EGFRm NSCLC Research Articles

OA09.04 Osimertinib with or without SRS for Brain Metastases from EGFRm NSCLC: Pooled Analysis of Two RCTs

OA09.04 Osimertinib with or without SRS for Brain Metastases from EGFRm NSCLC: Pooled Analysis of Two RCTs

Real-world outcomes among patients with advanced EGFRm NSCLC previously treated with osimertinib and platinum-based chemotherapy.

396 Background: For patients with advanced EGFR-mutant non-small cell lung cancer (EGFRm aNSCLC) progressing after osimertinib (OSI) and platinum-based chemotherapy (PBC) no uniformly accepted standard of care exists. The study was to provide updated results with a refreshed dataset for a previous study describing clinical outcomes of treatment regimens initiated after OSI and PBC in real-world patients with similar baseline characteristics to those in HERTHENA-Lung01 (HL-01), a multinational single-arm phase II trial evaluating the safety and efficacy of patritumab deruxtecan [1] . Methods: This study analyzed data from the US nationwide Flatiron Health electronic health record–derived aNSCLC de-identified database from approximately 280 US cancer clinics (~800 sites of care). Adult patients with an aNSCLC diagnosis (after 01 January 2011) and prior treatment with OSI and PBC, who initiated a subsequent line of therapy (index LOT) before 01 August 2022 were included in the study. Patients were chosen to closely match the HL-01 eligibility criteria (documented exon 19 deletion or L858R mutation; Eastern Cooperative Oncology Group Performance Status of 0 or 1; and absence of relevant comorbidities at index date). To further balance patient characteristics, the sample was propensity-score (PS) weighted based on nine covariates. Real-world overall survival (rwOS), progression-free survival (rwPFS) and overall response (rwORR, defined as partial or complete response with ≥2 assessments ≥28 days apart) were assessed from the start of the index LOT with corresponding 95% confidence intervals (CI). Results: 179 patients in the database fulfilled the eligibility criteria, increasing the sample size by 42% compared to the previous study 1 . Median age of the unweighted sample at index was 68 years, 65.9% of patients were female, 40.2% had a history of smoking and 26.3% received more than 3 LOTs prior to the index LOT. In the PS-weighted cohort (standard mean difference of all covariates was ≤0.127) the median rwOS was 9.1 months (95% CI: 7.3 – 11.3) and median rwPFS was 3.5 months (95% CI: 2.7 – 4.6). For a subsample of 75 patients with qualifying response assessments, rwORR was 12.7% (95% CI: 4.8 – 25.7). Conclusions: These observations in patients with EGFRm NSCLC after OSI and PBC demonstrate a limited clinical benefit with currently available therapies. The results are consistent with the previously published study and increase precision of the outcome estimates 1 . They highlight the high unmet need and provide further context on clinical outcomes of HL-01 trial results. [1] Patel et al. Clinical Outcomes of Real-World Treatment for Metastatic EGFRm NSCLC after Osimertinib and Platinum-Based Chemotherapy. 2023 Sep 9-12 Singapore. P2.31.

Abstract PO-037: Machine learning-enabled transomics identifies three therapeutic targets for MYC-driven diffuse large B cell lymphoma

Abstract MYC activation and dysregulation is a powerful oncogenic driver in multiple cancers, including diffuse large B cell lymphoma (DLBCL). There is a known correlation between MYC expression and poor prognosis. While the 5-year overall survival for DLBCL patients on first-line therapy, R-CHOP, is approximately 75%, the 5-year overall survival drops to a staggering 30% for patients co-expressing MYC and BCL2 (double expressor lymphoma). However, it is challenging to target MYC directly. Therefore, we identified a novel approach to circumvent targeting MYC directly by leveraging Pepper’s proprietary machine learning (ML) transomic analysis platform, COMPASS, to identify novel targets associated with high MYC activity that, when inhibited, are predicted to recapitulate the effect of MYC inactivation. Specifically, COMPASS unlocks functional drivers of disease to identify novel drug targets. To study the role of MYC in lymphoma biology, we utilize a MYC-conditional T cell acute lymphoblastic leukemia/lymphoma (T-ALL) cell line (4188) with tunable MYC expression. We collect genomic, transcriptomic, proteomic, and phosphoproteomic data from samples with MYC transgene expression “on” and “off” and compare these biological cell states via COMPASS to identify novel targets that reproduce MYC inactivation. This provides new hope for patients suffering from MYC driven DLBCL. The MYC-conditional cell line allows the regulation of MYC expression via the tetracycline regulatory (Tet-Off) system. Four omic datasets were collected from each sample: genomics (next-generation sequencing, NGS), transcriptomics (NGS), proteomics (mass spectrometry), and phosphoproteomics (mass spectrometry). We employed the COMPASS target prioritization algorithm to identify and rank novel targets that mimic “turning MYC off”. Targets were then filtered to select those with an available pharmacological tool compound (PTC). The PTCs were used to evaluate the targets in the SU-DHL-06 xenograft model of DLBCL. The PTCs inhibited tumor growth from 8-91%. A total of 20 targets were tested of which 13/20 (65%) were validated as evidenced by significant inhibition of tumor growth (p<0.05, two-way ANOVA). All targets were kinases or related to kinase activity and pathways. Three of the PTCs resulted in maximum tumor growth inhibition of 86%, 89% and 91% at end of treatment, resulting in stasis of tumor growth and increased survival compared with control vehicle-treated mice. We have previously shown how the COMPASS transomics analysis approach can identify novel drug targets for drug-resistant EGFRm NSCLC and for MYC-driven hepatocellular carcinoma (HCC). The success rate of target validation across several indications including EGFRm NSCLC, HCC and lymphoma is 73%. The data presented here on MYC-driven DLBCL further validates this approach. Further validation studies will investigate novel targets using gene silencing, as PTCs were unavailable for many of the novel high-ranked targets identified in this study. Citation Format: Simon P Fricker, Christopher J Nicholson, Samuel J Roth, Arudhir Singh, Caitlin Brown, Jon Hu, Petronela Buiga, Vishnu P Kanakaveti, Anja Deutzmann, Dean Felsher, Samantha D Strasser. Machine learning-enabled transomics identifies three therapeutic targets for MYC-driven diffuse large B cell lymphoma [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-037.

ALK+/EGFRm NSCLC: Lorlatinib Wows; Toward Sub-Q Amivantamab

ALK+/EGFRm NSCLC: Lorlatinib Wows; Toward Sub-Q Amivantamab

Efficacy and safety of perioperative, neoadjuvant or adjuvant immunotherapy alone or in combination chemotherapy in early-stage non-small cell lung cancer: A systematic review and meta-analysis of randomized clinical trials.

8025 Background: Adjuvant (AD), neoadjuvant(NE), or perioperative(PE) immunotherapy in early-stage non-small cell lung cancer (eNSCLC) has been validated in multiple clinical trials in recent years. However, the comparations of efficacy and safety among three treatment modalities remain unclear. Methods: The PubMed, Embase, and Cochrane databases were searched for randomized controlled trials (RCTs) of immune checkpoint inhibitors (ICI) plus chemotherapy (CT) for eNSCLC. We calculated hazard ratios (HRs) or advantage ratios (ORs) for binary endpoints with 95% confidence intervals (CIs). Network meta-analysis was performed using a Bayesian framework to indirectly compare the three treatment modalities. Results: A total of 11 RCTs (2 NE, 6 PE, and 3 AD) including 6951 NSCLC patients were included. Among the three treatment modalities, indirect comparisons revealed that efficacy differed between PE and AD immunotherapy was only observed in the EFS/DFS (HR=0.68, 95%CI: 0.49-0.89). Compared with the control group, NE/PE immunotherapies significantly improved pathologic complete response (pCR) (OR=7.56, 95%CI: 5.24-10.92), major pathologic response(MPR) (OR=5.46, 95%CI: 3.97-7.51), EFS(HR=0.58, 95% CI: 0.50-0.67), and AD immunotherapy significantly improved DFS (HR=0.83, 95% CI: 0.73-0.94). No significant OS difference was observed in NE and AD setting (HR=0.62, 95% CI: 0.36-1.05; HR=0.90, 95% CI: 0.76-1.06, respectively), and only PE immunotherapy showed OS benefits(HR=0.67, 95%CI: 0.54-0.84). In addition, EFS was significantly improved in the PE treatment subgroup regardless of stage, pathologic response, histology, PD-L1 expression, and gender (Table), but no significant benefit in the EGFRm NSCLC subgroup(HR=0.54, 95% CI: 0.21-1.43). AD (OR 1.52, 95% CI: 1.01-2.30) and PE (OR 1.29, 95% CI: 1.08-1.54) immunotherapies were significantly associated with higher grade ≥3 adverse events (AEs) compared with controls. Rash was the most common grade ≥3 irAEs. Conclusions: PE immunotherapy seems to be more effective than NE and AD immunotherapy in three treatment modes. NE and PE immunotherapy significantly improved pCR, MPR, EFS, and AD immunotherapy significantly improved DFS in eNSCLC patients in comparison with the control group, but only PE immunotherapy significantly improved OS. [Table: see text]

Stereotactic radiotherapy vs whole brain radiation therapy in EGFR mutated NSCLC: Results & reflections from the prematurely closed phase III HYBRID trial

BackgroundAll known randomized trials of stereotactic radiotherapy (SRT) versus whole brain radiotherapy (WBRT) for brain metastases (BMs) comprise mixed histologies. The phase III HYBRID trial (NCT02882984) attempted to evaluate the non-inferiority of SRT vs. WBRT specifically for EGFR-mutated non-small cell lung cancer (EGFRm NSCLC) BMs. MethodsInclusion criteria were ≤ 5 BMs (any size) from treatment-naïve EGFRm NSCLC. All patients started a first-generation tyrosine kinase inhibitor on the first day of WBRT (37.5 Gy/15 fractions) or SRT (25–40 Gy/5 fractions per tumor volume). The primary endpoint was 18-month intracranial progression-free survival (iPFS; intention-to-treat). ResultsThe trial commenced in June 2015 and was closed in April 2021 after screening 208 patients but enrolling 85 (n = 41 WBRT, n = 44 SRT; median follow-up 31 and 36 months, respectively). Respectively, 9.5 % vs. 10.2 % of patients experienced intracranial progression at 18 months, and the median iPFS was 21.4 vs. 22.3 months (p > 0.05 for all). The SRT arm experienced higher overall survival and cognitive preservation (p < 0.05 for all). The most notable reason for low enrollment was patients not wishing to risk neurocognitive decline from WBRT. ConclusionsAlthough this phase III trial was underpowered, there was no evidence that SRT yielded outcome detriments compared to WBRT for EGFRm NSCLC BMs. Lessons from prematurely closed trials are valuable, as they often provide important experiential perspectives for investigators designing/executing future trials. In the current era, randomized trials involving WBRT without cognitive sparing measures may be at high risk of underaccrual; trial investigators are encouraged to carefully consider our experience when attempting to design such trials. However, trials of molecular-/biologically-stratified patients are highly recommended as the notion of “individualized medicine/oncology” continues to expand.

Abstract LB005: Identification of novel targets for MYC-driven hepatocellular carcinoma via transomics

Abstract Hepatocellular carcinoma (HCC) is an aggressive tumor, and treatment options for patients with unresectable HCC are limited to targeted therapies and immunotherapy. The activation and dysregulation of MYC have been implicated in multiple cancers, including HCC, where approximately 30% of human HCC samples show MYC gene amplification. However, it is challenging to target MYC directly. Therefore, we applied a novel approach to circumvent targeting MYC directly by leveraging Pepper’s proprietary transomic analysis platform, COMPASS, to identify novel targets that are predicted to mimic the effect of turning MYC off. Specifically, COMPASS unlocks functional drivers of disease to identify novel drug targets. To study the role of MYC in tumor biology, we utilize an HCC cell line with tunable MYC expression. We generate genomic, transcriptomic, proteomic, and phosphoproteomic data from samples with MYC-on and MYC-off and compare via COMPASS to identify novel targets that mimic turning MYC off. The MYC-conditional HCC cell line (EC4) allows the regulation of MYC expression via the tetracycline regulatory (Tet-Off) system. Four omic datasets were collected from each sample: genomics (next-generation sequencing, NGS), transcriptomics (NGS), proteomics (mass spectrometry), and phosphoproteomics (mass spectrometry). We employed the COMPASS target prioritization algorithm to identify and rank novel targets that mimic turning MYC off. Targets were then filtered to select those with an available pharmacological tool compound (PTC). The PTCs were used to evaluate the targets in the Huh-7 xenograft model of HCC. All targets were kinases or related to kinase activity and pathways. All PTCs inhibited tumor growth from 18.1-78.3%. One multi-tyrosine kinase inhibitor resulted in maximum tumor growth inhibition, resulting in stasis of tumor growth and increased survival compared with control vehicle-treated mice. We have previously shown how the COMPASS transomics analysis approach can identify novel drug targets for drug resistant EGFRm NSCLC. The data presented here on MYC-driven HCC further validates this approach for novel target identification. Ongoing work will investigate novel targets using gene silencing, as PTCs were unavailable for many of these novel high-ranked targets identified in this study. Further validation studies are ongoing against other difficult-to-treat MYC-driven cancers to identify novel clinical targets and drug candidates to circumvent the MYC pathway. Citation Format: Simon P. Fricker, Christopher J. Nicholson, Samuel J. Roth, Arudhir Singh, Caitlin Brown, Jon Hu, Petronela Buiga, Vishnu P. Kanakaveti, Anja Deutzmann, Dean Felsher, Samantha D. Strasser. Identification of novel targets for MYC-driven hepatocellular carcinoma via transomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB005.

96 Real-World Evidence About Efficacy and Post-progression Outcomes of Second Line Osimertinib in EGFRm NSCLC

96 Real-World Evidence About Efficacy and Post-progression Outcomes of Second Line Osimertinib in EGFRm NSCLC

EE204 Saving Lives through Early Access: Exploring the Impact of a Managed Access Agreement in Adjuvant EGFRm NSCLC

EE204 Saving Lives through Early Access: Exploring the Impact of a Managed Access Agreement in Adjuvant EGFRm NSCLC

Real-World Data From First-Line EGFRm NSCLC Treatment

Real-World Data From First-Line EGFRm NSCLC Treatment

MO1-2 Subgroup analysis of atezo + bev + carbo + pac for previously treated patients with EGFRm NSCLC (NEJ043)

MO1-2 Subgroup analysis of atezo + bev + carbo + pac for previously treated patients with EGFRm NSCLC (NEJ043)

Mutational Prognosis of Survival by Liquid Biopsy in Advanced EGFRm NSCLC

Mutational Prognosis of Survival by Liquid Biopsy in Advanced EGFRm NSCLC

EP07.05-11 Efficacy and Safety of Osimertinib Therapy in High-Risk Stage I EGFRm NSCLC after R0 Resection(OSTAR): A Prospective, Single-Arm Study

EP07.05-11 Efficacy and Safety of Osimertinib Therapy in High-Risk Stage I EGFRm NSCLC after R0 Resection(OSTAR): A Prospective, Single-Arm Study

OA22.06 Changes in Cognition after Osimertinib, with or without SRS, in EGFRm NSCLC with Brain Metastases: a Pooled Analysis of RCTs

OA22.06 Changes in Cognition after Osimertinib, with or without SRS, in EGFRm NSCLC with Brain Metastases: a Pooled Analysis of RCTs

P2.31-10 Clinical Outcomes of Real-World Treatment for Metastatic EGFRm NSCLC after Osimertinib and Platinum-Based Chemotherapy

P2.31-10 Clinical Outcomes of Real-World Treatment for Metastatic EGFRm NSCLC after Osimertinib and Platinum-Based Chemotherapy

1343P Amivantimab as a salvage strategy post TKI (osimertinib/mobocertinib) in EGFRm NSCLC

1343P Amivantimab as a salvage strategy post TKI (osimertinib/mobocertinib) in EGFRm NSCLC

1335P Phase Ib study to evaluate the safety and tolerability of osimertinib with ipilimumab in EGFRm NSCLC

1335P Phase Ib study to evaluate the safety and tolerability of osimertinib with ipilimumab in EGFRm NSCLC

Tepotinib + osimertinib for EGFR mutant (EGFRm) NSCLC with MET amplification (METamp) after first-line (1L) osimertinib.

9021 Background: METamp is a common resistance mechanism developed in patients (pts) with EGFRm NSCLC treated with osimertinib. MET tyrosine kinase inhibitors (TKIs) such as tepotinib may be effective in treating these pts after osimertinib. Here we report interim data from the INSIGHT 2 study evaluating tepotinib + osimertinib in EGFRm NSCLC with METamp previously treated with osimertinib. Methods: In this open-label Phase II study (INSIGHT 2, NCT03940703), pts with advanced EGFRm NSCLC with METamp after progression on 1L osimertinib received tepotinib 500 mg (450 mg active moiety) + osimertinib 80 mg once daily. METamp was centrally detected in tissue biopsy (TBx) by FISH ( MET gene copy number [GCN] ≥5 and/or MET/ CEP7 ≥2) and/or in liquid biopsy (LBx) by NGS ( MET plasma GCN ≥2.3; Archer). The primary endpoint was objective response by Independent Review Committee in tepotinib + osimertinib treated pts with centrally detected METamp by FISH (FISH+). Efficacy data are reported for pts with ≥3 months’ follow-up, and safety for all pts who received one dose of tepotinib + osimertinib by Sep 26, 2022 (data cut-off). Results: Among 472 pts prescreened, 451 pts had METamp results by either TBx FISH and/or LBx NGS, of which 175 (38.8%) were positive for METamp. 122 pts received tepotinib + osimertinib (median age 61 years [range 20–84], 59.8% female, 59.8% Asian, 68.0% never smoker, 72.1% ECOG PS 1). In 98 pts with FISH METamp (29.6% had &lt; 12 months on 1L osimertinib; median GCN 11 [range 5.0–50.6]; mean ± SD sum of target lesion diameters [SOLD] 73.2 ± 47.1 mm), objective response rate (ORR) was 43.9% (95% CI 33.9, 54.3), median (m) DOR was 9.7 months (95% CI 5.6, ne), mPFS was 5.4 months (95% CI 4.2, 7.1), and mOS was not reached (95% CI 11.1, ne). Of the 98 pts, treatment is ongoing in 42 pts. In 31 pts with METamp detected by LBx NGS, of which 24 were also FISH+ (mean ± SD SOLD 93.9 ± 51.4 mm), ORR was 51.6% (95% CI 33.1, 69.8), mDOR was 5.6 months (95% CI 2.9, ne), mPFS was 4.6 months (95% CI 2.7, 6.9), and mOS was not reached (95% CI 6.8, ne). Of 122 pts treated with tepotinib + osimertinib, any grade treatment-related AEs were reported by 99 (81.1%) pts including 34 (27.9%) Grade ≥3. Most common ( &gt; 15% pts) treatment-related AEs included diarrhea 46.7% (0% Grade ≥3), peripheral edema 34.4% (4.1% Grade ≥3), paronychia 20.5% (0.8% Grade ≥3), decreased appetite 18.0% (3.3% Grade ≥3), and nausea 16.4% (1.6% Grade ≥3). Treatment-related AEs led to a dose reduction in 21 (17.2%) pts, following either or both treatments and led to treatment discontinuation in 7 pts (5.7%). Conclusions: In this interim analysis of INSIGHT 2, tepotinib + osimertinib was highly active with durable responses, and was well tolerated in pts with EGFRm NSCLC with METamp after progression on 1L osimertinib. Tepotinib + osimertinib provides a potential chemotherapy-sparing oral targeted therapy option in this population with a high unmet need. Clinical trial information: NCT03940703 .

Patients with EGFR mutant (m) MET-altered NSCLC receiving tepotinib with an EGFR tyrosine kinase inhibitor (TKI): A case series.

9070 Background: Oncogenic activation of MET is a common mechanism of acquired resistance to EGFR TKIs in patients (pts) with EGFRm NSCLC, with MET amplification (amp) constituting the most frequent cause of bypass pathway activation. Currently, there are no approved targeted treatment options for these pts. Data from the Phase II INSIGHT (NCT01982955) and INSIGHT 2 (NCT03940703) studies indicate the combination of the selective MET TKI tepotinib plus an EGFR TKI has encouraging activity. We present a case series of pts with EGFRm MET-altered NSCLC receiving tepotinib plus an EGFR TKI outside of clinical trials. Methods: Access to tepotinib was provided to pts with EGFRm MET-altered NSCLC and resistance to EGFR TKIs through unsolicited compassionate use requests. All pts received tepotinib (500 mg [450 mg active moiety] once daily; first dose by Oct 2022) plus an EGFR TKI. Participating physicians provided case information up to January 2023. Results: 28 cases of pts with EGFRm NSCLC and MET alterations who received tepotinib plus an EGFR TKI were collated. 21 pts had METamp after EGFR TKI treatment, 5 had MET overexpression, and 2 had MET exon 14 skipping. Pts were aged 41–86 years, 15 were Asian, 13 were white, 19 were female, 8 had smoking history, and all had adenocarcinoma histology. METamp was detected by tissue biopsy in 17 pts, and liquid biopsy in 4 pts. Of 12 pts with METamp detected by FISH, gene copy number ranged from 5.3–33.4, and MET:CEP7 ratio from 0.7–15.1. EGFR TKIs received in combination with tepotinib were osimertinib (n = 21, 19 of whom received prior osimertinib), gefitinib (n = 6), dacomitinib (n = 1), afatinib (n = 1), with 1 pt received gefitinib followed by osimertinib. Tepotinib plus EGFR TKI was received by 9 pts as second-line, 9 as third-line, and 10 as fourth-or-later line. Median treatment duration was 8.8 months (range 1.3–20.6), with treatment ongoing in 13 pts (10 with current duration ≥10 months). Per the physician’s assessment, 25/28 pts (89%) had clinical benefit, 16 of whom (57%) were considered to have a partial response (PR). Clinical benefit was reported in 18/21 (86%) pts with METamp (12 PR, 57%), in 5/5 with MET overexpression (2 PR), and 2/2 with MET exon 14 skipping (2 PR). The most reported adverse event (AE) considered related to tepotinib was edema in 15 pts (most commonly peripheral edema). Grade 3 AEs related to tepotinib were reported in 5 pts (including Grade 3 edema in 2 pts), 1 of whom discontinued the combination due to Grade 3 pneumonitis. Conclusions: Tepotinib plus an EGFR TKI showed promising clinical activity in pts with MET-altered NSCLC who have progressed on a previous EGFR TKI, including those with several lines of prior treatment. Clinical benefit was observed irrespective of MET alteration type in this case series of pts treated outside of clinical trials, with a large proportion of patients continuing to benefit from ongoing treatment.

Detection of MET amplification (METamp) in patients with EGFR mutant (m) NSCLC after first-line (1L) osimertinib.

9074 Background: METamp is a common resistance mechanism to osimertinib in patients with EGFRm NSCLC and is associated with sensitivity to MET TKIs. Reported METamp rates vary considerably depending on the type of biopsy and assay used. Here, we report a large comprehensive analysis of METamp detected by TBx FISH (FISH+) and/or LBx NGS (L+) after 1L osimertinib. Methods: During prescreening of the INSIGHT 2 study (NCT03940703) of tepotinib + osimertinib in post 1L osimertinib patients (pts) with EGFRm NSCLC, METamp was centrally assessed by TBx FISH ( MET GCN ≥5 and/or MET/ CEP7 ≥2) and/or by LBx NGS ( MET plasma GCN ≥2.3; Archer). Results: Of 472 pre-screened pts (64% female, 57% Asian, 97% adenocarcinoma), 350 provided TBx and 443 provided LBx. After excluding 36 TBx and 7 LBx ‘not analyzed/not evaluable’ samples, there were 314 TBx (163 from primary tumors, 151 from metastases) and 436 LBx samples with METamp results (positive or negative). Overall, FISH+ METamp was detected in 159/314 pts (50.6%), with similar FISH+ rates in the primary tumor (77/163, 47.2%) and metastases (82/151, 54.3%). FISH+ METamp detection by region was: 43.6% (82/188) in Asia, 61.5% (72/117) in Europe, and 55.6% (5/9) in the US. When limiting analysis to sites without reported local prescreening, the overall FISH+ METamp rate was 46.5% (93/200) and by region was: 43.5% (60/138) in Asia, 52.7% (29/55) in Europe, and 57.1% (4/7) in the US. In 159 FISH+ pts, median GCN was 11.8 (range 5.0–50.6) and median MET/CEP7 ratio was 2.3 (range 0.8–12.7). Mean TBx turn-around time (TAT) from shipment to results was 6.8 days. Overall, L+ METamp was detected in 51/436 pts (11.7%). In 35 L+ pts who were also FISH+, the median GCN was 16.6 (range 5.3–45.3) and median MET/CEP7 ratio was 4.5 (range 1.0–12.7). 299 pts had both central TBx FISH and LBx NGS results (Table), of whom 152 (50.8%) were FISH+ and 38 (12.7%) were L+. LBx NGS identified METamp with high specificity (negative percentage agreement [NPA] 98.0%) but low sensitivity (positive percentage agreement [PPA] 23.0%) compared with TBx FISH: only 3/38 L+ samples were FISH− but 117/152 FISH+ samples (77.0%) were L−. Clinical activity of tepotinib + osimertinib was comparable in FISH+ and L+ pts. Conclusions: In this large comprehensive analysis, FISH+ METamp was detected in ~50% of pts progressing on 1L osimertinib, while L+ METamp was detected in only 11.7% of pts. METamp, which is the most common mechanism of resistance post 1L osimertinib, can frequently be undetected by using LBx NGS only. Given high specificity but low sensitivity of LBx, L+ pts can receive a MET TKI while a negative METamp result by LBx should be confirmed by FISH. FISH allows optimal identification of METamp post 1L osimertinib, can be delivered in a clinically meaningful timeframe, and may allow more pts to benefit from an oral MET TKI. Clinical trial information: NCT03940703 . [Table: see text]