, offering renewed optimism and prospects for enhanced quality of life and extended survival rates.
The news of these promising results from the CABINET trial brings a sense of anticipation and optimism within the medical community, particularly among healthcare professionals specializing in oncology and, most significantly, among individuals battling NET. It signifies a potential breakthrough in addressing the unmet medical needs of NET patients, offering a ray of hope for improved treatment outcomes and potentially transforming the standard of care in the management of these complex and challenging conditions.
Dr. Chan expressed excitement about these results, seeing it as a potential addition to the treatment options available for neuroendocrine tumor patients, particularly for those who have exhausted known effective therapies. The trial, active since 2018, recently concluded with its outcomes announced in July of this year.
Drs. Rahul Gosain, MD and Rohit Gosain, MD, referred to as the oncology brothers, reflected on the impressive content presented at ESMO 2023. They segmented the lung cancer highlights into two key studies: KEYNOTE 671 focusing on resectable non-small cell lung cancer and the Alina trial for ALK-positive patients. They were joined by Dr. Joshua Reuss from Georgetown Lombardi Kansas Center.
KEYNOTE 671, a phase 3 study, examined the peroperative IO chemo combination and its impact on overall survival. The results showed an overall survival benefit, demonstrating a hazard ratio of 72 in favor of the IO chemo combination. This benefit was observed across different disease parameters, indicating practice-changing implications. The FDA also approved this regimen for certain patient criteria, marking a significant step in enhancing patient outcomes.
Regarding the selection between CHECKMATE 816 and KEYNOTE 671 for patients, they emphasized the need for additional data, especially focusing on factors like pathologic response, disease stage, and biomarker analysis. This discussion highlighted the complexities of treatment decisions in this evolving landscape.
The ALINA trial investigated the role of alectinib in resectable non-small cell lung cancer with ALK-positive mutation, displaying a notable benefit in disease-free survival, particularly in the CNS, which could be groundbreaking for this patient population. The conversation explored the balance between chemotherapy and alectinib in treatment strategies for these patients.
In metastatic non-small cell lung cancer, the discussion covered the TROPION Lung 01 study, exploring the antibody-drug conjugate dat DxD compared to standard treatment. The results revealed a modest progression-free survival advantage, primarily visible in non-adenocarcinoma subgroups. The conversation also touched upon the potential role of dat DxD in patients with actionable mutations who have progressed on upfront TKIs.
The dialogue addressed the need for further investigation and data analysis in these areas. Dr. Reuss highlighted the potential of other compounds, such as patritumab deruxtecan, in the treatment landscape, especially in patients with EGFR mutations, offering more options in this challenging space.
In summary, the discussion reflected on significant advancements in lung cancer treatment, emphasizing the need for additional data to refine treatment choices and further expand the available options for different patient subsets. The exploration of these studies showcased the potential for improving patient outcomes and the ongoing evolution in lung cancer therapy.
Petros Grivas, MD, Ph.D. of the University of Washington; Fred Hutchinson Cancer Research Center speaks about the ESMO 2020 abstract Avelumab first-line (1L) maintenance + best supportive care (BSC) vs BSC alone for advanced urothelial carcinoma (UC): Association between clinical outcomes and exploratory biomarkers.
Avelumab (anti-PD-L1 IgG1 antibody) 1L maintenance + BSC substantially extended overall survival ( OS) in the phase 3 JAVELIN Bladder 100 (NCT02603432) study vs BSC alone in patients (pts) with advanced disease-free UC progression with 1L induction chemotherapy in both randomized pts and pts with PD-L1 + tumors. We publish studies of exploratory biomarkers.
Prior to randomization, tumor biopsies were obtained. Tumor studies included immunohistochemistry of PD-L1 (Ventana SP263 assay) and CD8, whole-exome sequencing (including genotypes of FCGR2A and FCGR3A), whole-transcriptome sequencing, and sequencing of T-cell receptors (TCR). Baseline C-reactive protein (CRP) level and neutrophil: lymphocyte ratio (NLR) as well as TCR sequencing were included in peripheral blood examination before and after treatment. Using the Cox proportional hazards model, associations between OS or progression-free survival and biomarkers were evaluated. Danger ratios and nominal p values were registered and no changes to multiplicity were made (statistical significance level of 5 percent).
Increased OS gain with avelumab 1L maintenance + BSC vs BSC alone was positively correlated with invasive margin or tumor center CD8 + T cells, high tumor mutation burden, and innate and adaptive immune response signatures of tumor gene expression. The number of FCGR2A / FCGR3A alleles encoding high-affinity Fcγ receptors for IgG1 was also positively correlated with increased OS advantage. Avelumab's OS benefits were negatively correlated with tumor epithelial cell gene signatures, fibroblast growth factor receptor signaling mutations, CRP, and NLR. Lower expression of TGFb was correlated with greater OS gain for avelumab in pts with elevated immune gene expression signatures. Further studies, including findings of exploratory PD-L1 cutoffs in tumor vs. immune cells, will be provided.
The OS benefits of the maintenance of avelumab 1L in pts with advanced UC are positively correlated with immune response biomarkers and negatively associated with tumor homeostasis and chronic inflammation biomarkers.
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