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Name:
VJBM-2022-0003
Description:
VJBM-2022-0003
Thumbnail URL:
https://cadmoremediastorage.blob.core.windows.net/1ece010d-d972-4ba8-b361-1562e790fa98/videoscrubberimages/Scrubber_4.jpg?sv=2019-02-02&sr=c&sig=5I2oaurUOccONMv2kQWlruiON%2FZAdDK8QAnL3tFCNgw%3D&st=2025-02-21T04%3A11%3A23Z&se=2025-02-21T08%3A16%3A23Z&sp=r
Duration:
T00H11M53S
Embed URL:
https://stream.cadmore.media/player/1ece010d-d972-4ba8-b361-1562e790fa98
Content URL:
https://cadmoreoriginalmedia.blob.core.windows.net/1ece010d-d972-4ba8-b361-1562e790fa98/Publication perspectives video_V10.mp4?sv=2019-02-02&sr=c&sig=zAIocQlJe3rkwf72lALxVBWZjlpbKdXZT7T4Qpq9tXs%3D&st=2025-02-21T04%3A11%3A24Z&se=2025-02-21T06%3A16%3A24Z&sp=r
Upload Date:
2022-04-05T00:00:00.0000000
Transcript:
Language: EN.
Segment:0 .
[MUSIC PLAYING]
EGBERT SMIT: The INSIGHT 2 study was initiated because of the unmet need for targeted treatments for patients with EGFR-mutant non-small-cell lung cancer who develop resistance to EGFR TKIs through MET amplification. EGFR mutations are a common oncogenic driver in patients with metastatic non-small-cell lung cancer and are a predictive marker for response to EGFR TKIs, such as osimertinib. The efficacy and safety of osimertinib for metastatic EGFR mutant non-small-cell lung cancer has been demonstrated in phase III trials, and osimertinib has now become the standard of care for first-line management of metastatic non-small-cell lung cancer which has an EGFR mutation.
EGBERT SMIT: Although first-line osimertinib can provide effective disease control in patients with non-small-cell lung cancer, most patients develop resistance after about 16 to 20 months of treatment. Apart from chemotherapy, which did not have very encouraging results in a post-EGFR TKI setting, there are no further clear-cut therapeutic options for EGFR-mutant non-small-cell lung cancer after progression on osimertinib, representing, therefore, a clear unmet medical need.
EGBERT SMIT: MET amplification is a common cause of acquired resistance to EGFR tyrosine kinase inhibitors therapy, and occurs in about 7% to 15% of patients who progress on first-line osimertinib therapy. However, this has been reported in up to 30% of patients, depending on both the method and the criteria used for detecting MET amplification. Tepotinib is a once-daily, orally available, potent, and highly selective MET tyrosine kinase inhibitor that blocks MET-mediated signaling pathways.
EGBERT SMIT: Tepotinib is approved for the treatment of adult patients with metastatic non-small-cell lung cancer harboring MET exon 14 skipping alterations in several countries, including Japan, the US, Canada, Great Britain, South Korea, and Brazil. And in preclinical models, tepotinib was able to overcome acquired resistance to EGFR tyrosine kinase inhibitors due to MET amplification.
EGBERT SMIT: In the phase Ib/II INSIGHT study, tepotinib plus gefitinib was compared with chemotherapy in patients with relapsed EGFR-mutant non-small-cell lung cancer with MET overexpression immunohistochemistry scores 2-plus and 3-plus and/or MET amplification with acquired resistance to EGFR tyrosine kinase inhibitors. In this exploratory analysis, in 12 patients treated with the tepotinib plus gefitinib, there was improvement versus seven patients given chemotherapy, an efficacy outcome including investigator-reported median progression-free survival of 16.6 months versus 4.2 months with a hazard ratio of 0.13, and a median overall survival of 37.3 months versus 13.1 months with a hazard ratio of 0.08. Thus, because osimertinib is standard of care for first-line therapy in EGFR-mutant non-small-cell lung cancer and MET amplification is a common mechanism of resistance to osimertinib, the INSIGHT 2 clinical trial was initiated to assess the efficacy and safety of the tepotinib and osimertinib combination in patients with EGFR-mutant non-small-cell lung cancer.
EGBERT SMIT: The primary endpoint of the INSIGHT 2 study is objective response, including confirmed complete response or partial response by independent review committee using RECIST version 1.1 criteria. For the primary endpoint, MET amplification is determined centrally by FISH. This will be the primary efficacy analysis set. Tumor assessments are carried out every six weeks following cycle 1 day 1 visit until nine months, and every 12 weeks thereafter, until disease progression, death, or study discontinuation.
EGBERT SMIT: Secondary endpoints include duration of response, progression-free survival, overall survival, health-related quality of life, and safety. INSIGHT 2 is a global, two-arm, open-label phase II trial assessing the efficacy, safety, and tolerability of tepotinib plus osimertinib in patients with advanced metastatic non-small-cell lung cancer harboring activating EGFR mutations who have progressed on first-line osimertinib and have MET amplification.
EGBERT SMIT: The trial consists of the safety run-in period, followed by a main treatment period. The safety run-in was completed in August 2020, which determined the recommended phase II dose to be tepotinib 500 milligrams taken once daily, plus osimertinib 80 milligrams taken once daily. Initially, eligible patients detected as positive for MET amplification by central or local FISH testing are randomly assigned in a ratio of 2 to 1 to either the combination of tepotinib plus osimertinib or tepotinib alone.
EGBERT SMIT: Following the enrollment of 12 patients in the monotherapy arm with MET amplification centrally tested by FISH, all subsequent patients are assigned to the combination. Patients who are randomized to tepotinib monotherapy will have the opportunity to switch over to the combination at a time of disease progression, which is determined by an independent review committee. For both the monotherapy and combination arms of the study, treatment continues until disease progression, death, an adverse event leading to discontinuation, study withdrawal, or consent withdrawal.
EGBERT SMIT: Once written informed patient consent for prescreening procedures is obtained, tumor tissue and a blood sample, both obtained after progression on first-line osimertinib, are submitted for central assessment of MET amplification by FISH in tissue and NGS testing in blood. Patients with MET amplification detected by local FISH can proceed to screening and study treatment initiation while the tumor tissue and the blood sample are sent for central confirmation of the MET amplification.
EGBERT SMIT: Following MET amplification detection, patients will be assessed for study eligibility 28 days prior to day one of tepotinib plus osimertinib coadministration. The screening period will include a baseline tumor assessment per RECIST version 1.1 and the confirmation of measurable tumor disease by two independent radiologists. One of the INSIGHT 2 protocol amendments included the requirement for MET amplification to be determined by FISH testing on tumor tissue biopsy.
EGBERT SMIT: The reason for using tissue biopsy is to improve the robustness of the detection of MET amplification and to avoid the potential underestimation of MET amplification with liquid biopsy next-generation sequencing due to nonshedding tumors. Patients with MET amplification centrally confirmed by FISH testing are used as the primary efficacy analysis set in INSIGHT 2 because FISH is a gold standard for detecting MET amplification, which can be missed by current NGS assays.
EGBERT SMIT: Eligible patients include adults over the age of 18 years of age with locally advanced or metastatic non-small-cell lung cancer with activating EGFR mutations and the presence of at least one independently verified measurable lesion. Patients must have MET amplification determined by central or local FISH testing, with a gene copy number being greater than or equal to 5 and/or a MET/CEP7 ratio greater than or equal to 2, or MET amplification determined by central liquid biopsy using next-generation sequencing with a gene copy number being greater than or equal to 2.3. Enrollment is allowed based on local FISH testing while awaiting central confirmation of MET amplification.
EGBERT SMIT: Patients should have received first-line therapy with osimertinib and have acquired resistance with radiological documentation of disease progression on first-line osimertinib and have had an objective clinical benefit documented during previous osimertinib therapy. And this is defined by either partial or complete radiological response, or durable stable disease lasting for more than six months after initiation.
EGBERT SMIT: Key exclusion criteria include any unresolved NCI Criteria for Adverse Event Toxicity of grade 2 or more from previous therapies. And patients are excluded if they have inadequate hematologic, liver, renal, or cardiac function, or a history of interstitial lung disease. Patients must not have a contraindication to osimertinib and must not have had prior hepatocyte growth factor or MET pathway-targeted therapy or be participating in another interventional clinical study within 30 days prior to the first dose.
EGBERT SMIT: We hope to show that combining an EGFR tyrosine kinase inhibitor with a MET inhibitor may overcome MET amplification resistance. The data from this study will enable a robust characterization of the benefit-to-risk ratio of the combination therapy of tepotinib and osimertinib and assess the potential to fulfill an unmet need by providing a targeted therapy option for patients with EGFR-mutant non-small-cell lung cancer who progress on first-line osimertinib.
EGBERT SMIT: The INSIGHT 2 study is estimated to enroll 120 patients, with 80 patients planned for the primary analysis set and 12 patients planned for the monotherapy arm. 17 countries are expected to participate in the study, and enrollment is ongoing. And please visit the link showing on the screen now to see a list of all recruiting sites. Thank you for your attention. [MUSIC PLAYING]
Segment:0 .
[MUSIC PLAYING]
EGBERT SMIT: The INSIGHT 2 study was initiated because of the unmet need for targeted treatments for patients with EGFR-mutant non-small-cell lung cancer who develop resistance to EGFR TKIs through MET amplification. EGFR mutations are a common oncogenic driver in patients with metastatic non-small-cell lung cancer and are a predictive marker for response to EGFR TKIs, such as osimertinib. The efficacy and safety of osimertinib for metastatic EGFR mutant non-small-cell lung cancer has been demonstrated in phase III trials, and osimertinib has now become the standard of care for first-line management of metastatic non-small-cell lung cancer which has an EGFR mutation.
EGBERT SMIT: Although first-line osimertinib can provide effective disease control in patients with non-small-cell lung cancer, most patients develop resistance after about 16 to 20 months of treatment. Apart from chemotherapy, which did not have very encouraging results in a post-EGFR TKI setting, there are no further clear-cut therapeutic options for EGFR-mutant non-small-cell lung cancer after progression on osimertinib, representing, therefore, a clear unmet medical need.
EGBERT SMIT: MET amplification is a common cause of acquired resistance to EGFR tyrosine kinase inhibitors therapy, and occurs in about 7% to 15% of patients who progress on first-line osimertinib therapy. However, this has been reported in up to 30% of patients, depending on both the method and the criteria used for detecting MET amplification. Tepotinib is a once-daily, orally available, potent, and highly selective MET tyrosine kinase inhibitor that blocks MET-mediated signaling pathways.
EGBERT SMIT: Tepotinib is approved for the treatment of adult patients with metastatic non-small-cell lung cancer harboring MET exon 14 skipping alterations in several countries, including Japan, the US, Canada, Great Britain, South Korea, and Brazil. And in preclinical models, tepotinib was able to overcome acquired resistance to EGFR tyrosine kinase inhibitors due to MET amplification.
EGBERT SMIT: In the phase Ib/II INSIGHT study, tepotinib plus gefitinib was compared with chemotherapy in patients with relapsed EGFR-mutant non-small-cell lung cancer with MET overexpression immunohistochemistry scores 2-plus and 3-plus and/or MET amplification with acquired resistance to EGFR tyrosine kinase inhibitors. In this exploratory analysis, in 12 patients treated with the tepotinib plus gefitinib, there was improvement versus seven patients given chemotherapy, an efficacy outcome including investigator-reported median progression-free survival of 16.6 months versus 4.2 months with a hazard ratio of 0.13, and a median overall survival of 37.3 months versus 13.1 months with a hazard ratio of 0.08. Thus, because osimertinib is standard of care for first-line therapy in EGFR-mutant non-small-cell lung cancer and MET amplification is a common mechanism of resistance to osimertinib, the INSIGHT 2 clinical trial was initiated to assess the efficacy and safety of the tepotinib and osimertinib combination in patients with EGFR-mutant non-small-cell lung cancer.
EGBERT SMIT: The primary endpoint of the INSIGHT 2 study is objective response, including confirmed complete response or partial response by independent review committee using RECIST version 1.1 criteria. For the primary endpoint, MET amplification is determined centrally by FISH. This will be the primary efficacy analysis set. Tumor assessments are carried out every six weeks following cycle 1 day 1 visit until nine months, and every 12 weeks thereafter, until disease progression, death, or study discontinuation.
EGBERT SMIT: Secondary endpoints include duration of response, progression-free survival, overall survival, health-related quality of life, and safety. INSIGHT 2 is a global, two-arm, open-label phase II trial assessing the efficacy, safety, and tolerability of tepotinib plus osimertinib in patients with advanced metastatic non-small-cell lung cancer harboring activating EGFR mutations who have progressed on first-line osimertinib and have MET amplification.
EGBERT SMIT: The trial consists of the safety run-in period, followed by a main treatment period. The safety run-in was completed in August 2020, which determined the recommended phase II dose to be tepotinib 500 milligrams taken once daily, plus osimertinib 80 milligrams taken once daily. Initially, eligible patients detected as positive for MET amplification by central or local FISH testing are randomly assigned in a ratio of 2 to 1 to either the combination of tepotinib plus osimertinib or tepotinib alone.
EGBERT SMIT: Following the enrollment of 12 patients in the monotherapy arm with MET amplification centrally tested by FISH, all subsequent patients are assigned to the combination. Patients who are randomized to tepotinib monotherapy will have the opportunity to switch over to the combination at a time of disease progression, which is determined by an independent review committee. For both the monotherapy and combination arms of the study, treatment continues until disease progression, death, an adverse event leading to discontinuation, study withdrawal, or consent withdrawal.
EGBERT SMIT: Once written informed patient consent for prescreening procedures is obtained, tumor tissue and a blood sample, both obtained after progression on first-line osimertinib, are submitted for central assessment of MET amplification by FISH in tissue and NGS testing in blood. Patients with MET amplification detected by local FISH can proceed to screening and study treatment initiation while the tumor tissue and the blood sample are sent for central confirmation of the MET amplification.
EGBERT SMIT: Following MET amplification detection, patients will be assessed for study eligibility 28 days prior to day one of tepotinib plus osimertinib coadministration. The screening period will include a baseline tumor assessment per RECIST version 1.1 and the confirmation of measurable tumor disease by two independent radiologists. One of the INSIGHT 2 protocol amendments included the requirement for MET amplification to be determined by FISH testing on tumor tissue biopsy.
EGBERT SMIT: The reason for using tissue biopsy is to improve the robustness of the detection of MET amplification and to avoid the potential underestimation of MET amplification with liquid biopsy next-generation sequencing due to nonshedding tumors. Patients with MET amplification centrally confirmed by FISH testing are used as the primary efficacy analysis set in INSIGHT 2 because FISH is a gold standard for detecting MET amplification, which can be missed by current NGS assays.
EGBERT SMIT: Eligible patients include adults over the age of 18 years of age with locally advanced or metastatic non-small-cell lung cancer with activating EGFR mutations and the presence of at least one independently verified measurable lesion. Patients must have MET amplification determined by central or local FISH testing, with a gene copy number being greater than or equal to 5 and/or a MET/CEP7 ratio greater than or equal to 2, or MET amplification determined by central liquid biopsy using next-generation sequencing with a gene copy number being greater than or equal to 2.3. Enrollment is allowed based on local FISH testing while awaiting central confirmation of MET amplification.
EGBERT SMIT: Patients should have received first-line therapy with osimertinib and have acquired resistance with radiological documentation of disease progression on first-line osimertinib and have had an objective clinical benefit documented during previous osimertinib therapy. And this is defined by either partial or complete radiological response, or durable stable disease lasting for more than six months after initiation.
EGBERT SMIT: Key exclusion criteria include any unresolved NCI Criteria for Adverse Event Toxicity of grade 2 or more from previous therapies. And patients are excluded if they have inadequate hematologic, liver, renal, or cardiac function, or a history of interstitial lung disease. Patients must not have a contraindication to osimertinib and must not have had prior hepatocyte growth factor or MET pathway-targeted therapy or be participating in another interventional clinical study within 30 days prior to the first dose.
EGBERT SMIT: We hope to show that combining an EGFR tyrosine kinase inhibitor with a MET inhibitor may overcome MET amplification resistance. The data from this study will enable a robust characterization of the benefit-to-risk ratio of the combination therapy of tepotinib and osimertinib and assess the potential to fulfill an unmet need by providing a targeted therapy option for patients with EGFR-mutant non-small-cell lung cancer who progress on first-line osimertinib.
EGBERT SMIT: The INSIGHT 2 study is estimated to enroll 120 patients, with 80 patients planned for the primary analysis set and 12 patients planned for the monotherapy arm. 17 countries are expected to participate in the study, and enrollment is ongoing. And please visit the link showing on the screen now to see a list of all recruiting sites. Thank you for your attention. [MUSIC PLAYING]
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