Results from a phase Ib study of telisotuzumab vedotin in combination with osimertinib in patients with c-Met protein-overexpressing, EGFR-mutated locally advanced/metastatic non-small-cell lung cancer (NSCLC) after progression on prior osimertinib.

Osimertinib is the standard first-line treatment for advanced epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). However, treatment resistance is inevitable and increased c-Met protein expression correlates with resistance. Telisotuzumab vedotin (Teliso-V) is an antibody-drug conjugate that targets c-Met protein overexpression. In this article, we report the results of a phase I/Ib trial evaluating Teliso-V plus osimertinib in patients with NSCLC after progression on osimertinib. This multicenter, open-label study (NCT02099058) enrolled patients with advanced EGFR-mutated, c-Met protein-overexpressing, non-squamous NSCLC that had progressed on prior osimertinib. Patients received Teliso-V (intravenously, every 2 weeks) plus osimertinib (orally, 80 mg once daily). Teliso-V was evaluated at 1.6 mg/kg in a safety lead-in phase and escalated to 1.9 mg/kg. Dose expansion included both doses. Endpoints included safety and tolerability, pharmacokinetics, objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS). A total of 38 patients received Teliso-V (1.6 mg/kg, n = 20; 1.9 mg/kg, n = 18) plus osimertinib and were included in this analysis. No dose-limiting toxicities were observed. Most frequent any-grade treatment-emergent adverse events (TEAEs) were peripheral sensory neuropathy (50%), peripheral edema (32%), and nausea (24%). Most common grade 3/4 TEAEs were anemia (11%) and pulmonary embolism (8%). Five TEAEs led to death; none were reported as being related to Teliso-V or osimertinib. The pharmacokinetic profile of Teliso-V plus osimertinib was similar to Teliso-V monotherapy. After a median follow-up of 7.4 months, the ORR was 50.0% per independent central review (ICR) (DOR not reached), and median PFS per ICR was 7.4 months (95% confidence interval 5.4 months-not reached). Teliso-V plus osimertinib had promising activity and a manageable safety profile in patients with c-Met protein-overexpressing, EGFR-mutated non-squamous NSCLC after progression on osimertinib. This combination has the potential to address an unmet medical need in this patient population.

Horinouchi H ，Cho BC ，Camidge DR ，Goto K ，Tomasini P ，Li Y ，Vasilopoulos A ，Brunsdon P ，Hoffman D ，Shi W ，Bolotin E ，Blot V ，Goldman J ... -  《-》

Tepotinib plus osimertinib in patients with EGFR-mutated non-small-cell lung cancer with MET amplification following progression on first-line osimertinib (INSIGHT 2): a multicentre, open-label, phase 2 trial.

Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) and MET amplification as a mechanism of resistance to first-line osimertinib have few treatment options. Here, we report the primary analysis of the phase 2 INSIGHT 2 study evaluating tepotinib, a highly selective MET inhibitor, combined with osimertinib in this population. This open-label, phase 2 study was conducted at 179 academic centres and community clinics in 17 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and advanced or metastatic EGFR-mutated NSCLC of any histology, with MET amplification by tissue biopsy fluorescence in-situ hybridisation (FISH; MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy next-generation sequencing (MET plasma gene copy number of ≥2·3), following progression on first-line osimertinib. Patients received oral tepotinib 500 mg plus oral osimertinib 80 mg once daily. The primary endpoint was independently assessed objective response in patients with MET amplification by central FISH treated with tepotinib plus osimertinib with at least 9 months of follow-up. Safety was analysed in patients who received at least one study drug dose. This study is registered with ClinicalTrials.gov, NCT03940703 (enrolment complete). Between Feb 13, 2020, and Nov 4, 2022, 128 patients (74 [58%] female, 54 [42%] male) were enrolled and initiated tepotinib plus osimertinib. The primary activity analysis population included 98 patients with MET amplification confirmed by central FISH, previous first-line osimertinib and at least 9 months of follow-up (median 12·7 months [IQR 9·9-20·3]). The confirmed objective response rate was 50·0% (95% CI 39·7-60·3; 49 of 98 patients). The most common treatment-related grade 3 or worse adverse events were peripheral oedema (six [5%] of 128 patients), decreased appetite (five [4%]), prolonged electrocardiogram QT interval (five [4%]), and pneumonitis (four [3%]). Serious treatment-related adverse events were reported in 16 (13%) patients. Deaths of four (3%) patients were assessed as potentially related to either trial drug by the investigator due to pneumonitis (two [2%] patients), decreased platelet count (one [1%]), respiratory failure (one [1%]), and dyspnoea (one [1%]); one death was attributed to both pneumonitis and dyspnoea. Tepotinib plus osimertinib showed promising activity and acceptable safety in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib, suggesting a potential chemotherapy-sparing oral targeted therapy option that should be further investigated. Merck (CrossRef Funder ID: 10.13039/100009945).

Wu YL ，Guarneri V ，Voon PJ ，Lim BK ，Yang JJ ，Wislez M ，Huang C ，Liam CK ，Mazieres J ，Tho LM ，Hayashi H ，Nhung NV ，Chia PL ，de Marinis F ，Raskin J ，Zhou Q ，Finocchiaro G ，Le AT ，Wang J ，Dooms C ，Kato T ，Nadal E ，Hin HS ，Smit EF ，Wermke M ，Tan D ，Morise M ，O'Brate A ，Adrian S ，Pfeiffer BM ，Stroh C ，Juraeva D ，Strotmann R ，Goteti K ，Berghoff K ，Ellers-Lenz B ，Karachaliou N ，Le X ，Kim TM ，INSIGHT 2 investigators ... -  《-》

FLAIR: A Phase II, Open Label, Randomized Study of Osimertinib Plus Bevacizumab Versus Osimertinib in Recurrent or Metastatic Treatment-Naïve NSCLC Patients Harboring EGFR 21L858R Mutation.

Osimertinib, the 3rd generation EGFR-TKI, has emerged as standard first-line treatment for patients with advanced EGFR mutated nonsmall cell lung cancer (NSCLC). Patients with exon 21 L858R mutation showed lower efficacy with EGFR-TKIs than those with 19Del mutation, even with osimertinib, it remains an unmet medical need to further improve the efficacy in L858R population. We present the rationale and design for FLAIR (NCT04988607), which will investigate the efficacy and safety of osimertinib plus bevacizumab versus osimertinib monotherapy in treatment-naïve recurrent or metastatic NSCLC patients harboring EGFR exon 21 L858R mutation. FLAIR is a prospective, multicenter, randomized, open label study, which is initiated by Chinese Thoracic Oncology Group (CTONG2002). Patients age ≥18 years with primary recurrent or metastatic nonsquamous NSCLC who are treatment-naïve with documented EGFR exon 21 L858R mutation is eligible. Patients will be randomized 1:1 to receive osimertinib 80 mg once daily plus bevacizumab 15mg/kg every 3 weeks or osimertinib monotherapy 80 mg once daily until progression or another discontinuation criterion is met. The primary endpoint is investigator-assessed progression free survival (PFS). Secondary endpoints include: overall survival rate at 24 months, time to treatment failure (TTF), overall response rate (ORR), disease control rate (DCR), duration of response (DoR), central nervous system (CNS) PFS, CNS ORR and safety. FLAIR has completed the enrollment, and results are expected in the fourth quarter of 2025 (depending on the actual event rate). This study will offer better perspectives on the efficacy and safety of osimertinib plus bevacizumab combination therapy in treatment-naïve recurrent or metastatic NSCLC patients harboring EGFR exon 21 L858R mutation, providing valuable guidance for clinical practice.

Zhou Q ，Li J ，Cang SD ，Lin JX ，Tu HY ，Du Y ，Qin JW ，Liang XH ，Yu Y ，Lan HT ，Shi HQ ，Hua D ，Liu SM ，Wu YL ... -  《-》

The efficacy of continuing osimertinib with platinum pemetrexed chemotherapy upon progression in patients with metastatic non-small cell lung cancer harboring sensitizing EGFR mutations.

For patients with EGFR mutant NSCLC who progress on osimertinib, the clinical benefit of continuing osimertinib with next line platinum pemetrexed chemotherapy remains unknown. In this international, multi-center, retrospective cohort study, a total of 159 patients with EGFR mutant NSCLC who progressed on osimertinib and received platinum-pemetrexed therapy on progression from 2013 to 2023 were included. The data cutoff was December 31, 2023. Data analysis was conducted from January 2024 to June 2024. The primary endpoints were progression free survival (PFS) and overall survival (OS), analyzed using Kaplan-Meier methods. Multivariable Cox regression adjusting for patient-specific and cancer-specific factors was performed. 421 patients with EGFR mutant NSCLC with progression on osimertinib were identified, of which159 patients who met pre-specified inclusion criteria were divided into two groups: Cohort 1 (osimertinib + platinum-pemetrexed) included 50 patients (median [IQR] age, 59 [30 - 83] years; 36 [72.0 %] female; 11 [22.4 %] Asian) and Cohort 2 (platinum-pemetrexed alone) included 109 patients (median [IQR] age, 54 [25 - 80] years; 62 [56.9 %] female; 74 [64.9 %] Asian). Most patients were never smokers (Cohort 1, 37 [74.0 %]; Cohort 2, 66 [60.6 %]). One third of patients had baseline brain metastases (Cohort 1, 19 [38.0 %]; Cohort 2, 36 [38.3 %]). Both cohorts had a median of two prior lines of anti-cancer therapy. The addition of bevacizumab or immune checkpoint inhibitors (ICI) to next-line platinum-pemetrexed chemotherapy was more common in Cohort 2 (bevacizumab use, 30.3 % vs 8.0 %, p = 0.002; ICI use, 33.0 % vs 2.0 %, p = 0.001). With a median duration of follow up of 30 months, there was a significant PFS benefit to continuing osimertinib with next line platinum pemetrexed chemotherapy (9.0 vs 4.5 months; HR 0.49, 95 % CI 0.32 - 0.74, p = 0.0032), also seen in subset analyses of patients who received first line osimertinib (n = 55, 11.0 vs 6.2 months; HR 0.41, 95 % CI 0.25 - 0.73, p = 0.002). Among patients with EGFR mutant NSCLC without brain metastases after progression on osimertinib, we found that continuing osimertinib with next line platinum pemetrexed significantly reduced the median time to CNS progression (n = 38; 7.0 vs 4.1 months; HR 0.47, 95 % CI 0.48 - 0.98, p = 0.01). After adjusted analysis, there was no significant OS difference between Cohorts 1 and 2 (19 months vs 13 months; HR 0.92, 95 % CI 0.60 - 1.39, p = 0.68). For patients with EGFR mutant NSCLC who progress on osimertinib, there is a significant PFS, but not OS, benefit to continuing osimertinib with next line platinum pemetrexed chemotherapy. The continuation of osimertinib with next line platinum pemetrexed chemotherapy appears to reduce the risk of CNS progression.

Patil T ，Gao D ，Watson A ，Sakamoto M ，Nie Y ，Gibson A ，Dean ML ，Yoder BA ，Miller E ，Stalker M ，Aisner DL ，Bunn PA ，Schenk EL ，Marmarelis ME ，Bennati C ，Navani V ，Zhang Y ，Camidge DR ... -  《-》

Trastuzumab deruxtecan in patients with metastatic non-small-cell lung cancer (DESTINY-Lung01): primary results of the HER2-overexpressing cohorts from a single-arm, phase 2 trial.

DESTINY-Lung01 is a multicentre, open-label, phase 2 study evaluating the antitumour activity and safety of trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate, in patients with HER2-overexpressing or HER2 (ERBB2)-mutant unresectable or metastatic non-small-cell lung cancer (NSCLC). The results of the HER2-mutant cohort (cohort 2) have been reported elsewhere. Herein, we report the primary analysis of cohorts 1 and 1A, which aimed to evaluate the activity and safety of trastuzumab deruxtecan 5·4 mg/kg and 6·4 mg/kg in patients with HER2-overexpressing NSCLC. Patients aged 18 years or older with unresectable or metastatic (or both unresectable and metastatic) non-squamous NSCLC who had relapsed following or were refractory to standard treatment or for whom no standard treatment was available, with an HER2 immunohistochemistry score of 3+ or 2+ (without known HER2 mutations) and an Eastern Cooperative Oncology Group performance status score of 0 or 1, were enrolled at 20 specialist hospitals in France, Japan, the Netherlands, Spain, and the USA. Patients were assigned to cohorts sequentially, first to cohort 1, to receive trastuzumab deruxtecan 6·4 mg/kg (cohort 1), then to cohort 1A, to receive trastuzumab deruxtecan 5·4 mg/kg, both administered intravenously once every 3 weeks. The primary endpoint was confirmed objective response rate by independent central review and was assessed in the full analysis set, which included all patients who signed an informed consent form and were enrolled in the study. Safety was assessed in all enrolled patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT03505710, and is ongoing (closed to recruitment). Between Aug 27, 2018, and Jan 28, 2020, 49 patients were enrolled in cohort 1 (median age 63·0 years [IQR 58·0-68·0], 30 [61%] male, 19 [39%] female, and 31 [63%] White), and from June 16 to Dec 9, 2020, 41 patients were enrolled in cohort 1A (median age 62·0 years [IQR 56·0-66·0], 22 [54%] male, 19 [46%] female, and 31 [76%] White). As of data cutoff (Dec 3, 2021), the median treatment duration was 4·1 months (IQR 1·4-7·1) in cohort 1 and 5·5 months (1·4-8·7) in cohort 1A, and median follow-up was 12·0 months (5·4-22·4) in cohort 1 and 10·6 months (4·5-13·5) in cohort 1A. Confirmed objective response rate by independent central review was 26·5% (95% CI 15·0-41·1; 13 of 49, all partial responses) in cohort 1 and 34·1% (20·1-50·6; 14 of 41; two complete responses and 12 partial responses) in cohort 1A. The most common treatment-emergent adverse events of grade 3 or worse were neutropenia (12 [24%] of 49 in cohort 1, none in cohort 1A), pneumonia (six [12%] and two [5%], respectively), fatigue (six [12%] and three [7%], respectively), and disease progression (six [12%] and four [10%], respectively). Drug-related treatment-emergent adverse events of grade 3 or worse occurred in 26 (53%) of 41 patients in cohort 1 and nine (22%) of 49 patients in cohort 1A. Drug-related serious adverse events were reported in ten (20%) patients and three (7%) patients, respectively. Deaths due to treatment-emergent adverse events occurred in ten (20%) patients in cohort 1 (disease progression in six (12%) patients and bronchospasm, hydrocephalus, respiratory failure, and pneumonitis in one [2%] patient each), and in seven (17%) patients in cohort 1A (due to disease progression in four (10%) patients and dyspnoea, malignant neoplasm, and sepsis in one (2%) patient each). One death due to a treatment-emergent adverse event was determined to be due to study treatment by the investigator, which was in cohort 1 (pneumonitis). Independent adjudication of interstitial lung disease or pneumonitis found that drug-related interstitial lung disease or pneumonitis occurred in ten (20%) patients in cohort 1 (two [4%] grade 1, five [10%] grade 2, and three [6%] grade 5) and two (5%) patients in cohort 1A (one [2%] grade 2 and one [2%] grade 5). An additional patient in cohort 1A had grade 4 pneumonitis after the data cutoff, which was subsequently adjudicated as drug-related grade 5 interstitial lung disease or pneumonitis. Given the low antitumour activity of existing treatment options in this patient population, trastuzumab deruxtecan might have the potential to fill a large unmet need in HER2-overexpressing NSCLC. Our findings support further investigation of trastuzumab deruxtecan in patients with HER2-overexpressing NSCLC. Daiichi Sankyo and AstraZeneca.

Smit EF ，Felip E ，Uprety D ，Nagasaka M ，Nakagawa K ，Paz-Ares Rodríguez L ，Pacheco JM ，Li BT ，Planchard D ，Baik C ，Goto Y ，Murakami H ，Saltos A ，Pereira K ，Taguchi A ，Cheng Y ，Yan Q ，Feng W ，Tsuchihashi Z ，Jänne PA ... -  《-》