The Phase 2b COPERNICUS Study of Subcutaneous Amivantamab with Lazertinib for EGFR-Mutated NSCLC

00:00:00: You are listening to an AIDIS Journal podcast.

00:00:10: Hello everyone and welcome to our broadcast.

00:00:13: I'm Dr.

00:00:14: Boulash Homo's professor at the Albert Einstein College of Medicine and associate director for clinical science at the Montefiore Einstein Comprehensive Cancer Center in the Bronx, New York.

00:00:26: Joining me for this broadcast is Dr.

00:00:28: Melissa Johnson.

00:00:30: We are pleased to present the Phase IIB Copernicus study evaluating subcutaneous aminventumab with Lysertinibus first-line treatment or with chemotherapy as second-line treatment for aegia for a mutated non-small cell lung cancer.

00:00:44: Thank you, Dr.

00:00:45: Hamas, for the introduction.

00:00:47: I'm Dr.

00:00:47: Melissa Johnson, Director of the Lung Cancer Research Program at Sarah Cannon Research Institute in Nashville, Tennessee.

00:00:55: The intent of this podcast is to review the study designed for Copernicus, highlighting how it combines pragmatic elements to assess the efficacy and safety of subcutaneous amyvantamab with supportive care for prevention and management of adverse events in a diverse participant population.

00:01:14: We will also briefly review overall survival data from amyvantamab plus lizard nib.

00:01:20: from the Mariposa study, benefits of subcutaneous amyvantamab from the Paloma II and Paloma III studies, and the results from the cocoon trial for management of EGFR-related dermatologic side effects associated with amyvantamab plus lizard tinnib.

00:01:38: Epidermal growth factor receptor, or EGFR, is involved in signaling pathways that control cell division and survival.

00:01:47: EGFR mutations are among the most common in non-small cell lung cancer, accounting for about seventeen percent of oncogenic mutations.

00:01:56: Approximately eighty-five to ninety percent of these EGFR mutations are exon-nineteen deletions, or exon-twenty-one L-a-five-eight-r substitutions.

00:02:06: Their frequency varies by ethnicity, with the highest seen in Asian populations.

00:02:12: Furthermore, Significant disparities in mutation testing rates have been observed between black and white patients with non-small cell lung cancer.

00:02:20: in real-world setting, and therefore, mutation prevalence in minority populations may be underestimated.

00:02:28: It is also important to note that many patients with EGFR-mutated non-small cell lung cancer have no smoking history.

00:02:35: Although third-generation EGFR tyrosine kinase inhibitors like Osimertinib have shown promising efficacy in the EGFR-mutated non-small cell lung cancer setting, nearly all patients treated with these agents eventually develop resistance to treatment.

00:02:51: The mechanisms of resistance are diverse and polyclonal, highlighting the need for more effective treatments.

00:02:58: Notably, lower rates of EGFR-targeted therapy are observed in minority populations due to the aforementioned differential mutation testing rates.

00:03:09: In addition, minority populations consistently show lower participation in screening, treatment, and clinical trials, likely due to factors such as socioeconomic status, language barriers, and limited healthcare access.

00:03:24: Based on this unmet need, it is important for new therapies to target multiple pathways simultaneously.

00:03:31: Amivantanab is a fully human egia format by specific antibody with a triple mechanism of action.

00:03:38: First, it targets the extracellular domain of EGF for blocking ligand engagement, inducing apoptosis and promoting receptor internalization and degradation.

00:03:50: Secondly, an eventenab targets the metreceptor.

00:03:53: Met is often overexpressed as a resistance mechanism to current EGF for targeted therapies.

00:04:00: And third, an eventenab harnesses the immune system to promote tumor cell death.

00:04:06: When MEVENTA-MAB is combined with LASERTA-NIB, a highly selective brain penetrant third-generation EGFR-TKI with activity against the T-seven-ninety-M resistance mutation, the combination results in synergistic EGFR inhibition with LASERTA-NIB targeting the EGFR receptor intracellularly.

00:04:27: MEVENTA-MAB-Base regimens are promising therapy options in the EGFR-mutated non-smol cell lung cancer setting.

00:04:34: and may address treatment-resistance mechanisms.

00:04:38: Intravenous amyvantumab is approved by the FDA and the EMA for multiple indications in EGFR-mutated non-small cell lung cancer, including in combination with Lizertinib as a first-line treatment for locally advanced or metastatic non-small cell lung cancer, with EGFR-xon-nineteen deletions or L-H-a-t-fifty-eight-R substitution mutations based on the results of the Mari-Posa study.

00:05:01: Now, let's review some key findings from Mariposa, randomized phase-three study evaluating the efficacy of intravenous amyventamab plus lezertonib versus azimertanib as first-line treatment for patients with advanced non-small cell lung cancer with EGF or Exxon-IX deletions or L-Eight-Fifty-Eight-R mutations.

00:05:22: The total of one-thousand seventy-four participants were randomized in a two-to-two-to-one ratio to receive MEVENTANAP plus LASERTANIB, ASSIMERTANIB, or LASERTANIB alone.

00:05:35: The LASERTANIB alone arm was included to study the contribution of LASERTANIB to the overall treatment regimen.

00:05:41: The primary endpoint was progression-free survival and overall survival was a key secondary endpoint.

00:05:49: At a median follow-up of thirty-seven point eight months, amyventana plus lasertanib significantly and clinically meaningfully improved overall survival versus azimertanib.

00:06:00: The median overall survival was not reached for amyventana plus lasertanib versus thirty-six point seven months for azimertanib.

00:06:08: The substantial overall survival improvement was seen despite the fact that patients in mariposa did not receive enhanced prophylactic measures for dermatologic adverse events, infusion-related reactions, and venous thromboembolic events, which were later developed to improve the overall treatment experience.

00:06:28: We will now discuss key findings on a subcutaneous formulation of amyvantumab, which was developed for ease of treatment administration and enhanced patient convenience, and was evaluated in the Paloma-III study.

00:06:42: Paloma-III is a Phase III randomized study assessing the pharmacokinetics, efficacy, and safety of subcutaneous versus intravenous amyvantamab administered every two weeks, both combined with lizard nib in patients with EGFR-mutated advanced non-small cell lung cancer after disease progression on OC-mirtinib and platinum-based chemotherapy.

00:07:06: A total of six hundred and thirty-five participants were randomly assigned in a one-to-one ratio to receive subcutaneous or intravenous amyvantamab, both in combination with lizard nib.

00:07:18: Subcutaneous amyvantamab plus lizardinib demonstrated non-inferior pharmacokinetics and overall response rate versus intravenous amyvantamab plus lizardinib.

00:07:29: Compared with intravenous amyvantamab, subcutaneous amyvantamab reduced infusion-related reactions by five-fold.

00:07:38: In addition, subcutaneous amyvantamab was associated with a notable reduction in venous thromboembolic events.

00:07:45: and a substantially shorter administration time of less than five minutes versus approximately five hours for intravenous amyvantumab.

00:07:55: Substantial improvements were also observed in healthcare resource utilization and patient reported outcomes.

00:08:02: Based on these results, subcutaneous amyvantumab administered every two weeks was recently approved by the European Commission.

00:08:11: Based on these clinical trial findings with MEVENTAMAD, several prophylactic management approaches have been designed and evaluated to improve the overall treatment experience.

00:08:21: Prophylactic regimens for dermatologic adverse events, infusion-related reactions, and venous thrombioembolic events are evaluated in the cocoon, skipper, and paloma-II studies respectively.

00:08:33: Now let's look at the data from each of these studies.

00:08:36: The cocoon dermatologic regimen resulted in a two-fold reduction in grade two or higher dermatologic adverse events associated with intravenous amyvantimab compared with standard dermatologic management at thirty eight point six percent versus seventy six point five percent respectively.

00:08:54: However, despite using the cocoon dermatologic management regimen, Caution is still recommended while monitoring dermatologic adverse events associated with subcutaneous amyvantameth, and reactive management may still be needed based on severity.

00:09:12: The Skipper prophylactic regimen, in order to reduce infusion-related reactions with oral eight milligrams of dexamethasone, resulted in a three-fold reduction in the rate of IRRs versus standard prophylaxis at twenty-two point five percent versus sixty-seven point four percent respectively.

00:09:30: Similarly, in the Paloma II study, use of prophylactic oral anticoagulation for the first four months of subcutaneous amyvantamab plus lizard and of treatment reduced venous thromboembolic events by approximately two-fold.

00:09:44: Thus, durable benefits from treatment can be achieved by integrating these recent developments with the efficacy and safety profile of AMI-VantMAP plus LASERGNIP.

00:09:56: Despite these new learnings across multiple clinical trials, there's currently no study that evaluates the efficacy and safety of subcutaneous AMI-VantMAP regimens.

00:10:06: combined with these advancements we discussed for supportive care to prevent and proactively manage adverse events while also using elements of a pragmatic study design to recruit participants with diverse backgrounds.

00:10:20: The phase two B Copernicus study aims to enroll a representative population of participants with EGFR mutated non small cell lung cancer in the US and EMEA with diverse backgrounds to complement data from the Meriposa and Meriposa to registrational trials by utilizing eligibility criteria that are more reflective of the real world population.

00:10:43: In addition, It combines the advancements in supportive care with the subcutaneous formulation of M-eventenab, including different dosing schedules, such as a once every four weeks dose, to prevent and mitigate adverse events, substantially improving the benefit-risk profile of M-eventenab plus lizardenab or chemotherapy.

00:11:04: Copernicus also minimizes the clinical trial burden on the sites with the pragmatic approach.

00:11:11: by aligning screening criteria and trial data collection to standard practice, by reducing the toll of treatment associated adverse events to improve patient experience and quality of life, while maximizing long-term treatment benefits, and also by validating a more tolerable and convenient approach to cancer care using the subcutaneous formulation.

00:11:32: Copernicus seeks to integrate the findings from various amyvantamab clinical trials covered earlier into one single comprehensive study.

00:11:41: This study will thoroughly assess the most convenient dosing regimen for subcutaneous amyvantamab along with effective adverse event management strategies and the efficacy of amyvantamab-based treatment combinations.

00:11:55: In addition, Copernicus incorporates additional measures to improve clinical trial accessibility for underrepresented population.

00:12:04: This study covers a broad geographic network incorporating satellite locations and community clinics.

00:12:11: It involves a network of community leaders, academic key opinion leaders, as well as patient advocates.

00:12:18: Tools for patient screening and awareness are utilized along with patient-facing materials.

00:12:24: The Pernicus is an open-labeled, two-cohort study that uses pragmatic elements and less stringent eligibility criteria to support enrollment of a study that is more reflective of the real-world population.

00:12:36: This study aimed to evaluate the efficacy and safety of subcutaneous amyvantumab administered every four weeks, plus oral lizard nib in cohort one, with approximately three hundred participants in the U.S.

00:12:50: and a hundred and fifty participants in EMEA or subcutaneous amyventumab plus chemotherapy in cohort two with approximately thirty participants in the U.S Participants in cohorts one and two will be on prophylactic management for dermatologic adverse events, while venous thromboembolism prophylaxis will only be administered in cohort one.

00:13:16: As shown here, progression-free survival by investigative review is the primary endpoint.

00:13:22: Other key secondary endpoints include the incidence and severity of venous thromboembolic events and dermatologic adverse events, overall survival, overall response rate, duration of response, intracranial outcomes, and patient compliance with prophylactic regiments.

00:13:41: Comparison of clinical and health economic outcomes to appropriate covariate balanced real-world comparator cohorts will be performed under a separate protocol to assess real-world outcomes, thereby providing an estimate of real-world efficacy and safety of amyventma-based combinations and generating results directly applicable to diverse patient populations.

00:14:05: Let's now take a look at eligibility for Copernicus.

00:14:09: Overall, Copernicus implements less stringent inclusion and exclusion criteria.

00:14:14: Adult participants with one or more measurable lesions per resis version one point one and an ECoC performance status score of zero or one will be eligible.

00:14:24: Participants in cohort one will receive oral anticoagulant therapy.

00:14:28: Renal function criteria are less stringent than those typically found in registrational trials and are based on actual data from patients treated with M-eventenab plus lasertenab or M-eventenab plus chemotherapy respectively including any considerations from the chemotherapy prescribing information.

00:14:46: Certain laboratory-based eligibility criteria were modified to be inclusive of ethnic variability.

00:14:53: As with other MEVM TANAP studies, participants with symptomatic untreated brain metastasis, uncontrolled medical conditions, or active interstitial lung disease will be excluded.

00:15:04: The Copernicus study incorporates many pragmatic elements to help eliminate potential barriers to enrollment, by simplifying eligibility criteria, thereby facilitating access to a clinically proven treatment.

00:15:18: In this study, participants are allowed to receive one cycle of first-line platinum-based chemotherapy while waiting for biomarker testing results.

00:15:27: Only chest scans are mandatory.

00:15:29: Other locations may also be scanned at the investigator's discretion.

00:15:33: Assessment schedules are reduced based on clinical practice.

00:15:37: This study also permits liquid biopsies for diagnosis and broader organ function blood count limits, among other elements.

00:15:46: Using a pragmatic study design provides additional general benefits beyond those specific to the trial.

00:15:52: For instance, this trial reflects real-world conditions, will provide results that are directly applicable to clinical decision-making, involves a diverse patient population, is cost-effective, may provide information on unexpected benefits or harms of interventions, may reduce the potential for selection bias, and is more generalizable to real-world populations.

00:16:22: Copernicus has started enrolling eligible participants since December of twenty twenty-four and is currently enrolling in multiple locations, including a hundred and twenty-three sites in the U.S.

00:16:33: and fifty sites across eleven countries in EMEA.

00:16:37: Participants will be treated until disease progression, unacceptable treatment related toxicity, non-compliance with treatment, diagnosis of pregnancy, withdrawal of consent, or receipt of non-protocol anti-cancer treatment by the participant or study termination.

00:16:55: We would like to encourage eligible patients to participate in this clinical trial using the clinically proven subcutaneous formulation of MEVENTANAB, which is now approved in Europe, to be administered as an every two-week regimen.

00:17:08: Please contact us at this number or email address for more information.

00:17:13: In summary, Copernicus aims to fill a critical gap by systematically evaluating a more tolerable and convenient subcutaneous formulation of amybantamab combined with supportive management.

00:17:26: It emphasizes inclusivity and real-world applicability by recruiting a diverse patient population across multiple regions.

00:17:34: The study approach seeks to reduce the overall treatment burden on both patients and health care providers while improving patient safety, quality of life, and treatment experience.

00:17:46: The study design has pragmatic elements aligned closely with standard clinical practice to facilitate improved access to ME-Vantaman-based regimens across all clinically relevant populations.

00:17:59: And finally, We encourage patients to join this clinical trial to gain access to a clinically proven, effective and convenient treatment for EJFR-mutated non-small-cell lung cancer.

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